A novel LC-MS/MS analytical method for detection of articaine and mepivacaine in blood and its application to a preliminary pharmacokinetic study.

Local anaesthetics (LAs) are commonly used in surgery, especially in dentistry. They cause a transitory inhibition of nerve signal due to the blockade of the voltage-gated sodium channels. LAs are administrated alone or with vasoconstriction agents, such as adrenaline. Toxicity of LAs is associated to neurological and cardiovascular alterations. Tachycardia, arrhythmia, tremors, tonic-clonic seizure and respiratory depression (at high doses) are the main symptoms of intoxication by LAs. Lidocaine, articaine and mepivacaine are among the most used anaesthetics. This study aimed to fully validated a new method for the simultaneous detection of articaine and mepivacaine in whole blood. Sample treatment consisted in a liquid-liquid extraction with phosphate buffer (pH 8, 0.1 M) and ethyl-acetate. Analysis was performed by liquid chromatography-tandem mass spectrometry in multiple reaction monitoring mode (transitions: articaine, 285→8658 m/z; mepivacaine, 247→9870 m/z; lidocaine - internal standard -, 235→8658 m/z). The method proved to be highly sensitive with limit of quantifications for articaine and mepivacaine of 0.8 and 0.1 ng/mL, respectively. Accuracy and precision were always within the acceptance criteria. The new procedure was also successfully applied to a preliminary pharmacokinetics study.

Impact of dexmedetomidine on the tissue distribution, anesthetic action, and hemodynamic effects of mepivacaine.

The present study investigated the regional blood flow, tissue distribution, local anesthetic action, and hemodynamic effects of mepivacaine containing dexmedetomidine hydrochloride (DEX) in rats. Blood flow was measured after injection of 0.5% mepivacaine (M group), 12.5 µg/ml DEX (D group), or 0.5% mepivacaine containing 12.5 µg/ml DEX (DM group) into the upper lip. Mepivacaine distribution was autoradiographically observed in maxillary bone resected after injection of 0.5% 3H-mepivacaine (HM group) or 0.5% 3H-mepivacaine containing 12.5 µg/ml DEX (DHM group) into the palatal mucosa adjacent to the right maxillary first molar. Radioactivity was also measured using a liquid scintillation counter. SEP were measured to analyze anesthetic action. Blood pressure and heart rate were measured to compare hemodynamic effect. The addition of DEX significantly decreased blood flow compared to M group from 10 to 60 min after injection. The addition of DEX significantly increased the amount of radioactivity compared to HM group in the palatal mucosa from 5 to 60 min after injection and in the body of the maxilla from 2 to 60 min after injection. Maximum blood radioactivity was measured at 5 min after injection in HM group and 50 min after injection in DHM group. The addition of DEX significantly decreased peak-to-peak amplitudes compared to M group until 60 min after injection. No significant hemodynamic differences were observed. DEX enhances the action of mepivacaine in reducing regional blood flow prolongs its tissue retention, and increases the local anesthetic action without affecting hemodynamics on local administration.

A novel LC-MS/MS method for mepivacaine determination and pharmacokinetic study in a single-dose two-period crossover in healthy subjects.

The objective of this work was to develop a simple, selective, and sensitive LC-MS/MS method for the quantitation of the mepivacaine in Chinese biological matrix. The calibration curve of mepivacaine ranged from 0.5 to 2000 ng/mL with the lower limit of quantitation being 0.5 ng/mL. This sensitivity was high enough to describe the profile of blood mepivacaine level versus time. Thereby it was very desirable for the pharmacokinetic study because of its high sensitivity and accuracy. The study used a single-dose two-period crossover design principle. For the pharmacokinetic analysis of plasma, the mean (SD) values obtained were as follows: t1/2, 1.63 (0.43) h; Cmax, 435.3 (67.4) ng/ml; AUC0-t, 1546.9 (339.7) ng/ml·h; AUC0-∞, 1982.3 (421.4) ng/ml·h; Tmax, 0.62 (0.31) h. The validated method has been successfully applied to assess the pharmacokinetic study of mepivacaine after a single administration to Chinese volunteers.

3D ultrasound estimation of the effective volume for popliteal block at the level of division. / Estimación del volumen de anestésico local en contacto con el nervio ciático en el bloqueo poplíteo.

