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

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

The effects of target-controlled infusion of lidocaine undergoing vocal cord polypectomy: A randomized controlled trial (CONSORT compliant).

BACKGROUND: The present study aimed to assess the efficacy and safety of general anesthesia-assisted target-controlled plasma infusion of lidocaine in patients with vocal cord polypectomy using a supporting laryngoscope. METHODS: In total, 80 patients undergoing vocal cord polypectomy using a supporting laryngoscope were randomly divided into an intervention group and a control group; each group contained 40 subjects: both groups received general anesthesia; subjects in the intervention also received an additional 3 mg/L of lidocaine by target-controlled plasma infusion during induction and maintenance of anesthesia; heart rate (HR) mean arterial pressure (MAP), propofol and urapidil consumption (Uradil, which is a blood pressure drug that blocks alpha-1, is called Urapidi Hydrochloride Injection. It is produced by Germany, the enterprise name is Nycomed Deutschland GmbH, the import drug registration number is H20090715, and it is widely used in China), recovery time, and cough score (measured by Minogue et al's 5-grade scoring method) during extubation, and throat pain score (measured by visual analogue scale,[VAS]) after extubation and adverse events were recorded. RESULTS: Significant differences were observed in HR (P < .05) and MAP (P < .05) immediately after intubation (T2), immediately after the operation starting to support laryngoscope exposure (T3), immediately after operation field adrenergic tampon hemostasis (T4), and 5 minutes after hemostasis (T5) between the 2 groups, and significant differences were also observed in HR (P < .05) before intubation (T1). Moreover, significant differences were observed in propofol consumption (P < .05), urapidil consumption (P < .05), cough score during extubation (P < .05), and throat pain score after extubation (P < .05). However, no significant difference was observed in the recovery time (P > .05). Furthermore, no adverse events were detected in either group. CONCLUSION: The results of this study showed that target-controlled plasma infusion of lidocaine can reduce propofol consumption in patients undergoing vocal cord polypectomy by supporting laryngoscopy, and the hemodynamics are more stable and reduce the coughing reaction in the wake period and throat pain after extubation without adverse events.

LID study: Plasma lidocaine levels following airway topicalisation for paediatric microlaryngobronchoscopy (MLB).

OBJECTIVES: A dose of 5 mg/kg lidocaine is considered appropriate for paediatric airway topicalisation. Existing literature suggests that younger children are susceptible to toxic lidocaine plasma levels and achieve this at a faster rate. MAIN OUTCOME MEASURES: The primary outcome of this study was to ascertain peak plasma lidocaine levels after topicalisation for airway endoscopy. Secondary endpoints included: time to peak lidocaine plasma levels, signs of lidocaine toxicity (restricted to ECG changes or seizures when under anaesthesia) and clinical adverse events of laryngospasm, coughing or desaturation during the procedure. SETTING: Data were collected prospectively over 18 months at Royal Manchester Children's Hospital. PARTICIPANTS: Children aged 0-8 years undergoing elective diagnostic or therapeutic airway endoscopy were included within the study. DESIGN: Standardised 2% lidocaine was used for airway topicalisation. Dose varied depending upon the practitioner's usual practice. Venous bloodsampling occurred at 5, 10, 15 and 20 min post-administration and plasma lidocaine levels (ng/ml) were analysed. RESULTS: A significant relationship exists between higher peak plasma levels and ages <18 months (p = .00973). Strong linear correlation exists between body weight and age for our cohort (r = .88). Higher peak plasma lidocaine levels occur with total dose volumes between 2 and 3 mls of 2% lidocaine local anaesthetic (p = .03) compared with <2 ml total dose volumes. Data suggest a potential relationship of lower body weights achieving higher peak plasma levels (p = .0516). Reduced interquartile variation of peak plasma lidocaine levels exists when lidocaine dosing is <5 mg/kg. CONCLUSIONS: Age and total dose volume of topicalised lidocaine have a significant relationship with plasma lidocaine levels. A dose of 5 mg/kg topicalised lidocaine for paediatric airway endoscopy is safe and provides good operating conditions. Lower patient body weights trend towards higher peak lidocaine plasma concentrations and require further investigation.

