The Safety and Efficacy of Ultrasound-Guided Bilateral Dual Transversus Abdominis Plane (BD-TAP) Block in ERAS Program of Laparoscopic Hepatectomy: A Prospective, Randomized, Controlled, Blinded, Clinical Study.

PURPOSE: Postoperative pain management for patients undergoing hepatic resection is still a challenge due to the risk of perioperative liver dysfunction. The transversus abdominis plane (TAP) block is a promising regional analgesic technique. However, the correct guidelines regarding the dose and regimen of local anesthetics in patients undergoing hepatic resection have yet to be established completely. This study aimed to evaluate the safety and efficacy of ultrasound-guided BD-TAP block with a large dose of ropivacaine in laparoscopic hepatectomy. PATIENTS AND METHODS: This prospective, blinded, randomized, controlled study was conducted with 50 patients who were scheduled for selective laparoscopic hepatectomy. Patients who received a BD-TAP block (3 mg/kg of ropivacaine diluted to 60 mL) with general anesthesia were categorized into the BD-TAP block group (n = 25), and those who received general anesthesia were categorized into the control group (n = 25). The primary outcomes were consumption of sufentanil within 48 hours post-operation and plasma ropivacaine concentration. The secondary outcomes were the severity of pain (at rest and upon coughing), nausea and/or vomiting, and quality of recovery. RESULTS: Compared with the control group, the patients in BD-TAP block group had a significant reduction of postoperative sufentanil consumption at 2 hours (P = 0.019), 24 hours (P = 0.001), and 48 hours (P = 0.001), and the visual analog scale (VAS) scores on coughing were significantly lower at postoperative 2 hours (P = 0.004). There were no statistically significant differences in postoperative nausea and/or vomiting, flatus, catheter removal, off-bed activity, liver function, or postoperative hospital stay. The mean peak total ropivacaine concentration was 1,067.85 ng/mL, which occurred 1 hour after administering the block, and mean free ropivacaine concentration was 52.32 ng/mL. The highest individual peak plasma concentration was 2,360.90 ng/mL at 45 min postinjection, and the free ropivacaine concentration was 139.29 ng/mL. CONCLUSION: Ultrasound-guided BD-TAP block provides effective postoperative analgesia after laparoscopic hepatectomy. This study also confirms that ultrasound-guided BD-TAP blocks with 3 mg/kg ropivacaine during laparoscopic hepatectomy almost never results in the plasma ropivacaine concentrations associated with neurotoxicity.

Validation according to European and American regulatory agencies guidelines of an LC-MS/MS method for the quantification of free and total ropivacaine in human plasma.

Background Ropivacaine is a widely used local anaesthetic drug, highly bound to plasma proteins with a free plasma fraction of about 5%. Therefore, the monitoring of free drug concentration is most relevant to perform pharmacokinetic studies and to understand the drug pharmacokinetic/pharmacodynamic (PK/PD) relationship. Methods A high-sensitivity liquid chromatography-tandem mass spectrometry (LC-MS/MS) method using reverse-phase LC and electrospray ionisation mass spectrometry with multiple reaction monitoring (MRM) is described for the quantitation of both free and total ropivacaine in human plasma. Ropivacaine-d7 was used as an internal standard (IS). Results The method was validated in the range 0.5-3000 ng/mL, with five levels of QC samples and according to the European Medicine Agency and Food and Drug Administration guidelines. The performance of the method was excellent with a precision in the range 6.2%-14.7%, an accuracy between 93.6% and 113.7% and a coefficient of variation (CV) of the IS-normalised matrix factor below 15%. This suitability of the method for the quantification of free and total ropivacaine in clinical samples was demonstrated with the analysis of samples from patients undergoing knee arthroplasty and receiving a local ropivacaine infiltration. Conclusions A method was developed and validated for the quantification of free and total ropivacaine in human plasma and was shown suitable for the analysis of clinical samples.

Does intraperitoneal ropivacaine reduce postoperative inflammation? A prospective, double-blind, placebo-controlled pilot study.

