Plasma Ropivacaine Research Articles

Population Pharmacokinetic-Pharmacodynamic Modeling of Ropivacaine in Spinal Anesthesia.

Ropivacaine is frequently used in spinal anesthesia but the relationship between plasma concentrations and sensory block level remains unknown. The aim of this study was to assess the relationship between plasma ropivacaine concentrations and effects during spinal anesthesia. Sixty patients aged between 18 and 82years were included in this study after providing written informed consent. Patients were randomly assigned to receive intrathecal administration of ropivacaine 15, 20 or 25mg. Blood samples were drawn to determine ropivacaine concentrations, and sensory blockade was assessed using pinprick testing. Ropivacaine plasma concentrations and sensory block level were analyzed using a nonlinear mixed-effects modeling approach with Monolix 4.2.2.Uncertainty of parameters was estimated by bootstrapping. Overall, 216 plasma ropivacaine values and 407 sensory block-related data were available for pharmacokinetic-pharmacodynamic (PK-PD) model evaluation. A two-compartment open model connected to a spinal compartment was selected to describe the PKs of ropivacaine. Sensory block modeling was performed using a sigmoid E max model assuming an equilibration delay between the amount in the depot or spinal compartment and at the effect site. Using multiple linear regression analysis, we were able to demonstrate the importance of dose, age and weight as major predictors of sensory block-level kinetics. This first population PK-PD model for ropivacaine in spinal anesthesia confirms the relationship between plasma ropivacaine concentrations and effect. We also clarify the relationship between the spread of sensory block level and dose, age and, for the first time, weight. This study was approved by the Reims University Hospital Ethics Committee (protocol: PHRC-2005; registered at Agence Nationale de Sécurité du Médicament et des Produits de Santé ANSM: D60890). This was an open, prospective, monocentric study conducted in the University Hospital of Reims (France).

Efficacy of ultrasound-guided continuous transverses abdominis plane block when used for postoperative analgesia in patients undergoing total hysterectomy

Objective To evaluate the efficacy of ultrasound-guided continuous transverses abdominis plane (TAP) block when used for postoperative analgesia in the patients undergoing total hysterectomy. Methods Forty American Society of Anesthesiologists physical status Ⅰ or Ⅱpatients, aged 38-64 yr, weighing 50-80 kg, undergoing elective total hysterectomy with general anesthesia, were divided into 2 groups using a random number table: continuous TAP block group (CTAP group, n=21) and patient-controlled intravenous analgesia (PCIA) group (n=19). In group CTAP, bilateral TAP block was performed with 0.2% ropivacaine 20 ml under ultrasound guidance before operation, and 0.2% ropivacaine 5 ml/h was infused into bilateral TAPs after extubation.In group PCIA, the patients received PCIA with sufentanil 1 μg/ml after extubation, and the PCIA pump was set up to deliver a 2 ml bolus dose, a 15 min lockout interval and background infusion at a rate of 2 ml/h.Analgesia lasted until 72 h after operation in both groups.When visual analog scale>4, morphine 5 mg was intramuscularly injected as rescue analgesic.The recovery time of postoperative intestinal function, length of hospital stay, patient′s satisfaction with analgesia, requirement for rescue analgesia, TAP block-related adverse reactions and development of postoperative nausea and vomiting were recorded.In group CTAP, blood samples were collected from the peripheral vein immediately after the end of operation and at 2, 6, 12, 24, 48 and 72 h after operation for determination of concentrations of ropivacaine in plasma and free ropivacaine in plasma using high-performance liquid chromatography. Results Compared with group PCIA, the requirement for rescue analgesia and incidence of nausea and vomiting were significantly decreased, the recovery time of postoperative intestinal function was shortened, the score for patient′s satisfaction with analgesia was increased (P 0.05). No TAP block-related adverse reactions were found in group CTAP.In group CTAP, the concentration of ropivacaine in plasma began to increase at 2 h after operation and peaked at 48 h after operation, the concentration of free ropivacaine in plasma began to increase at 2 h after operation and peaked at 24 h after operation (P<0.05). Conclusion Ultrasound-guided continuous TAP block produces good analgesic efficacy when used for the patients undergoing total hysterectomy. Key words: Nerve block; Transverses abdominis plane; Ultrasonography; Analgesia