Effects of intravenous lidocaine, dexmedetomidine, and their combination on IL-1, IL-6 and TNF-α in patients undergoing laparoscopic hysterectomy: a prospective, randomized controlled trial.

BACKGROUND: Surgical-related inflammatory responses have negative effects on postoperative recovery. Intravenous (IV) lidocaine and dexmedetomidine inhibits the inflammatory response. We investigated whether the co-administration of lidocaine and dexmedetomidine could further alleviate inflammatory responses compared with lidocaine or dexmedetomidine alone during laparoscopic hysterectomy. METHODS: A total of 160 patients were randomly allocated into four groups following laparoscopic hysterectomy: the control group (group C) received normal saline, the lidocaine group (group L) received lidocaine (bolus infusion of 1.5 mg/kg over 10 min, 1.5 mg/kg/h continuous infusion), the dexmedetomidine group (group D) received dexmedetomidine (bolus infusion of 0.5 µg/kg over 10 min, 0.4 µg/kg/h continuous infusion), and the lidocaine plus dexmedetomidine group (group LD) received a combination of lidocaine (bolus infusion of 1.5 mg/kg over 10 min, 1.5 mg/kg/h continuous infusion) and dexmedetomidine (bolus infusion of 0.5 µg/kg over 10 min, 0.4 µg/kg/h continuous infusion). The levels of plasma interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) at different time points were the primary outcomes. Secondary outcomes included hemodynamic variables, postoperative visual analogue scale (VAS) scores, time to first flatus, and incidence of nausea and vomiting after surgery. RESULTS: The levels of plasma IL-1, IL-6, and TNF-α were lower in groups D and LD than in group C and were lowest in group LD at the end of the procedure and 2 h after the operation (P < 0.05). The VAS scores were decreased in groups D and LD compared with group C (P < 0.05). The heart rate (HR) was decreased at the end of the procedure and 2 h after the operation in groups D and LD compared to groups C and L (P < 0.001). The mean blood pressure (MBP) was lower at 2 h after the operation in groups L, D, and LD than in group C (P < 0.001). There was a lower incidence of postoperative nausea and vomiting (PONV) in group LD than in group C (P < 0.05). CONCLUSIONS: The combination of lidocaine and dexmedetomidine significantly alleviated the inflammatory responses, decreased postoperative pain, and led to fewer PONV in patients undergoing laparoscopic hysterectomy. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT03276533 ), registered on August 23, 2017.

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

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

The Safety and Efficacy of Ultrasound-Guided Bilateral Dual Transversus Abdominis Plane (BD-TAP) Block in ERAS Program of Laparoscopic Hepatectomy: A Prospective, Randomized, Controlled, Blinded, Clinical Study.

PURPOSE: Postoperative pain management for patients undergoing hepatic resection is still a challenge due to the risk of perioperative liver dysfunction. The transversus abdominis plane (TAP) block is a promising regional analgesic technique. However, the correct guidelines regarding the dose and regimen of local anesthetics in patients undergoing hepatic resection have yet to be established completely. This study aimed to evaluate the safety and efficacy of ultrasound-guided BD-TAP block with a large dose of ropivacaine in laparoscopic hepatectomy. PATIENTS AND METHODS: This prospective, blinded, randomized, controlled study was conducted with 50 patients who were scheduled for selective laparoscopic hepatectomy. Patients who received a BD-TAP block (3 mg/kg of ropivacaine diluted to 60 mL) with general anesthesia were categorized into the BD-TAP block group (n = 25), and those who received general anesthesia were categorized into the control group (n = 25). The primary outcomes were consumption of sufentanil within 48 hours post-operation and plasma ropivacaine concentration. The secondary outcomes were the severity of pain (at rest and upon coughing), nausea and/or vomiting, and quality of recovery. RESULTS: Compared with the control group, the patients in BD-TAP block group had a significant reduction of postoperative sufentanil consumption at 2 hours (P = 0.019), 24 hours (P = 0.001), and 48 hours (P = 0.001), and the visual analog scale (VAS) scores on coughing were significantly lower at postoperative 2 hours (P = 0.004). There were no statistically significant differences in postoperative nausea and/or vomiting, flatus, catheter removal, off-bed activity, liver function, or postoperative hospital stay. The mean peak total ropivacaine concentration was 1,067.85 ng/mL, which occurred 1 hour after administering the block, and mean free ropivacaine concentration was 52.32 ng/mL. The highest individual peak plasma concentration was 2,360.90 ng/mL at 45 min postinjection, and the free ropivacaine concentration was 139.29 ng/mL. CONCLUSION: Ultrasound-guided BD-TAP block provides effective postoperative analgesia after laparoscopic hepatectomy. This study also confirms that ultrasound-guided BD-TAP blocks with 3 mg/kg ropivacaine during laparoscopic hepatectomy almost never results in the plasma ropivacaine concentrations associated with neurotoxicity.

