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).

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.

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.

Local sustained delivery of bupivacaine HCl from a new castor oil-based nanoemulsion system.

Bupivacaine HCl (1-butyl-2',6'-pipecoloxylidide hydrochloride), an amide local anesthetic compound, is a local anesthetic drug utilized for intraoperative local anesthesia, post-operative analgesia and in the treatment of chronic pain. However, its utility is limited by the relative short duration of analgesia after local administration (approximately 9 h after direct injection) and risk for side effects. This work is aimed to develop a nanoemulsion of bupivacaine HCl with sustained local anesthetics release kinetics for improved pain management, by exhibiting extended analgesic action and providing reduced peak levels in the circulation to minimize side effects. Herein, biodegradable oils were evaluated for use in nanoemulsions to enable sustained release kinetics of bupivacaine HCl. Only with castor oil, a clear and stable nanoemulsion was obtained without the occurrence of phase separation over a period of 3 months. High loading of bupivacaine HCl into the castor oil-based nanoemulsion system was achieved with about 98% entrapment efficiency and the resulting formulation showed high stability under stress conditions (accelerated stability test) regarding changes in visual appearance, drug content, and droplet size. We show herein that the in vitro release and in vivo pharmacokinetic profiles as well as pharmacodynamic outcome (pain relief test) after subcutaneous administration in rats correlate well and clearly demonstrate the prolonged release and extended duration of activity of our novel nanoformulation. In addition, the lower Cmax value achieved in the blood compartment suggests the possibility that the risk for systemic side effects is reduced. We conclude that castor oil-based nanomulsion represents an attractive pain treatment possibility to achieve prolonged local action of bupivacaine HCl.

Isobolographic analysis of the cutaneous antinociceptive interaction between bupivacaine co-injected with serotonin in rats.

BACKGROUND: The aim of this experiment was to investigate a long-lasting local anesthetic bupivacaine combined with serotonin at inducing cutaneous antinociception. METHODS: The skin antinociception, characterized by an inhibition of the cutaneous trunci muscle reflex (CTMR) following the pinprick on the dorsal skin of rats, was evaluated. The cutaneous antinociceptive effects of bupivacaine alone, serotonin alone, or bupivacaine co-injected with serotonin in a dose-dependent fashion were constructed, while the drug-drug interactions were evaluated by isobologram. RESULTS: Subcutaneous serotonin, as well as the local anesthetic bupivacaine provoked dose-related cutaneous antinociception. On an equipotent basis (50% effective dose [ED50]), the relative potency was bupivacaine (0.43 [0.37-0.50] µmol)>serotonin (1.27 [1.15-1.40] µmol) (p<0.01). At the equi-anesthetic doses (ED75, ED50 and ED25), the duration of bupivacaine was similar to that of serotonin at producing cutaneous antinociceptive effects. Co-administration of bupivacaine and serotonin displayed a synergistic antinociception. CONCLUSIONS: The preclinical data demonstrated that serotonin is less potent in eliciting cutaneous antinociceptive effects but has the similar duration of action, compared with bupivacaine. We also found a more significant depth of the sensory block with bupivacaine+serotonin than bupivacaine alone.

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.

Multi-modal contributions to detoxification of acute pharmacotoxicity by a triglyceride micro-emulsion.

Triglyceride micro-emulsions such as Intralipid® have been used to reverse cardiac toxicity induced by a number of drugs but reservations about their broad-spectrum applicability remain because of the poorly understood mechanism of action. Herein we report an integrated mechanism of reversal of bupivacaine toxicity that includes both transient drug scavenging and a cardiotonic effect that couple to accelerate movement of the toxin away from sites of toxicity. We thus propose a multi-modal therapeutic paradigm for colloidal bio-detoxification whereby a micro-emulsion both improves cardiac output and rapidly ferries the drug away from organs subject to toxicity. In vivo and in silico models of toxicity were combined to test the contribution of individual mechanisms and reveal the multi-modal role played by the cardiotonic and scavenging actions of the triglyceride suspension. These results suggest a method to predict which drug toxicities are most amenable to treatment and inform the design of next-generation therapeutics for drug overdose.