Ropivacaine, Interleukin-6 and Tumor Necrosis Factor Alpha Plasma Levels during Intermittent Epidural and Continuous Wound Infusion of Ropivacaine for Analgesia after Hysterectomy or Myomectomy: An Observational Study

Background/Aims: The concentration-time profile of the long-acting local anesthetic ropivacaine after epidural (EP) administration at fixed time intervals or continuous subcutaneous (SC) infusion has not been fully evaluated. The objective of this work was to determine total plasma concentrations of ropivacaine and changes in cytokine interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) levels during EP and SC. Methods: In this prospective randomized controlled trial, 18 patients undergoing abdominal hysterectomy or myomectomy were randomly selected to receive ropivacaine either every 6 h via an EP catheter or by continuous wound infusion along the skin incision, after a bolus dose, for 48 h. Total plasma ropivacaine concentrations were measured before the bolus and 2, 4, 8, 24, 48, and 50 h after the bolus using high-performance liquid chromatography-UV and IL-6 and TNF-α levels were measured at 0, 8 and 24 h with ELISA and analyzed statistically. Results: During EP, mean ± SD ropivacaine concentrations were relatively stable up to 50 h postoperatively, that is, 239 ± 89 ng/ml, while during SC, initial concentrations between 2 and 8 h were comparatively lower (101.5 ± 42.9 ng/ml) than 24-50 h concentrations (437.1 ± 206 ng/ml). An increase in IL-6 levels was noted between 0 and 24 h during EP and SC, but TNF-α levels increased slightly, between 0 and 24 h, only during EP. Conclusion: Ropivacaine plasma concentrations with both EP and SC were found to be safe throughout the administration time interval. IL-6 levels increased during the same time interval, while TNF levels varied only slightly.

Local anaesthetic toxicity after bilateral thoracic paravertebral block in patients undergoing coronary artery bypass surgery.

We conducted a small pilot observational study of the effects of bilateral thoracic paravertebral block (BTPB) as an adjunct to perioperative analgesia in coronary artery bypass surgery patients. The initial ropivacaine dose prior to induction of general anaesthesia was 3 mg/kg, which was followed at the end of the surgery by infusion of ropivacaine 0.25% 0.1 ml/kg/hour on each side (e.g. total 35 mg/hour for a 70 kg person). The BTPB did not eliminate the need for supplemental opioids after CABG in the eight patients studied. Moreover, in spite of boluses that were within the manufacturer's recommendation for epidural and major nerve blocks, and an infusion rate that was only slightly higher than what appeared to be safe for epidural infusion, potentially toxic total plasma ropivacaine concentrations were common. We also could not exclude the possibility that the high ropivacaine concentrations were contributing to postoperative mental state changes in the postoperative period. Also, one patient developed local anaesthetic toxicity after the bilateral paravertebral dose. As a result, the study was terminated early after four days. The question of whether paravertebral block confers benefits in cardiac surgery remains unanswered. However, we believe that the bolus dosage and the injection rate we used for BTPB were both too high, and caution other clinicians against the use of these doses. Future studies on the use of BTPB in cardiac surgery patients should include reduced ropivacaine doses injected over longer periods.

Feasibility and pharmacokinetics of caudal blockade in children and adolescents with 30-50 kg of body weight.

