Plasma Bupivacaine Research Articles

The preventive efficacy of lipid emulsion on the occurrence of local anesthetic systemic toxicity in patients receiving local infiltration analgesia for total joint arthroplasty

BackgroundMotor-sparing local infiltration analgesia (LIA) enhances recovery after total hip arthroplasty (THA) and total knee arthroplasty (TKA). However, LIA can induce local anesthetic systemic toxicity (LAST), sometimes necessitating rescue lipid emulsion therapy. Our institute initiated a pilot study to pretreat patients with lipid emulsion (SMOFlipid®) to test its efficacy in mitigating LIA-induced LAST events.MethodsThis retrospective study enrolled 1,621 adult patients who received LIA with bupivacaine (2–3 mg/kg, maximum 300 mg) for unilateral primary THA or TKA under general anesthesia between January 2020 and April 2022. A total of 439 patients received lipid pretreatment, while 1,182 did not. Demographics, surgical and anesthesia profiles, along with LAST events affecting the neurological, cardiovascular, and respiratory systems, were compared after propensity score matching for age, sex, body mass index (BMI), and surgery type.ResultsThe incidence of severe LAST events requiring rescue lipid emulsion slightly decreased after lipid pretreatment (from 2.54 to 2.28 per 1000). Lipid pretreatment significantly reduced the incidence of bradycardia and new-onset arrhythmia (odds ratio: 0.13, adjusted p-value: 0.024) but increased postoperative opioid requirement (odds ratio: 1.71, adjusted p-value: 0.032) after Benjamini-Hochberg correction for multiplicity.ConclusionsThe efficacy of lipid pretreatment (SMOFlipid® 1.5 ml/kg, maximum 100 ml) in mitigating LIA-induced LAST remains controversial. While lipid pretreatment reduced the incidence of new-onset arrhythmia, it showed no clear benefits for neurologic and respiratory outcomes. Additionally, lipid pretreatment might hinder postoperative recovery by increasing the need for rescue opioid analgesia. Further prospective pharmacokinetic studies are required to assess plasma bupivacaine concentrations following LIA and lipid pretreatment, examine their relationship to LAST events, and establish the efficacy and safety of lipid pretreatment.

Efficacy and safety of different bupivacaine concentrations in periarticular infiltration combined with adductor canal block for bilateral total knee arthroplasty: a randomized controlled trial

BackgroundPain management for bilateral total knee arthroplasty (BTKA) often combines adductor canal block (ACB) with periarticular infiltration (PAI). However, concerns arise regarding local anesthetic toxicity. This study evaluated the efficacy and safety of different bupivacaine concentrations in simultaneous BTKA.MethodsPatients undergoing simultaneous BTKA under spinal anesthesia were included in the study. They received ACB with 50 mg bupivacaine for each thigh. The patients were then randomized into two groups. Group A was administered a PAI of 100 mg bupivacaine per knee (totaling 300 mg bupivacaine for ACB and PAI). Group B received a PAI with 50 mg bupivacaine per knee (totaling 200 mg bupivacaine for ACB and PAI). Postoperative pain was assessed using a visual analog scale at 4-h intervals for 48 h after surgery. Plasma bupivacaine concentrations were measured at eight specified times. Postsurgery walking ability was also evaluated.ResultsAmong the 57 participants analyzed, visual analog scale pain scores revealed no significant differences between the two groups. An interim analysis of plasma bupivacaine concentrations in both groups indicated no significant disparities. In group B, 93.1% managed to walk with assistance within 48 h, as opposed to group A’s 71.4% (P = 0.041).ConclusionsCombining ACB with 100 mg bupivacaine and PAI with another 100 mg bupivacaine provided effective pain relief. This combination also had a better safety profile and led to more patients walking postsurgery than when combining ACB with 100 mg bupivacaine and PAI with 200 mg bupivacaine. Thus, ACB combined with PAI with a total dose of 200 mg bupivacaine appears suitable for simultaneous BTKA.Trial registration: ClinicalTrials.gov (NCT03249662).