Local anesthetics in liposuction: considerations for new practice advisory guidelines to improve patient safety.

The Practice Advisory on Liposuction published by the American Society of Plastic Surgeons provides a thorough review of anesthetic techniques and guidelines for surgeons who perform liposuction. However, there is evidence to support several changes to the anesthetic infiltrate guidelines that will improve patient safety. These proposed recommendations will have the most impact on patients undergoing office-based procedures, where dedicated anesthesia providers may not be present, but they should also guide practice in both ambulatory care centers and hospitals. The primary foci of the proposed changes include restrictions on bupivacaine use and creation of lidocaine concentration guidelines.

Contribución del bloqueo del plano transverso abdominal guiado por ultrasonidos a la analgesia postoperatoria tras la cesárea / Contribution to post-caesarean analgesia of ultrasound-guided transversus abdominis plane block

Objetivo. El objetivo principal de nuestro estudio fue valorar la contribución de la analgesia producida por el bloqueo del plano transverso abdominal (TAP), mediante punción ecoguiada, a la calidad analgésica obtenida con opioides intratecales, en cesáreas programadas. Material y métodos. Estudio prospectivo, aleatorizado en pacientes programadas para cesárea electiva con anestesia intradural con bupivacaína 0,5% hiperbara. Las pacientes se distribuyeron aleatoriamente en 3 grupos, según el fármaco complementario añadido para analgesia. En el grupo A 0,1mg de morfina, en el grupo B 10μg de fentanilo y en el grupo C 10μg de fentanilo y bloqueo TAP bilateral. El bloqueo TAP bilateral consistió en la inyección tras la cirugía de 20ml de levobupivacaína 0,5% a cada lado. En los grupos A y B, se inyectaron 20ml de suero salino. La analgesia postoperatoria se llevó a cabo con morfina iv en bolos, mediante un sistema de analgesia controlada por la paciente. Se estudió el dolor según una escala visual analógica a las 12 y 24h en reposo y movimiento, el tiempo en que se administró el primer bolo de analgesia y el número de bolos en 24h. También se valoraron los efectos adversos como: náuseas/vómitos, somnolencia y prurito. Se preguntó por el grado de satisfacción de la paciente. Resultados. Se incluyó a 90 pacientes. En reposo, el valor en la escala visual analógica 12/24h fue: grupo A, a las 12h 2,1±1,2, a las 24h 4,7±1,6; en el grupo B, a las 12h 4,3±2,9, a las 24h 4,8±2,0; y en el grupo C, a las 12h 1,9±1,1, y a las 24h 2,3±1,2 (p<0,05). En movimiento, la analgesia fue mejor en el grupo C (p≤0,02). El tiempo en solicitar el primer bolo fue inferior en el grupo B: en el grupo A 9,3±4,9 (p=0,02 respecto al grupo C); en el grupo B 2,0±1,8 (p<0,001 respecto al grupo C); y en el grupo C 13,2±2,1h. El número de bolos en 24h fue: en el grupo B de 38±5, en el grupo A de 10±2 (p<0,05) y en el grupo C de 5±2 (p<0,001). La incidencia de náuseas fue superior en el grupo B (36,6%) y la de prurito fue mayor en el grupo A (36,6%). Conclusiones. El bloqueo TAP mediante ultrasonidos (US), mejoró la eficacia de los opioides intratecales, reduciendo el dolor en las primeras 24h del postoperatorio, el consumo de opiáceos y los efectos secundarios(AU)