Caudal blockade, although an important technique of pediatric regional anesthesia, is rarely used in children heavier than 30 kg. This reservation is due to anatomical concerns and lack of pharmacokinetic data. We therefore set out to evaluate, in pediatric patients weighing 30-50 kg, the feasibility of ultrasound-guided caudal blockade and the pharmacokinetics of caudally administered ropivacaine. Twenty consecutive children were included. General anesthesia was used to ensure a secured airway. For the caudal punctures, we applied the same clinical standards as in smaller children, administering ropivacaine 3.1 mg·ml-1 for a volume of 1 ml·kg-1 via ultrasound guidance. Pharmacokinetic analysis was based on total plasma ropivacaine levels and included maximum concentration (Cmax ), time to Cmax (tmax ), terminal elimination half-life, area under the concentration-time curve for the 4-h sampling period, apparent total body clearance, and apparent volume of distribution. In all 19 cases of successful puncture, we identified the relevant anatomical structures (sacral cornua, sacral hiatus, dura mater) and verified correct administration of the local anesthetic by visualizing its cranial spread. Surgical blockade was successful in 18 of 20 cases (90%; one puncture was technically not possible and one child received intraoperatively 50 μg fentanyl). The pharmacokinetic profile of the administered ropivacaine 3.1 mg·ml-1 indicated plasma levels within safe ranges in pediatric patients weighing 30-50 kg. Based on our pharmacodynamic and pharmacokinetic results, we suggest that the body weight of 50 kg it is feasible to perform effective and safe caudal blockade in children up to 50 kg body weight.

A Novel Proliposomal Ropivacaine Oil: Pharmacokinetic-Pharmacodynamic Studies After Subcutaneous Administration in Pigs.

Liposomal local anesthetics are limited by a short liposomal shelf-life, even when under refrigeration. We describe a novel proliposomal ropivacaine that produces liposomes in situ, only after exposure to aqueous media. In vitro: Nanoparticles were assessed (particle size distribution analyzer, cryo-transmission electron microscopy) at baseline and after exposure to saline/plasma. In porcine wound healing study (n = 12), healing was assessed by photography, clinical assessment, and histology. Pharmacodynamics: Seventeen young piglets were randomly assigned to plain 0.5% ropivacaine (n = 5), proliposomal 4% ropivacaine (n = 6), or sham (n = 6). Tactile threshold was assessed using von Frey filaments applied to the surgical wound; the nonoperated skin was used as a control. Tactile threshold over time was determined using area under the curve (AUC) and assessed by 1-way analysis of variance. 8 young piglets were randomly assigned to plain 0.5% (25 mg, n = 4) or proliposomal 4% (200 mg, n = 4) ropivacaine. Plasma ropivacaine was assessed by high-performance liquid chromatography at baseline and at intervals over 36 hours. Paired ropivacaine concentration (from wound exudate and plasma) was obtained at 96 hours. Data were analyzed using noncompartmental and compartmental models. In vitro: On exposure to saline and plasma, the study drug was transformed from a homogenous oil to an emulsion containing liposomes of approximately 1.4-μm diameter; this effect was dilution dependent and stable over time. All wounds healed well; no effect of drug group was observed. Pharmacodynamics: Plain and proliposomal ropivacaine provided sensory anesthesia for approximately 6 and 30 hours, respectively. There was an approximately 7-fold increase in the AUC of anesthesia for proliposomal ropivacaine compared with plain ropivacaine (mean difference, 1010; 95% confidence interval [CI], 625-1396 g·h/mm; P < 0.0001). There was no difference in Cmax (2.31 ± 0.74 vs 2.32 ± 0.46 mg/L), despite an approximately 8-fold difference in dose. However, proliposomal ropivacaine was associated with a marked prolongation of Tmax (6.50 ± 6.35 vs 0.5 ± 0.0 hours), terminal half-life (16.07 ± 5.38 vs 3.46 ± 0.88 hours; P = 0.0036), and ropivacaine-time AUC (47.72 ± 7.16 vs 6.36 ± 2.07 h·mg/L; P < 0.0001), when compared with plain ropivacaine. The proliposomal formulation provided an approximately 250-fold higher ropivacaine concentration in the surgical wound (mean difference, 3783 ng/mL; 95% CI, 1708-5858; P = 0.001) and an approximately 25-fold higher wound:plasma ropivacaine concentration ratio (mean difference, 126; 95% CI 38-213; P = 0.011). Proliposomal ropivacaine exerted prolonged anesthesia with delayed elimination, typical for liposomal drugs. The advantage of this novel proliposomal ropivacaine is its ease of preparation and its extended shelf-stability (>2 years) at room temperature.

