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.

Periarticular Knee Injection With Liposomal Bupivacaine and Continuous Femoral Nerve Block for Postoperative Pain Management After Total Knee Arthroplasty: A Randomized Controlled Trial.

BACKGROUND: Local periarticular infiltration (PAI) analgesia has emerged as an important component of multimodal approaches to treat total knee arthroplasty postoperative pain. Liposomal bupivacaine may provide prolonged analgesic duration when injected into the surrounding tissues. The purpose of this study was to compare the analgesic efficacy and serum bupivacaine levels of a continuous femoral nerve block (CFNB) with bupivacaine to PAI with liposomal bupivacaine. METHODS: Sixty-five patients undergoing primary unilateral total knee arthroplasty were randomized into 2 groups: (1) CFNB and PAI with bupivacaine (CFNB group) or (2) PAI with bupivacaine:liposomal bupivacaine mixture at the end of surgery (LB group). The primary outcome was pain intensity at maximum knee flexion 24 hours following surgery. Secondary outcomes included pain intensities at rest and movement at timed intervals and serum bupivacaine levels. RESULTS: Patients in the CFNB group experienced lower pain scores at maximum knee flexion at 24 hours (7.91; 95% confidence interval, 7.19-8.61) compared to the LB group (8.95; 95% confidence interval, 8.42-9.48; P = .02). The mean peak serum bupivacaine level in the LB group up to 72 hours was 0.55 µg/mL versus 1.4 µg/mL for CFNB group (P = .0008) with one patient in the CFNB group exceeding the reported minimum serum bupivacaine threshold for toxicity. CONCLUSION: While similar pain control was observed on the day of surgery for both groups, patients with a CFNB experienced lower pain intensities during maximum knee flexion at 24 hours. Total serum concentrations in LB group remained below the toxicity threshold over the study period.

Blood Bupivacaine Concentrations After a Combined Single-Shot Sciatic Block and a Continuous Femoral Nerve Block in Pediatric Patients: A Prospective Observational Study.

We evaluated blood bupivacaine concentrations in children having a single-shot sciatic and continuous femoral blocks after anterior cruciate ligament repair. Dried blood spot samples were analyzed for bupivacaine levels at 0, 5, 15, 30, 60, and 120 minutes and 4, 24, and 48 hours. The highest 99% upper confidence interval limit was 135 ng/mL at the 4-hour evaluation point. The 99% upper confidence interval was below potentially toxic levels (1500 ng/mL) across all sampling times. The risk of local anesthetic toxicity in pediatric patients receiving single-shot sciatic and continuous femoral nerve blocks is very low.

Plasma bupivacaine concentrations following orbital injections in cats.

OBJECTIVE: To determine plasma bupivacaine concentrations after retrobulbar or peribulbar injection of bupivacaine in cats. STUDY DESIGN: Randomized, crossover, experimental trial with a 2 week washout period. ANIMALS: Six adult healthy cats, aged 1-2 years, weighing 4.6 ± 0.7 kg. METHODS: Cats were sedated by intramuscular injection of dexmedetomidine (36-56 µg kg-1) and were administered a retrobulbar injection of bupivacaine (0.75 mL, 0.5%; 3.75 mg) and iopamidol (0.25 mL), or a peribulbar injection of bupivacaine (1.5 mL, 0.5%; 7.5 mg), iopamidol (0.5 mL) and 0.9% saline (1 mL) via a dorsomedial approach. Blood (2 mL) was collected before and at 5, 10, 15, 22, 30, 45, 60, 120, 240 and 480 minutes after bupivacaine injection. Atipamezole was administered approximately 30 minutes after bupivacaine injection. Plasma bupivacaine and 3-hydroxybupivacaine concentrations were determined using liquid chromatography-mass spectrometry. Bupivacaine maximum plasma concentration (Cmax) and time to Cmax (Tmax) were determined from the data. RESULTS: The bupivacaine median (range) Cmax and Tmax were 1.4 (0.9-2.5) µg mL-1 and 17 (4-60) minutes, and 1.7 (1.0-2.4) µg mL-1, and 28 (8-49) minutes, for retrobulbar and peribulbar injections, respectively. In both treatments the 3-hydroxybupivacaine peak concentration was 0.05-0.21 µg mL-1. CONCLUSIONS AND CLINICAL RELEVANCE: In healthy cats, at doses up to 2 mg kg-1, bupivacaine peak plasma concentrations were approximately half that reported to cause arrhythmias or convulsive electroencephalogram (EEG) activity in cats, and about one-sixth of that required to produce hypotension.