BACKGROUND: Postoperative inflammation is a common consequence of surgery and the ensuing stress response. Local anesthetics have anti-inflammatory properties. The primary aim of this study was to evaluate if LA administrated intraperitoneally perioperatively might inhibit expression of inflammatory cytokines. METHODS: This was a, randomized, double blind, placebo-controlled study (ClinicalTrial.gov reg no: NCT02256228) in patients undergoing surgery for ovarian cancer. Patients were randomized to receive: intraperitoneal ropivacaine (Group IPLA) or saline (Group P) perioperatively. Except for study drug, patients were treated similarly. At the end of surgery, a multi-port catheter was inserted intraperitoneally, and ropivacaine 2 mg/mL or 0.9% saline, 10 mL was injected intermittently every other hour during 72 hours postoperatively. Systemic expression of cytokines and plasma ropivacaine were determined before and 6, 24, and 48 hours after surgery. Stress response was measured by serum glucose, cortisol, and insulin. RESULTS: Forty patients were recruited, 20 in each group. There was no statistical significant difference in systemic cytokine between the groups at any time point. Serum cortisol was significantly lower in the IPLA group at 6 hours, median 103 nmol/L (IQR 53-250) compared to placebo, median 440 nmol/L (IQR 115-885), P = 0.023. Serum glucose and insulin were similar between the groups. Total and free serum concentrations of ropivacaine were well below toxic concentrations. CONCLUSION: In this small study, perioperative intraperitoneal ropivacaine did not reduce the systemic inflammatory response associated with major abdominal surgery. Total and free ropivacaine concentrations were below known toxic concentrations in humans.

Development and Evaluation of Ropivacaine Loaded Poly(Lactic-Co-Glycolic Acid) Microspheres with Low Burst Release.

BACKGROUND: The local anesthetic drugs, especially ropivacaine, were considered favorable analgesia for postoperative management because of their effective local pain relief and low adverse effects. However, the short half-life and the resulting in bolus doses lead to the indistinctive improvement of these drugs in postoperative pain relief. Therefore, the ropivacaine microspheres with sustained release and low initial burst release were anticipated. METHODS: Three methods including oil in water (O/W), water in oil in water (W/O/W), and solid in oil in water (S/O/W) emulsion solvent evaporation method were used to optimize the ropivacaine loaded PLGA microspheres. The microspheres were evaluated both in vitro and in rats. The in vitro-in vivo correlation (IVIVC) was also investigated. RESULTS: The microspheres prepared by O/W method showed more satisfactory properties and the microspheres used for evaluation were prepared by O/W method. The particle size, drug loading, encapsulation efficiency and burst release were 11.19±1.24 µm, 28.37±1.15%, 98.15±3.98%, and 10.96±5.37% for microspheres with PLGA of 12 kDa, and 6.64±0.61 µm, 19.62±0.89%, 92.74±4.21%, and 18.42±5.12% for microspheres with PLGA of 8 kDa, respectively. These microspheres were also injected into rats by subcutaneous, intramuscular and intraperitoneal route, respectively. It was indicated that the detectable concentration of ropivacaine could last for at least 20 days for both kinds of microspheres in spite of injection routes. The low burst releases at 1 d were also manifested in rats and they were 6.62%, 6.99%, 6.48% for the microspheres with PLGA of 12 kDa, and 4.72%, 4.33%, 4.48% for the microspheres with PLGA of 8 kDa by intraperitoneal, intramuscular and subcutaneous route, respectively. A linear relationship between the in vitro release and the in vivo adsorption of ropivacaine from microspheres was also established. CONCLUSION: The ropivacaine microspheres with sustained release and low burst release were acquired, which indicated that the postoperative pain relief might last longer and the side effects might get lower. Therefore, the ropivacaine microspheres prepared in this paper have great potential for clinical use.

Preclinical Evaluation of Ropivacaine in 2 Liposomal Modified Systems.

BACKGROUND: Our research group has recently developed liposomes with ionic gradient and in a combined manner as donor and acceptor vesicles containing ropivacaine (RVC; at 2% or 0.75%). Looking for applications of such novel formulations for postoperative pain control, we evaluated the duration of anesthesia, pharmacokinetics, and tissue reaction evoked by these new RVC formulations. METHODS: The formulations used in this study were large multivesicular vesicle (LMVV) containing sodium acetate buffer at pH 5.5 or in a combined manner with LMVV as donor and large unilamellar vesicles (LUVs) as acceptor vesicles with an external pH of 7.4. Wistar rats were divided into 6 groups (n = 6) and received sciatic nerve block (0.4 mL) with 6 formulations of RVC (LMVVRVC0.75%, LMVV/LUVRVC0.75%, LMVVRVC2%, LMVV/LUVRVC2%, RVC 0.75%, and RVC 2%). To verify the anesthetic effect, the animals were submitted to the pain pressure test and the motor block was also monitored. Histopathology of the tissues surrounding the sciatic nerve region was also assessed 2 and 7 days after treatment. Rats (n = 6) were submitted to a hind paw incision, and mechanical hypersensitivity was measured via the withdrawal response using von Frey filaments after injection of the 6 formulations. Finally, New Zealand white rabbits (n = 6) received sciatic nerve block (3 mL) with 1 of the 6 formulations of RVC. Blood samples were collected predose (0 minutes) and at 15, 30, 45, 60, 90, 120, 180, 240, 300, 360, 420, 480, and 540 minutes after injection. RVC plasma levels were determined using a triple-stage quadrupole mass spectrometer. RESULTS: Duration and intensity of the sensory block were longer with all liposomal formulations, when compared to the plain RVC solution (P < .05). Histopathological evaluation showed greater toxicity for the positive control (lidocaine 10%), when compared to all formulations (P < .05). After the hind paw incision, all animals presented postincisional hypersensitivity and liposomal formulations showed longer analgesia (P < .05). LMVVRVC0.75% presented higher time to reach maximum concentration and mean residence time than the remaining formulations with RVC 0.75% (P < .05), so LMVV was able to reduce systemic exposure of RVC due to slow release from this liposomal system. CONCLUSIONS: All new liposomal formulations containing 0.75% RVC were able to change the pharmacokinetics and enhance anesthesia duration due to slow release of RVC from liposomes without inducing significant toxic effects to local tissues.