Proliposomal Ropivacaine Oil: Pharmacokinetic and Pharmacodynamic Data After Subcutaneous Administration in Volunteers.

Slow-release liposomal formulations of local anesthetics prolong plasma redistribution and reduce peak plasma drug concentration, allowing safer administration of larger doses and further prolonging sensory effects. However, their clinical applicability is limited by expensive manufacture and liposomal leakage. Previously, we described the simple preparation of a novel proliposomal ropivacaine oil that produces multilamellar liposomal vesicles on exposure to aqueous media and that has a shelf-life of >2 years at room temperature. In this study, we present both pharmacodynamic and pharmacokinetic data in healthy volunteers after subcutaneous injection of this novel proliposomal preparation of ropivacaine. In the pharmacodynamic phase of this study, 15 volunteers received 3 separate subcutaneous injections of 2.5 mL containing 1 of the following drugs: proliposomal 4% ropivacaine, plain 0.5% ropivacaine, and the ropivacaine-free proliposomal vehicle. Drugs were administered into the lower back, and their location was randomized and blinded; a separate area was used as an uninjected, open control. Experimental sensory assessment was made at repeated intervals over 72 hours using both pinprick sensation and experimental heat pain tolerance (assessed using quantitative sensory testing). In a separate pharmacokinetic phase of this study, 9 volunteers received subcutaneous injections of 2.5 mL of either proliposomal 4% ropivacaine (n = 6) or plain 0.5% ropivacaine (n = 3); these participants had plasma ropivacaine concentrations assessed at repeated intervals over 72 hours. The mean ± SE duration of pinprick anesthesia after proliposomal and plain ropivacaine administration lasted 28.8 ± 6.0 and 15.9 ± 3.5 hours, respectively (mean difference, 16.8 hours; 95% confidence interval, 10.0-23.7; P = 0.001). For experimental heat pain, the anesthesia duration was approximately 36 and 12 hours, respectively, with mean ± SE area under the curve of the normalized heat pain tolerance over time 55.0 ± 28.8 Δ°C·min for proliposomal ropivacaine and 9.6 ± 26.0 Δ°C·min for plain ropivacaine (mean difference, 64.6 Δ°C·min; 95% confidence interval, 10.2-119.0; P = 0.036). In the pharmacokinetic study, there was no significant difference in peak plasma concentration in the proliposomal ropivacaine group (164 ± 43 ng/mL compared with 100 ± 41 ng/mL in the plain ropivacaine group; P = 0.07) despite an 8-fold increase in ropivacaine dose in the proliposomal group. The 99% upper prediction limit for peak plasma concentrations (351 ng/mL proliposomal; 279 ng/mL plain) was well below the putative toxic plasma concentration for both groups. The mean ± SE terminal half-life and area under the curve for proliposomal ropivacaine versus plain ropivacaine were 13.8 ± 3.6 hours vs 5.9 ± 2.3 hours (P = 0.011) and 5090 ± 1476 h·ng/mL vs 593 ± 168 h·ng/mL (P = 0.0014), respectively. The prolonged pharmacodynamic effect of proliposomal ropivacaine, together with its delayed elimination and prolonged redistribution to plasma, is compatible to depot-related slow-release and similar to the performance of other liposomal local anesthetics. The advantage of the proliposomal oil is its ease of preparation and its extended shelf-stability at room temperature.

