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.

Absorption and pharmacokinetics of bupivacaine after bilateral topical administration in tonsillar fossae for posttonsillectomy pain relief.

No previous studies have investigated the systemic absorption of bupivacaine when used topically for posttonsillectomy pain. The present study was undertaken to investigate the pharmacokinetics of bupivacaine after administration by a swab in the tonsillar fossae over 4 min after tonsillectomy. Eleven adult patients undergoing elective tonsillectomy were recruited. After removal of both tonsils, each of the two tonsillar fossae was covered with a swab moistened with 2 mL of bupivacaine 5 mg/mL, that is, a total of 20 mg bupivacaine. Blood samples were drawn after 0, 5, 10, 20, 30, 45, and 60 min. Bupivacaine was analyzed with an ultra-high-performance liquid chromatography-tandem mass spectrometry method. The highest single measured bupivacaine serum concentration was 23.2 ng/mL and took place 10 min after drug administration. Mean (±SD) Cmax was 11.4 ± 6.0 ng/mL and mean tmax was 11.3 ± 4.7 min. Mean t1/2 was 31.6 ± 9.3 min. As the toxic concentration threshold has been reported to be in the interval 1500-4500 ng/mL, the concentrations measured were well below 2% of the lowest cited toxic threshold. In conclusion, this study shows that applying 4 mL of bupivacaine 5 mg/mL by a swab in the tonsillar fossae posttonsillectomy yields very low plasma concentrations, suggesting its safe application without any risk of systemic toxic effects.

Micro-pharmacokinetics of lidocaine and bupivacaine transfer across a myelinated nerve fiber.

BACKGROUND: The aim of the present study was to predict the time to onset and duration of action of two local anesthetics (lidocaine and bupivacaine) based on experimental dimensions of a typical nerve and experimental octanol/water partition coefficients. METHODS: We began our compilation of experimental data with a numerical solution of the Smoluchowski equation for the transfer of lidocaine and bupivacaine across the axon membrane in the region of the node of Ranvier (axolemma) and across the Schwann cell. The difference between the aqueous and lipid environments of the neuron was simulated by including the coordinate-dependent chemical potential. In the second step, the permeation rates calculated using the diffusion equation were used to solve a system of four ordinary differential equations. This approach allowed us to simulate the cellular environment for a longer time and to compare our model with pharmacokinetic properties (time to onset and duration of action) of local anesthetics from the literature. The behavior of local anesthetics under physiological conditions and in case of local acidosis was also simulated. RESULTS: We demonstrated that local anesthetics cross the axolemma in a time span of less than 1 µs. The time to onset of action, controlled by diffusion from the epineurium to an axon with a typical distance of 500 µm, was 167 s and 186 s for lidocaine and bupivacaine, respectively. The calculated half-life, which is a measure of the duration of action, was 41 min and 328 min for lidocaine and bupivacaine, respectively. CONCLUSIONS: Duration of action is controlled by the storage capacity of lipophilic compartments around the axon, which is higher for bupivacaine but lower in local acidosis. For the latter case, the literature, including textbooks, provides a misinterpretation, namely that protonated species cannot penetrate the membrane.

Synthesis of nanocapsules blended polymeric hydrogel loaded with bupivacaine drug delivery system for local anesthetics and pain management.