Objective. The aim of this study was to evaluate the contribution made by ultrasound-guided transversus abdominis plane block (TAP) to the quality of the analgesia with intrathecal opioids obtained in patients undergoing elective caesarean delivery. Material and methods. A prospective, randomized study in patients submitted to elective caesarean section with spinal anaesthesia with 0.5% hyperbaric bupivacaine. The patients were randomized into 3 groups according to the added complementary drug for analgesia: group A morphine 0.1mg; group B fentanyl 10μg; group C 10μg fentanyl+bilateral TAP block. The TAP block with 20ml of 0.5% levobupivacaine on each side, after surgery. Groups A and B, were injected with 20ml of saline. Postoperative analgesia was performed with morphine bolus through a system of patient-controlled analgesia (PCA). We studied the pain on a visual analogue scale at 12 and 24h at rest and movement, the time elapsed to require the first bolus, and morphine bolus in 24h. Secondary effects such as nausea, vomiting, pruritus, and drowsiness, were also evaluated. The level of patient satisfaction was also recorded. Results. A total of 90 patients were included. At rest the 12/24h VAS score was: group A, at 12h 2.1±1.2, at 24h 4.7±1.6; group B at 12h 4.3±2.9, at 24h 4.8±2; group C at 12h 1.9±1.09, at 24h 2.3±1.2 (P<.05). Walking improved analgesia more in group C (P≤.02). The time of asking for the first bolus was lower in group B: group A 9.3±4.9h (P=.02 compared to group C), in group B 2±1.8h (P<.001 compared to group C) and group C 13.2±2.1h. The number of bolus in 24h in group B was 38±5, in group A 10±2 (P<.05), group C 5±2 (P<.001). Delayed nausea was increased in group B (36.6%) and pruritus was greater in group A (36.6%). Conclusions. Ultrasound (US)-guided TAP block improves spinal opioid analgesia, with a decrease in VAS scores in the first 24h, and reduces opioid requirement and secondary effects after caesarean delivery(AU)

Síndrome de Rett: doble catéter epidural para control del dolor postoperatorio tras cirugía de escoliosis. Revisión de la bibliografía / Rett syndrome: double epidural catheter for the control of postoperative pain after scoliosis surgery. A literature review

El síndrome de Rett es una enfermedad neurológica grave e incapacitante por un defecto estructural en el brazo corto del cromosoma X (Xq28). Afecta a mujeres y consta de múltiples discapacidades neurológicas progresivas que se manifiestan desde edades tempranas causando invalidez y dependencia de por vida. La escoliosis aparece en más del 50% de los pacientes, con necesidad de corrección quirúrgica en casos de graves angulaciones. Es imprescindible una evaluación preanestésica cuidadosa con el fin de identificar los factores de riesgo y así disminuir la morbimortalidad asociada con el procedimiento quirúrgico. Presentamos el caso de una paciente afectada por este síndrome y escoliosis, programada para la realización de una artrodesis vertebral toracolumbar mediante instrumentación con anestesia general, que transcurrió sin incidentes. Evaluamos las connotaciones específicas de este síndrome, sus potenciales complicaciones y su manejo desde un punto de vista anestésico; remarcando el control del dolor postoperatorio conseguido mediante un doble catéter epidural con infusión de anestésicos locales y fentanilo tras la cirugía(AU)

Rett syndrome is a severe and incapacitating neurological disease caused by a structural defect in the short arm of the X chromosome (Xq28). It affects females and consists of multiple and progressive neurological impairments that start from a young age, leading to lifelong disability and dependency. Scoliosis appears in more than 50% of patients and requires surgical correction in cases where the curvature is severe. Pre-anaesthetic assessment is essential in order to identify the risk factors and thus reduce the morbidity and mortality associated with the surgical procedure. We present the case of a patient affected by this syndrome and scoliosis, who was scheduled to have an instrumented thoracolumbar spine arthrodesis with general anaesthesia, which passed without incident. We evaluate the specific details of this syndrome, its potential complications, and its management from an anaesthetic point of view, emphasising the control of postoperative pain using a double epidural catheter with an infusion of local anaesthetics and fentanyl(AU)

El hallazgo de glucosa en el fluido obtenido por el catéter epidural después de su inserción durante la anestesia combinada intradural-epidural realizada con bupivacaína hiperbara es un suceso habitual / The finding of glucose in the fluid obtained by epidural catheter after its insertion during combined intradural-epidural anaesthesia with hyperbaric bupivacaine is a usual occurrence