Perioperative Analgesic Management of Newborn Bladder Exstrophy Repair Using a Directly Placed Tunneled Epidural Catheter with 0.1% Ropivacaine

Effective multimodal analgesia and sedation reduce the postoperative morbidity and mortality associated with newborn bladder exstrophy repair. Epidural analgesia is safe and effective for major surgery in neonates and infants, reducing the need for muscle relaxants, opioids, and ventilator support postoperatively. The risk of epidural catheter colonization typically dictates removal after 3 to 5 days. Tunneling the catheter subcutaneously reduces the risk of colonization, providing prolonged analgesia for patients requiring an extended immobilization to prevent compromise of the repair. In this report, we describe the postoperative analgesic management of an infant undergoing bladder exstrophy repair using a directly placed tunneled epidural catheter with ropivacaine 0.1% infusion. Because of the prolonged infusion, we also monitored plasma ropivacaine levels to preclude systemic toxicity from local anesthetic overdose.

Effects of ropivacaine combined with morphine at 0.15 and 0.2 mg kg(-1) in bitches undergoing epidural anesthesia.

To investigate cardiorespiratory effects and serum concentration of ropivacaine combined with morphine at different doses. Sixteen healthy adult female dogs weighting 9.8 ± 4.1 kg were included in the study. Twenty minutes after being premedicated with acepromazine and midazolam, the animals were randomly assigned to receive an epidural injection according to each group: RM0.15 = ropivacaine + morphine (0.15 mg kg(-1)) and RM0.2 = ropivacaine + morphine (0.2 mg kg(-1)). Variables recorded consisted of: heart rate and cardiac rhythm, respiratory rate, oxyhemoglobin saturation, inspired oxygen fraction, end-tidal carbon dioxide tension, systolic, mean and diastolic arterial pressures, serum cortisol, plasma ropivacaine and morphine. SAP, MAP and DAP were significantly increased at TPR in RM0.15 but returned to normal values at the end of the procedure. Arterial pH was decreased in T30 and TESu in both groups and also returned to acceptable ranges at TR. Both PaO2 and PaCO2 were increased along the duration period of the epidural blockade (T30 and TESu) and returned to acceptable values at TR. Serum cortisol was lower at TB, T30 and TR when compared to TESu. The procedures were performed safely and minimal changes in cardiovascular and respiratory variables.

Ropivacaine plasma levels following high-dose local infiltration analgesia for total knee arthroplasty.

We measured total and free plasma concentrations of ropivacaine following high-volume, high-dose local infiltration analgesia in 28 patients aged 65 years or over undergoing unilateral total knee arthroplasty. Patients received infiltration of ropivacaine 400 mg followed by infusion at 20 mg.h(-1) through an intra-articular catheter. Total and free plasma levels of ropivacaine were measured at specified time intervals during a 24-h period after tourniquet release. Patients were monitored for symptoms and signs of local anaesthetic toxicity. Total levels of plasma ropivacaine varied from 0.147 to 3.093 μg.ml(-1) (mean (SD) 1.105 (0.518) μg.ml(-1) ). Free levels of plasma ropivaca-ine varied from 0.001 to 0.104 μg.ml(-1) (mean (SD) 0.037 (0.020) μg.ml(-1) ). Six samples had total plasma ropivacaine levels greater the toxic threshold of 2.2 μg.ml(-1) . No samples reached the toxic threshold for free venous ropivacaine concentration. We conclude that the use of high-dose ropivacaine infiltration and catheter infusion for total knee arthroplasty in an elderly population does not result in free plasma ropivacaine levels previously associated with toxicity but that raised total plasma levels may be observed.

Symptomatic Local Anesthetic Toxicity and Plasma Ropivacaine Concentrations After Transversus Abdominis Plane Block for Cesarean Section

Symptomatic Local Anesthetic Toxicity and Plasma Ropivacaine Concentrations After Transversus Abdominis Plane Block for Cesarean Section

Plasma ropivacaine concentration following ultrasound-guided subcostal transversus abdominis plane block in adults.