Ultrasound-Guided Oblique Sub-Costal Transversus Abdominis Plane Block as the Principal Anesthesia Technique in Peritoneal Dialysis Catheter Implantation and Plasma Ropivacaine Concentration Evaluation in ESRD Patients: A Prospective, Randomized, Double-Blinded, Controlled Trial.

BACKGROUND: The ultrasound-guided transversus abdominis plane (TAP) block is generally used for analgesia but not for anesthesia. A TAP block has a partial analgesic effect on the parietal peritoneum in abdominal surgeries. We hypothesized that an ultrasound-guided oblique subcostal TAP block, used as the principal anesthesia technique, could provide a better anesthetic effect on peritoneum stimulation in peritoneal dialysis catheter (PDC) implantation in end-stage renal diseases (ESRD) patients than local anesthetic infiltration (LAI). METHODS: End-stage renal disease patients undergoing PDC implantation were randomized into 3 groups: LAI Group, unilateral TAP group (Uni-TAP Group) and bilateral TAP group (Bi-TAP Group). A 40-mL dose of 0.25% ropivacaine was used for the regional block (LAI or TAP). The quality of anesthesia, visual analogue scale (VAS) of pain, cumulative rescuing sufentanil consumption, and venous plasma ropivacaine concentrations were compared among the 3 groups. RESULTS: Sixty-nine patients were enrolled, and higher 'Satisfied' anesthesia rates from nephrologists and patients were recorded in the 2 TAP groups, compared with the LAI Group. Significantly lower VAS scores were observed in the Uni-TAP Group at a majority of time points compared with the LAI Group. Less cumulative rescuing sufentanil was used in the 2 TAP groups (2.5 ± 2.7 and 3.0 ± 2.8 µg, respectively) compared with the LAI Group (5.8 ± 2.6 µg, p < 0.05). The median peak venous plasma ropivacaine concentrations were below the reported toxic threshold in all 3 groups. CONCLUSIONS: As the principal anesthesia technique, an ultrasound-guided unilateral oblique subcostal TAP block with 40 mL of 0.25% ropivacaine provided better anesthetic effect in PDC implantations in ESRD patients than LAI.

Pharmacokinetics of 400 mg Locally Infiltrated Ropivacaine After Total Knee Arthroplasty Without Perioperative Tourniquet Use.

BACKGROUND AND OBJECTIVES: Local infiltration analgesia (LIA) with ropivacaine for total knee arthroplasty (TKA) is increasingly used. Despite the high doses of ropivacaine, LIA is considered safe, and this perception is sustained by pharmacokinetic data demonstrating that maximum concentrations of ropivacaine stay well below the toxic threshold in plasma. These pharmacokinetic studies all involve TKA procedures with the use of a tourniquet. Recently, performing TKA without the use of a tourniquet is gaining popularity, but no pharmacokinetic data exist when LIA is administered for TKA without the use of a tourniquet. The purpose of this study was to describe the pharmacokinetic profile of a single-shot ropivacaine (200 mL 0.2%) and 0.75 mg epinephrine (1000 µg/mL) when used for LIA in patients for TKA without a tourniquet. METHODS: In this prospective cohort study, 20 patients treated with LIA for TKA without a tourniquet were studied. Plasma samples were taken at 20, 40, 60, 90, 120, 240, 360, 480, 600, 720, and 1440 minutes after local anesthetic infiltration, in which total and unbound ropivacaine concentrations were determined. RESULTS: Results are given as median (interquartile range [IQR]). Median peak ropivacaine concentration was 1.16 µg/mL (IQR, 0.46); median peak unbound ropivacaine concentration was 0.05 µg/mL (IQR, 0.02). The corresponding times to reach the maximum concentration for total and unbound ropivacaine were 360 (IQR, 240) and 360 (IQR, 360) minutes, respectively. CONCLUSIONS: Although great interindividual variability in ropivacaine concentration was found, both total and unbound maximum serum concentrations remained below the assumed systemic toxic thresholds in all samples. CLINICAL TRIAL REGISTRATION: This study was registered at Netherlands Trial Registry (http://www.trialregister.nl), trial ID NTR6306.