Blood Bupivacaine Concentrations After Transversus Abdominis Plane Block in Neonates: A Prospective Observational Study.

BACKGROUND: Untreated pain can have instant and prolonged consequences to behavioral and neurologic outcomes in neonates. Although the use of transversus abdominis plane (TAP) block to minimize postsurgical pain has been demonstrated in neonates, no data regarding the safety of this procedure are available for this patient population. For instance, it is unknown whether plasma levels of local anesthetics are safe in neonates after TAP blocks. The main objective of the current investigation was to evaluate plasma bupivacaine concentrations in neonates having an ultrasound-guided TAP block. METHODS: The study was a prospective, observational study. After general anesthesia was induced, neonates received an ultrasound-guided TAP block with 0.125% bupivacaine and a total volume of 1 mL/kg. Dried blood spot samples were obtained and analyzed for bupivacaine levels at 0, 5, 15, 30, 60, 120 minutes, 4, and 24 hours after the TAP block. RESULTS: Ten neonates were included in the study. The highest 99% upper prediction limit for blood concentration, 0.38 µg/mL, occurred at the 30-minute interval, but it was significantly lower than potentially toxic plasma levels (1.5-2.0 µg/mL). The highest individual concentration was 0.26 µg/mL and occurred at the 30-minute interval. None of the patients demonstrated any potential signs of local anesthetic toxicity. CONCLUSIONS: Our results suggest a low risk of local anesthetic toxicity in neonates after a TAP block. Future studies to determine the efficacy of the TAP block to minimize postsurgical pain in this patient population are warranted.

The Effect of Lipid Emulsion on Pharmacokinetics of Bupivacaine in Rats: Long-Chain Triglyceride Versus Long- and Medium-Chain Triglyceride.

BACKGROUND: Lipid infusions have been proposed to treat local anesthetic-induced cardiac toxicity. This study compared the effects of long-chain triglyceride (LCT) emulsions with those of long- and medium-chain triglyceride (LCT/MCT) emulsions on the pharmacokinetics of bupivacaine in a rat model. METHODS: After administration of intravenous infusion of bupivacaine at 2 mg·kg·min for 5 minutes in Sprague-Dawley (SD) rats, either Intralipid 20%, an LCT emulsion (LCT group, n = 6), or Lipovenoes 20%, an LCT/MCT emulsion (LCT/MCT group, n = 6), was infused at 2mg·kg·min for 5 minutes. The concentrations of total plasma bupivacaine and bupivacaine that were not bound by lipid (lipid unbound) were measured by a liquid chromatography-tandem mass spectrometric method. A 2-compartmental analysis was performed to calculate the lipid-bound percentage of bupivacaine and its pharmacokinetics. RESULTS: In the LCT group, the clearance (15 ± 2 vs 10 ± 1 mL·min·kg, P = .003) was higher; the volume of distribution (0.57 ± 0.10 vs 0.36 ± 0.11 L·kg, P = .007) and K21 (0.0100 ± 0.0018 vs 0.0070 ± 0.0020 min, P = .021, P' = .032) were larger; and the area under the blood concentration-time curve 0 - t; (605 ± 82 vs 867 ± 110 mgL·min, P =.001) and the area under the blood concentration-time curve (0 - ∞) (697 ± 111 vs 991 ± 121 mgL·min, P =.001) were less, when compared with the LCT/MCT group. CONCLUSIONS: LCT emulsions are more effective than LCT/MCT emulsions in the metabolism of bupivacaine through demonstration of a superior pharmacokinetic profile.

