Blood bupivacaine concentrations after pecto-serratus and serratus anterior plane injections of plain and liposomal bupivacaine in robotically-assisted mitral valve surgery: Sub-study of a randomized trial.

STUDY OBJECTIVE: To investigate the timing of peak blood concentrations and potential toxicity when using a combination of plain and liposomal bupivacaine for thoracic fascial plane blocks. DESIGN: Pharmacokinetic analysis. SETTING: Operating room. PATIENTS: Eighteen adult patients undergoing robotically-assisted mitral valve surgery. INTERVENTIONS: Ultrasound-guided pecto-serratus and serratus anterior plane blocks using a mixture of 0.5% bupivacaine HCl up to 2.5 mg/kg and liposomal bupivacaine up to 266 mg. MEASUREMENTS: Arterial plasma bupivacaine concentration. MAIN RESULTS: Samples from 13 participants were analyzed. There was substantial inter-patient variability in plasma concentrations. A geometric mean maximum bupivacaine concentration was 1492 ng/ml (range 660 to 4650 ng/ml) at median time of 30 min after injection. In 4/13 (31%) patients, plasma bupivacaine concentrations exceeded our predefined 2000 ng/ml toxic threshold. A second much smaller peak was observed about 32 h after the injection. No obvious signs of local anesthetic toxicity were observed. CONCLUSIONS: Combined injection of plain and liposomal bupivacaine for pecto-serratus/serratus anterior plane blocks produced a biphasic pattern, with the highest arterial plasma concentrations observed within 30 min. Maximum concentrations exceeded the potential toxic threshold in nearly a third of patients, but without clinical evidence of toxicity. Clinicians should not assume that routine combinations of plain and liposomal bupivacaine for thoracic fascial plane blocks are inherently safe.

Studying the effect of vasopressors on therapeutic drug monitoring of two local anesthetics using hybrid micelle liquid chromatography as an analysis tool.

A hybrid micelle based mobile phase was used to develop and validate a liquid chromatographic method for the separation and quantification of two local anesthetics namely; lidocaine hydrochloride (LID), and bupivacaine hydrochloride (BPV) in presence of the frequently co administered vasopressors phenyl ephrine (PHR) and ephedrine (EPH). Optimization of chromatographic separation conditions was performed applying experimental one factor at a time tool, and design of experiment, where the retention behavior of all analytes using both optimization protocols was in accordance. Chromatographic separation was carried on a C8 column operating at 40 °C at a flow rate of 1.5 mL/min. using a mobile phase consisting of 0.18 M sodium dodecyl sulphate, 10% acetonitrile, containing 0.3% triethyl amine and adjusted to pH 7 using 2 M ortho phosphoric acid, adopting UV detection at 230 nm. The proposed method was fully validated and applied to both in vitro and in vivo analysis of rat blood samples. The pharmacokinetics of both LID and BPV was followed when they were solitary injected or when co administered with either PHR or EPH. Moreover, the in vitro spiked experiment was also subjected to documented bio-analytical validation procedures.

Bupivacaine Pharmacokinetics and Breast Milk Excretion of Liposomal Bupivacaine Administered After Cesarean Birth.

OBJECTIVE: To evaluate bupivacaine concentrations in maternal plasma and transfer into breast milk in women undergoing liposomal bupivacaine infiltration in the transversus abdominis plane after cesarean birth. METHODS: Prospective cohort study of healthy pregnant women who underwent cesarean birth at term followed by a transversus abdominis plane block using 52 mg bupivacaine hydrochloride 0.25% (20 mL) and 266 mg liposomal bupivacaine 1.3% (20 mL). Simultaneous blood and milk samples were collected in a staggered fashion, three to four samples per patient at the following timepoints after block administration: 2, 6, 12, 24, 48, 72, and 96 hours. Quantification of bupivacaine was performed by liquid chromatography-tandem mass spectrometry. Neonatal drug exposure was modeled by calculating milk/plasma area under the curve (AUC) ratios, neonatal dosage, and relative neonatal dosage of bupivacaine at each sampling time. RESULTS: Thirty patients were enrolled. Concentrations in breast milk peaked at 6 hours (mean 58 ng/mL), followed by constant and steady decline to low levels at 96 hours (mean 5.2 ng/mL). Maternal plasma concentrations had two peaks, first at 6 hours (mean 155.9 ng/mL) and then at 48 hours (mean 225.8 ng/mL), followed by steady decline. Milk/plasma AUC0-t ratios ranged between AUC0-2 of 0.45 (80% CI 0.38-0.52) and AUC0-96 of 0.15 (80% CI 0.14-0.17). Neonatal dosage ranged between a mean of 355.9 ng/kg at 0-2 hours and a mean of 15,155.4 ng/kg at 0-96 hours. Relative neonatal dosage was less than 1% at all time intervals. No serious adverse reactions occurred in any neonate. CONCLUSION: Bupivacaine is excreted in breast milk after local infiltration of liposomal bupivacaine and bupivacaine hydrochloride mixture into transversus abdominis plane blocks after cesarean birth. Relative neonatal dosages of less than 1% (less than 10% is considered to be unlikely to be of clinical concern) suggest minimal risks for breastfeeding healthy, term neonates after the administration of this combination of local anesthetics to mothers. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT03526419.

