Effects of a Single Intra-Articular Injection of 2% Lidocaine or 0.5% Bupivacaine on Synovial Fluid Acute Phase Protein Concentrations in Healthy Horses.

The purpose of this study was to compare the extent of inflammation response in the middle carpal joints of healthy horses following intra-articular injection of 2% lidocaine, 0.5% bupivacaine, or 0.9% saline solution. The right middle carpal joint of 20 horses was injected with 5 mL of 0.5% bupivacaine (GB, n = 10) or 5 mL of 2% lidocaine (GL, n = 10). The left middle carpal joint of horses was used as a control (5 mL 0.9% saline). Serum and synovial fluid (SF) were aseptically collected before and at predetermined times after each injection. Serum and synovial fluid protein, albumin, transferrin, haptoglobin, ceruloplasmin, α1-antitripsin, and α1-acid glycoprotein concentrations were measured by sodium dodecyl sulfate polyacrylamide gel electrophoresis and compared among treatments. The results were submitted to analysis of variance using the SAS statistical program, and means were compared by the Student-Newman-Keuls test (P < .05). Both lidocaine and bupivacaine induced serum and SF changes indicative of inflammation, but the magnitude of those changes was more pronounced for lidocaine. Administration of 0.9% saline also induced an inflammatory reaction, but the magnitude of these changes was less pronounced than those caused by GB and GL. The results suggested that bupivacaine is safer than lidocaine for intra-articular injection in horses. Saline solution should not be used as an adjunct to intra-articular injections in horses.

Electroacupuncture alleviates multifidus muscle injury by modulating mitochondrial function and Ca2+ uptake.

Multifidus muscles maintain the stability of the lumbar spine and play a crucial role in the pathogenesis of nonspecific lower back pain. Previous studies have shown that electroacupuncture (EA) can relieve the symptoms of low back pain and reduce injury to the lumbar multifidus muscles. In this study, a rat model of lumbar multifidus muscle injury was established by 0.05% bupivacaine injection and subsequently treated with EA at bilateral "Weizhong" (BL40) acupoints. Disruption of the function and structure of multifidus muscles, increased cytosolic Ca2+ in multifidus myocytes, and reduced mitochondrial fission and ATP production were observed in the model group. Additionally, increased expression of the mitochondrial calcium uniporter (MCU) promoted mitochondrial reuptake of Ca2+ , reversing the excessive increase in cytoplasmic Ca2+ . However, the excessive increase in MCU not only aggravated the increased cytoplasmic Ca2+ but also decreased the expression of the mitochondrial division proteins dynamin-related protein 1 (Drp1) and mitochondrial fission factor (MFF). EA inhibited the overexpression of MCU, promoted mitochondrial reuptake of Ca2+ , and reversed cytosolic Ca2+ overload. Furthermore, EA regulated the expression of the mitochondrial fission proteins Drp1 and MFF and promoted the production of ATP, helping the recovery of mitochondrial function after multifidus injury. Therefore, EA can protect against bupivacaine-induced mitochondrial dysfunction, possibly by attenuating MCU overexpression in the inner mitochondrial membrane and reducing Ca2+ overloading in muscle cells, thereby protecting mitochondrial function and maintaining the normal energy demand of muscle cells.

Comparison of Liposomal Bupivacaine and Conventional Local Anesthetic Agents in Regional Anesthesia: A Systematic Review.

BACKGROUND: Pain is one of the most common adverse events after surgery. Regional anesthesia techniques are effective for pain control but have limited duration of action. Liposomal bupivacaine is a long-acting formulation of bupivacaine. We conduct this systematic review to assess whether liposomal bupivacaine may prolong the analgesic duration of regional anesthesia compared to conventional local anesthetic agents. METHODS: We systematically searched PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE (Ovid), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Google Scholar, Web of Science citation index, US clinical trials register, and recent conference abstracts for relevant studies. RESULTS: We identified 13 randomized controlled trials that compared the use of liposomal bupivacaine to conventional local anesthetics in regional anesthesia. There were 5 studies on transversus abdominis plane (TAP) block, 3 of which reported longer duration of analgesia with liposomal bupivacaine. One study reported comparable analgesia with liposomal bupivacaine TAP block compared to TAP block catheter. There were 3 studies on brachial plexus block, 2 of which reported that liposomal bupivacaine may provide longer analgesia. Studies on other techniques did not report significantly longer analgesia with liposomal bupivacaine. CONCLUSIONS: Currently, there is limited evidence suggesting that liposomal bupivacaine provides longer analgesia than conventional local anesthetics when used in regional anesthesia. The analyses of multiple studies on liposomal bupivacaine for TAP blocks and brachial plexus blocks have yielded conflicting results. As a result, no definitive conclusions can be drawn about its efficacy compared to plain bupivacaine.