A comparison of plasma levobupivacaine concentrations following transversus abdominis plane block and rectus sheath block.

Levobupivacaine is commonly used as the local anaesthetic of choice in peripheral nerve blocks, but its pharmacokinetics have not been fully investigated. We compared the changes in plasma concentrations of levobupivacaine following transversus abdominis plane block and rectus sheath block. Fifty woman undergoing laparoscopy were randomly allocated to receive either a transversus abdominis plane block or an rectus sheath block. In both groups, 2.5 mg.kg(-1) levobupivacaine was administered, and blood samples were obtained 15 min, 30 min, 60 min and 120 min after injection. The mean maximum plasma concentration (Cmax) and mean time to reach Cmax (Tmax) as determined by non-linear regression analysis were 1.05 µg.ml(-1) and 32.4 min in the transversus abdominis plane group and 0.95 µg.ml(-1) and 60.9 min in the rectus sheath group, respectively. The plasma concentration of levobupivacaine peaked earlier in the transversus abdominis plane group than in the rectus sheath group and the maximum plasma concentration depended on the dose administered but not the procedure.

Local pathology and systemic serum bupivacaine after subcutaneous delivery of slow-releasing bupivacaine microspheres.

BACKGROUND: Prolonged local anesthesia, particularly desirable to minimize acute and chronic postoperative pain, has been provided by microspheres that slowly release bupivacaine (MS-Bup). In this study, we report on the systemic drug concentrations and the local dermatopathology that occur after subcutaneous injection of MS-Bup. METHODS: Rats (approximately 300 g) were injected under the dorsolumbar skin with MS-Bup containing 40 mg of bupivacaine (base) or with 0.4 mL of 0.5% bupivacaine-HCl (BupHCl; 1.78 mg bupivacaine). Blood was drawn, under sevoflurane anesthesia, at 10 minutes to 144 hours, and the serum analyzed for total bupivacaine by liquid chromatography-tandem mass spectrometry. In different animals, skin punch biopsies (4 mm) were taken at 1, 3, 7, 14, and 30 days after the same drug injections, sectioned at 5 µm, and stained with hematoxylin-eosin. Samples from skin injected with BupHCl, with MS-Bup suspended in carboxymethyl cellulose (MS-Bup.CMC), or in methyl cellulose (MS-Bup.MC) were compared with their respective drug-free controls (placebos). RESULTS: Serum bupivacaine reached a maximal average value (n = 8) of 194.9 ng/mL at 8 hours after injection of MS-Bup (95% upper prediction limit = 230.2 ng/mL), compared with the maximal average (n = 6) serum level of 374.9 ng/mL (95% prediction limit = 470.6 ng/mL) at 30 minutes after injection of BupHCl. Serum bupivacaine decreased to undetectable levels (<3.23 ng/mL) at 8 hours after BupHCl and was detectable at approximately 20% of the maximal value at 144 hours after MS-Bup injection. BupHCl injection resulted in moderate lymphocytic infiltration of skeletal muscle at 1 and 3 days. MS-Bup.CMC and placebo-CMC caused extensive infiltration of macrophages, lymphocytes, and some neutrophils at 1 to 7 days, whereas MS-Bup.MC and placebo-MC caused only mild inflammation. CONCLUSIONS: Subcutaneous administration of microspheres releasing bupivacaine results in lower blood levels lasting for much longer times than those from bupivacaine solution.

A Comparison of Differences Between the Systemic Pharmacokinetics of Levobupivacaine and Ropivacaine During Continuous Epidural Infusion: A Prospective, Randomized, Multicenter, Double-Blind Controlled Trial.