Integration of Solid-Phase Extraction and Reversed-Phase Chromatography in Single Protein-Coated Columns for Direct Injection of Bupivacaine in Human Serum.

A rapid, reliable and precise integrated solid-phase extraction (SPE) and reversed-phase liquid chromatography method was developed and validated to determine bupivacaine in human serum using single protein-coated analytical columns. The protein-coated columns were packed with four different sorbents: TSK-ODS, LiChrosorb RP-8, LiChrosorb RP-2 and µ-Bondapak CN-bonded silica. The method involved direct injection of serum sample onto the columns for trapping of the analyte, clean-up from weakly retained serum endogenous components, as well as the final separation. The protein-coated columns operated in two different chromatographic modes. Serum proteins were extracted and cleaned up by SPE, whereas the final separation of bupivacaine was based on reversed-phase chromatography. The protein-coated TSK-ODS column resulted in more accurate peak integration and more reproducible results. A linear relationship between the concentrations of drug and peak areas was confirmed in the range of 100-2000 ng/mL. Detection and quantification limits were 24.85 and 85.36 ng/mL, respectively. The average recovery for bupivacaine ranged from 96.48% to 98.81%. The present methodology was successfully applied, with a high degree of confidence, to analyze clinical samples obtained from patient receiving 0.5% bupivacaine therapy.

Population Pharmacokinetics of Intraperitoneal Bupivacaine Using Manual Bolus Atomization Versus Micropump Nebulization and Morphine Requirements in Young Children.

BACKGROUND: Intraperitoneal (IP) administration of local anesthetics is used in adults and children for postoperative analgesia after laparoscopic surgery. Population pharmacokinetics (PK) of IP bupivacaine has not been determined in children. Objectives of this study were (1) to develop a population PK model to compare IP bupivacaine administered via manual bolus atomization and micropump nebulization and (2) to assess postoperative morphine requirements after intraoperative administration. We hypothesized similar PK profiles and morphine requirements for both delivery methods. METHODS: This was a prospective, sequential, observational study. After institutional review board (IRB) approval and written informed parental consent, 67 children 6 months to 6 years of age undergoing robot-assisted laparoscopic urological surgery received IP bupivacaine at the beginning of surgery. Children received a total dose of 1.25 mg/kg bupivacaine, either diluted in 30-mL normal saline via manual bolus atomization over 30 seconds or undiluted bupivacaine 0.5% via micropump nebulization into carbon dioxide (CO2) insufflation tubing over 10-17.4 minutes. Venous blood samples were obtained at 4 time points between 1 and 120 minutes intraoperatively. Samples were analyzed by liquid chromatography with mass spectrometry. PK parameters were calculated using noncompartmental and compartmental analyses. Nonlinear regression modeling was used to estimate PK parameters (primary outcomes) and Mann-Whitney U test for morphine requirements (secondary outcomes). RESULTS: Patient characteristics between the 2 delivery methods were comparable. No clinical signs of neurotoxicity or cardiotoxicity were observed. The range of peak plasma concentrations was 0.39-2.44 µg/mL for the manual bolus atomization versus 0.25-1.07 µg/mL for the micropump nebulization. IP bupivacaine PK was described by a 1-compartment model for both delivery methods. Bupivacaine administration by micropump nebulization resulted in a significantly lower Highest Plasma Drug Concentration (Cmax) and shorter time to reach Cmax (Tmax) (P < .001) compared to manual bolus atomization. Lower plasma concentrations with less interpatient variability were observed and predicted by the PK model for the micropump nebulization (P < .001). Adjusting for age, weight, and sex as covariates, Cmax and area under the curve (AUC) were significantly lower with micropump nebulization (P < .001). Regardless of the delivery method, morphine requirements were low at all time points. There were no differences in cumulative postoperative intravenous/oral morphine requirements between manual bolus atomization and micropump nebulization (0.14 vs 0.17 mg/kg; P = .85) measured up to 24 hours postoperatively. CONCLUSIONS: IP bupivacaine administration by micropump nebulization demonstrated lower plasma concentrations, less interpatient variability, low risk of toxicity, and similar clinical efficacy compared to manual bolus atomization. This is the first population PK study of IP bupivacaine in children, motivating future randomized controlled trials to determine efficacy.