The effect of extracorporeal shockwave on liposomal bupivacaine in a tibial plateau leveling osteotomy model.

OBJECTIVE: To determine the effect of extracorporeal shock wave (ESWT) on liposomal bupivacaine in a tibial-plateau-leveling osteotomy model. STUDY DESIGN: In vitro study. SAMPLE POPULATION: Ten samples per group. METHODS: In addition to a control group (sham treatment), five treatment groups were defined as A, energy (E) 3 (0.22 mJ/mm2 ), 360 pulses per minute (p/m); B, E6 (0.29 mJ/mm2 ), 360 p/m; C, E8 (0.39 mJ/mm2 ), 360 p/m; D, E6, 480 p/m; E, E8 480 p/m. Two-milliliter aliquots of liposomal bupivacaine were placed in a gelatin chamber and treated with 1000 pulses according to group. All samples remained in the chamber for 170 seconds to reflect the longest treatment group. Free bupivacaine concentrations were determined after treatment with high-performance liquid chromatography. RESULTS: The median free bupivacaine concentration was reported as control, 1.90 mg/mL; A, 2.10 mg/mL; B, 2.03 mg/mL; C, 2.94 mg/mL; D, 2.71 mg/mL; E, 4.35 mg/mL. Groups C (P = .027), D (P = .034), and E (P = .002) were different from the control group. Groups C (P = .0025) and D (P = .0025) were different from group E. Additional intertreatment group differences were found. CONCLUSION: Extracorporeal shock wave therapy caused a dose-dependent release of bupivacaine; however, there was no significant release of bupivacaine from liposomes when ESWT was applied at currently recommended therapeutic settings in this model. CLINICAL SIGNIFICANCE: This in vitro study provides evidence that concurrent electrohydraulic ESWT and liposomal bupivacaine is likely safe at currently recommended settings, however, higher energy and pulse frequency settings should be avoided.

Citrem-phosphatidylcholine nano-self-assemblies: solubilization of bupivacaine and its role in triggering a colloidal transition from vesicles to cubosomes and hexosomes.

Improvement of pain management strategies after arthroscopic surgery by multimodal analgesia may include the use of long-acting amide local anesthetics. Among these anesthetics, the low molecular weight local anesthetic agent bupivacaine (BUP) is attractive for use in postoperative pain management. However, it has a relatively short duration of action and imposes a higher risk of systemic toxicity at relatively large bolus doses. Bupivacaine encapsulation in lipid-based delivery systems is an attractive strategy for prolonging its local anaesthetic effect and reducing the associated undesirable systemic side effects. Here, we discuss the potential development of liquid crystalline nanocarriers for delivering BUP by using a binary lipid mixture of citrem and soy phosphatidylcholine (SPC) at different weight ratios. The produced safe-by-design family of citrem/SPC nanoparticles is attractive for use in the development of nanocarriers owing to the previously reported hemocompatibility. BUP encapsulation efficiency (EE), depending on the lipid composition, was in the range of 65-77%. In this study, nanoparticle tracking analysis (NTA) and synchrotron small-angle X-ray scattering (SAXS) were employed to gain insight into the effect of BUP solubilization and lipid composition on the size and structural characteristics of the produced citrem/SPC nanodispersions. BUP loading led to a slight change in the mean sizes (diameters) and size distributions of citrem/SPC nanoparticles. However, we found that BUP accommodation into the self-assembled interiors of nanoparticles, triggers significant structural alterations in BUP concentration- and lipid composition-dependent manners, which involve vesicle-cubosome and vesicle-hexosome transitions. The structural tunability of citrem/SPC nanoparticles and the implications for potential applications in intra-articular BUP delivery are discussed.

New local anesthetics.