Objetivos. Evaluar si la aparición de glucosa en el fluido obtenido espontáneamente del catéter epidural tras su inserción, durante la anestesia combinada intradural-epidural realizada con bupivacaína hiperbara, es un suceso habitual. Pacientes y métodos. Estudio observacional prospectivo en 34 pacientes con anestesia combinada intradural-epidural a los que después de localizar el espacio epidural con solución salina, insertar la aguja espinal e inyectar bupivacaína hiperbara, se les introdujo un catéter epidural. Tras observar si goteaba espontáneamente algún fluido por él, se determinó si este contenía glucosa. Retirada la aguja epidural y lavada su luz con solución salina, se comprobó si en el lavado existía glucosa. Las muestras se analizaron con un glucómetro. Cuando desapareció el bloqueo motor se administró una dosis de anestésico local por el catéter epidural. Se valoró la asociación de los parámetros demográficos con el goteo espontáneo por el catéter epidural. Resultados. En 22 pacientes se produjo goteo espontáneo por el catéter epidural tras su inserción. Todas las muestras obtenidas contenían glucosa. En 9 de 34 muestras del lavado de aguja epidural existía glucosa. Ningún paciente sufrió bloqueo sensitivomotor excesivo. Se encontró asociación estadísticamente significativa (p<0,05) de la edad con el goteo espontáneo por el catéter (a más edad, más goteo). Conclusión. El hallazgo de glucosa en el fluido obtenido por el catéter epidural es un suceso frecuente y sin significación clínica. Proponemos que pudo deberse a fuga de líquido cefalorraquídeo por el agujero de punción dural durante o después de la administración de la bupivacaína hiperbara y al derrame de esta en el espacio epidural(AU)

Objectives. To determine whether the appearance of glucose in the fluid spontaneously obtained by the epidural catheter after its insertion during combined intradural-epidural anaesthesia with hyperbaric bupivacaine is a usual occurrence. Patients and methods. A prospective, observational study was conducted on 34 patients with combined intradural-epidural anaesthesia in whom an epidural catheter was introduced, after locating the epidural space with a saline solution, inserting a spinal needle and injecting hyperbaric bupivacaine. After observing whether any fluid was spontaneously dripping from it, it was determined if this contained glucose. Withdrawal of the needle and washing its lumen with saline solution, it was checked whether there was glucose in washout. The samples were analysed using a glucose meter. When the motor block disappeared a dose of local anaesthetic was administered through the epidural catheter. The relationship of the demographic parameters with the spontaneous dripping of the epidural catheter was evaluated. Results. Spontaneous dripping by the epidural catheter after its insertion was observed in 22 patients. All the samples obtained contained glucose. There was glucose in 9 out of 34 epidural needle wash samples. None of the patients suffered from excessive motor-sensory block. There was a statistically significant relationship between patient age (P<.05) and spontaneous dripping by the catheter (the higher the age, more dripping). Conclusion. The finding of glucose in the fluid obtained by the epidural catheter is a frequent occurrence and is of no clinical significance. We propose that it could be due to a leak of cerebrospinal fluid by the dural puncture needle during or after the administering of the hyperbaric bupivacaine and the spillage of this into the epidural space(AU)

In vitro and in vivo entrapment of bupivacaine by lipid dispersions.

Intravenous lipid emulsion is recommended as treatment for local anesthetic intoxication based on the hypothesis that the lipophilic drug is entrapped by the lipid phase created in plasma. We compared a 15.6 mM 80/20 mol% phosphatidyl choline (PC)/phosphatidyl glycerol (PG)-based liposome dispersion with the commercially available Intralipid® emulsion in a pig model of local anesthetic intoxication. Bupivacaine-lipid interactions were studied by electrokinetic capillary chromatography. Multilamellar vesicles were used in the first in vivo experiment series. This series was interrupted when the liposome dispersion was discovered to cause cardiovascular collapse. The toxicity was decreased by an optimized sonication of the 50% diluted liposome dispersion (7.8 mM). Twenty anesthetized pigs were then infused with either sonicated PC/PG liposome dispersion or Intralipid®, following infusion of a toxic dose of bupivacaine which decreased the mean arterial pressure by 50% from baseline. Bupivacaine concentrations were quantified in blood samples using liquid chromatography/mass spectrometry. No significant difference in the context-sensitive plasma half-life of bupivacaine was detected (p=0.932). After 30 min of lipid infusion, the bupivacaine concentration was 8.2±1.5 mg/L in the PC/PG group and 7.8±1.8 mg/L in the Intralipid® group, with no difference between groups (p=0.591). No difference in hemodynamic recovery was detected between groups (p > 0.05).