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

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

Serum Concentrations of Lidocaine During Bariatric Surgery.

Lidocaine has been shown to be clinically beneficial during bariatric surgery. However, information about lidocaine serum concentrations in this setting is scarce. This prospective clinical trial included 42 obese patients undergoing laparoscopic bariatric surgery. They received lidocaine based on adjusted body weight. Administration began with a 1.5 mg·kg bolus of intravenous lidocaine followed by a continuous infusion of 2 mg·kg·hour. After skin closure, administration was decreased to 1 mg·kg·hour until discharge from the recovery room. No serum concentrations of lidocaine were outside the usual accepted range (1.5-5 µg·mL).

Selective extraction of cocaine from biological samples with a miniaturized monolithic molecularly imprinted polymer and on-line analysis in nano-liquid chromatography.

We report the on-line coupling of a monolithic molecularly imprinted polymer to nano-liquid chromatography for the selective analysis of cocaine and its main metabolite, benzoylecgonine, in complex biological samples. After the screening of different synthesis conditions, a monolithic molecularly imprinted polymer was in situ synthesized into a 100 µm internal diameter fused-silica capillary using cocaine as template, methacrylic acid as functional monomer, and trimethylolpropane trimethacrylate as cross-linker. Scanning electron microscopy was used to assess the homogeneous morphology of the molecularly imprinted polymer and its permeability was measured. Its selectivity was evaluated by nano-liquid chromatography-ultraviolet, leading to imprinting factors of 3.2 ±â€¯0.5 and 2.2 ±â€¯0.3 for cocaine and benzoylecgonine, respectively, on polymers resulting from three independent syntheses, showing the high selectivity and the repeatability of the synthesis. After optimizing the extraction protocol to promote selectivity, the monolithic molecularly imprinted polymer was successfully on-line coupled with nano-liquid chromatography-ultraviolet for the direct extraction and analysis of cocaine present in spiked human plasma and saliva samples. The repeatability of the obtained extraction recovery, between 85.4 and 98.7% for a plasma sample spiked at 100 ng mL-1, was high with relative standard deviation values lower than 5.8% for triplicate analyses on each of the three independently synthesized molecularly imprinted polymers. A linear calibration range was achieved between 100 and 2000 ng mL-1 (R2 = 0.999). Limits of quantification of 14.5 ng mL-1 and 6.1 ng mL-1 were achieved in plasma and urine samples, respectively. The very clean-baseline of the resulting chromatogram illustrated the high selectivity brought by the monolithic molecularly imprinted polymer that allows the removal of a huge peak corresponding to the elution of interfering compounds and the easy determination of the target analyte in these complex biological samples.

Truncal regional nerve blocks in clinical anesthesia practice.