Local anesthetics are used for performing various regional anesthesia techniques to provide intraoperative anesthesia and analgesia, as well as for the treatment of acute and chronic pain. Older medications such as lidocaine and bupivacaine as well as newer ones such as mepivacaine and ropivacaine are being used successfully for decades. Routes of administration include neuraxial, perineural, intravenous, various infiltrative approaches, topical, and transdermal. There are new innovations with the use of older local anesthetics in a novel manner, in addition to the development and use of new formulations. This chapter seeks to summarize the pharmacokinetics of local anesthetics and address the role of newer local anesthetics, as well as clinical implications, safety profiles, and the future of local anesthetic research. Finally, some clinical pearls are highlighted.

Synergy between chemical permeation enhancers and drug permeation across the tympanic membrane.

Chemical permeation enhancers (CPEs) can enable antibiotic flux across the tympanic membrane. Here we study whether combinations of CPEs (sodium dodecyl sulfate, limonene, and bupivacaine hydrochloride) are synergistic and whether they could increase the peak drug flux. Synergy is studied by isobolographic analysis and combination indices. CPE concentration-response (i.e. trans-tympanic flux of ciprofloxacin) curves are demonstrated for each CPE, isobolograms constructed for pairs of CPEs, and synergy demonstrated for all three pairs. Synergy is much greater at earlier (6 h) than later (48 h) time points, although the effect sizes are greater later. Synergy is also demonstrated with the three-drug combination. Combinations of CPEs also greatly enhance the maximum drug flux achievable over that achieved by individual CPEs.

Development of bupivacaine decorated reduced graphene oxide and its local anesthetic effect-In vivo study.

The present works aims to develop bupivacaine modified reduced graphene oxide (BPV/RGO), and comparative evaluation of their anesthetic effect with free bupivacaine (BPV). The prepared BPV/RGO was studied by using various spectroscopic and microscopic characterization studies. In vitro drug release from BPV/RGO was studied using HPLC analysis. The cytotoxicity of BPV/RGO was studied against fibroblast (3T3) cells. In vivo evaluation of anesthetic effects was performed on animal models. BPV/RGO showed a prolonged in vitro release and lower cytotoxicity when compared to free BPV. Also, BPV/RGO showed a significantly prolonged analgesic effect when compared to free BPV. Further, the prepared BPV/RGO drug delivery system demonstrated to function as gifted to overcome the drawbacks of free BPV and other available drug delivery systems by prolonging the anesthetic effect with poor cytotoxicity.

The Lateral Femoral Cutaneous Nerve: Description of the Sensory Territory and a Novel Ultrasound-Guided Nerve Block Technique.

BACKGROUND AND OBJECTIVES: Nerve blockade of the lateral femoral cutaneous (LFC) nerve provides some analgesia after hip surgery. However, knowledge is lacking about the extent of the cutaneous area anesthetized by established LFC nerve block techniques, as well as the success rate of anesthetic coverage of various surgical incisions. Nerve block techniques that rely on ultrasonographic identification of the LFC nerve distal to the inguinal ligament can be technically challenging. Furthermore, the branching of the LFC nerve is variable, and it is unknown if proximal LFC nerve branches are anesthetized using the current techniques. The primary aim of this study was to investigate a novel ultrasound-guided LFC nerve block technique based on injection into the fat-filled flat tunnel (FFFT), which is a duplicature of the fascia lata between the sartorius and the tensor fasciae latae muscle, in order to assess the success rate of anesthetizing the proximal LFC nerve branches and covering of the different surgical incisions used for hip surgery. METHODS: First, a cadaveric study was conducted in order to identify an FFFT injection technique that would provide adequate injectate spread to the proximal LFC nerve branches. Second, a clinical study was conducted in a group of 20 healthy volunteers over 2 consecutive days. On trial day 1, successful complete anesthesia of the LFC nerve was defined by performing a suprainguinal fascia iliaca block bilaterally in each subject. On trial day 2, a triple-blind randomized controlled trial compared the effect of the novel ultrasound-guided LFC nerve block technique for bupivacaine versus placebo. The primary end point was the success rate of anesthesia of the proximal cutaneous area innervated by the LFC nerve for the FFFT injection with bupivacaine versus placebo. RESULTS: Adequate spread of injectate to the proximal LFC nerve branches in cadavers was obtained by injecting 10 mL with dynamic needle-tip tracking in the FFFT. Application of this technique in the randomized controlled trial provided anesthesia of the lateral thigh with a success rate of 95% (95% confidence interval, 73.9%-99.8%) for the active side and 0% for placebo (P < 0.001). The proximal branches were anesthetized with a success rate of 68% (95% confidence interval, 43.4%-87.4%) on the active side. The proximal extent of the anesthetized cutaneous area was on average 7.9 cm distal to the greater trochanter. CONCLUSIONS: This novel LFC nerve block technique is easy and quick and reliably produces anesthesia of the lateral thigh. The greater trochanter is rarely included in the area of anesthesia, which reduces the coverage of each specific surgical incision. The success rate of 68% in anesthetizing the proximal nerve branches must be further evaluated by future research.