Plasma and synovial fluid concentrations and cartilage toxicity of bupivacaine following intra-articular administration of a liposomal formulation to horses.

BACKGROUND: The use of intra-articular (IA) local anaesthetics has proven to be an effective means to treat post-operative pain. The effects of local anaesthetics on equine chondrocytes are mixed with some studies reporting chondrodestruction and others no adverse effects. A liposomal formulation of bupivacaine is used in people and dogs by intra- and peri-articular administration to provide up to 72 h of analgesia. The potential uses, side effects including chondrotoxicity, and likelihood of abuse (long-term analgesic effects) has not been evaluated in horses. OBJECTIVES: Describe bupivacaine concentrations following IA administration and assess biomarkers as indicators of the effects of liposomal bupivacaine on chondrocytes in vivo. STUDY DESIGN: Parallel design. METHODS: Sixteen exercised horses received a single IA administration of 0.12 mg/kg liposomal bupivacaine or 0.9% saline. Blood and urine samples were collected for 96 h post-drug administration. Six horses treated with bupivacaine and those receiving saline, underwent daily arthrocentesis. Six additional bupivacaine treated horses underwent arthrocentesis at 96 h. Drug concentrations were measured using LC-MS/MS and pharmacokinetic analyses performed. Immunoassays were used to measure markers of collagen degradation (C2C, C12C) and cartilage matrix synthesis (CPII, CS846) in synovial fluid. RESULTS: The bupivacaine plasma elimination half-life was 17.8 ± 5.42 and 11.9 ± 5.17 h for horses from which synovial fluid was collected daily and at 96 h respectively. Bupivacaine concentrations in the joint were still detectable at 96 h. Significant increases in C12C and C2C were noted at 96 h in horses undergoing arthrocentesis at 96 h only. CPII was increased at 48 h and CS846 at 24 and 48 h in horses sampled daily. MAIN LIMITATIONS: Limited number of animals and absence of liposome control group. CONCLUSIONS: Sustained concentrations of IA bupivacaine suggest viability of this medication as an intra-articular analgesic. Effects on equine chondrocytes need further study.

Analysis of bupivacaine enantiomers in plasma as total and unbound concentrations using LC-MS/MS: Application in a pharmacokinetic study of a parturient with placental transfer.

Bupivacaine, a drug used in obstetric anesthesia and analgesia, is commercially available as a racemic mixture of the R-bupivacaine and S-bupivacaine enantiomers, which show differences in pharmacokinetics, efficacy and toxicity. Changes in bupivacaine plasma protein binding is of clinical relevance considering its high protein binding (approximately 95%) and its classification as an intermediate hepatic extraction ratio drug (E = 0.38). Furthermore, the plasma protein binding of bupivacaine is also of clinical relevance considering that pregnancy is a physiological condition associated with reduced plasma albumin concentration. Also, different pathological conditions, such as pre-eclampsia, can reduce the maternal plasma protein concentrations and consequently increase the bupivacaine placental transfer. This report describes the development and validation of analytical methods for the sequential analysis of the total and unbound concentrations of bupivacaine enantiomers in human plasma using liquid chromatography coupled to mass spectrometry (LC-MS/MS) with a sensitivity compatible with application in pharmacokinetic studies including placental transfer. Aliquots of 200 µL of plasma or plasma ultra-filtrate were extracted with n-hexane in alkaline medium after the deproteinization of the matrix with acetonitrile and water. The separation of bupivacaine enantiomers was obtained on a Chirex® 3020 chiral stationary phase column using as a mobile phase a mixture of 95% n-hexane:ethanol (80:20, v/v) at a flow rate of 0.8 mL/min. The lower limit of quantification was 0.25 ng of each enantiomer/mL of plasma as the total concentration and 0.125 ng of each enantiomer/mL of plasma as the unbound concentration. The methods were applied to study the pharmacokinetics of bupivacaine enantiomers after the administration of 2.5 mg of 0.5% racemic bupivacaine hydrochloride with 1:200,000 epinephrine via the epidural route to an HIV-positive parturient woman undergoing antiretroviral treatment. The parturient showed lower AUC0-∞ (25.42 vs. 30.57 ng.h/mL) and higher volume of distribution (841.96 vs 655.05 L) and total clearance (98.34 vs 81.79 L/h) for the R-bupivacaine enantiomer. The pharmacokinetics of bupivacaine were enantioselective displaying a lower plasma proportion of the enantiomer R-bupivacaine (AUC(R)/(S) ratio equal to 0.83). The placental transfer was approximately 60% for both bupivacaine enantiomers. The unbound fraction (Fu) for the R-bupivacaine enantiomer was higher (10.84%) than the eutomer S-bupivacaine (6.29%).