Assessment of the Safety and Efficiency of a Preperitoneal Continuous Infusion Using Bupivacaine after Abdominal Laparotomy in Digestive Carcinology.

The purpose of this paper is to evaluate the safety and efficacy of continuous preperitoneal wound infiltration using bupivacaine after abdominal laparotomy in relation to plasma bupivacaine concentration and visual analog scale. Our study was performed on 60 adult patients with digestive cancer, operated at laparotomy, and randomized into two groups: bupivacaine and saline groups. The wound infiltration was through a multiperforated catheter along the scar. For the bupivacaine group, 0.25% bupivacaine was used; however, for the saline group, only saline (0.9%) was infiltrated. The pain was assessed by using the visual analog scale (VAS) in both groups. Plasma bupivacaine concentration was measured by high-performance liquid chromatography. The bupivacaine group had significantly lower postoperative morphine consumption and lower postoperative pain than the saline group (P < 0.0001). The majority of patients in the bupivacaine group had significant relief with the VAS scores of less than 3/10 cm at rest and 6/10 cm on mobilization. However, for the saline group, the VAS scores were higher than 6/10 cm either at rest or with mobilization. There was no clinical sign of toxicity and no technical complications for the bupivacaine group. Only eleven patients required morphine in this group, but the majority of patients received morphine at different doses in the saline group. Plasma bupivacaine was at very low concentrations. Overall, the current study has confirmed that continuous preperitoneal wound infiltration as postoperative analgesia is a simple, effective, and safe technique. It allows decreasing of morphine consumption and subsequently canceling their side effects.

Development and in vivo validation of phospholipid-based depots for the sustained release of bupivacaine

By direct deposition of the drug at the local site of action, injectable depot formulations – intended for treatment of a local disease or for local intervention – are designed to limit the immediate exposure of the active principle at a systemic level and to reduce the frequency of administration. To overcome known drawbacks in the production of some marketed phospholipid-based depots, here we propose to manufacture drug-loaded negatively charged liposomes through conventional technologies and to control their aggregation mixing a solution of divalent cations prior to administration. We identified phosphatidylglycerol (PG) as the most suitable phospholipid for controlled aggregation of the liposomes and to modulate the release of the anesthetic bupivacaine (BUP) from liposomal depots. In vivo imaging of the fluorescently-labelled liposomes showed a significantly higher retention of the PG liposomes at the injection site with respect to zwitterionic ones. In situ mixing of PG liposomes with calcium salts significantly extended the area under the curve of BUP in plasma compared to the non-depot system. Overall, controlling the aggregation of negatively charged liposomes with divalent cations not only modulated the particle clearance from the injection site but also the release in vivo of a small amphipathic drug such as BUP.

Plasma bupivacaine levels (total and free/unbound) during epidural infusion in liver resection patients: a prospective, observational study

IntroductionLiver resection patients may be at an increased risk of local anesthetic (LA) toxicity because the liver is essential for metabolizing LA and producing proteins (mainly α1-acid glycoprotein (AAG)) that...

Peak plasma concentration of total and free bupivacaine after erector spinae plane and pectointercostal fascial plane blocks.