BACKGROUND: Epidural infusion of levobupivacaine and ropivacaine provides adequate postoperative pain management by minimizing side effects related to IV opioids and improving patient outcome. The safety profile of different drugs can be better estimated by comparing their pharmacokinetic profiles than by considering their objective side effects. Because levobupivacaine and ropivacaine have different pharmacokinetic properties, our aim was to investigate whether there is a difference in the pharmacokinetic variability of the 2 drugs in a homogeneous population undergoing continuous epidural infusion. This double-blind, multicenter, randomized, controlled trial study was designed to compare the pharmacokinetics of continuous thoracic epidural infusion of levobupivacaine 0.125% or ropivacaine 0.2% for postoperative pain management in adult patients who had undergone major abdominal, urological, or gynecological surgery. This study is focused on the evaluation of the coefficient of variation (CV) to assess the equivalence in the systemic exposure and interindividual variability between levobupivacaine and ropivacaine and, therefore, the possible differences in the predictability of the plasmatic concentrations of the 2 drugs during thoracic epidural infusion. METHODS: One hundred eighty-one adults undergoing major abdominal surgery were enrolled in the study. Patients were randomized to receive an epidural infusion of levobupivacaine 0.125% + sufentanil 0.75 µg/mL or of ropivacaine 0.2% + sufentanil 0.75 µg/mL at 5 mL/h for 48 hours. The primary end point of this study was to analyze the variability of plasma concentration of levobupivacaine and ropivacaine via an area under the curve within a range of 15% of the CV during 48 hours of continuous epidural infusion. The CV shows how the concentration values of local anesthetics are scattered around the median concentration value, thus indicating the extent to which plasma concentration is predictable during infusion. Secondary end points were to assess the pharmacologic profile of the local anesthetics used in the study, including an analysis of mean peak plasma concentrations, and also to assess plasma clearance, side effects, pain intensity (measured with a verbal numeric ranging score, i.e., static Numeric Rating Scale [NRS] and dynamic NRS]), and the need for rescue doses. RESULTS: The comparison between the 2 CVs showed no statistical difference: the difference between area under the curve was within the range of 15%. The CV was 0.54 for levobupivacaine and 0.51 for ropivacaine (P = 0.725). The plasma concentrations of ropivacaine approached the Cmax significantly faster than those of levobupivacaine. Clearance of ropivacaine decreases with increasing patient age. There were no significant differences in NRS, dynamic NRS scores, the number of rescue doses, or in side effects between groups. CONCLUSIONS: Considering the CV, the interindividual variability of plasma concentration for levobupivacaine and ropivacaine is equivalent after thoracic epidural infusion in adults. We found a reduction in clearance of ropivacaine depending on patient age, but this finding could be the result of some limitations of our study. The steady-state concentration was not reached during the 48-hour infusion and the behavior of plasma concentrations of ropivacaine and levobupivacaine during continuous infusions lasting more than 48 hours remains to be investigated, because they could reach toxic levels. Finally, no differences in the clinical efficacy or in the incidence of adverse effects between groups were found for either local anesthetic.

Plasma concentrations of levobupivacaine associated with two different intermittent wound infusion regimens following surgical ductus ligation in preterm infants.

BACKGROUND: Administration of local anesthetics by a surgically placed wound catheter has recently been shown to reduce the need for postoperative morphine administration in extremely preterm infants undergoing ductus ligation. The primary aim of this randomized safety study was to define the plasma levels of levobupivacaine (LB) following two different intermittent infusion regimens. METHODS: Eighteen preterm infants 23-27 gestational weeks, median birthweight 721 g scheduled for ductus ligation were included in the study. All patients were anesthetized according to a standardized protocol based on high-dose fentanyl (25-50 µg·kg(-1) ). Before skin closure, a subcutaneous catheter was inserted into the wound. The patients were randomized to receive one of the two intermittent infusion regimens: Group BII: Initial bolus plus early start of the intermittent infusion or Group DII: No bolus plus delayed start (8 h) of the intermittent infusion. Blood samples for determination of LB plasma concentrations were obtained on six occasions during the 24-h postoperative observation period, as well as hourly postoperative pain assessments using the Echelle Douleur Inconfort Noveau (EDIN) pain scale. RESULTS: Plasma concentrations of LB ranged from 0.094 to 1.682 µg·ml(-1) and 0 to 0.549 µg·ml(-1) in group BII and DII, respectively. Both regimens were associated with low postoperative EDIN pain scores (24 h median of 0 and 1 in group BII and DII, respectively). No signs of systemic local anesthetic toxicity were noted. CONCLUSIONS: The two studied intermittent infusion regimens were associated with plasma levels below potentially toxic levels and were both associated with adequate postoperative pain scores.