Periarticular Knee Injection With Liposomal Bupivacaine and Continuous Femoral Nerve Block for Postoperative Pain Management After Total Knee Arthroplasty: A Randomized Controlled Trial.

BACKGROUND: Local periarticular infiltration (PAI) analgesia has emerged as an important component of multimodal approaches to treat total knee arthroplasty postoperative pain. Liposomal bupivacaine may provide prolonged analgesic duration when injected into the surrounding tissues. The purpose of this study was to compare the analgesic efficacy and serum bupivacaine levels of a continuous femoral nerve block (CFNB) with bupivacaine to PAI with liposomal bupivacaine. METHODS: Sixty-five patients undergoing primary unilateral total knee arthroplasty were randomized into 2 groups: (1) CFNB and PAI with bupivacaine (CFNB group) or (2) PAI with bupivacaine:liposomal bupivacaine mixture at the end of surgery (LB group). The primary outcome was pain intensity at maximum knee flexion 24 hours following surgery. Secondary outcomes included pain intensities at rest and movement at timed intervals and serum bupivacaine levels. RESULTS: Patients in the CFNB group experienced lower pain scores at maximum knee flexion at 24 hours (7.91; 95% confidence interval, 7.19-8.61) compared to the LB group (8.95; 95% confidence interval, 8.42-9.48; P = .02). The mean peak serum bupivacaine level in the LB group up to 72 hours was 0.55 µg/mL versus 1.4 µg/mL for CFNB group (P = .0008) with one patient in the CFNB group exceeding the reported minimum serum bupivacaine threshold for toxicity. CONCLUSION: While similar pain control was observed on the day of surgery for both groups, patients with a CFNB experienced lower pain intensities during maximum knee flexion at 24 hours. Total serum concentrations in LB group remained below the toxicity threshold over the study period.

Efficacy and pharmacokinetics of bupivacaine with epinephrine or dexmedetomidine after intraperitoneal administration in cats undergoing ovariohysterectomy.

The aim of this study was to determine the efficacy and pharmacokinetics of bupivacaine in combination with epinephrine or dexmedetomidine after intraperitoneal administration in cats undergoing ovariohysterectomy. Sixteen healthy adult cats (3.3 ± 0.6 kg) were included in a prospective, randomized, masked clinical trial after obtaining owners' consent. Anesthetic protocol included buprenorphine-propofol-isoflurane. Meloxicam [0.2 mg/kg body weight (BW)] was administered subcutaneously before surgery. Cats were randomly divided into 2 groups to receive 1 of 2 treatments. Intraperitoneal bupivacaine 0.25% (2 mg/kg BW) was administered with epinephrine (BE group; 2 µg/kg BW) or dexmedetomidine (BD group; 1 µg/kg BW) before ovariohysterectomy (n = 8/group). A catheter was placed in the jugular vein for blood sampling. Blood samples were collected for up to 8 h after bupivacaine was administered. Plasma concentrations and pharmacokinetics of bupivacaine were determined using liquid chromatography tandem mass spectrometry (LC-MS/MS) and non-compartmental model, respectively. Pain was evaluated using the UNESP-Botucatu multidimensional composite pain scale (MCPS), the Glasgow composite feline pain scale (GPS), and a dynamic visual analog scale up to 8 h after extubation. Rescue analgesia was provided with buprenorphine if MCPS was ≥ 6. Repeated measures linear models were used for analysis of pain and sedation scores (P < 0.05). Maximum bupivacaine plasma concentrations (Cmax) for BE and BD were 1155 ± 168 ng/mL and 1678 ± 364 ng/mL (P = 0.29) at 67 ± 13 min (Tmax) and 123 ± 59 min (P = 0.17), respectively. Pharmacokinetic parameters and pain scores were not different between treatments (P > 0.05). One cat in the BE group received rescue analgesia (P = 0.30). Intraperitoneal bupivacaine with epinephrine or dexmedetomidine produced concentrations below toxic levels and similar analgesic effects. It is therefore safe to administer these drug combinations in cats undergoing ovariohysterectomy.