Local anesthetics are used clinically for the control of postoperative pain management. This study aimed to develop chitosan (CS) with genipin (GP) hydrogels as the hydrophilic lipid shell loaded poly(ε-caprolactone) (PC) nanocapsules as the hydrophobic polymeric core composites (CS-GP/PC) to deliver bupivacaine (BPV) for the prolongation of anesthesia and pain relief. The swelling ratio, in vitro degradation, and rheological properties enhancement of CS-GP/PC polymeric hydrogel. The incorporation of PC nanocapsules into CS-GP hydrogels was confirmed by SEM, FTIR, and XRD analysis. Scanning electron microscopy results demonstrated that the CS-GP hydrogels and CS-GP/PC polymeric hydrogels have a porous structure, the pore dimensions being non-uniform with diameters between 25 and 300 µm. The in vitro drug release profile of CS-GP/PC polymeric hydrogel has been achieved 99.2 ± 1.12% of BPV drug release in 36 h. Cellular viability was evaluated using the CCK-8 test on 3T3 fibroblast cells revealed that the obtained CS-GP/PC polymeric hydrogel with BPV exhibited no obvious cytotoxicity. The CS-GP/PC polymeric hydrogel loaded with BPV showed significant improvement in pain response compared to the control group animals for at least 7 days. When compared with BPV solution, CS-GP hydrogel and CS-GP/PC polymeric hydrogel improved the skin permeation of BPV 3-fold and 5-fold in 24 h, respectively. In vitro and in vivo results pointed out PC nanocapsules loaded CS-GP hydrogel can act as effective drug carriers, thus prolonging and enhancing the anesthetic effect of BPV. Histopathological results demonstrated the excellent biodegradability and biocompatibility of the BPV-loaded CS-GP/PC polymeric hydrogel system on 7, 14, and 21 days without neurotoxicity.HIGHLIGHTSPreparation and characterization of CS-GP/PC polymeric hydrogel system.BPV-loaded CS-GP/PC exhibited prolonged in vitro release in PBS solution.Cytotoxicity of BPV-loaded CS-GP/PC polymeric hydrogel against fibroblast (3T3) cells.Development of CS-GP/PC a promising skin drug-delivery system for local anesthetic BPV.

Pharmacokinetics and safety of liposomal bupivacaine after local infiltration in healthy Chinese adults: a phase 1 study.

BACKGROUND: Liposomal bupivacaine (LB) is a long-acting formulation of bupivacaine. The safety and efficacy of LB has been demonstrated across surgical procedures. However, pharmacokinetic (PK) parameters and safety of LB in the Chinese population have not been assessed. METHODS: In this single-arm, single center, phase 1, open-label study, PK and safety of local infiltration with LB 266 mg were assessed in healthy Chinese adults. Eligible participants were aged 18 to 55 years with biologic parents and grandparents of Chinese ethnicity, in generally good health (i.e., no clinically significant abnormalities), and with a body mass index (BMI) 19.0 to 24.0 kg/m2 (inclusive) and body weight ≥ 50 kg. RESULTS: Participants (N = 20) were predominantly men (80 %); mean age was 32 years; and mean BMI was 21.8 kg/m2. After LB administration, mean plasma levels of bupivacaine rapidly increased during the first hour and continued to increase through 24 h; plasma levels then gradually decreased through 108 h followed by a monoexponential decrease through 312 h. Geometric mean maximum plasma concentration was 170.9 ng/mL; the highest plasma bupivacaine concentration detected in any participant was 374.0 ng/mL. Twenty-two treatment-emergent adverse events were reported (mild, n = 21; moderate, n = 1). CONCLUSIONS: After single-dose administration of LB, PK measures were similar to a previously reported profile in US adults. The highest observed peak plasma concentration of bupivacaine was several-fold below the plasma concentration threshold accepted as being associated with neurotoxicity or cardiotoxicity (2000-4000 ng/mL). These data support that LB is well tolerated and safe in individuals of Chinese descent. TRIAL REGISTRATION: NCT04158102 (ClinicalTrials.gov identifier), Date of registration: November 5, 2019.

Osmotically balanced, large unilamellar liposomes that enable sustained bupivacaine release for prolonged pain relief in in vivo rat models.

To efficiently prolong analgesic effects, we developed osmotically balanced, large unilamellar liposomes (~ 6 µm in diameter) in which highly concentrated bupivacaine (up to 30 mg/mL) was encapsulated, and their sustained bupivacaine release was highly effective in relieving postoperative pain over 24 h in a rat model. Our reverse-phase evaporation method based on non-toxic alcohol, ethanol, enabled simple and cost-effective production of bupivacaine-loaded liposomes, of which osmotic pressure was readily balanced to improve the structural stability of the enlarged unilamellar liposomes along with extension of their shelf life (> a month). The in vitro release profile verified that the release duration of the bupivacaine-loaded liposomes extended up to 6 days. For the in vivo study, male Sprague-Dawley rats were used for the incisional pain model, simulating postoperative pain, and the mechanical withdrawal threshold (MWT) was measured using a von Frey filament. Compared to the control group that received intraplantar administration of normal saline, the group of liposomal bupivacaine showed that the initially increased MWT gradually decreased up to 24 h, and importantly, the analgesic effect of the liposomal bupivacaine was maintained 6 times longer than that of bupivacaine only, proving the potential of effective long-acting anesthetics.