Local anaesthetic injection between the tibial and commmon peroneal nerves within connective tissue sheath results in a predictable diffusion and allows for a reduction in the volume needed to achieve a consistent sciatic popliteal block. Using 3D ultrasound volumetric acquisition, we quantified the visible volume in contact with the nerve along a 5cm segment. METHODS: We included 20 consecutive patients scheduled for bunion surgery. Ultrasound guided popliteal block was performed using a posterior, out of plane approach at the level of división of the sciatic nerve. Thirty ml of mepivacaine 1.5% and levobupivacaine 0.5% were slowly injected while assessing the injection pressure and the diffusion of the local anaesthetic. Volumetric acquisition was performed before and after the block to quantify the the volume of the sciatic nerve and the volume of the surrounding hypoechoic halo contained inside the connective tissue in a 5cm segment. RESULTS: All blocks were successful within 20min after the injection. The total estimated volume contained inside the common connective tissue sheath was 6.8±2.6cm3. Of this, the volume of the halo sorrounding the nerve was 4.4±1.7cm3 and the volume inside the sciatic nerve was 2.4±1.7cm3. CONCLUSIONS: The volume of local anaesthetic in close contact with the sciatic nerve can be estimated by volumetric acquisition. Our results suggest that the effective volume of local anaesthetic needed for a successful sciatic popliteal block could be reduced to less than 7ml.

The Effects of Mepivacaine Hydrochloride on Antimicrobial Activity and Mechanical Nociceptive Threshold During Amikacin Sulfate Regional Limb Perfusion in the Horse.

OBJECTIVE: To determine the effect of intravenous regional limb perfusion (IVRLP) with a combination of mepivacaine hydrochloride and amikacin sulfate on synovial fluid amikacin sulfate concentration, antimicrobial activity, and mechanical nociceptive threshold (MNT). STUDY DESIGN: Experimental study. ANIMALS: Healthy adult horses (n=9). METHODS: One IVRLP treatment was randomly administered by cephalic vein of each limb: amikacin alone (1 g amikacin in 60 mL saline) or amikacin with mepivacaine (1 g amikacin and 500 mg mepivacaine in 60 mL saline). Opposite treatments were repeated after a 24 hour wash-out period. Amikacin concentration and antimicrobial activity were determined for synovial fluid from middle carpal joints at tourniquet removal and 30 minutes following. Zone of inhibition was determined for Staphylococcus aureus and Escherichia coli. MNT was determined at 3 dorsal metacarpal locations prior to and after sedation, after Esmarch tourniquet application, and 30 minutes after IVRLP prior to and after tourniquet removal. RESULTS: Two limbs from each treatment group were removed because of undetectable amikacin concentrations for a total of 14 data sets analyzed. Synovial fluid amikacin concentrations and zone of inhibition were not significantly different between treatments at any time point. MNT were significantly increased 30 minutes after IVRLP prior to and following tourniquet removal using amikacin and mepivacaine (median, range; 40.0 µg/mL, 38.7-40.0 and 40.0, 25.8-40.0, respectively) compared to amikacin alone (19.5 µg/mL, 18.7-25.6 and 15.3, 13.2-20.5, respectively). CONCLUSION: Addition of mepivacaine to amikacin for IVRLP in the horse as a means of providing analgesia without decreasing antimicrobial activity.

Distribution of Injectate and Sensory-Motor Blockade After Adductor Canal Block.

BACKGROUND: The analgesic efficacy reported for the adductor canal block may be related to the spread of local anesthetic outside the adductor canal. METHODS: Fifteen patients undergoing knee surgery received ultrasound-guided injections of local anesthetic at the level of the adductor hiatus. Sensory-motor block and spread of contrast solution were assessed. RESULTS: Sensation was rated as "markedly diminished" or "absent" in the saphenous nerve distribution and "slightly diminished" in the sciatic nerve territory without motor deficits. Contrast solution was found in the popliteal fossa. CONCLUSIONS: The spread of injectate to the popliteal fossa may contribute to the analgesic efficacy of adductor canal block.

Diffusion of mepivacaine to adjacent synovial structures after intrasynovial analgesia of the digital flexor tendon sheath.