Regional anesthetic techniques are important components of successful multimodal analgesic strategies. When used successfully, truncal nerve blocks of the chest wall, abdomen, and, paraneuraxial nerves, in combination with other analgesic modalities, may offer similar analgesic efficacy as neuraxial techniques, which are associated with a greater risk profile. Moreover, in comparison to neuraxial techniques, truncal nerve blocks are relatively simple to perform and technically straightforward to learn. The transversus abdominus plane (TAP) block is often incorporated into the multimodal analgesia regimen for surgical patients undergoing various abdominal and gynecological procedures. Rectus sheath blocks (RSB) were originally introduced to help relax the anterior abdominal wall during surgery and as an adjunct pain therapy. With the advancement of technology and the development of ultrasound guided techniques, RSB now have a more ubiquitous role and have been shown to decrease postoperative pain and opioid consumption. Different variations of the quadratus lumborum block may provide visceral and sensory analgesic coverage. Moreover, truncal blocks, including ilioinguinal, iliohypogastric, pectoralis nerve (PECS) blocks, serratus anterior, intercostal, and erector spinae plane blocks, have gained routine clinical use for various surgeries. In this review, we discuss the techniques, anatomy, indications, complications, and benefits of truncal nerve blocks commonly used in clinical practice.

Matrix effect-free on-line pass-through cleanup procedure for the fast determination of local anesthetic drug by LC-MS/MS.

A novel nano-titania modified covalent organic frameworks (NTM-COFs) has been synthesized and characterized by transmission electron microscopy (TEM) and scanning electron micrographs (SEM). Besides, NTM-COFs, as efficient sorbent, has also been evaluated in the on-line pass-through cleanup procedure prior to the analysis of local anesthetic drugs (lidocaine, bupivacaine and tetracaine) in human plasma by liquid chromatography-tandem quadrupole mass spectrometry (LC-MS/MS). Under optimum conditions, the level of matrix effects can be dramatically reduced by the NTM-COFs based on-line pass-through cleanup procedure, with acceptable recoveries ranging from 88.8% to 103%. Satisfactory trueness and precision of the proposed method were also obtained, with the within- and between-run RSDs less than 7.0% and relative error (REs) less than 12%. The limits of detections (LODs) of lidocaine, bupivacaine and tetracaine were 0.029 µg·L-1, 0.027 µg·L-1 and 0.016 µg·L-1, respectively. The analytical method has been successfully applied for the determination of the plasma concentrations of bupivacaine in five parturients who received an epidural administration of bupivacaine hydrochloride during vaginal delivery. Results demonstrate the applicability of the developed NTM-COFs on-line pass-through cleanup procedure coupled with LC-MS/MS method to clinical studies.

Polyacrylonitrile / graphene oxide nanofibers for packed sorbent microextraction of drugs and their metabolites from human plasma samples.

In the present study, a new graphene based nanofibers material (Polyacrylonitrile/Graphene Oxide (PAN/GO)) was used for microextraction by packed sorbent (MEPS). The PAN/GO nanofiber was synthesized using the electrospinning technique. MEPS online with liquid chromatography-tandem mass spectrometry (LC-MS/MS) was utilized for the extraction and determination of two local anesthetic drugs (lidocaine, prilocaine) and their major metabolites (2,6-xylidine, o-toluidine) in human plasma samples. Parameters affecting the extraction efficiency were investigated and optimized (including sample pH, washing solution and elution solution). The validation of the method was based on FDA (Food and Drug Administration) guidelines for bioanalytical methods. The calibration curve ranged from 2.00 to 2000 nmol/L for lidocaine and prilocaine, and from 10.0 to 2000 nmol/L for 2,6-xylidine and o-toluidine. The coefficient of determination (R2) values were 0.996, 0.995, 0.995, 0.996 (n = 3) for lidocaine, prilocaine, 2,6-xylidine and o-toluidine, respectively. The extraction recovery was 93.0% for lidocaine, 96.0% for prilocaine, 68.0% for 2,6-xylidine and 69.0% for o-toluidine. The limits of detection (LODs) were 0.25, 0.50, 2.50, 1.25 nmol/L for lidocaine, prilocaine, 2,6-xylidine and o-toluidine, respectively. The lower limits of quantification (LLOQs) were 2.0 nmol/L for lidocaine and prilocaine, and 10 nmol/L for 2,6-xylidine and o-toluidine, respectively. The accuracy values for the quality control (QC) samples were in the range of 91.0-111% for lidocaine, 92.0-118% for prilocaine, 84.0-98.0% for 2,6-xylidine and 82.0-90.0% for o-toluidine. The inter-day precisions for QC samples ranged from 7.0% to 11.8% for lidocaine, from 8.6% to 11.7% for prilocaine, from 8.0% to 10.0% for 2,6-xylidine and from 8.0% to 9.0% for o-toluidine. The matrix effect values were in the range of -2.3% to -8.6% for lidocaine, -2.7% to -10.2% for prilocaine, 4.8%-5.2% for 2, 6-xylidine and -8.2% to 9.4% for o-toluidine.