Erector spinae plane blocks (ESPB) and pectointercostal fascial (PIFB) plane blocks are novel interfascial blocks for which local anesthetic (LA) doses and concentrations necessary to achieve safe and effective analgesia are unknown. The goal of this prospective observational study was to provide the timing (Tmax) and concentration (Cmax) of maximum total and free plasma bupivacaine after ESPB in breast surgery and after PIFB in cardiac surgery patients. Erector spinae plane blocks or PIFBs (18 patients per block; total, 36 patients) were performed with 2 mg⋅kg-1 of bupivacaine with epinephrine 5 μg⋅mL-1. Our principal outcomes were the mean or median Cmax of total and free plasma bupivacaine measured 10, 20, 30, 45, 60, 90, 180, and 240 min after LA injection using liquid chromatography with tandem mass spectrometry. For ESPB, the mean (standard deviation [SD]) total bupivacaine Cmax was 0.37 (0.12) μg⋅mL-1 (range, 0.19 to 0.64), and the median [interquartile range (IQR)] Tmax was 30 [50] min (range, 10-180). For ESPB, the mean (SD) free bupivacaine Cmax was 0.015 (0.017) μg⋅mL-1 (range, 0.003-0.067), and the median [IQR] Tmax was 30 [20] min (range, 10-120). After PIFB, mean plasma concentrations plateaued at 60-240 min. For PIFB, the mean (SD) total bupivacaine Cmax was 0.32 (0.21) μg⋅mL-1 (range, 0.14-0.95), with a median [IQR] Tmax of 120 [150] min (range, 30-240). For PIFB, the mean (SD) free bupivacaine Cmax was 0.019 (0.010) μg⋅mL-1 (range, 0.005-0.048), and the median [IQR] Tmax was 180 [120] min (range, 30-240). For both ESPB and PIFB, we observed no correlations between pharmacokinetic and demographic parameters. Total and free bupivacaine Cmax observed after ESPB and PIFB with 2 mg⋅kg-1 of bupivacaine with epinephrine 5 μg⋅mL-1 were five to twenty times lower than levels considered toxic in the literature.

A multicenter study to evaluate the pharmacokinetics and safety of liposomal bupivacaine for postsurgical analgesia in pediatric patients aged 6 to less than 17 years (PLAY)

Study objectiveTo evaluate the pharmacokinetics and safety of liposomal bupivacaine in pediatric patients undergoing spine or cardiac surgery. DesignMulticenter, open-label, phase 3, randomized trial (PLAY; NCT03682302). SettingOperating room. PatientsTwo separate age groups were evaluated (age group 1: patients 12 to <17 years undergoing spine surgery; age group 2: patients 6 to <12 years undergoing spine or cardiac surgery). InterventionRandomized allocation of liposomal bupivacaine 4 mg/kg or bupivacaine hydrochloride (HCl) 2 mg/kg via local infiltration at the end of spine surgery (age group 1); liposomal bupivacaine 4 mg/kg via local infiltration at the end of spine or cardiac surgery (age group 2). MeasurementsThe primary and secondary objectives were to evaluate the pharmacokinetics (eg, maximum plasma bupivacaine concentrations [Cmax], time to Cmax) and safety of liposomal bupivacaine, respectively. Main resultsBaseline characteristics were comparable across groups. Mean Cmax after liposomal bupivacaine administration was lower versus bupivacaine HCl in age group 1 (357 vs 564 ng/mL); mean Cmax in age group 2 was 320 and 447 ng/mL for spine and cardiac surgery, respectively. Median time to Cmax of liposomal bupivacaine occurred later with cardiac surgery versus spine surgery (22.7 vs 7.4 h). In age group 1, the incidence of adverse events (AEs) was comparable between liposomal bupivacaine (61% [19/31]) and bupivacaine HCl (73% [22/30]). In age group 2, 100% (5/5) and 31% (9/29) of patients undergoing spine and cardiac surgery experienced AEs, respectively. AEs were generally mild or moderate, with no discontinuations due to AEs or deaths. ConclusionsPlasma bupivacaine levels following local infiltration with liposomal bupivacaine remained below the toxic threshold in adults (~2000–4000 ng/mL) across age groups and procedures. AEs were mild to moderate, supporting the safety of liposomal bupivacaine in pediatric patients undergoing spine or cardiac surgery.Clinical trial number and registry URL: ClinicalTrials.gov identifier: NCT03682302

Pharmacokinetics and safety of liposomal bupivacaine after local infiltration in healthy Chinese adults: a phase 1 study