REASONS FOR PERFORMING STUDY: Controversy exists about the specificity of diagnostic analgesia of the digital flexor tendon sheath (DFTS) in horses. OBJECTIVES: To evaluate the degree of diffusion of mepivacaine from the equine DFTS to adjacent synovial structures. STUDY DESIGN: Crossover experiment. METHODS: Under general anaesthesia, the DFTS of one front and one hindlimb of 8 horses were injected simultaneously with mepivacaine. Synovial fluid samples of the injected DFTS, the adjacent metacarpo-/metatarsophalangeal (MCP/MTP) joint, proximal interphalangeal joint, distal interphalangeal joint, navicular bursa and contralateral MCP/MTP joint were collected 15 min post injection (T15) from one of the injected limbs and 60 min post injection (T60) from the other limb. Venous blood samples were obtained at T0, T15 and T60 to evaluate systemic distribution of mepivacaine. After a 2-week washout period, the procedure was repeated using the same limbs but reversing the time of sampling (front vs. hindlimbs). The concentration of mepivacaine in samples was measured with a commercial ELISA kit. RESULTS: Mepivacaine concentrations in the DFTS samples, at both T15 (5077 mg/l) and T60 (3503 mg/l), exceeded those estimated sufficient to produce synovial analgesia (100 mg/l or 300 mg/l). Mepivacaine was found in all synovial structures adjacent to the injected DFTS and in the contralateral MCP/MTP joints, but concentrations were low, with a maximum value of only 3.2 mg/l. With the exception of the navicular bursa samples, the mepivacaine concentrations in the adjacent synovial structures were significantly higher at T60 than at T15 (P<0.03). Significantly higher mepivacaine concentrations were found in the ipsilateral than the contralateral MCP/MTP joints at T60 (P<0.001). Blood samples had significantly higher mepivacaine concentrations at T15 and T60 than at T0 (P<0.001). CONCLUSIONS: Mepivacaine injected into the DFTS of horses diffuses towards adjacent synovial structures without achieving clinically relevant concentrations.

In vivo diffusion characteristics following perineural injection of the deep branch of the lateral plantar nerve with mepivacaine or iohexol in horses.

REASONS FOR PERFORMING STUDY: Hindlimb proximal suspensory desmopathy is a common injury of sport horses but diagnosis can be difficult because diagnostic analgesia of the region lacks specificity. Perineural analgesia of the deep branch of the lateral plantar nerve (DBLPN) has been proposed as a more specific method of isolating pain of the proximal aspect of the suspensory ligament but the technique has not been evaluated in vivo. OBJECTIVES: To determine the extent of diffusion of contrast medium and mepivacaine following DBLPN analgesia using a single-needle injection technique and to determine if there is inadvertent involvement of the tarsal sheath and/or tarsometatarsal (TMT) joint using this technique. STUDY DESIGN: In vivo experimental study. METHODS: Perineural injection of the DBLPN was performed in 16 limbs with 3 ml of either mepivacaine hydrochloride or positive contrast medium. Contrast medium-injected limbs were radiographed 5, 15, and 30 min post injection and diffusion characteristics were described. In mepivacaine-injected limbs, synovial fluid from the TMT joint was obtained 10 and 20 min post injection and mepivacaine concentrations were analysed. RESULTS: At 5, 15 and 30 min post injection, the contrast medium extended, on average, 19.6, 20.6 and 21.0 mm proximal and 38.0, 43.5 and 51.9 mm distal to the injection site, respectively. Three of 8 (37.5%) limbs had evidence of contrast medium in the tarsal sheath. Two of 8 (25%) limbs had mepivacaine concentrations within the TMT joint sufficient to produce analgesia (>300 mg/l) at 10 min post injection. CONCLUSIONS: Contrast medium diffused further in a distal direction than in a proximal direction. Analgesia of the DBLPN can result in inadvertent involvement of the tarsal sheath and/or TMT joint.

Effects of approach and injection volume on diffusion of mepivacaine hydrochloride during local analgesia of the deep branch of the lateral plantar nerve in horses.