Clinical Concentrations of Local Anesthetics Bupivacaine and Lidocaine Differentially Inhibit Human Kir2.x Inward Rectifier K+ Channels.

BACKGROUND: Inward rectifier K channels of the Kir2.x subfamily are widely expressed in neuronal tissues, controlling neuronal excitability. Previous studies reported that local anesthetics (LAs) do not affect Kir2 channels. However, the effects have not been studied at large concentrations used in regional anesthesia. METHODS: This study used the patch-clamp technique to examine the effects of bupivacaine and lidocaine on Kir2.1, Kir2.2, and Kir2.3 channels expressed in human embryonic kidney 293 cells. RESULTS: When applied extracellularly in whole-cell recordings, both LAs inhibited Kir2.x currents in a voltage-independent manner. Inhibition with bupivacaine was slow and irreversible, whereas that with lidocaine was fast and reversible. Kir2.3 displayed a greater sensitivity to bupivacaine than Kir2.1 and Kir2.2 (50% inhibitory concentrations at approximately 5 minutes, 0.6 vs 8-10 mM), whereas their sensitivities to lidocaine were similar (50% inhibitory concentrations, 1.5-2.7 mM). Increases in the charged/neutral ratio of the LAs at an acidic extracellular pH attenuated their inhibitory effects, and a permanently charged lidocaine derivative QX-314 exhibited no effects when applied extracellularly. Inside-out experiments demonstrated that inhibition of Kir2.1 with cytoplasmic lidocaine and QX-314 was rapid and reversible, whereas that induced by bupivacaine was slow and irreversible. Furthermore, dose-inhibition relations for the charged form of bupivacaine and lidocaine obtained at different cytoplasmic pHs could be approximated by a single relation for each LA. CONCLUSIONS: The results indicate that both LAs at clinical concentrations equilibrated rapidly with the intracellular milieu, differentially inhibiting Kir2.x channel function from the cytoplasmic side.

Impaired autophagosome clearance contributes to local anesthetic bupivacaine-induced myotoxicity in mouse myoblasts.

BACKGROUND: The current study examined the role(s) of autophagy in myotoxicity induced by bupivacaine in mouse myoblast C2c12 cells. METHODS: C2c12 cells were treated with bupivacaine. Myotoxicity was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay (n = 3 to 30), live/dead assay (n = 3 to 4), and morphological alterations (n = 3). Autophagosome formation was reflected by microtubule-associated protein light chain 3 conversion (n = 4 to 12) and light chain 3 punctation (n = 4 to 5). Autophagosome clearance was evaluated by p62 protein level (n = 4) and autolysosomes generation (n = 3). RESULTS: Bupivacaine induced significant cell damage. Notably, there was a significant increase in autophagosome generation as evidenced by light chain 3 puncta formation (72.7 ± 6.9 vs. 2.1 ± 1.2) and light chain 3 conversion (2.16 ± 0.15 vs. 0.33 ± 0.04) in bupivacaine-treated cells. Bupivacaine inactivated the protein kinase B/mammalian target of rapamycin/p70 ribosomal protein S6 kinase signaling. However, cellular levels of p62 protein were significantly increased upon bupivacaine treatment (1.29 ± 0.15 vs. 1.00 ± 0.15), suggesting that the drug impaired autophagosome clearance. Further examination revealed that bupivacaine interrupted autophagosome-lysosome fusion (10.87% ± 1.48% vs. 32.94% ± 4.22%). Administration of rapamycin increased autophagosome clearance and, most importantly, improved the survival in bupivacaine-treated cells. However, knockdown of autophagy-related protein 5 (atg5) exacerbated bupivacaine-induced impairment of autophagosome clearance and myotoxicity. CONCLUSIONS: The data suggest that autophagosome formation was induced as a stress response mechanism after bupivacaine challenge; however, autophagosome clearance was impaired due to inadequate autophagosome-lysosome fusion. Therefore, impairment of autophagosome clearance appears to be a novel mechanism underlying bupivacaine-induced myotoxicity.