Ultrasound-guided subcostal transversus abdominis plane block (TAPB) is widely used for abdominal surgery; however, arterial plasma concentration of the anesthetic ropivacaine after the blockade is still unclear. We evaluated ropivacaine concentration after subcostal TAPB in adult patients undergoing upper abdominal surgery. Twelve patients with American Society of Anesthesiologists physical status 1-2 were enrolled. They received ultrasound-guided subcostal TAPB with 0.45 % ropivacaine at 3 mg/kg. Arterial plasma samples were collected at 15, 30, 45, 60, 90, and 120 min after the blockade and analyzed for total ropivacaine concentration using liquid chromatography and mass spectrometry. At every time point, the maximum concentrations (C(max)), and time to the C max (T(max)) were recorded. The mean C(max) and T(max) were 1.87 (0.78) µg/ml and 31.3 (16.7) min, respectively. No adverse events or clinical symptoms indicating systemic toxicity were observed during this study. The study demonstrated that administration of ropivacaine at 3 mg/kg during subcostal TAPB led to rapid increases in plasma concentration of the anesthetic during the first 2 h after the blockade. C(max) nearly reached the threshold for systemic toxicity.

Ropivacaine plasma levels following local infiltration analgesia for primary total hip arthroplasty

We measured total and free plasma concentrations of ropivacaine following high-volume, high-dose local infiltration analgesia in 19 patients aged 65 years or over undergoing unilateral total hip arthroplasty. The patients received 180 ml ropivacaine 0.2% (360 mg), which was injected into the deep and peri-capsular tissues, the gluteal muscles and fascia lata, and the subcutaneous tissues and skin. Patients were monitored for clinical symptoms and signs of systemic local anaesthetic toxicity. Total levels of plasma ropivacaine varied from 0.081 to 1.707 μg.ml(-1) (mean (SD) 0.953 (0.323) μg.ml(-1) ). Free levels of plasma ropivacaine varied from 0.000 to 0.053 μg.ml(-1) (mean (SD) 0.024 (0.011) μg.ml(-1) ). No samples reached the toxic threshold for venous ropivacaine concentration, although four patients exhibited mild symptoms consistent with local anaesthetic toxicity. One patient had episodes of complete heart block on ECG monitoring, but plasma ropivacaine levels were below toxic levels. We conclude that plasma levels for ropivacaine associated with toxicity in a volunteer population (total 2.2 μg.ml(-1) , free 0.15 μg.ml(-1) ) are not reached during local infiltration analgesia for hip arthroplasty in elderly patients.

Symptomatic Local Anaesthetic Toxicity and Plasma Ropivacaine Concentrations After Transversus Abdominis Plane Block for Caesarean Section

Background The transversus abdominis plane (TAP) block involves injecting a large volume of local anaesthetic between the muscles of the abdominal wall. Plasma concentrations of ropivacaine after gynaecological laparotomy are potentially high enough to result in systemic toxicity, and there are pharmacokinetic reasons why pregnancy may increase susceptibility to local anaesthetic toxicity. Methods Adult female patients (n=30) undergoing elective Caesarean section under spinal anaesthesia received bilateral ultrasound-guided TAP blocks after wound closure (2.5 mg kg−1 of ropivacaine diluted to 40 ml). Venous blood samples were collected at 10, 20, 30, 45, 60, 90, 120, 180 and 240 min following the block. Blood samples were assayed for total and free ropivacaine concentrations. Patients were assessed for symptoms of local anaesthetic toxicity. Results The mean [standard deviation ( sd )] peak total concentration of ropivacaine occurred at 30 min post-injection and was 1.82 (0.69) μg ml−1. The maximum detected concentration in any patient was 3.76 μg ml−1 (at 10 min post-injection). Three patients reported symptoms of mild neurotoxicity, and the mean ( sd ) peak levels were elevated in these patients, 2.70 (0.46) µg ml−1. Conclusions TAP blocks can result in elevated plasma ropivacaine concentrations in patients undergoing Caesarean section, which may be associated with neurotoxicity.