OBJECTIVE: To compare the effects of 2 approaches and 2 injection volumes on diffusion of mepivacaine hydrochloride for local analgesia of the deep branch of the lateral plantar nerve (DBLPN) in horses. DESIGN: Experimental study. ANIMALS: 16 adult horses. PROCEDURES: Either 2 mL (low volume) or 8 mL (high volume) of mepivacaine hydrochloride-iohexol (50:50 mixture) was injected by means of 1 of 2 techniques to produce analgesia of the DBLPN. For technique 1, the needle was inserted 15 mm distal to the head of the fourth metatarsal bone and directed perpendicular to the limb. For technique 2, the needle was inserted 20 mm distal to the head of the fourth metatarsal bone and was directed in a proximodorsal direction. Lateromedial radiographs were obtained before and 5, 15, 30, and 60 minutes after injection. Radiographs were evaluated to determine the proximal and distal extent of diffusion of the contrast solution and presumably anesthetic agent and whether contrast agent appeared to be present in the tarsal sheath or tarsometatarsal joint. RESULTS: A high degree of variability in contrast solution diffusion was noted among injections. High-volume injections diffused significantly further proximally and distally than did low-volume injections. Contrast agent was documented within the tarsal sheath in 5 of 32 (16%) injections and within the tarsometatarsal joint in 2 of 32 (6%) injections. No significant difference was found for risk of inadvertent tarsal sheath or tarsometatarsal joint injection between the 2 techniques or the 2 volumes of anesthetic used. Mepivacaine diffused significantly further distally with technique 1 than with technique 2 but diffused significantly further proximally with technique 2 than with technique 1. For both techniques, diffusion in the distal but not the proximal direction significantly increased over time. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that the proximal and distal diffusion of the mepivacaine-iohexol solution was quite variable following either DBLPN nerve block technique.

Does circumferential spread of local anaesthetic improve the success of peripheral nerve block?

BACKGROUND: The relation between the pattern of local anaesthetic (LA) spread and the quality of peripheral nerve block is unclear. METHODS: Twenty-one volunteers were randomized to receive a median nerve block with intended circumferential or intended non-circumferential spread of LA. Different predetermined volumes and needle placement techniques were used to produce the different patterns of LA spread. Volumetric, multiplanar 3D ultrasound imaging was performed to evaluate the pattern and extent of LA spread. Sensory block was assessed at predetermined intervals. RESULTS: Complete circumferential spread of LA was achieved in only 67% of cases in the intended circumferential study group and in 33% of cases in the intended non-circumferential group. Block success was similar (90%) and independent of whether circumferential or non-circumferential spread of the LA was achieved. All block failures (n=4) occurred in the intended non-circumferential group with low volumes of LA. The onset of sensory block (independent of group allocation) was faster with circumferential spread of LA [median (IQR) onset time, 15 (8; 20) min] compared with non-circumferential spread of LA [median (IQR) onset time, 20 (15; 30) min]. More LA was used for circumferential blocks [median (IQR) volume of LA 2.8 (1.3; 3.6) vs 1.3 (1.1; 2.4) ml]. CONCLUSIONS: Even under optimal conditions, it was not possible to achieve circumferential spread of LA in all intended cases. The success of median nerve block seems to be independent of the pattern of LA spread. CLINICAL TRIAL REGISTRATION: DRKS 00003826.

Cardiovascular effect of dental anesthesia with articaine (40 mg with epinefrine 0,5 mg % and 40 mg with epinefrine 1 mg%) versus mepivacaine (30mg and 20 mg with epinefrine 1 mg%) in medically compromised cardiacpatients: A cross-over, randomized, single blinded study

Objectives: The aim of the present study is to compare cardiovascular safety profiles of two dental anesthetics: articaine versus two standard mepivacaine solutions used during etiological periodontal treatment in cardiovascular patients. Study Design: Using a cross-over study design, ten cardiovascular patients were randomly assigned to dental treatment with 1.8mL of a local anesthetic injected on each quadrant of the mouth: Articaine (40mg with Epinephrine 0.5mg % and 40mg with Epinephrine 1mg %) or Mepivacaine (30mg and 20mg with Epinephrine 1mg %). A computer programme enabled continuous longitudinal data collection: O2 saturation, blood pressure (BP) and heart rate (HR).Results: No severe clinical side effects were observed. During the treatment period, we observed statistically significant differences as regards HR between injections with and without adrenalin (p< 0.039) and as regards systolic (p< 0.046) and diastolic (p < 0.046) blood pressure during the stabilization period. In both cases, the parameters under study increase. Age, gender, jaw treated, treatment duration and the rest of cardiovascular variables did not affect the results. None of the patients underwent ischemic alterations or any other complication derived from the treatment or the anesthesia.Conclusions: According to the results of our study, dental anesthetics with standard concentrations of Epinephrine seem to alter HR and BP. Although no cardiac ischemic alterations or any other cardiovascular complications have been observed, we must be cautious with the administration of anesthetics containing vasoconstrictors in patients with cardiovascular diseases (AU)