Assessment of tandem mass spectrometry and high-resolution mass spectrometry for the analysis of bupivacaine in plasma.

Triple quadrupole mass spectrometers coupled with high performance liquid chromatography are workhorses in quantitative bioanalyses. They provide substantial benefits including reproducibility, sensitivity and selectivity for trace analysis. Selected reaction monitoring allows targeted assay development but datasets generated contain very limited information. Data mining and analysis of nontargeted high-resolution mass spectrometry profiles of biological samples offer the opportunity to perform more exhaustive assessments, including quantitative and qualitative analysis. The objectives of this study were to test method precision and accuracy, to statistically compare bupivacaine drug concentration in real study samples and to verify if high-resolution and accurate mass data collected in scan mode can actually permit retrospective data analysis, more specifically, extract metabolite related information. The precision and accuracy data presented using both instruments provided equivalent results. Overall, the accuracy ranged from 106.2 to 113.2% and the precision observed was from 1.0 to 3.7%. Statistical comparisons using a linear regression between both methods revealed a coefficient of determination (R(2)) of 0.9996 and a slope of 1.02, demonstrating a very strong correlation between the two methods. Individual sample comparison showed differences from -4.5 to 1.6%, well within the accepted analytical error. Moreover, post-acquisition extracted ion chromatograms at m/z 233.1648 ± 5 ppm (M - 56) and m/z 305.2224 ± 5 ppm (M + 16) revealed the presence of desbutyl-bupivacaine and three distinct hydroxylated bupivacaine metabolites. Post-acquisition analysis allowed us to produce semi-quantitative evaluations of the concentration-time profiles for bupicavaine metabolites.

Plasma levels of levobupivacaine during continuous infusion via a wound catheter after major surgery in newborn infants: An observational study.

BACKGROUND: Epidurals may be challenging in neonatal patients due to technical difficulties relating to insertion and the risk of local anaesthesia toxicity. The use of wound catheters with an infusion of local anaesthetic has been shown to be well tolerated in adults and older children. There are few data concerning wound catheter techniques in neonatal patients. OBJECTIVES: The primary aim of this study was to analyse plasma levels of levobupivacaine associated with continuous wound infiltration via a catheter following neonatal surgical procedures. Secondary parameters, including the quality of postoperative analgesia and wound healing, were also noted. DESIGN: A prospective, observational study. SETTING: Paediatric ICU at the Karolinska University Hospital, Stockholm, Sweden, from March 2008 to December 2010. PATIENTS: Twenty newborn infants (median weight 3.48 kg) scheduled for major abdominal or thoracic surgery were included. Exclusion criteria were known or suspected hepatic dysfunction. Before skin closure, a subcutaneous catheter was inserted into the wound followed by a 0.5 mg kg(-1) bolus of levobupivacaine (0.125%, 0.4 ml kg(-1)) through the catheter. A continuous infusion was started 20 to 30 min later at a rate of 0.2 mg kg(-1)h(-1) (0.16 ml kg(-1) h(-1)). MAIN OUTCOME MEASURES: Plasma concentrations of levobupivacaine (total and unbound) at 12, 24, 48 and 72 h postoperatively. Morphine consumption, pain scores and wound healing were also analysed. RESULTS: Median concentrations of unbound and total levobupivacaine at 72 h were 0.018 and 1.305 µg ml(-1), respectively. In 18 out of 20 infants [90%; 95% confidence interval (CI) 68.3 to 98.8], the unbound plasma concentration of levobupivacaine remained relatively stable and below 0.05 µg ml(-1) throughout the 72 h observation period. Pain scores and morphine consumption levels were low. All wounds except one healed within 10 days. CONCLUSION: The studied infusion regimen was associated with plasma levels of levobupivacaine well below those associated with toxicity. Adequate wound healing, low pain scores and a reduced need for opioids were also noted.