Synovial fluid bupivacaine concentrations following single intra-articular injection in normal and osteoarthritic canine stifles.

Intra-articular bupivacaine helps alleviate pain in animals receiving joint surgery, but its use has become controversial as ex vivo studies have illuminated the potential for chondrotoxicity. Such studies typically involve cell cultures incubated in solutions containing high bupivacaine concentrations for long durations. The aim of this study was to measure the actual synovial fluid bupivacaine concentrations after intra-articular injection. Eight healthy beagles with normal stifles and 22 large and giant-breed dogs with stifle osteoarthritis (OA) were treated with a single intra-articular injection of bupivacaine (1 mg/kg) into a stifle. Joint fluid samples were taken from the treated stifle immediately after injection and 30 min after injection and analyzed for bupivacaine concentrations. Immediately after injection, the median bupivacaine concentrations in normal and OA stifles were 3.6 and 2.5 mg/mL, respectively. Thirty minutes after injection, bupivacaine concentrations in normal and OA stifles were 0.4 and 0.6 mg/mL, respectively. These results provide insight into the pharmacokinetics of bupivacaine after injection into a joint. Given its immediate dilution and rapid drop in synovial fluid concentration, bupivacaine is unlikely to damage chondrocytes when administered as a single intra-articular injection.

Deaths from homicides: a historical series / Mortes por homicídios: série histórica / Muertes por homicidios: serie histórica

OBJECTIVE: to describe mortality from homicides in Itabuna, in the State of Bahia. METHOD: study with hybrid, ecological and time-trend design. The mortality coefficients per 1,000 inhabitants, adjusted by the direct technique, proportional mortality by sex and age range, and Potential Years of Life Lost were all calculated. RESULTS: since 2005, the external causes have moved from third to second most-common cause of death, with homicides being responsible for the increase. In the 13 years analyzed, homicides have risen 203%, with 94% of these deaths occurring among the male population. Within this group, the growth occurred mainly in the age range from 15 to 29 years of age. It was ascertained that 83% of the deaths were caused by firearms; 57.2% occurred in public thoroughfares; and 98.4% in the urban zone. In 2012, the 173 homicides resulted in 7,837 potential years of life lost, with each death causing, on average, the loss of 45.3 years. CONCLUSIONS: mortality by homicide in a medium-sized city in Bahia reaches levels observed in the big cities of Brazil in the 1980s, evidencing that the phenomenon of criminality - formerly predominant only in the big urban centers - is advancing into the rural area of Brazil, causing changes in the map of violent homicide in Brazil. .

OBJETIVO: descrever a mortalidade por homicídios em Itabuna, Bahia. MÉTODO: estudo com delineamento híbrido, ecológico e de tendência temporal. Foram calculados os coeficientes de mortalidade por 1.000 habitantes, ajustados pela técnica direta, mortalidade proporcional segundo sexo e faixa etária e anos potenciais de vida perdidos. RESULTADOS: desde 2005 as causas externas passaram de terceira para segunda causa de morte, sendo os homicídios responsáveis pelo incremento. Nos 13 anos analisados, os homicídios ascenderam 203%, com 94% desses óbitos incidindo na população masculina. Entre essa, o crescimento se deu principalmente na faixa etária de 15 a 29 anos de idade. Apurou-se que 83% das mortes foram por arma de fogo, 57,2% ocorreram em via pública e 98,4% na zona urbana. Em 2012, os 173 homicídios ocasionaram 7.837 anos potenciais de vida perdidos, com cada óbito provocando, em média, a perda de 45,3 anos. CONCLUSÕES: a mortalidade por homicídios em uma cidade de médio porte, na Bahia, atinge índices observados nas grandes metrópoles do país na década 1980, evidenciando que o fenômeno da criminalidade violenta - antes predominante apenas nos grandes centros urbanos - avança para o interior, provocando mudanças no mapa da violência homicida do país. .