High-resolution MRI demonstrates detailed anatomy of the axillary brachial plexus. A pilot study.

BACKGROUND: Axillary block is the most commonly performed brachial plexus block and may be guided by nerve stimulation or ultrasound. Magnetic resonance imaging (MRI) has proven to be beneficial in presenting anatomy of interest for regional anaesthesia and in demonstrating spread of local anaesthetic. The aim of this pilot study was to demonstrate the anatomy as shown by MRI of the brachial plexus in the axillary region. METHODS: Nine volunteers and nine patients were examined in a 3.0 Tesla MR. The patients had two different brachial plexus blocks. Subsequently, they were scanned by MRI and finally tested clinically for block efficacy before operation. Axial images, with and without local anaesthetics injected, were viewed in a sequence loop to identify the anatomy. RESULTS: With the high-resolution MRI, we obtained images of good quality, and cords and all terminal nerves could be identified. When local anaesthetics are injected, neurovascular structures are displaced, and the vein is compressed. Viewing the images in a sequence loop facilitates identification of the different nerves and has high instructive value (links S1-3 to these loops are enclosed). CONCLUSION: Clinical high-field 3.0 Tesla MRI scanner gives good visualization of brachial plexus in the axilla. The superior ability to detect local anaesthetics after it has been injected and the multiplanar imaging capability make MRI a useful tool in studies of the brachial plexus.

Pharmacokinetic study of liposome-encapsulated and plain mepivacaine formulations injected intra-orally in volunteers.

OBJECTIVES: The pharmacokinetics of commercial and liposome-encapsulated mepivacaine (MVC) injected intra-orally in healthy volunteers was studied. METHODS: In this double blind, randomized cross-over study, 15 volunteers received, at four different sessions, 1.8 ml of the following formulations: 2% MVC with 1 : 100 000 epinephrine (MVC(2%EPI) ), 3% MVC (MVC(3%) ), 2% and 3% liposome-encapsulated MVC (MVC(2%LUV) and MVC(3%LUV) ). Blood samples were collected pre dose (0 min) and at 15, 30, 45, 60, 90, 120, 180, 240, 300, 360 min after injections. Liquid chromatography-tandem mass spectrometry was used to quantify plasma MVC concentrations. RESULTS: Pharmacokinetic analysis showed that the maximum plasma concentration (Cmax) and the areas under the curves (AUC(0-360) and AUC(0-∞)) after MVC(2%LUV) and MVC(2%EPI) injections were smaller (P < 0.05) than the equivalent figures for MVC(3%) and MVC(3%LUV). The time to maximum plasma concentration (Tmax) and the half-life of elimination (t½beta) obtained after the treatment with MVC(2%LUV), MVC(2%EPI), MVC(3%) and MVC(3%LUV) presented no statistically significant differences (P > 0.05). Cmax, AUC(0-360) and AUC(0-∞) after injection of the 2% formulations (MVC(2%LUV) and MVC(2%EPI) ) did not exhibit statistically significant differences (P > 0.05). The pharmacokinetics of MVC(2%LUV) were comparable to the pharmacokinetics of MVC(2%EPI). CONCLUSION: The liposomal formulation of 2% MVC exhibits similar systemic absorption to the local anesthetic with vasoconstrictor.

Assessment of the tissue diffusion of anesthetic agent following administration of a low palmar nerve block in horses.