A randomized double-blind clinical trial of a continuous 96-hour levobupivacaine infiltration after open or laparoscopic colorectal surgery for postoperative pain management--including clinically important changes in protein binding.

BACKGROUND: Continuous local anesthetic infiltration has been used for pain management after open colorectal surgery. However, its application to patients undergoing laparoscopic colorectal surgery has not been examined. The aim of this prospective, randomized, double-blind, placebo-controlled clinical trial was to study the use of a commercial infiltration device in patients undergoing open or laparoscopic colorectal surgery, along with plasma concentrations of levobupivacaine, its acute-phase binding protein (alpha-1 acid glycoprotein, AAG), and the stress marker, cortisol. METHODS: Eligible patients were randomized (2:1) to receive a continuous infiltration of either levobupivacaine or placebo using a commercial device (ON-Q PainBuster) inserted in the preperitoneal layer at the end of surgery. Blood was sampled for determination of levobupivacaine and AAG and cortisol concentrations. Other outcomes measured were pain scores, morbidity and mortality, time to bowel movement, mobilization, and length of hospitalization. RESULTS: In patients having open surgery, the levobupivacaine treatment showed a trend toward reduced total opioid consumption. No patients reported adverse effects attributable to levobupivacaine, despite 11 patients having concentrations at some time(s) during the 96-hour infiltration of up to 5.5 mg/L exceeding a putative toxicity threshold of 2.7 mg/L. AAG concentrations measured postsurgery increased by a mean of 55% (P < 0.001) at 48 hours. Cortisol concentrations also increased significantly by a mean of 191% at 1 hour. CONCLUSIONS: Continuous local anesthetic infiltration may be more beneficial in open surgery. The threshold for adverse effects from highly bound local anesthetic drugs established in healthy volunteers is of limited usefulness in clinical scenarios in which AAG concentration increases in response to surgical stress. Hence, there is scope to adopt higher doses to enhance therapeutic benefit.

Inhibition of murine cardiomyocyte respiration by amine local anesthetics.

The hydrophobic amino acyl amide-linked local anesthetics (e.g., lidocaine and bupivacaine) impose potent cardiac toxicity and direct mitochondrial dysfunction. To investigate these adverse events, an in vitro system was employed to measure their effects on O2 consumption (cellular respiration) by murine myocardium. Specimens were collected from the ventricular myocardium and immediately immersed in ice-cold Krebs-Henseleit buffer saturated with 95 % O2:5 % CO2. O2 concentration was determined as a function of time from the phosphorescence decay rates of Pd(II)-meso-tetra-(4-sulfonatophenyl)-tetrabenzoporphyrin. Myocardial O2 consumption was linear with time (zero-order kinetics); its rate (k, in µM O2 min(-1)), thus, was the negative of the slope of [O2] vs. time. Cyanide inhibited O2 consumption, confirming the oxidation occurred in the respiratory chain. Lidocaine and bupivacaine produced immediate and sustained inhibition of cellular respiration at plasma concentrations of the drugs (low micromolar range). Bupivacaine was twice as potent as lidocaine. The inhibition was dose-dependent, saturating at concentrations ≥30 µM. At saturating doses, lidocaine produced ~20 % inhibition and bupivacaine ~40 % inhibition. Cellular ATP was also decreased in the presence of 30 µM lidocaine or bupivacaine. The studied amines inhibited myocardial cellular respiration. This effect is consistent with their known adverse events on mitochondrial function. The described approach allows accurate assessments and comparisons of the toxic effects of local anesthetics on heart tissue bioenergetics.

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.

Application of the continual reassessment method to dose-finding studies in regional anesthesia: an estimate of the ED95 dose for 0.5% bupivacaine for ultrasound-guided supraclavicular block.