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

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

Safety and Pharmacokinetics of Levobupivacaine Following Fascia Iliaca Compartment Block in Elderly Patients.

BACKGROUND: Fascia iliaca compartment block (FICB) is an increasingly popular analgesic technique in elderly patients with hip fracture. Despite requiring large volumes of local anaesthetic, there are no plasma pharmacokinetic data on FICB in elderly patients. OBJECTIVES: The objective of this study was to determine the pharmacokinetic profile of a levobupivacaine 75 mg (30 mL 0.25%) FICB dose in patients aged ≥ 80 years with fractured femur. METHODS: This was a single-arm descriptive pilot study. Twelve adults aged ≥ 80 years with hip fracture received FICB performed under ultrasound guidance. Venous blood was sampled at 10, 20, 30, 45, 60, 75, 90, 105, 120 and 240 min after injection. Total plasma levobupivacaine concentration was measured by mass spectrometry. The main outcome measures were pharmacokinetic parameters, including maximum observed plasma concentration (Cmax), time to reach Cmax (tmax) and area under the plasma concentration-time curve. RESULTS: The median (interquartile range [IQR]) Cmax was 0.82 µg/mL (0.47-1.03). tmax was 45 min (41:20-60:00). No evidence of toxicity was identified. Plasma levobupivacaine concentrations were below the threshold associated with toxicity in younger, healthy patients (2.6 µg/mL). No association was found between individual patient Cmax and α1-acid glycoprotein, weight or body mass index, although the study was not powered for these outcomes. CONCLUSIONS: Absorption of levobupivacaine was slow and all patients had plasma concentrations below the toxic threshold. This pharmacokinetic analysis concludes that the technique appears to be well-tolerated and efficacious at reducing pain and is associated with systemic plasma concentrations unlikely to be associated with major adverse effects in elderly patients. CLINICAL TRIAL REGISTRATION: ISRCTN27364035 (UK Clinical Trials Gateway).

Benefits of a multimodal analgesia compared to local anesthesia alone to alleviate pain following castration in sheep: a multiparametric approach.

Castration of male ruminants is a common livestock management practice, but induces pain. However, little is known about the effectiveness of multimodal analgesia compared to local anesthesia (LA) alone in reducing pain associated with burdizzo castration in sheep. This study aimed to monitor the pain response induced by castration in sheep and to assess the efficacy of analgesia strategies. Twenty-four 12-month-old male Texel sheep were burdizzo-castrated after administration of physiological serum (Burd), local anesthetic (Burd+LA) or LA plus non-steroidal anti-inflammatory drug (Burd+LA+NSAID). Sheep responses were monitored using behavioral and physiological indices of pain. Sampling occurred from 24 h pre-castration to 78 h post-castration, split into four periods based on the duration of analgesia: P0 (T-24 to T-1 h), P1 (T0 to T+2 h), P2 (T+3 to T+32 h) and P3 (T+36 to T+78 h). Behavioral indices were attention and head position, ear position, position of the eyelid, other facial expression, standing/lying postures, postures of the legs, clinical signs and abnormal activities. Physiological indices consisted in indicators of inflammation (haptoglobin, serum amyloid A (SAA), body temperature), hypothalamo-pituitary-adrenal axis (cortisol, non-esterified fatty acids, glucose), autonomous nervous system (heart rate variability (HRV)) and oxidative stress. The variables contributing most to discrimination of the period×treatment groups were analyzed by factorial discrimination analysis. Pre-castration (P0), there was no significant difference between treatments for all indicators (P > 0.05). Post-castration, eight indicators varied significantly according to period and treatment: cortisol, clinical signs, ratio of low frequency/high frequency (LF/HF) bands of the HRV, attention and head position, SAA, haptoglobin, body temperature and glucose. The treatment×periods groups were well discriminated by the 23 indicators. Burd in P0, Burd+LA in P0 and Burd+LA+NSAID in P0, P1 and P2 had low values for all indicators, likely reflecting absence of pain and discomfort. Burd in P1 and P2 and Burd+LA in P2 showed clinical signs and reduced attention, high LF/HF and high cortisol levels, reflecting acute pain. Burd and Burd+LA in P3 had high temperature, high haptoglobin, high glucose and high SAA, but no response from other pathways. These results suggest that (i) behavioral signs of pain were apparent up to 32 h post-castration, (ii) LA was partially effective, but only during its time of action (2 h) and (iii). multimodal analgesia (LA and NSAID) was effective for up to 3 days post-castration. These findings, and especially those related to sheep behavior, can help veterinarians and farmers better detect pain and refine their pain alleviation methods.