OBJECTIVE: To investigate tissue diffusion of anesthetic agent following administration of low palmar nerve blocks (LPBs) in horses. DESIGN: Randomized clinical trial. ANIMALS: 12 adult horses. PROCEDURES: In 9 horses, mepivacaine hydrochloride-iohexol (50:50 dilution) injections were administered bilaterally (2 or 4 mL/site) to affect the medial and lateral palmar and palmar metacarpal nerves (4 sites). Lateral radiographic views of both metacarpal regions were obtained before and at 5, 15, 30, 60, 90, and 120 minutes after block administration; proximal and distal extents of contrast medium (and presumably anesthetic agent) diffusion from palmar and palmar metacarpal injection sites were measured and summed to determine total diffusion. Methylene blue solution was injected in forelimbs of 3 other horses that were subsequently euthanized to determine the potential route of anesthetic agent diffusion to the proximal suspensory ligament region. RESULTS: Mean extents of proximal and total contrast medium diffusion were 4.0 and 6.6 cm, respectively, for the palmar metacarpal nerves and 4.3 and 7.1 cm, respectively, for the palmar nerves. Subtle proximal diffusion secondary to lymphatic drainage was evident in 17 of the 18 limbs. Contrast medium was detected in the metacarpophalangeal joint or within the digital flexor tendon sheath in 8 and 7 limbs, respectively. In the cadaver limbs, methylene blue solution did not extend to the proximal suspensory ligament region. CONCLUSIONS AND CLINICAL RELEVANCE: In horses, LPBs resulted in minimal proximal diffusion of anesthetic agent from the injection sites. Limbs should be aseptically prepared prior to LPB administration because inadvertent intrasynovial injection may occur.

[Spread of hyperbaric local anesthetics in a spinal canal model. The influence of Trendelenburg position and spinal configuration]. / Ausbreitung hyperbarer Lokalanästhetika im Spinalkanalmodell. Einfluss von Lagewechsel und Wirbelsäulenkonfiguration.

BACKGROUND: The influence of Trendelenburg positions and variations in spinal canal configuration on the spread of hyperbaric spinal anesthetics was examined in two models of the subarachnoid space. METHODS: Both models included simulations of the spinal cord, filum terminale and cerebrospinal fluid. Model I had a straight shape, thus omitting replications of lumbar lordosis and thoracic kyphosis. It allowed the evaluation of fluid dynamics and the spread of 0.5% hyperbaric bupivacaine and 4% hyperbaric mepivacaine in 0° (supine position), 5° and 10° head-down tilt positions. Model II included reconstructions of average adult spinal curvatures for closer analysis of the intrathecal spread of 0.5% hyperbaric bupivacaine in 0°, 5°, 10° and 15° head-down tilt positions. Concentration gradients within the artificial cerebrospinal fluid were calculated using a digital image processing technique. Data from both model investigations were compared to elaborate the effect of varying lumbar lordosis angles. RESULTS: Model I: Only the 5° head-down tilt caused a significant difference in maximum spread of both local anesthetics. Model II: A 15° head-down tilt resulted in the local anesthetic solution spilling over lumbar lordosis and effusing into the thoracic areas. With increasing degree of head-down tilt, the local anesthetic solution was also detectable in ventral parts of the spinal canal cross-section. CONCLUSIONS: Diffusion processes represent the decisive factor for distribution patterns of hyperbaric anesthetics in the supine position. Only the 5° head-down tilt demonstrated an influence of specific gravity. When tilted 10° head-down gravitation prevailed over differences in density. A 15° head-down tilt is a precondition for the mobilization of sacrally pooled local anesthetic. Data comparison of both model investigations showed that the extent of spread depends more on initial bidirectional distribution of the local anesthetic than on increasing flow rate due to the slope of lumbar lordosis.

Pharmacokinetic and local toxicity studies of liposome-encapsulated and plain mepivacaine solutions in rats.

The pharmacokinetics and the local toxicity of commercial and liposome-encapsulated mepivacaine formulations injected intra-orally in rats were studied. Animals were divided in groups (n = 4-6) and treated with 0.1 mL of the formulations: 2% mepivacaine with 1:100,000 epinephrine (MVC(2%EPI)), 3% mepivacaine (MVC(3%)), and 2% liposome-encapsulated mepivacaine (MVC(LUV)). The results showed that the 2% liposome-encapsulated mepivacaine reduced C(max), prolonged AUC(0-infinity) and t(1/2) compared with 3% plain and 2% vasoconstritor-associated mepivacaine, after intraoral injection. In addition, it was also observed that liposomal mepivacaine might protect the tissue against local inflammation evoked by plain or vasoconstrictors-associated mepivacaine, giving supporting evidence for its safety and possible clinical use in dentistry.