Enhancement of the Mechanical and Drug-Releasing Properties of Poloxamer 407 Hydrogels with Casein.

PURPOSE: Topical therapy of local disease (e.g. skin) is advantageous over oral therapy since there is less systemic drug distribution (so fewer side-effects), no first-pass effect, etc. However, patient compliance with topical therapy can be poor as it may require many applications a day and can last months. Here we propose a topical controlled release formulation with thermoresponsive gelation at body temperature and improved adhesiveness, making it easier to remain in contact with the body. METHODS: The formulation contains two excipients, poloxamer 407 (P407) and casein. Casein can modify the properties of the hydrogel through molecular entanglement. In addition, tissue reaction and drug release profile were evaluated. RESULTS: Changes in casein concentration affected adhesive strength, viscosity, mechanical properties and drug release, presumably by hydrophobic interactions between casein and P407. Two different concentrations of P407 were tested with two different concentrations of casein. Formulations containing 5% and 10% casein released 80% of model drug in 48 h, while formulations without casein released the same fraction in around 24 h hours. Formulations with 10% casein had almost twice the adhesive strength of those without casein. CONCLUSIONS: Addition of casein modified the mechanical properties and drug release rate of the hydrogel. There was no inflammation or injury after brief exposure in vivo.

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.

An Observational Study of the Pharmacokinetics of Surgeon-Performed Intercostal Nerve Blockade With Liposomal Bupivacaine for Posterior-Lateral Thoracotomy Analgesia.

BACKGROUND: Intercostal nerve blocks with liposomal bupivacaine are commonly used for thoracic surgery pain management. However, dose scheduling is difficult because the pharmacokinetics of a single-dose intercostal injection of liposomal bupivacaine has never been investigated. The primary aim of this study was to assess the median time to peak plasma concentration (Tmax) following a surgeon-administered, single-dose infiltration of 266 mg of liposomal bupivacaine as a posterior multilevel intercostal nerve block in patients undergoing posterolateral thoracotomy. METHODS: We chose a sample size of 15 adults for this prospective observational study. Intercostal injection of liposomal bupivacaine was considered time 0. Serum samples were taken at the following times: 5, 15, and 30 minutes, and 1, 2, 4, 8, 12, 24, 48, 72, and 96 hours. The presence of sensory blockade, rescue pain medication, and pain level were recorded after the patient was able to answer questions. RESULTS: Forty patients were screened, and 15 patients were enrolled in the study. Median (interquartile range [IQR]) Tmax was 24 (12) hours (confidence interval [CI], 19.5-28.5 hours) with a range of 15 minutes to 48 hours. The median (IQR) peak plasma concentration (Cmax) was 0.6 (0.3) µg/mL (CI, 00.45-0.74 µg/mL) in a range of 0.3-1.2. The serum bupivacaine concentration was undetectable (<0.2 µg/mL) at 96 hours in all patients. There was significant variability in reported pain scores and rescue opioid medication across the 15 patients. More than 50% of patients had return of normal chest wall sensation at 48 hours. All patients had resolution of nerve blockade at 96 hours. No patients developed local anesthetic toxicity. CONCLUSIONS: This study of the pharmacokinetics of liposomal bupivacaine following multilevel intercostal nerve blockade demonstrates significant variability and delay in systemic absorption of the drug. Peak serum concentration occurred at 48 hours or sooner in all patients. The serum bupivacaine concentration always remained well below the described toxicity threshold (2 µg/mL) during the 96-hour study period.

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.

Injectable in situ forming nanogel: A hybrid Alginate-NLC formulation extends bupivacaine anesthetic effect.