Weight-based volume of injection influences cranial to caudal spread of local anesthetic solution in ultrasound-guided transversus abdominis plane blocks in canine cadavers.

OBJECTIVE: To determine if the volume of injected local anesthetic solution affects cranial to caudal spread when performing ultrasound-guided transversus abdominis plane (TAP) blocks in dogs. STUDY DESIGN: Prospective experimental study. ANIMALS: Adult Beagle cadavers (n = 20) METHODS: Bilateral TAP blocks using ultrasound guidance was performed in 20 Beagle cadavers (mean ± SD weight, 9.3 ± 1.4 kg) using a 1:1 solution of methylene blue/bupivacaine injected at volumes of 0.25, 0.5, 0.75, and 1.0 mL/kg. Cadavers were dissected to determine injectate spread within the transversus abdominis fascial plane. RESULTS: The transversus abdominis fascial plane was adequately identified by ultrasonography, injected, and dissected in 38 beagle hemi-abdominal walls; injectate was not identified in 2 hemi-abdominal walls. Dermatomal spread (number of ventral nerve roots saturated by injected solution) was volume dependent (P = .026, Kruskal Wallis): 2.9 ± 0.74 nerve roots for 0.25 mL/kg; 3.4 ± 1.1 for 0.5 mL/kg; 4.0 ± 0.67 for 0.75 mL/kg; and 4.2 ± 1.2 for 1 mL/kg. CONCLUSION: In Beagle cadavers, the volume of injected local anesthetic solution significantly affects cranial to caudal spread within the TAP during ultrasound-guided TAP blocks. The volume of local anesthetic injected could potentially be used to augment the spread of analgesic coverage for a given surgical procedure in dogs.

A prospective, randomized, triple-blind comparison of articaine and bupivacaine for maxillary infiltrations

Objectives: To compare the clinical anesthetic efficacy of 0.5% bupivacaine and 4% articaine (both with 1:200.000adrenaline) for anterior maxillary infiltration in healthy volunteers. Material and methods: A triple-blind split-mouth randomized clinical trial was carried out in 20 volunteers. A supraperiosteal buccal injection of 0.9 ml of either solution at the apex of the lateral incisor was done in 2 appointments separated 2 weeks apart. The following outcome variables were measured: latency time, anesthetic efficacy(dental pulp, keratinized gingiva, alveolar mucosa and upper lip mucosa and tissue) and the duration of anesthetic effect. Hemodynamic parameters were monitored during the procedure. Results: Latency time recorded was similar for both anesthetic solutions (p>0.05). No statistically significant differences were found in terms of anesthetic efficacy for dental pulp, keratinized gingiva or alveolar mucosa. Articaine had a significant higher proportion of successful anesthesia at 10 minutes after infiltration in lip mucosa and lip skin (p=0.039). The duration of anesthesia was 336 minutes for bupivacaine and 167 minutes for articaine. (p<0.001). No significant hemodynamic alterations were noted during the procedure. Conclusions: Articaine and bupivacaine exhibited similar anesthetic efficacy for maxillary infiltrations. The duration of anesthesia was longer with the bupivacaine solution, but lip anesthesia was better with articaine (AU)

Association of sustained cardiovascular recovery with epinephrine in the delayed lipid-based resuscitation from cardiac arrest induced by bupivacaine overdose in rats.