Brain penetration of local anaesthetics in the rat: Implications for experimental neuroscience.

Multiple experimental neuroscience techniques rely on the use of general anaesthesia to minimize the discomfort associated to animal restraint and to achieve a more effective control of relevant physiological parameters. In order to minimise potential interference on brain neuronal activity, such studies are typically conducted at low anaesthetic doses. This practice is often coupled to peripheral infiltration of local anaesthetics to provide supplementary analgesia and prevent sub-threshold activation of pain pathways that may confound central measurements of brain function. However, little is known of the effect of peripheral anaesthesia on central measurements of brain activity in small laboratory animal species. In order to begin to address this question, we measured total and free brain exposure of five different local anaesthetics following subcutaneous infiltration of analgesic doses in a surgical protocol widely used in rodent neuroimaging and electrophysiology studies. Notably, all the anaesthetics exhibited detectable total and free brain concentrations at all the time points examined. Lidocaine and mepivacaine showed the highest free brain exposures (>525 ng/g), followed by bupivacaine and ropivacaine (>70 ng/g). The ester-type local anaesthetic tetracaine produced the lowest free brain exposure (<8.6 ng/g). Our data suggest that peripheral administration of local anaesthetics in small laboratory animals could result in pharmacologically active brain exposures that might influence and confound central measurements of brain function. The use of the ester-type anaesthetic tetracaine produced considerably lower brain exposure, and may represent a viable experimental option when local anaesthesia is required.

Estabilidad temporal de mepivacaína al 1.5% alcalinizada / Alkalinized 1.5% mepivacaine stability over time

Objetivos: Estudiar la estabilidad en el tiempo de la mepivacaína alcalinizada en cuanto a valores de pH y formación de precipitados, ya que apenas existe información en la literatura acerca de la estabilidad temporal de este anestésico, y la información disponible aconseja alcalinizarla justo antes de su empleo. Material y métodos: Fueron preparadas tres jeringas (A, B y C) de 20 mL conteniendo mepivacaína al 1.5%. La jeringa A fue utilizada como control de pH, y las jeringas B y C fueron alcalinizadas adicionando 2 mL de bicarbonato al 8.4%. Fue medido el pH y calculado el porcentaje de base libre asociado en cada jeringa previamente a la alcalinización y posteriormente cada 10 minutos hasta completar una hora, salvo para la jeringa C en los últimos 30 minutos, que permaneció cerrada como control de fuga de CO2. Las soluciones fueron inspeccionadas visualmente durante todo el procedimiento para identificar eventuales precipitados macroscópicos y, tras la hora de estudio, fueron filtradas para indagar sobre la formación de precipitados microscópicos. Tras el filtrado, el pH de cada solución anestésica fue medido de nuevo. Resultados: Tras la alcalinización de la mepivacaína al 1.5% se produjo un aumento inmediato y significativo de los valores de pH y del porcentaje calculado de base libre en las jeringas alcalinizadas B y C con respecto a la de control A, y en todas las jeringas el pH permaneció muy estable durante una hora. Además, a los 60 minutos apenas existieron diferencias entre los valores de pH de las jeringas B y C, lo que indica que no se produjo fuga significativa de CO2. En este tiempo no hubo sospecha de formación de precipitados por inspección visual, y las mínimas diferencias encontradas entre los pesos secos de los filtros indican que no hubo formación de precipitados significativa (…) (AU)