Finding an ideal anesthetic agent for postoperative pain control, with long action and low side effects, is still a challenge. Local anesthetics have potential for such application if their time of action is improved. This work introduces a new hybrid formulation formed by the association of a nanostructured lipid carrier with a biopolymeric system to encapsulate bupivacaine (BVC). The hybrid formulation was physicochemical and structurally characterized by DLS, TEM, DSC, XRD and FTIR-ATR, and it remained stable for 12 months at room temperature. In vivo analgesia and imaging tests showed that the hybrid system was able to modulate the release, and to increase the concentration of BVC at the site of action, by forming a nanogel in situ. Such nanogel improved over 5 times (>24 h) the anesthesia duration, when compared to free BVC at clinical (0.5%) doses. Therefore, this novel in situ-forming nanogel shows great potential to be used in postsurgical pain control, improving the action of BVC, without losing its versatility of (infiltrative) application.

Local and regional anaesthesia in dogs and cats: Overview of concepts and drugs (Part 1).

Pain management in veterinary patients is a crucial component of appropriate patient care. Multimodal analgesia that includes both systemically and locally/regionally administered drugs is generally the most effective approach to providing pain relief. Local anaesthetic drugs used in local and regional blockade are unique in that they can completely block the transmission of pain (in conscious patients) or nociceptive (in anaesthetized patients) signals, thereby providing profound analgesia. In addition, local and regional administration of drugs, when compared with systemic bolus administration, generally results in a lower incidence of dose-related adverse effects. Due to the potential to provide profound analgesia and the high safety margin (when used correctly) of this drug class, local anaesthetics are recommended as part of the analgesic protocol in the majority of patients undergoing surgical procedures or suffering traumatic injuries. This manuscript, Part 1 of a two-part instalment, emphasizes the importance of using local and regional anaesthesia as a component of multimodal analgesia, provides a review of the basic pharmacokinetics/pharmacodynamics of local anaesthetic drugs in general, lists information on commonly used local anaesthetic drugs for local and regional blockade in dogs and cats, and briefly introduces the novel liposome-encapsulated bupivacaine (NOCITA®). Part 2 is a review of local and regional anaesthetic techniques used in dogs and cats (Grubb & Lobprise, 2020).

The Duration of Nerve Block from Local Anesthetic Formulations in Male and Female Rats.

PURPOSE: It is unknown whether there are sex differences in response to free or encapsulated local anesthetics. METHODS: We examined nerve block duration and toxicity following peripheral nerve blockade in male and female rats. We studied the local anesthetic bupivacaine (free or encapsulated) as well as tetrodotoxin, which acts on a different site of the same voltage-gated channel. RESULTS: Sensory nerve blockade was 158.5 [139-190] minutes (median [interquartile range]) (males) compared to 173 [134-171] minutes (females) (p = 0.702) following bupivacaine injection, N = 8 male, 8 female. Motor nerve blockade was 157 [141-171] minutes (males) compared to 172 [146-320] minutes (females) (p = 0.2786). Micellar bupivacaine (N = 8 male, 8 female) resulted in sensory nerve blockade of 266 [227-320] minutes (males) compared to 285 [239-344] minutes (females) (p = 0.6427). Motor nerve blockade was 264 [251-264] minutes (males) compared to 287 [262-287] minutes (females) (p = 0.3823). Liposomal bupivacaine (N = 8 male, 8 female) resulted in sensory nerve blockade of 240 [207-277] minutes (males) compared to 289 [204-348] minutes (females) (p = 0.1654). Motor nerve blockade was 266 [237-372] minutes (males) compared to 317 [251-356] minutes (females) (p = 0.6671). Following tetrodotoxin injection (N = 12 male,12 female) sensory nerve blockade was 54.8 [5-117] minutes (males) compared to 54 [14-71] minutes (females) (p = 0.6422). Motor nerve blockade was 72 [40-112] minutes (males) compared to 64 [32-143] minutes (females) (p = 0.971). CONCLUSIONS: We found no statistically significant sex differences associated with the formulations tested. In both sexes, durations of nerve block were similar between micellar and liposomal bupivacaine formulations, despite the micellar formulation containing less drug.