OBJETIVO: describir la mortalidad por homicidios en Itabuna-Bahía. MÉTODO: estudio con delineamiento híbrido, ecológico y de tendencia temporal. Fueron calculados los coeficientes de mortalidad por 1.000 habitantes ajustados por la técnica directa, la mortalidad proporcional según sexo e intervalo de edad y los Años Potenciales de Vida Perdidos. RESULTADOS: desde 2005 las causas externas pasaron de la tercera para la segunda causa de muerte, siendo los homicidios responsables por el incremento. En los 13 años analizados, los homicidios ascendieron 203%, con 94% de esas muertes ocurriendo en la población masculina. Entre esta, el crecimiento sucedió principalmente en el intervalo de edad de 15 a 29 años de edad. Se encontró que 83% de las muertes fueron por arma de fuego; 57,2% ocurrieron en la vía pública; y 98,4% en la zona urbana. En 2012, los 173 homicidios ocasionaron 7.837 años potenciales de vida perdidos, con cada muerte provocando, en promedio, la pérdida de 45,3 años. CONCLUSIONES: la mortalidad por homicidios en una ciudad de porte medio en Bahía alcanza índices observados en las grandes metrópolis del país en la década de 1980, evidenciando que el fenómeno de la criminalidad violenta - antes predominante apenas en los grandes centros urbanos - avanza para el interior provocando cambios en el mapa de la violencia homicida del país. .

Potential avoidance of adverse analgesic effects using a biologically "smart" hydrogel capable of controlled bupivacaine release.

Acute pain remains a tremendous clinical and economic burden, as its prevalence and common narcotic-based treatments are associated with poorer outcomes and higher costs. Multimodal analgesia portends great therapeutic promise, but rarely allows opioid sparing, and new alternatives are necessary. Microparticles (MPs) composed of biodegradable polymers [e.g., poly(lactic-co-glycolic acid) or PLGA] have been applied for controlled drug release and acute pain treatment research. However, foreign particles' presence within inflamed tissue may affect the drug release or targeting, and/or cause a secondary inflammatory reaction. We examined how small alterations in the particulate nature of MPs affect both their uptake into and subsequent activation of macrophages. MPs composed of PLGA and chitosan (PLGA-Chi) loaded with bupivacaine (BP) were engineered at different sizes and their opsonization by J774 macrophages was assessed. Uptake of PLGA-Chi by macrophages was found to be size dependent, but they were not cytotoxic or proinflammatory in effect. Moreover, encapsulation of MPs in a thermoresponsive loading gel (pluronic F-127) effectively prevented opsonization. Finally, MPs displayed sustained, tunable release of BP up to 7 days. These results demonstrate our ability to develop a drug delivery system capable of controlled release of local anesthetics to treat acute/subacute pain while concurrently avoiding enhanced inflammation.

Local anaesthetics: 10 essentials.

This review seeks to address 10 essential questions regarding the clinical use of local anaesthetics. Each local anaesthetic has distinctive physicochemical properties but with the same mode of action; they block voltage-gated sodium channels in the axon. Sodium channel block is brought about by a conformational change and the creation of a positive charge in the channel pore. Different local anaesthetics can reach the local anaesthetic binding site in the axon from the cytoplasmic compartment (classic hydrophilic pathway), or directly via its lipid membrane (hydrophobic pathway), or can enter via large-pore channels (alternative hydrophilic pathway). Beyond the nervous system, local anaesthetics exert beneficial effects on pain and can affect the inflammatory response and the haemostatic system. There are problems with the efficacy of local anaesthetics in the presence of local inflammation, and with significant intravascular toxicity, which can be fatal. But when preventive measures are taken, the incidence of cardiac arrest is low. Intralipid has been proposed to treat systemic local anaesthetic overdose and has been enthusiastically adopted worldwide, even though the mechanism of action is incompletely understood. Intralipid is an aid to the management of local anaesthetic toxicity rather than an antidote and meticulous conduct of regional anaesthesia remains paramount. All local anaesthetics are toxic, in a dose- and time-dependent manner, on virtually all tissues, including nerves and muscles. The question of whether local anaesthetics protect against perioperative tumour progression cannot be answered at this moment, and results from clinical (retrospective) studies are equivocal. Future areas of interest will be the design of new subtype-specific sodium channel blockers, but as we look forward, older local anaesthetics such as 2-chloroprocaine are being reintroduced into the clinical setting. Multimodal perineural analgesia and liposomal bupivacaine may replace catheter techniques for some indications.