BACKGROUND: The role of epinephrine combined with lipid emulsion in rescuing cardiovascular collapse induced by local anaesthetic overdose remains unclear. The objective of this study was to explore the effect of epinephrine on delayed lipid-based treatment for bupivacaine-induced cardiac arrest in rats. METHODS: Thirty-two rats were subjected to bupivacaine to induce asystole. Basic life support was performed for 10 min before the rats received saline, epinephrine alone, or 20% lipid emulsion bolus with or without epinephrine pretreatment. ECG and invasive arterial pressure were monitored continuously. Arterial blood gas was analysed at 25 min; the right lungs and hearts of rats were harvested for measurement of dry-to-wet lung weight ratio and myocardial bupivacaine content, respectively. RESULTS: In the rats treated with epinephrine plus lipid emulsion, there was a marked improvement in haemodynamic parameters at 25 min compared with rats treated with lipid alone, P<0.05. The coronary perfusion pressure immediately after lipid rescue was higher in the epinephrine/lipid-treated rats when compared with rats given lipid only (70 and 24 mm Hg, respectively, P<0.05). The myocardial bupivacaine content was lower (8.34 nM g(-1)) in the epinephrine/lipid group relative to other groups (P<0.05). However, the rats treated with lipid alone which survived had higher PO(2), less severe acidosis, and better hypoxaemia relative to surviving rats given epinephrine plus lipid. CONCLUSIONS: Late intervention with epinephrine plus lipid emulsion contributed to sustained improvement in haemodynamic profile, but failed to alleviate deterioration of hypoxaemia and acidaemia in rats.

A randomized, double-blind, dose-ranging study comparing wound infiltration of DepoFoam bupivacaine, an extended-release liposomal bupivacaine, to bupivacaine HCl for postsurgical analgesia in total knee arthroplasty.

INTRODUCTION: DepoFoam bupivacaine is a novel liposomal formulation of bupivacaine designed to provide prolonged postsurgical analgesia. This dose-ranging study evaluated extent and duration of analgesia following administration of DepoFoam bupivacaine in patients undergoing total knee arthroplasty (TKA). METHODS: Efficacy, safety, and pharmacokinetics of DepoFoam bupivacaine doses of 133, 266, 399, or 532 mg were compared with bupivacaine HCl (150 mg) with epinephrine given as single injections via wound infiltration in TKA patients (N=138). Primary efficacy measure was AUC of pain intensity scores assessed by numeric rating scale with activity (NRS-A) through Day 4 postsurgery. Other assessments included pain intensity at rest (NRS-R), postsurgical opioid consumption, and safety, among others. RESULTS: Mean AUC of NRS-A scores through Day 4 were 20.7, 19.5, 18.8, and 19.1 for the 133-mg, 266-mg, 399-mg, and 532-mg DepoFoam bupivacaine groups vs 20.4 for bupivacaine HCl. With DepoFoam bupivacaine 532-mg, differences in NRS-R scores reached statistical significance (P<0.05) vs bupivacaine HCl on Days 1 and 5 and mean AUC NRS-R scores were significantly lower through Days 2-5; a dose-response trend was demonstrated. Mean rating for blinded care provider's satisfaction with analgesia was significantly higher for DepoFoam bupivacaine 532 mg vs bupivacaine HCl (P ≤ 0.05). Other efficacy measures showed no statistically significant differences. CONCLUSION: Exposure to bupivacaine increased in a dose-related manner, as reflected by mean and maximum plasma bupivacaine concentrations, and AUC(0-∞). Treatment with DepoFoam bupivacaine 532 mg was associated with statistically significantly greater analgesia while patients were at rest after surgery compared with bupivacaine HCl.

The safety and tolerability evaluation of DepoFoam bupivacaine (bupivacaine extended-release liposome injection) administered by incision wound infiltration in rabbits and dogs.