Effect of bupivacaine versus bupivacaine plus intrathecal dexmedetomidine in postoperative pain

Background: Pain is defined as "unpleasant sensory and sensory experience", associated with actual or potential tissue domage or described in terms of such damage. Objetive: To assess the effect of bupivacaine versus bupivacaine plus intrathecal dexmedetomidine in postoperative pain. Patients and method: An experimental design was made of a controlled clinical trial type, in patients scheduled for lower abdomen surgery or lower extremities. A sample of 60 patients was studied during the period from October 1 to december 15, 2018, who agreed to participate in the study through of signing consent under information. Results: It was observed that the time of the rescue analgesia was prolonged in more than 120 min in the case of dexmedetomidine when compared with bupivacaine (p<0.0001); also VAS scores at the time of analgesia rescue for the group with dexmedetomidine were 3.71 ± 1.27 and in the bupivacaine group of 5.7 ± 1.59, the difference of two pints of the VAS (p= <0.001) was significant, which demonstrates that dexmedetomidine is effective for prolong postoperative analgesia and decrease the analgesia requirements. Conclusions: Dexmedetomidine at a dose of 5 ug associated with bupivacaine administered intrathecally is more Effective in postoperative analgesia compared with this substance alone in abdominal surgery inferior and lower extremities (AU)

Delivery of bupivacaine from UHMWPE and its implications for managing pain after joint arthroplasty.

Total joint replacement is a widely used and successful surgical approach. Approximately 7 million US adults are currently living with a hip or knee replacement. However, the surgical procedures for total joint replacement are associated with significant postoperative pain, and current strategies do not adequately address this pain, which leads to patient dissatisfaction, reduced mobility, and increased risk of opioid addiction. We hypothesized that the ultra-high-molecular-weight polyethylene (UHMWPE) bearing surfaces used in total joint prosthetics could provide sustained release of the local anesthetic bupivacaine to provide relief from joint pain for an extended period of time after surgery. In this paper, we describe the production of bupivacaine-loaded UHMWPE (BPE) and measure the in vitro bupivacaine release kinetics of BPE. We found that bupivacaine could be released from BPE at clinically relevant rates for up to several days and that BPE possesses antibacterial effects. Therefore, bupivacaine-loaded UHMWPE is a promising material for joint replacement prostheses, and future studies will evaluate its safety and efficacy in in vivo models. STATEMENT OF SIGNIFICANCE: Total joint replacement is associated with significant pain and risk of infection. In our paper, we introduce bupivacaine-loaded ultra-high-molecular-weight polyethylene (BPE), which releases bupivacaine, a pain-treating drug, at doses comparable to currently used doses. Additionally, BPE inhibits the growth of infection-causing bacteria. Therefore, BPE may be able to reduce both postsurgical pain and risk of infection, potentially treating two of the most prominent complications associated with total joint replacement. To our knowledge, this is the first development of a material that can address both complications, and devices incorporating BPE would represent a significant advancement in joint arthroplasty prosthetics. More generally, the incorporation of therapeutic agents into ultra-high-molecular-weight polyethylene could impact many orthopedic procedures owing to its ubiquity.

Transversus Abdominal Plane Block in Children: Efficacy and Safety: A Randomized Clinical Study and Pharmacokinetic Profile.

BACKGROUND: The transversus abdominis plane (TAP) block has become a common regional anesthesia technique for pain management in a wide variety of abdominal procedures. Evidence to support any particular local anesthetic regimen as well as pharmacokinetic and systemic toxicity risks of TAP block remain insufficiently studied in children. The aim of this study was to compare the analgesic effects and investigate pharmacokinetic profile of levobupivacaine after ultrasound-guided TAP block using a low volume/high concentration (LVHC) or a high volume/low concentration (HVLC) solution in children. METHODS: This prospective randomized study included children scheduled for day-case inguinal surgery. Children were randomized to receive TAP block using 0.4 mg·kg levobupivacaine as either HVLC (0.2 mL·kg of 0.2% levobupivacaine) or LVHC (0.1 mL·kg of 0.4% levobupivacaine). The primary outcome was the number of children who required opioid rescue analgesia postoperatively. Pharmacokinetic profile study of levobupivacaine was also performed. RESULTS: Seventy patients were equally randomized, and 65 were included in the final analysis. Seventy-one percent of patients did not require any postoperative opioid analgesia. The number of patients who received rescue analgesia was 12 (35%) in the LVHC group and 7 (23%) in the HVLC group (relative risk, 0.64; 95% confidence interval [CI], 0.29-1.42; P = .26). Mean pain scores (FLACC [faces, legs, activity, cry, and consolability]) at postanesthesia care unit discharge did not differ between LVHC and HVLC groups, respectively, 0.39 ± 0.86 and 1 ± 1.71 with mean group difference -0.60 (95% CI, -1.27 to 0.06; P = .08). The pharmacokinetic profile of levobupivacaine was comparable in the 2 groups: the mean total and free levobupivacaine peak concentrations were 379 ± 248 and 3.95 ± 3.16 ng·mL, respectively, occurring 22.5 ± 11 minutes after injection. The highest total and free levobupivacaine concentrations collected, respectively, 1360 and 15.1 ng·mL, remained far below theoretical toxic thresholds. CONCLUSIONS: In children, quality of postoperative pain control provided by TAP block using levobupivacaine 0.4 mg·kg administered as either HVLC or LVHC did not differ and was associated with a very low risk of local anesthetic systemic toxicity.