Plasma ropivacaine concentrations after ultrasound-guided transversus abdominis plane block for open retropubic prostatectomy

Ropivacaine-induced vasoconstriction may affect the early absorption speed of ropivacaine; however, the effects of dose on pharmacokinetics following transversus abdominis plane (TAP) block have not been studied. In this study, we have examined plasma ropivacaine concentrations following TAP block with various ropivacaine concentrations (0.25, 0.5, and 0.75 %). With the approval of our University ethics committee and informed consent, 39 adult patients undergoing open retropubic prostatectomy were enrolled. Patients were randomly assigned to three groups (n = 13 each) receiving TAP block with 20 ml (10 ml each side) of different concentrations of ropivacaine. To determine plasma concentrations, blood samples were drawn before and 15, 30, 45, 60, 90, 120, and 180 min after completion of bilateral TAP blocks. Plasma ropivacaine concentrations were analyzed by gas chromatography with mass spectrometry. We found that the peak plasma concentrations (C(max)) increased dose dependently (0.41 ± 0.14, 0.89 ± 0.55, and 1.56 ± 0.50 µg/ml), but the times to C(max) (23.0 ± 15.8, 23.1 ± 14.5, and 20.8 ± 11.5 min) were not different between 0.25, 0.5, and 0.75 % ropivacaine doses, respectively. Terminal elimination half-life (t(1/2)), total body clearance (CL), and distribution volume (V(d)) were also not different among the three groups. Ropivacaine concentration did not alter pharmacokinetic profile following TAP blocks.

Development of a method to measure free and bound ropivacaine in human plasma using equilibrium dialysis and Hydrophilic interaction chromatography coupled to high resolution mass spectrometry

The pharmacodynamics of absorption of local anaesthetics used during surgical procedures into tissues is governed by the amount of free drug in plasma. Toxicity may occur during continuous infusions if the levels of free drug become too high which may occur if the binding capacity of the α-1-acid glycoprotein present in plasma is exceeded. In order to monitor this a method was developed for the determination of the amount of free and bound ropivacaine in human plasma during knee and hip surgery. Rapid equilibrium dialysis units were used to separate free and bound drug then protein and buffer salts were removed by solvent precipitation. Analysis was carried out using a ZICHILIC HPLC column interfaced with an LTQ Orbitrap mass spectrometer. The following extracted ion ranges ([M+H](+)) were monitored: m/z 275.21-275.22 for ropivacaine and m/z 235.175-235.185 for lidocaine. The method was calibrated by spiking ropivacaine, and a fixed amount of lidocaine as internal standard, into plasma over the range 0.01-1.5 µg/ml. The equation of the line was y=0.886x±4.2% (n=2), forcing the curve through zero since blank plasma was free of the analyte. The values obtained for the accuracy and precision of the analysis of plasma spiked at 0.03 µg/ml and 1.5 µg/ml were 93.2%±2.8% and 95.4%±1.5% respectively (n=5). Repeat analysis of a patient sample for free and bound drug gave the following values for levels of ropivacaine: bound 1.63 µg/ml±1.48%, unbound 0.0671 µg/ml±1.68% (n=5).

Plasma ropivacaine concentrations during bilateral transversus abdominis plane infusions

BackgroundThe transversus abdominis plane (TAP) block is a regional anaesthetic technique that blocks abdominal wall somatic afferent nerves. We conducted a prospective observational study to evaluate the venous plasma concentrations of ropivacaine during a continuous TAP infusion. MethodsTwenty patients who were planned to undergo intra-abdominal cavity surgery requiring a mid-line laparotomy incision were enrolled. Patients were excluded if they had a history of chronic pain, opioid tolerance, renal or hepatic impairment, or contraindication to study medications. Subjects received a standardized general anaesthetic, and at the completion of surgery, ultrasound-guided subcostal or posterior TAP blocks and catheters. A TAP infusion of 2 mg ml−1 ropivacaine was administered for 72 h after operation. Data collection during the 72 h included morphine requirements, pain scores, and plasma ropivacaine levels. ResultsTAP blocks and catheters were successfully inserted in all recruited subjects. The fourth subject experienced neurological symptoms attributed to local anaesthetic toxicity, but did not have high plasma ropivacaine concentrations. However, the protocol was amended for the subsequent 16 subjects, to a weight-based dosing regimen. The range of total plasma ropivacaine concentrations was 0.98–3.41 mg litre−1 for posterior infusions and 0.96–3.48 mg litre−1 for subcostal infusions. Four subjects had total ropivacaine levels >3.4 mg litre−1. The range of unbound plasma ropivacaine concentrations was 0.022–0.135 mg litre−1 for posterior infusions and 0.031–0.120 mg litre−1 for subcostal infusions. ConclusionGiven the potential for high plasma concentrations from a bilateral TAP infusion technique, attention should be paid to individualized dosing strategies.