L'objectif de cette étude était de déterminer la pharmacocinétique de la bupivacaïne avec de l'épinéphrine ou de la dexmedetomidine après son administration intrapéritonéale chez des chats subissant une ovariohystérectomie. Seize chats adultes en bonne santé (3,3 ± 0,6 kg) ont été inclus dans un essai prospectif, randomisé et «à l'aveugle¼. Le protocole anesthésique comprenait la buprénorphine-propofol-isoflurane. Méloxicam (0,2 mg/kg) a été administré par voie sous-cutanée avant la chirurgie. Un cathéter a été placé dans la veine jugulaire pour l'échantillonnage du sang. La bupivacaïne 0,25 % a été administrée intrapéritonéale (2 mg/kg) avec de l'épinéphrine (BE, 2 µg/kg) ou de la dexmedetomidine (BD, 1 µg/kg) avant l'ovariohystérectomie (n = 8/groupe). Des échantillons de sang ont été prélevés jusqu'à 8 heures après l'administration de bupivacaïne. Les concentrations plasmatiques et les données pharmacocinétiques de la bupivacaïne ont été déterminées par l'aide de la chromatographie liquide-spectrométrie de masse (LC-MS) et la représentation graphique avec un modèle noncompartimentale. La douleur a été évaluée à l'aide de l'échelle composite multidimensionnelle de la douleur (MCPS), de l'échelle composite de Glasgow de la douleur féline (GPS) et d'une échelle visuelle analogique dynamique jusqu'à 8 heures après l'extubation. L'analgésie de secours a été fournie avec la buprénorphine si MCPS ≥ 6. Les modèles linéaires de mesures répétées ont été utilisés pour l'analyse des scores de douleur et de sédation (P < 0,05). Les concentrations plasmatiques maximales de bupivacaïne (Cmax) pour BE et BD étaient de 1155 ± 168 ng/mL et 1678 ± 364 ng/mL (P = 0,29) à 67 ± 13 minutes (Tmax) et 123 ± 59 minutes (P = 0,17), respectivement. Les paramètres pharmacocinétiques et les scores de douleur n'étaient pas différents entre les traitements (P > 0,05). Un chat de BE a reçu analgésie de secours (P = 0,30). La bupivacaïne avec de l'épinéphrine ou de la dexmedetomidine intra-péritonéale a produit des concentrations inférieures aux niveaux toxiques et des effets analgésiques similaires. Il est donc sécuritaire d'administrer ces combinaisons de médicaments chez les chats subissant une ovariohysterectomie.(Traduit par les auteurs).

Blood concentration of bupivacaine and duration of sensory and motor block following ultrasound-guided femoral and sciatic nerve blocks in dogs.

Peripheral nerve blocks are becoming increasingly popular for perioperative use as anesthetics and analgesics in small animals. This prospective study was performed to investigate the duration of motor and sensory blockade following use of bupivacaine for ultrasound-guided femoral and sciatic nerve blocks in dogs and to measure the plasma concentrations of bupivacaine that result from these procedures. Six dogs were anesthetized twice using a randomized cross-over design. At the first anesthetic, dogs were assigned to receive either an ultrasound-guided femoral nerve block or sciatic nerve block with 0.15 mL kg-1 of bupivacaine 0.5%. Two months later, the other nerve block was performed during a second anesthetic. At 5, 10, 15, 20, 30 and 60 minutes after injection, arterial blood samples were collected for laboratory measurement of bupivacaine. After 60 minutes, dogs were recovered from anesthesia. Starting at two hours post-injection, video-recordings of the dogs were made every two hours for 24 hours. The videos were randomized and the degree of motor and sensory blockade was evaluated using a three-point scoring system (0 = no effect, 1 = mild effect, 2 = complete blockade) by two blinded assessors. The median (range) times to full recovery from motor blockade were 11 (6-14) hours (femoral) and 12 (4-18) hours (sciatic), and 15 (10-18) hours (femoral) and 10 (4-12) hours (sciatic) for sensory blockade. There were no differences in the median times to functional recovery for the two techniques. Plasma concentrations of bupivacaine were no different following the blocks and were less than 0.78 µg mL-1 at all times. These results suggest that these ultrasound-guided nerve blocks do not result in potentially toxic systemic levels of local anesthetic and that their duration of action is useful for providing anesthesia and analgesia for pelvic limb procedures.

A prospective, randomized, open label, controlled study investigating the efficiency and safety of 3 different methods of rectus sheath block analgesia following midline laparotomy.

BACKGROUND: There is a controversy regarding the efficacy of rectus sheath block (RSB). The aim of the present study was to evaluate analgesic efficacy and safety of three different methods of RSB in postoperative pain management after midline laparotomy. METHODS: A prospective, randomized, controlled, open-label clinical trial with 4 parallel groups was conducted in a tertiary care hospital in Finland. A total of 57 patients undergoing midline laparotomy were randomized to the control group (n = 12) or to 1 of the 3 active RSB analgesia groups: single-dose (n = 16), repeated-doses (n = 12), or continuous infusion (n = 17). Opioid consumption with iv-patient-controlled analgesia pump was recorded, and pain scores and patients' satisfaction were surveyed on an 11-point numeric rating scale for the first 48 postoperative h. Plasma concentrations of oxycodone and levobupivacaine were analyzed. All adverse events during the hospital stay were recorded. RESULTS: Oxycodone consumption was less during the first 12 h in the repeated-doses and in the continuous infusion groups (P = .07) and in numerical values up to 48 h in the repeated-doses group. Plasma oxycodone concentrations were similar in all 4 groups. Pain scores were lower in the repeated-doses group when coughing during the first 4 h (P = .048 vs. control group), and at rest on the first postoperative morning (P = .034 vs. the other 3 groups) and at 24 h (P = .006 vs. the single-dose group). All plasma concentrations of levobupivacaine were safe. The patients' satisfaction was better in the repeated-doses group compared with the control group (P = .025). No serious or unexpected adverse events were reported. CONCLUSIONS: RSB analgesia with repeated-doses seems to have opioid sparing efficacy, and it may enhance pain relief and patients' satisfaction after midline laparotomy.