OBJECTIVE: DepoFoam bupivacaine (DB) is in development for prolonged postoperative analgesia. Studies were conducted to evaluate the potential local and systemic toxicity and any effect on wound healing after wound infiltration. METHODS: The model simulates an inguinal hernia (skin incision ∼2.5 and 5.5 cm). Animals (four/sex/group of each species) received DB 9, 18 or either 25 or 30 mg/kg, bupivacaine solution (B(sol); 7.5 mg/ml, 9 mg/kg) or saline. DB was given at 0.6, 1.2 and 1.0 or 1.2 ml/kg, respectively, and B(sol) or saline at 1.2 ml/kg. Each dose was infiltrated in small fractions on Day 1. End points included histology on Days 3 and 15. Wound healing was recorded on Day 2 through Day 15. RESULTS: There was no adverse effect in either species. Notably, granulomatous inflammation was noted in surgical sites from 8 of 24 rabbits in the DB groups only. Based on the minimal to mild severity on Day 15, this was considered a normal reaction against the liposomes. Except for granulomatous inflammation, there were no differences in overall incidence or severity of histologic changes in the sites dosed to DB, saline or B(sol). CONCLUSIONS: The data reported here are the first demonstration of the safety of DB in toxicology species.

Long-acting poly(DL:lactic acid-castor oil) 3:7-bupivacaine formulation: effect of hydrophobic additives.

PURPOSE: To reduce formulation viscosity of bupivacaine/poly(DL lactic acid co castor oil) 3:7 without increasing bupivacaine release rates. METHODS: Poly(DL lactic acid) 3:7 was synthesized and bupivacaine formulation prepared by mixing with additives ricinoleic acid or castor oil. In vitro release measurements identified optimum formulation. Anesthetized ICR mice were injected around left sciatic nerve using nerve stimulator with 0.1 mL of formulation. Animals received 10% bupivacaine-polymer formulation with 10% castor oil (p(DLLA:CO)3:7-10% bupi-10% CO) or 15% bupivacaine-polymer with 10% castor oil (p(DLLA:CO)3:7-15% bupi-10% CO). Sensory and motor block were measured. RESULTS: Viscosity of 10% and 15% bupivacaine-p(DLLA:CO)3:7 formulations was reduced using hydrophobic additives; however, castor oil reduced bupivacaine release rates and eliminated burst effect. Less than 10% of the incorporated bupivacaine was released during 6 h, and less than 25% released in 24 h in vitro. In vivo formulation injection resulted in a 24 h motor block and a sensory block lasting at least 72 h. CONCLUSIONS: Incorporation of hydrophobic low-viscosity additive reduced viscosity in addition to burst release effects. Bupivacaine-polymer formulation with castor oil additive demonstrated prolonged sensory analgesia in vivo, with reduced duration of motor block.

Comparison of neosaxitoxin versus bupivacaine via port infiltration for postoperative analgesia following laparoscopic cholecystectomy: a randomized, double-blind trial.

BACKGROUND AND OBJECTIVES: Wound infiltration with available local anesthetics generally provides analgesia for less than 8 hrs. The site 1 sodium-channel toxin neosaxitoxin (neoSTX) produced analgesia for over 24 hrs in animals and human volunteers. In this randomized, double-blind trial, we examined the postoperative course of patients undergoing laparoscopic cholecystectomy under a standardized general anesthesia with wound infiltration using either neoSTX or bupivacaine. We hypothesized that neoSTX would reduce pain compared with bupivacaine at 12 hrs postoperatively. METHODS: Patients received preincisional infiltration of laparoscope entry sites with 20 mL containing either neoSTX (total dose, 100 µg) or bupivacaine 0.25% (total dose, 50 mg). The primary outcome measure was the visual analog pain score at 12 hrs postoperatively. Secondary outcomes included repeated pain scores at rest and with movement,analgesic use, functional recovery, and adverse effects. Groups were compared using Mann-Whitney U tests for pain scores, Fisher exact test for proportions of patients with severe pain and complete analgesia, and Kaplan-Meier curves for time to full recovery. RESULTS: Among 137 subjects, 69 were randomized to neoSTX and 68 to bupivacaine. Median pain scores at rest and with movement 12 hrs postoperatively were lower in the neoSTX group compared with the bupivacaine group (P<0.01). Additional pain measures and recovery parameters also favored neoSTX. No serious adverse events occurred,and no adverse events were more frequent in the neoSTX group. CONCLUSIONS: NeoSTX shows promise as a long-acting local anesthetic. Future studies will examine dose response, combination formulations, and safety with dose escalation.