Ropivacaine Wound Infiltration for Pain Management After Breast Cancer Mastectomy: A Population Pharmacokinetic Analysis.

Ropivacaine continuous wound infusions (CWIs) are extensively used as a component of multimodal analgesia. The rational application of CWI of ropivacaine requires a thorough understanding of its pharmacokinetics to investigate the risk of potential systemic toxicity. A population pharmacokinetic (popPK) study was undertaken to describe the pharmacokinetics of ropivacaine CWI during 75 hours. Women undergoing a unilateral mastectomy were scheduled to receive CWI for 40 hours for postoperative analgesia. A 10-mL ropivacaine 0.75% bolus followed by continuous infusion (400 mL of 0.2% ropivacaine at a flow rate of 10 mL/h) was administered via a multihole catheter placed on the major pectoral muscle. PopPK analysis was performed using the nonlinear mixed-effects model. A 1-compartment disposition model with an absorption compartment and a transit compartment for the infusion best describes the data (67 observations from 10 women). Population parameter estimates (between-subject variability, %) are apparent central volume (V/F) 269 L (39.1%), apparent clearance (CL/F) 18.8 h-1 (74.9%), and absorption rate (K12) 0.406 h-1 . The model predicted Cmax as 1.45 ± 0.80 µg/mL, which occurred in the 42.4th hour (39-45.9 hours). This popPK model describes the pharmacokinetics of ropivacaine during continuous wound infusion and confirms the safety profile of the present technique.

Plasma Ropivacaine Concentrations Following Local Infiltration Analgesia in Total Knee Arthroplasty: A Pharmacokinetic Study to Determine Safety Following Fixed-Dose Administration.

BACKGROUND AND OBJECTIVES: The primary aim of this study was to examine the pharmacokinetics of ropivacaine in patients undergoing elective total knee arthroplasty with local infiltration analgesia as the primary analgesic method. We also sought to determine the incidence of biochemical toxicity through measurement of plasma ropivacaine concentrations over the first 24 hours postoperatively. METHODS: This was a prospective, observational study of 15 patients undergoing elective total knee arthroplasty. Local infiltration analgesia was administered by standard technique with 300 mg ropivacaine and epinephrine 5 µg/mL. Total ropivacaine concentrations were taken at specified time intervals in the 24 hours after tourniquet release and analyzed by liquid chromatography-mass spectrometry. RESULTS: Fifteen patients were enrolled into the study. The median peak ropivacaine concentration was 0.57 µg/mL, with a range of 0.32 to 0.88 µg/mL, and occurred between 6 and 24 hours. Age (P = 0.04), weight (P = 0.04), creatinine (P = 0.02), and female sex (P = 0.03) were important predictors of peak concentration. Age (P = 0.02), female sex (P = 0.01), and baseline α1 acid glycoprotein concentrations (P = 0.03) were important predictors for the area under the curve from a ropivacaine concentration versus time plot. CONCLUSIONS: The peak total ropivacaine concentration was below quoted toxic concentrations (2.2 µg/mL) in all patients. This peak occurred later than has previously been described in those undergoing neuraxial or peripheral nerve block, occurring between 6 and 24 hours. The influence of age, weight, and renal function on systemic ropivacaine concentration should be considered when planning local infiltration analgesia. Female sex is a factor that has not previously been associated with peak ropivacaine concentrations.

Population Pharmacokinetic-Pharmacodynamic Modeling of Ropivacaine in Spinal Anesthesia.

BACKGROUND: Ropivacaine is frequently used in spinal anesthesia but the relationship between plasma concentrations and sensory block level remains unknown. OBJECTIVE: The aim of this study was to assess the relationship between plasma ropivacaine concentrations and effects during spinal anesthesia. METHODS: Sixty patients aged between 18 and 82 years were included in this study after providing written informed consent. Patients were randomly assigned to receive intrathecal administration of ropivacaine 15, 20 or 25 mg. 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. RESULTS: 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. CONCLUSIONS: 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. STUDY REGISTRATION: 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).