Injectable in situ forming gel based on lyotropic liquid crystal for persistent postoperative analgesia.

Local anesthetics have been widely used for postoperative analgesia. However, multiple injections or local infiltration is required due to the short half-lives of local anesthetics after single injection, which results in poor compliance and increasing medical expense. In this study, an in situ forming gel (ISFG) based on lyotropic liquid crystal was developed to deliver bupivacaine hydrochloride (BUP) for long-acting postoperative analgesia. BUP-ISFG was designed to be administrated as a precursor solution which would spontaneously transform into gel with well-defined internal nanostructures for sustained drug release at the site of administration when exposed to physiological fluid. A lamellar-hexagonal-cubic phase transition occurred during the in situ gelation. The lamellar phase of the precursor solution endows it with low viscosity for good syringeability while the unique nanostructures of hexagonal and cubic phases of the in situ gel provide sustained drug release. Persistent analgesia effect in vivo was achieved with BUP-ISFG, and the plasma BUP concentration was found to be steadier compared to commercially available BUP for injection. In addition, the ISFG displayed acceptable biocompatibility and good biodegradability. The findings are positive about ISFG as a sustained release system for persistent postoperative analgesia. STATEMENT OF SIGNIFICANCE: To address the issue of insufficient postoperative analgesia associated with short half-lives of local anesthetics after single injection, an in situ forming gel (ISFG) based on lyotropic liquid crystal was developed to deliver bupivacaine hydrochloride (BUP) for postoperative analgesia over three days. The results demonstrated that persistent analgesia effect in vivo was achieved with single injection of BUP-ISFG, and the plasma BUP concentration was found to be steadier compared to commercially available BUP injection. The BUP-ISFG possessed a lamellar-hexagonal-cubic phase transition with corresponding crystal change in 3D nanostructure during the in situ gelation. The relationship between crystal nanostructure and carrier function, might provide some insights to the design and clinical applications of the drug delivery systems based on lyotropic liquid crystal.

Serum Bupivacaine Concentration After Periarticular Injection With a Mixture of Liposomal Bupivacaine and Bupivacaine HCl During Total Knee Arthroplasty.

BACKGROUND AND OBJECTIVES: A relatively new technique to reduce postoperative pain for total knee arthroplasty is to inject a mixture of 266 mg of liposomal bupivacaine and 125 mg of 0.25% bupivacaine HCl with epinephrine 1:300,000 around the knee joint at the time of surgery. Currently, no publications report serum bupivacaine concentrations over time after periarticular injection of liposomal mixed with free bupivacaine. This information is important to ensure safe serum bupivacaine concentrations are maintained especially when considering supplemental or rescue peripheral nerve blocks. METHODS: A total of 40 subjects scheduled for primary unilateral total knee arthroplasty with intraoperative periarticular injection of the liposomal bupivacaine and bupivacaine HCl mixture were included. Total serum bupivacaine concentrations were measured after the last injection at selected time points and calculated by gas chromatography. Quantile regression techniques were used to analyze the data over time. This study is registered with ClinicalTrials.gov (ID NCT02626559). RESULTS: Peak serum concentration ranged from 0.17 to 1.2 µg/mL and occurred from 10 minutes to 48 hours. Across all time points, the 48-hour interval had the highest mean concentration of total serum bupivacaine at 0.55 µg/mL (SD, 0.27). Quantile regression showed total serum bupivacaine concentrations increased over the 48 hours measured. None of the participants demonstrated signs or symptoms of local anesthetic toxicity. CONCLUSIONS: Total serum concentrations of bupivacaine after periarticular administration of liposomal bupivacaine mixed with bupivacaine HCl remained below the described toxicity threshold (2.5 µg/mL) within the first 48 hours, and no patients demonstrated signs or symptoms of toxicity. However, peak serum concentration time was not achieved within the 48-hour interval. Additional studies are needed to describe the course of serum bupivacaine levels after 48 hours and to ascertain the risk of toxicity when combining this method of periarticular injection with peripheral nerve blocks.