Growth inhibition by bupivacaine is associated with inactivation of ribosomal protein S6 kinase 1.

Bupivacaine is an amide type long acting local anesthetic used for epidural anesthesia and nerve blockade in patients. Use of bupivacaine is associated with severe cytotoxicity and apoptosis along with inhibition of cell growth and proliferation. Although inhibition of Erk, Akt, and AMPK seemingly appears to mediate some of the bupivacaine effects, potential downstream targets that mediate its effect remain unknown. S6 kinase 1 is a common downstream effector of several growth regulatory pathways involved in cell growth and proliferation known to be affected by bupivacaine. We have accordingly attempted to relate the growth inhibitory effects of bupivacaine with the status of S6K1 activity and we present evidence that decrease in cell growth and proliferation by bupivacaine is mediated through inactivation of S6 kinase 1 in a concentration and time dependent manner. We also show that ectopic expression of constitutively active S6 kinase 1 imparts substantial protection from bupivacaine induced cytotoxicity. Inactivation of S6K1 though associated with loss of putative mTOR mediated phosphorylation did not correspond with loss of similar phosphorylations in 4EBP1 indicating that S6K1 inhibition was not mediated through inactivation of mTORC1 signaling pathway or its down regulation.

The effect of lipid emulsion on intracellular bupivacaine as a mechanism of lipid resuscitation: an electrophysiological study using voltage-gated proton channels.

BACKGROUND: Lipid resuscitation has become a standard treatment for local anesthetic (LA) systemic toxicity, but its mechanisms remain to be fully elucidated. Although the partitioning effect is one of the proposed mechanisms, it is difficult to evaluate its impact independently from several other mechanisms or to examine the intracellular concentration of a LA, which is primarily responsible for LA systemic toxicity. We recently reported that LAs as weak bases reduced voltage-gated proton currents by increasing intracellular pH, which could be estimated from the reversal potentials of the channels (Vrev). Using this characteristic, we examined the partitioning effect in detail and showed its impact on lipid resuscitation. METHODS: A whole-cell voltage clamp technique was used to record proton channel currents in a rat microglial cell line (GMI-R1). We used Intralipid® 20% as lipid emulsion. The effects of lipid emulsion on the intracellular concentrations of LAs were evaluated by measuring the current amplitude and the Vrev. The intracellular concentrations of LAs were calculated by the Henderson-Hasselbalch equation, using estimated intracellular pH. To confirm the importance of partitioning, we separated lipid by centrifugation. Data are means ± SD unless otherwise stated. RESULTS: Bupivacaine (1 mM) decreased proton currents to 43% ± 10% of the control and shifted the Vrev to positive voltages (from -88.0 ± 4.1 to -76.0 ± 5.5 mV, n = 5 each, P = 0.02). An addition of the lipid emulsion recovered the currents to 79% ± 2% of the control and returned the Vrev toward the control value (to -86.0 ± 7.1 mV, n = 5, P = 0.03). Both recoveries of the current and Vrev in the centrifuged aqueous extract were almost the same as in the 4% lipid solution (-85.6 ± 4.9 mV, n = 5, P = 0.9, 95% confidence interval for difference = -9.3 to 8.6). When 1 mM bupivacaine was applied extracellularly, the intracellular concentration of the charged form of bupivacaine was estimated to reach about 18.1 ± 3.9 mM but decreased to 5.4 ± 1.8 mM by the 4% lipid solution. CONCLUSIONS: Here we quantitatively evaluated for the first time the partitioning effect of lipid emulsion therapy on the intracellular concentration of bupivacaine in real-time settings by analyzing behaviors of voltage-gated proton channels. Our results suggested that lipid emulsion markedly reduced the intracellular concentration of bupivacaine, which was mostly due to the partitioning effect. This could contribute to our understanding of the mechanisms underlying lipid resuscitation, especially the importance of the partitioning effect.

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)