BACKGROUND: Previously reported estimates of the ED95 doses for local anesthetics used in brachial plexus blocks vary. The authors used the continual reassessment method, already established in oncology trials, to determine the ED95 dose for 0.5% bupivacaine for the ultrasound-guided supraclavicular block. METHODS: A double-blind, prospective trial was scheduled for 40 patients of American Society of Anesthesiologists class I-III presenting for upper limb surgery and supraclavicular block. The study dose to be administered was arbitrarily divided into six dose levels (12, 15, 18, 21, 24, and 27 ml) with a priori probabilities of success of 0.5, 0.75, 0.90, 0.95, 0.98, and 0.99 respectively. A continual reassessment method statistical program created a dose-response curve, which would shift direction depending on the success or failure of the block. Our starting dose was 21 ml and the next allocated dose was reestimated by the program to be the dose level with the updated posterior response probability closest to 0.95. RESULTS: After recruitment of eight patients, our initial dose levels and associated probabilities were deemed too low to determine the ED95. Updated a prioris were calculated from the statistical program, and the study recommenced with a new starting dose of 30 ml. On completion, the ED95 dose was estimated to be 27 ml (95% CI, 24-28 ml). CONCLUSIONS: The continual reassessment method trial design provided a credible estimate for the ED95 dose for 0.5% bupivacaine for our technique of supraclavicular block and may be of value as a statistically robust method for dose-finding studies in anesthesiology.

Molecularly imprinted polymer in microextraction by packed sorbent for the simultaneous determination of local anesthetics: lidocaine, ropivacaine, mepivacaine and bupivacaine in plasma and urine samples.

This study presents the use of molecularly imprinted polymer (MIP) as packing material for microextraction by packed syringe (MEPS) to achieve higher extraction selectivity. Pentycaine was used as template for MIP. Development and validation of the determination of lidocaine, ropivacaine, mepivacaine and bupivacaine in human plasma and urine samples utilizing MIP-MEPS and liquid chromatography-tandem mass spectrometry (LC-MS/MS) were carried out. The MEPS MIP-cartridge could be used for 100 extractions before it was discarded. The extraction recovery ranged from 60 to 80%. The correlation coefficients values were >0.999 for all assays using lidocaine, ropivacaine, mepivacaine and bupivacaine in the calibration range 5-2000 nmol/L. The accuracy of the studied compounds, given as a percentage variation from the nominal concentration values, ranged from -4.9 to 8.4% using plasma and urine samples. The between-batch precision, given as the relative standard deviation, at three different concentrations (quality control samples) was ranged from -4.7 to 14.0% and from 1.8 to 12.7% in plasma and urine, respectively. The lower limit of quantification and limit of detection of the studied substances were 5.0 and 1.0 nm, respectively.

Transversus abdominis plane block provides postoperative analgesic effects after cesarean section: additional analgesia to epidural morphine alone.

AIM: The aim of our study was: (i) to investigate whether transversus abdominis plane (TAP) block confers additional analgesic effects to epidural morphine alone; and (ii) to determine plasma levels of local anesthetics after TAP block in post-cesarean women. MATERIAL AND METHODS: The subjects were parturients undergoing cesarean section under combined spinal-epidural anesthesia. Morphine (2 mg) was administered to the epidural space close to the end of surgery. Women who desired TAP block were allocated to the TAP group. Women who did not undergo TAP block were allocated to the control group. In the TAP group, 20 mL of either 0.375% ropivacaine or 0.3% levobupivacaine was infused to both sides of the transversus abdominis plane after surgery. All patients were placed on a patient-controlled i.v. analgesia regimen with morphine after surgery. Time to the first morphine request and amount of morphine consumption within 24 h after surgery were compared in patients with and without TAP block. Plasma concentrations of local anesthetics were determined at 15, 30 and 60 min after TAP block. RESULTS: Forty and 54 patients were allocated to the control and TAP group, respectively. The median time to the first morphine request was longer (555 vs 215 min), and the median cumulative morphine consumption within 24 h was lower (5.3 vs 7.7 mg) in the TAP group than in the control group. The maximum median concentrations of ropivacaine and bupivacaine after TAP block were 784 and 553 ng/mL, respectively. CONCLUSION: TAP block had additional analgesic effects to epidural morphine alone.