Serum levels of bupivacaine after pre-peritoneal bolus vs. epidural bolus injection for analgesia in abdominal surgery: A safety study within a randomized controlled trial.

BACKGROUND: Continuous wound infiltration (CWI) has become increasingly popular in recent years as an alternative to epidural analgesia. As catheters are not placed until the end of surgery, more intraoperative opioid analgesics might be needed. We, therefore, added a single pre-peritoneal bolus of bupivacaine at the start of laparotomy, similar to the bolus given with epidural analgesia. METHODS: This was a comparative study within a randomized controlled trial (NTR4948). Patients undergoing hepato-pancreato-biliary surgery received either a pre-peritoneal bolus of 30ml bupivacaine 0.25%, or an epidural bolus of 10ml bupivacaine 0.25% at the start of laparotomy. In a subgroup of patients, we sampled blood and determined bupivacaine serum levels 20, 40, 60 and 80 minutes after bolus injection. We assumed toxicity of bupivacaine to be >1000 ng/ml. RESULTS: A total of 20 patients participated in this sub-study. All plasma levels measured as well as the upper limit of the predicted 99% confidence intervals per time point were well below the toxicity limit. In a mixed linear-effect model both groups did not differ statistically significant (p = 0.131). The intra-operative use of opioids was higher with CWI as compared to epidural (86 (SD 73) µg sufentanil vs. 50 (SD 32). CONCLUSIONS: In this exploratory study, the pre-peritoneal bolus using bupivacaine resulted in serum bupivacaine concentrations well below the commonly accepted toxic threshold. With CWI more additional analgesics are needed intraoperatively as compared to epidural analgesia, although this is compensated by a reduction in use of vasopressors with CWI. TRIAL REGISTRATION: Netherlands Trial Register NTR4948.

Blood Bupivacaine Concentrations After a Combined Single-Shot Sciatic Block and a Continuous Femoral Nerve Block in Pediatric Patients: A Prospective Observational Study.

We evaluated blood bupivacaine concentrations in children having a single-shot sciatic and continuous femoral blocks after anterior cruciate ligament repair. Dried blood spot samples were analyzed for bupivacaine levels at 0, 5, 15, 30, 60, and 120 minutes and 4, 24, and 48 hours. The highest 99% upper confidence interval limit was 135 ng/mL at the 4-hour evaluation point. The 99% upper confidence interval was below potentially toxic levels (1500 ng/mL) across all sampling times. The risk of local anesthetic toxicity in pediatric patients receiving single-shot sciatic and continuous femoral nerve blocks is very low.

Plasma bupivacaine concentrations following orbital injections in cats.

OBJECTIVE: To determine plasma bupivacaine concentrations after retrobulbar or peribulbar injection of bupivacaine in cats. STUDY DESIGN: Randomized, crossover, experimental trial with a 2 week washout period. ANIMALS: Six adult healthy cats, aged 1-2 years, weighing 4.6 ± 0.7 kg. METHODS: Cats were sedated by intramuscular injection of dexmedetomidine (36-56 µg kg-1) and were administered a retrobulbar injection of bupivacaine (0.75 mL, 0.5%; 3.75 mg) and iopamidol (0.25 mL), or a peribulbar injection of bupivacaine (1.5 mL, 0.5%; 7.5 mg), iopamidol (0.5 mL) and 0.9% saline (1 mL) via a dorsomedial approach. Blood (2 mL) was collected before and at 5, 10, 15, 22, 30, 45, 60, 120, 240 and 480 minutes after bupivacaine injection. Atipamezole was administered approximately 30 minutes after bupivacaine injection. Plasma bupivacaine and 3-hydroxybupivacaine concentrations were determined using liquid chromatography-mass spectrometry. Bupivacaine maximum plasma concentration (Cmax) and time to Cmax (Tmax) were determined from the data. RESULTS: The bupivacaine median (range) Cmax and Tmax were 1.4 (0.9-2.5) µg mL-1 and 17 (4-60) minutes, and 1.7 (1.0-2.4) µg mL-1, and 28 (8-49) minutes, for retrobulbar and peribulbar injections, respectively. In both treatments the 3-hydroxybupivacaine peak concentration was 0.05-0.21 µg mL-1. CONCLUSIONS AND CLINICAL RELEVANCE: In healthy cats, at doses up to 2 mg kg-1, bupivacaine peak plasma concentrations were approximately half that reported to cause arrhythmias or convulsive electroencephalogram (EEG) activity in cats, and about one-sixth of that required to produce hypotension.

Preparation and investigation of a novel levobupivacaine in situ implant gel for prolonged local anesthetics.