Molecularly imprinted polymer in microextraction by packed sorbent for the simultaneous determination of local anesthetics: lidocaine, ropivacaine, mepivacaine and bupivacaine in plasma and urine samples

This study presents the use of molecularly imprinted polymer (MIP) as packing material for microextraction by packed syringe (MEPS) to achieve higher extraction selectivity. Pentycaine was used as template for MIP. Development and validation of the determination of lidocaine, ropivacaine, mepivacaine and bupivacaine in human plasma and urine samples utilizing MIP-MEPS and liquid chromatography-tandem mass spectrometry (LC-MS/MS) were carried out. The MEPS MIP-cartridge could be used for 100 extractions before it was discarded. The extraction recovery ranged from 60 to 80%. The correlation coefficients values were >0.999 for all assays using lidocaine, ropivacaine, mepivacaine and bupivacaine in the calibration range 5-2000 nmol/L. The accuracy of the studied compounds, given as a percentage variation from the nominal concentration values, ranged from -4.9 to 8.4% using plasma and urine samples. The between-batch precision, given as the relative standard deviation, at three different concentrations (quality control samples) was ranged from -4.7 to 14.0% and from 1.8 to 12.7% in plasma and urine, respectively. The lower limit of quantification and limit of detection of the studied substances were 5.0 and 1.0 nm, respectively.

Symptomatic local anaesthetic toxicity and plasma ropivacaine concentrations after transversus abdominis plane block for Caesarean section

The transversus abdominis plane (TAP) block involves injecting a large volume of local anaesthetic between the muscles of the abdominal wall. Plasma concentrations of ropivacaine after gynaecological laparotomy are potentially high enough to result in systemic toxicity, and there are pharmacokinetic reasons why pregnancy may increase susceptibility to local anaesthetic toxicity. Adult female patients (n=30) undergoing elective Caesarean section under spinal anaesthesia received bilateral ultrasound-guided TAP blocks after wound closure (2.5 mg kg(-1) of ropivacaine diluted to 40 ml). Venous blood samples were collected at 10, 20, 30, 45, 60, 90, 120, 180 and 240 min following the block. Blood samples were assayed for total and free ropivacaine concentrations. Patients were assessed for symptoms of local anaesthetic toxicity. The mean [standard deviation (SD)] peak total concentration of ropivacaine occurred at 30 min post-injection and was 1.82 (0.69) μg ml(-1). The maximum detected concentration in any patient was 3.76 μg ml(-1) (at 10 min post-injection). Three patients reported symptoms of mild neurotoxicity, and the mean (SD) peak levels were elevated in these patients, 2.70 (0.46) µg ml(-1). TAP blocks can result in elevated plasma ropivacaine concentrations in patients undergoing Caesarean section, which may be associated with neurotoxicity.

Plasma Ropivacaine Concentrations After Ultrasound-Guided Rectus Sheath Block in Patients Undergoing Lower Abdominal Surgery

A rectus sheath block can provide postoperative analgesia for midline incisions. However, information regarding the pharmacokinetics of local anesthetics used in this block is lacking. In this study, we detail the time course of ropivacaine concentrations after this block. Thirty-nine patients undergoing elective lower abdominal surgery were assigned to 3 groups receiving rectus sheath block with 20 mL of different concentrations of ropivacaine. Peak plasma concentrations were dose dependent, and there were no significant differences in the times to peak plasma concentrations. The present data also suggested a slower absorption kinetics profile for ropivacaine after rectus sheath block than other compartment blocks.