Poisoning associated with inappropriate use of a eutectic mixture of lidocaine and prilocaine before laser-assisted hair removal: about 3 cases.

BACKGROUND: Eutectic mixtures of lidocaine and prilocaine are used during painful dermatological procedures. Poisoning is rarely reported in adults. MATERIAL AND METHOD: We report three cases of women who experienced lidocaine and prilocaine poisoning after laser-assisted hair removal. Plasma levels of local anesthetics were assayed by a fully validated liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method. CASE REPORTS: The rules of application of the anesthetic cream were observed apart from the maximum dose and/or maximum surface area. One patient applied a higher dose than the maximum recommended dose (140 instead of 60 g) and all patients failed to comply with the maximum recommended surface area (600 cm2). The patients presented an unusual clinical pattern as compared with other local anesthetics overdose: signs of cardiac toxicity with no ECG changes or arrhythmia, neurological toxicity without seizures or coma, and methemoglobinemia. DISCUSSION: Health authorities should publish explicit recommendations targeting users and prescribers with particular emphasis on the maximal surface area of application.

A study of the dosage and duration for levobupivacaine infusion by the caudal-epidural route in infants aged 3-6 months.

BACKGROUND: The local anesthetic, levobupivacaine, is the safer enantiomer of racemic bupivacaine. Present protocols for levobupivacaine are based on studies and pharmacokinetic modeling with racemic bupivacaine. AIMS: The aim is to investigate total serum levobupivacaine concentrations after a caudalepidural loading dose followed by a maintenance infusion over 48 hours in infants aged 3-6 months. METHODS: The clinical trial was conducted in eight infants aged 3-6 months, undergoing bladder exstrophy repair. Pharmacokinetic modeling allowed optimization of clinical sampling to measure total levobupivacaine and α1 -acid glycoprotein and prediction of the effect of α1 -acid glycoprotein on levobupivacaine plasma protein binding. RESULTS: The observed median total levobupivacaine serum concentration was 0.30 mg/L (range: 0.20-0.70 mg/L) at 1 hour after the loading dose of 2 mg/kg. The median total levobupivacaine concentration after 47 hours of infusion, at 0.2 mg/kg/h, was 1.21 mg/L (0.07-1.85 mg/L). Concentrations of α1 -acid glycoprotein were found to rise throughout the study period. Pharmacokinetic modeling suggested that unbound levobupivacaine quickly reached steady state at a concentration of approximately 0.03 mg/L. CONCLUSION: The study allows the development of a pharmacokinetic model, combining levobupivacaine and α1 -acid glycoprotein data. Modeling indicates that unbound levobupivacaine quickly reaches steady state once the infusion is started. Simulations suggest that it may be possible to continue the infusion beyond 48 hours.

Inhibitory effect of lidocaine on colonic spasm during colonoscopy: A multicenter double-blind, randomized controlled trial.