In this study, levobupivacaine (LBP) was successfully incorporated into implant application based on the concept of in situ gel (PECE). The physicochemical characterization (preparation, phase transition temperature, in vitro release) were investigated. The results of viscosity measurement showed that the preparations behaved like a fluid but formed a rigid gel when exposed to increasing temperature (37 °C). In vitro release, LBP was graduated released from the gels as time lapsed, suggesting that LBP was well entrapped in PECE in situ gels. As is shown in pharmacokinetic parameters, the half-life of LBP injection (2.7 h) was shorter than that of LBP in situ gels (23.9 h), suggesting that LBP injection was taken up by other tissues more rapidly than gels. The area under the curve of LBP in situ gels was 2.18 times the size of that of LBP injection (P< 0.05). In pharmacodynamic test, even after nine hours of injection, gel group could still maintain rather good anesthesia effect and rats' stinging reaction maintained at a relatively low level, which had obvious statistical differences compared to injection group.

The effects of intravenous lipid emulsion on hemodynamic recovery and myocardial cell mitochondrial function after bupivacaine toxicity in anesthetized pigs.

Local anesthetic toxicity is thought to be mediated partly by inhibition of cardiac mitochondrial function. Intravenous (i.v.) lipid emulsion may overcome this energy depletion, but doses larger than currently recommended may be needed for rescue effect. In this randomized study with anesthetized pigs, we compared the effect of a large dose, 4 mL/kg, of i.v. 20% Intralipid® ( n = 7) with Ringer's acetate ( n = 6) on cardiovascular recovery after a cardiotoxic dose of bupivacaine. We also examined mitochondrial respiratory function in myocardial cell homogenates analyzed promptly after needle biopsies from the animals. Bupivacaine plasma concentrations were quantified from plasma samples. Arterial blood pressure recovered faster and systemic vascular resistance rose more rapidly after Intralipid than Ringer's acetate administration ( p < 0.0001), but Intralipid did not increase cardiac index or left ventricular ejection fraction. The lipid-based mitochondrial respiration was stimulated by approximately 30% after Intralipid ( p < 0.05) but unaffected by Ringer's acetate. The mean (standard deviation) area under the concentration-time curve (AUC) of total bupivacaine was greater after Intralipid (105.2 (13.6) mg·min/L) than after Ringer's acetate (88.1 (7.1) mg·min/L) ( p = 0.019). After Intralipid, the AUC of the lipid-un-entrapped bupivacaine portion (97.0 (14.5) mg·min/L) was 8% lower than that of total bupivacaine ( p < 0.0001). To conclude, 4 mL/kg of Intralipid expedited cardiovascular recovery from bupivacaine cardiotoxicity mainly by increasing systemic vascular resistance. The increased myocardial mitochondrial respiration and bupivacaine entrapment after Intralipid did not improve cardiac function.

The Effect of Lipid Emulsion on Pharmacokinetics of Bupivacaine in Rats: Long-Chain Triglyceride Versus Long- and Medium-Chain Triglyceride.

BACKGROUND: Lipid infusions have been proposed to treat local anesthetic-induced cardiac toxicity. This study compared the effects of long-chain triglyceride (LCT) emulsions with those of long- and medium-chain triglyceride (LCT/MCT) emulsions on the pharmacokinetics of bupivacaine in a rat model. METHODS: After administration of intravenous infusion of bupivacaine at 2 mg·kg·min for 5 minutes in Sprague-Dawley (SD) rats, either Intralipid 20%, an LCT emulsion (LCT group, n = 6), or Lipovenoes 20%, an LCT/MCT emulsion (LCT/MCT group, n = 6), was infused at 2mg·kg·min for 5 minutes. The concentrations of total plasma bupivacaine and bupivacaine that were not bound by lipid (lipid unbound) were measured by a liquid chromatography-tandem mass spectrometric method. A 2-compartmental analysis was performed to calculate the lipid-bound percentage of bupivacaine and its pharmacokinetics. RESULTS: In the LCT group, the clearance (15 ± 2 vs 10 ± 1 mL·min·kg, P = .003) was higher; the volume of distribution (0.57 ± 0.10 vs 0.36 ± 0.11 L·kg, P = .007) and K21 (0.0100 ± 0.0018 vs 0.0070 ± 0.0020 min, P = .021, P' = .032) were larger; and the area under the blood concentration-time curve 0 - t; (605 ± 82 vs 867 ± 110 mgL·min, P =.001) and the area under the blood concentration-time curve (0 - ∞) (697 ± 111 vs 991 ± 121 mgL·min, P =.001) were less, when compared with the LCT/MCT group. CONCLUSIONS: LCT emulsions are more effective than LCT/MCT emulsions in the metabolism of bupivacaine through demonstration of a superior pharmacokinetic profile.