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.

Effect of Artemisia Aucheri.L and Bupivacaine Encapsulated Nanoparticles on Nociceptive Pain.

AIM: The purpose of this study was to evaluate the antinociceptive interaction between bupivacaine and Artemisia aucheri. L encapsulated nanoparticles. METHODS AND MATERIALS: The effect of bupivacaine and Artemisia aucheri.L alone, and their encapsulated co-administration was assessed using the 3% formalin test in rat. Increasing doses of bupivacaine (31.6, 100, 178, and 316 mg/kg) or Artemisia aucheri.L (5.6, 10, 17.8, and 31.6 mg/kg) were given i.p. 10 min before 3% formalin administration. RESULTS: The possible mechanism(s) of action were analyzed for the encapsulated co-administration, naloxone (1 mg/kg) and N (G)-nitro-L-arginine methyl ester (L-NAME) (3 mg/kg) were used. Interaction index and isobolographic analysis and the demonstrated a synergistic effect. The experimental ED30 was lower as compared with theoretical ED30. Naloxone was shown to reduce the antinociceptive effect of the encapsulated co-administration. DISCUSSION: These data suggest that the bupivacaine and Artemisia aucheri.L encapsulated nanoparticles gave a synergistic effect.

Retrobulbar vs peribulbar regional anesthesia techniques using bupivacaine in dogs.

OBJECTIVE: To compare the effectiveness of retrobulbar anesthesia (RBA) and peribulbar anesthesia (PBA) in dogs. ANIMAL STUDIED: Six adult mixed-breed dogs (18-24 kg). PROCEDURES: In a randomized, masked, crossover trial with a 10-day washout period, each dog was sedated with intravenously administered dexmedetomidine and administered 0.5% bupivacaine:iopamidol (4:1) as RBA (2 mL via a ventrolateral site) or PBA (5 mL divided equally between ventrolateral and dorsomedial sites). The contralateral eye acted as control. Injectate distribution was evaluated by computed tomography. Following intramuscularly administered atipamezole, corneal and periocular skin sensation, intraocular pressure (IOP), and ocular reflexes, and appearance were evaluated for 24 hours. Comparisons were performed with mixed-effects linear regression (IOP) or the exact Wilcoxon signed rank test (scores). Significance was set at P ≤ .05. RESULTS: Injectate distribution was intraconal in 2/6 RBA- and 4/6 PBA-injected eyes. Eyes undergoing PBA had significantly reduced lateral, ventral, and dorsal periocular skin sensation for 2-3 hours, and significantly reduced corneal sensitivity for 4 hours, relative to control eyes. Chemosis and exophthalmos occurred in 33%-40% of eyes undergoing RBA and 83%-100% eyes undergoing PBA but resolved within 14 hours. Anterior uveitis developed in 2/6 and 1/6 eyes of RBA and PBA, respectively, of them corneal ulcer developed in one eye of each treatment. Both resolved 1-3 days following medical treatment. CONCLUSIONS: Peribulbar injection produced notable anesthesia more reliably than did retrobulbar injection. Both techniques may produce adverse effects, although the uveitis/ulcer could have resulted from the contrast agent used.

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%).