Intravenous lipid emulsion only minimally influences bupivacaine and mepivacaine distribution in plasma and does not enhance recovery from intoxication in pigs.

BACKGROUND: The reported successful use of IV lipid emulsions in local anesthetic intoxications is thought to be due to lipid sequestration of local anesthetics. However, controlled efficacy studies were lacking, and other mechanisms of action have also been suggested. We investigated the effect of lipid infusion on plasma concentrations and cardiovascular effects of 2 local anesthetics differing in lipophilicity, bupivacaine, and mepivacaine. METHODS: Bupivacaine (n = 20) or mepivacaine (n = 20) was infused into a central vein of anesthetized (isoflurane 1%, Fio(2) 0.21) pigs until mean arterial blood pressure decreased to 50% from baseline. Isoflurane was discontinued and Fio(2) was increased to 1.0. Ten pigs in each local anesthetic group were treated with 20% lipid emulsion (ClinOleic®), and 10 pigs with Ringer's solution: 1.5 mL/kg in 1 minute followed by an infusion of 0.25 mL · kg(-1) · min(-1) for 29 minutes. Five additional pigs were infused bupivacaine and Intralipid®. Total and nonlipid-bound local anesthetic concentrations were determined from repeated blood samples. RESULTS: There were no overall differences in total or nonlipid-bound plasma local anesthetic concentrations between the lipid and Ringer's groups. However, plasma median total bupivacaine concentration was 21% and 23% higher at 20 and 30 minutes, respectively, in the lipid group (P = 0.016 without Holm-Bonferroni correction). There was also no overall difference between lipid and Ringer's groups in the rate of recovery of hemodynamic and electrocardiographic variables. Median mean arterial blood pressure in the lipid group with bupivacaine intoxication was 16 mm Hg and 15 mm Hg higher than in the corresponding Ringer's group at 10 and 15 minutes, respectively (P = 0.016 and P = 0.021, respectively, without Holm-Bonferroni correction). Intralipid® also caused no difference between total plasma and nonlipid-bound concentrations of bupivacaine with no apparent enhancement of recovery. CONCLUSIONS: Lipid emulsion neither had any measurable effect on the disposition of the studied local anesthetics in plasma, nor did it improve the rate of recovery from intoxication by either local anesthetic as measured by hemodynamic variables.

Local infiltration analgesia with levobupivacaine compared with intrathecal morphine in total hip arthroplasty patients.

BACKGROUND: Recently, local infiltration analgesia (LIA) has been promoted for pain control after total hip arthroplasty (THA). We hypothesized that LIA would offer equal analgesic efficacy but less adverse effects, e.g., nausea and vomiting, when compared with an established regimen [intrathecal morphine (it-M)] after THA. METHODS: This randomized controlled trial comprised 60 patients undergoing THA under spinal anaesthesia. For LIA, the surgeon administered levobupivacaine, ketorolac and epinephrine at the surgical site intraoperatively. LIA patients received a LIA top-up through a wound catheter on the morning of the 1st post-operative day (POD). In group it-M, 0.1 mg morphine was given together with the spinal anaesthetic. Study parameters included pain scores, vital parameters and side effects, e.g., post-operative nausea and vomiting (PONV). Besides, levobupivacaine plasma concentrations were determined in 10 LIA patients. RESULTS: The median (25th/75th percentiles) rescue oxycodone demand differed significantly with LIA 15 (10/25) mg vs. 8.5 (1.5/15) mg with it-M (P < 0.006) during the day of surgery, but not anymore on 1st or 2nd POD. The LIA top-up had no effect. However, both analgesic regimens resulted in comparable pain scores and patient satisfaction. PONV incidence and medication did not vary significantly. LIA offered certain advantages regarding early post-operative mobilization. Maximum levobupivacaine plasma concentrations (229-580 ng/ml) remained under the toxic level. CONCLUSIONS: While LIA might enable earlier mobilization after THA, it was not associated with less nausea as compared with it-M. Less rescue oxycodone was given early after it-M, but urinary retention was more common in that group.