OBJECTIVES: Colonic spasm can interfere with colonoscopy, but antispasmodic agents can cause complications. This study aimed to assess the inhibitory effect of topical lidocaine compared with a placebo control. METHODS: In five tertiary-care hospitals in Japan, 128 patients requiring endoscopic resection of a colorectal lesion were enrolled and randomly and double-blindly allocated to colonoscopy with topical administration of 2% lidocaine solution 20mL (LID, n = 64) or normal saline 20mL (control, n = 64). During colonoscopy, the assigned solution was applied with a spray catheter near the lesion and the area was observed for three minutes. primary endpoint was the inhibitory effect at three time-points (1, 2 and 3 minutes after dispersion), using a three-point scale (excellent, fair, poor). Secondary endpoints were rebound spasm and adverse events. All endpoints were scored in real time. Serum lidocaine levels were measured in 32 patients (LID 16, control 16). RESULTS: There were no significant differences between groups in patient demographics. At all time-points, the proportion of patients with "excellent" scores was greater in LID group than control group, with significant differences observed at 2 minutes (p = 0.02) and 3 minutes (p = 0.02). In LID group, the rate of "excellent" scores increased by 12.5% at 2 minutes and was maintained at 3 minutes. Rebound spasm did not occur in LID group, compared with 15.6% of control group (p = 0.001). There were no adverse events in LID group. All serum lidocaine levels were below detectable levels. CONCLUSIONS: Topical lidocaine is an effective and safe method for suppressing colorectal spasm during colonoscopy (UMIN000024733).

Preclinical Evaluation of Ropivacaine in 2 Liposomal Modified Systems.

BACKGROUND: Our research group has recently developed liposomes with ionic gradient and in a combined manner as donor and acceptor vesicles containing ropivacaine (RVC; at 2% or 0.75%). Looking for applications of such novel formulations for postoperative pain control, we evaluated the duration of anesthesia, pharmacokinetics, and tissue reaction evoked by these new RVC formulations. METHODS: The formulations used in this study were large multivesicular vesicle (LMVV) containing sodium acetate buffer at pH 5.5 or in a combined manner with LMVV as donor and large unilamellar vesicles (LUVs) as acceptor vesicles with an external pH of 7.4. Wistar rats were divided into 6 groups (n = 6) and received sciatic nerve block (0.4 mL) with 6 formulations of RVC (LMVVRVC0.75%, LMVV/LUVRVC0.75%, LMVVRVC2%, LMVV/LUVRVC2%, RVC 0.75%, and RVC 2%). To verify the anesthetic effect, the animals were submitted to the pain pressure test and the motor block was also monitored. Histopathology of the tissues surrounding the sciatic nerve region was also assessed 2 and 7 days after treatment. Rats (n = 6) were submitted to a hind paw incision, and mechanical hypersensitivity was measured via the withdrawal response using von Frey filaments after injection of the 6 formulations. Finally, New Zealand white rabbits (n = 6) received sciatic nerve block (3 mL) with 1 of the 6 formulations of RVC. Blood samples were collected predose (0 minutes) and at 15, 30, 45, 60, 90, 120, 180, 240, 300, 360, 420, 480, and 540 minutes after injection. RVC plasma levels were determined using a triple-stage quadrupole mass spectrometer. RESULTS: Duration and intensity of the sensory block were longer with all liposomal formulations, when compared to the plain RVC solution (P < .05). Histopathological evaluation showed greater toxicity for the positive control (lidocaine 10%), when compared to all formulations (P < .05). After the hind paw incision, all animals presented postincisional hypersensitivity and liposomal formulations showed longer analgesia (P < .05). LMVVRVC0.75% presented higher time to reach maximum concentration and mean residence time than the remaining formulations with RVC 0.75% (P < .05), so LMVV was able to reduce systemic exposure of RVC due to slow release from this liposomal system. CONCLUSIONS: All new liposomal formulations containing 0.75% RVC were able to change the pharmacokinetics and enhance anesthesia duration due to slow release of RVC from liposomes without inducing significant toxic effects to local tissues.