PurposeIt is recommended to alkalinize mepivacaine just before employing it. However, data regarding alkalinized mepivacain estability over time are very scarce. The aim of this work was to investigate for pH stability and precipitation of alkalinized mepivacaine. Materials and Methods: Three syringes (A, B, C) containing 20mL of 1.5% mepivacaine each one were prepared. Syringe A served as pH control, and syringes B and C were alkalinized by adding 2mL of8.4% sodium bicarbonate solution. pH was measured into each syringe before alkalinization and every ten minutes lasting for one hour after. Associated free base percentage was calculated, except for the last 30 minutes for syringe C, which remained closed to serve as CO2 leakage control. Solutions were examinated by naked eyes looking for macroscopic precipitates, filtered after the procedure and the filters were weighed in order to looking for microscopic precipitates. After filtration pH was again measured. Results: Alkalinization resulted in immediate and significant increases in pH values and associated free base percentage of syringes B and C compared to syringe A. After that and for one hour pH values remained very stable. Besides, pH values between syringes B and C were very similar at 60 minutes, indicating no-significative leakage of CO2. The procedure was completed without evidence of precipitation by visual inspection, and differences between dry filters weights were minimalindicating no significative formation of microprecipitates. Conclusions: 1.5% mepivacaine solutions can be alkalinized and stored at room temperature in closed syringes for at least one hour before administration. In our opinion previous alkalinizationis much more convenient to daily clinical practice that actual recommendation of alkalinization just before use (AU)

Lumbar plexus block using high-pressure injection leads to contralateral and epidural spread.

BACKGROUND: The main advantage of lumbar plexus block over neuraxial anesthesia is unilateral blockade; however, the relatively common occurrence of bilateral spread (up to 27%) makes this advantage unpredictable. The authors hypothesized that high injection pressures during lumbar plexus block carry a higher risk of bilateral or neuraxial anesthesia. METHODS: Eighty patients undergoing knee arthroscopy (age 18-65 yr; American Society of Anesthesiologists physical status I or II) during a standard, nerve stimulator-guided lumbar plexus block using 35 ml mepivacaine, 1.5%, were scheduled to be studied. Patients were randomly assigned to receive either a low-pressure (< 15 psi) or a high-pressure (> 20 psi) injection, as assessed by an inline injection pressure monitor (BSmart; Concert Medical LLC, Norwell, MA). The block success rate and the presence of bilateral sensory and/or motor blockade were assessed. RESULTS: An interim analysis was performed at n = 20 after an unexpectedly high number of patients had neuraxial spread, necessitating early termination of the study. Five of 10 patients (50%) in the high-pressure group had a neuraxial block with a dermatomal sensory level T10 or higher. In contrast, no patient in the low-pressure group (n = 10) had evidence of neuraxial spread. Moreover, 6 patients (60%) in the high-pressure group demonstrated bilateral sensory blockade in the femoral distribution, whereas no patient in the low-pressure group had evidence of a bilateral femoral block. CONCLUSIONS: Injection of local anesthetic with high injection pressure (> 20 psi) during lumbar plexus block commonly results in unwanted bilateral blockade and is associated with high risk of neuraxial blockade.

The effects of general anesthesia on whole body and regional pharmacokinetics of local anesthetics at toxic doses.

BACKGROUND: Local anesthetic toxicity is often studied experimentally in anesthetized subjects, but clinical toxicity usually occurs in conscious patients. In this study, we determined the influence of general anesthesia on the pharmacokinetics of six local anesthetics administered i.v. at approximately the highest recommended doses. METHODS: Chronically instrumented ewes (approximately 45-50 kg, n = 18) were infused over 3 min with (base doses as HCl salts) bupivacaine (100 mg), levobupivacaine (125 mg), ropivacaine (150 mg), lidocaine (350 mg), mepivacaine (350 mg), or prilocaine (350 mg), on separate occasions when conscious and halothane anesthetized. Serial arterial, heart, and brain venous blood drug concentrations were measured by achiral/chiral high-performance liquid chromatography, as relevant. Whole body pharmacokinetics were assessed by noncompartmental analysis; heart and brain pharmacokinetics were assessed by mass balance. Drug blood binding, in the absence and presence of halothane, was assessed by equilibrium dialysis in vitro. RESULTS: Blood local anesthetic concentrations were doubled with anesthesia because of decreased whole body distribution and clearance (respectively, to 33% and 52% of values when conscious). Heart and brain net drug uptake were greater under anesthesia, reflecting slower efflux from both regions. Clearances of R-bupivacaine > S-bupivacaine and R-prilocaine > S-prilocaine, but, mepivacaine clearance was not enantioselective. Halothane did not influence blood binding of the local anesthetics. CONCLUSIONS: General anesthesia significantly changed whole body and regional pharmacokinetics of each local anesthetic as well as the systemic effects. General anesthesia is thus an important but frequently overlooked factor in studies of local anesthetic toxicity.