BackgroundLiposomal bupivacaine (LB) is a long-acting formulation of bupivacaine. The safety and efficacy of LB has been demonstrated across surgical procedures. However, pharmacokinetic (PK) parameters and safety of LB in the Chinese population have not been assessed.MethodsIn this single-arm, single center, phase 1, open-label study, PK and safety of local infiltration with LB 266 mg were assessed in healthy Chinese adults. Eligible participants were aged 18 to 55 years with biologic parents and grandparents of Chinese ethnicity, in generally good health (i.e., no clinically significant abnormalities), and with a body mass index (BMI) 19.0 to 24.0 kg/m2 (inclusive) and body weight ≥ 50 kg.ResultsParticipants (N = 20) were predominantly men (80 %); mean age was 32 years; and mean BMI was 21.8 kg/m2. After LB administration, mean plasma levels of bupivacaine rapidly increased during the first hour and continued to increase through 24 h; plasma levels then gradually decreased through 108 h followed by a monoexponential decrease through 312 h. Geometric mean maximum plasma concentration was 170.9 ng/mL; the highest plasma bupivacaine concentration detected in any participant was 374.0 ng/mL. Twenty-two treatment-emergent adverse events were reported (mild, n = 21; moderate, n = 1).ConclusionsAfter single-dose administration of LB, PK measures were similar to a previously reported profile in US adults. The highest observed peak plasma concentration of bupivacaine was several-fold below the plasma concentration threshold accepted as being associated with neurotoxicity or cardiotoxicity (2000–4000 ng/mL). These data support that LB is well tolerated and safe in individuals of Chinese descent.Trial registrationNCT04158102 (ClinicalTrials.gov identifier), Date of registration: November 5, 2019.

Simple HPLC-UV method for the quantification of bupivacaine in human plasma with one step protein precipitation

This research paper revolves around the process of the quantification of bupivacaine in human plasma through the selection of a sensitive high performance liquid chromatography method. The extraction of bupivacaine and ropivacaïne as an internal standard from plasma was performed through the use of hexane along with iso-propylalcohol. After liquid-liquid extraction we moved straightforward to the process of the mobile phase in which we had a combination of acetonitrile and potassium dihydrogen phosphate (65:35, v/v). The separation was carried out on a reversed phase C 18 column with UV-detector at 210 nm for bupivacaine and 230 nm for the internal standard. This particular examination exhibited excellent linearity ( r 2 = 0.999) in peak response over the concentration range of 0.1–1.5 μg/mL bupivacaine in human plasma. The mean absolute recoveries for 0.5 and 1.5 μg/mL of bupivacaine in plasma using the present extraction procedure were 97.43% and 95.03%, respectively. The intra- and inter-day coefficients of variation in the plasma were less than 12% at the lowest, and less than 10% at other concentrations, and the percent error values were less than 6%. The method displayed a high caliber of sensitivity and selectivity for therapeutic monitoring concentrations of bupivacaine in human plasma. Cet article de recherche s’articule autour du processus de quantification de la bupivacaïne dans le plasma humain à l’aide d’une méthode chromatographie liquide à haute performance. L’extraction de la bupivacaïne et de la ropivacaïne comme étalon interne à partir du plasma a été réalisée en utilisant de l’hexane avec de l’alcool isopropylique. Après l’extraction liquide-liquide, nous sommes passés directement au processus de préparation de la phase mobile qui est constituée par un mélange d’acétonitrile et de dihydrogénophosphate de potassium (65/35, v/v). La séparation a été effectuée sur une colonne C18 en phase inversée avec un détecteur UV à 210 nm pour la bupivacaïne et 230 nm pour l’étalon interne. Cette mise au point particulier a montré une excellente linéarité ( r 2 = 0,999) en réponse maximale sur la plage de concentration de 0,1–1,5 μg/mL de chlorhydrate de bupivacaïne dans le plasma humain. Les taux de récupération absolus moyens pour 0,5 et 1,5 μg/mL de chlorhydrate de bupivacaïne dans le plasma au moyen par le biais de mode d’extraction étaient respectivement de 97,43 % et 95,03 %. Les coefficients de variation dans le plasma intra et inter jours étaient inférieurs à 12 % aux valeurs les plus basses et inférieurs à 10 % aux autres concentrations, et les valeurs d’erreur en pourcentage étaient inférieures à 6 %. La méthode a montré une sensibilité et une sélectivité élevées pour le suivi thérapeutique des concentrations de bupivacaïne dans le plasma humain.

Dexmedetomidine elevates the lethal dose threshold of bupivacaine in rats: A dosing study.

Dexmedetomidine (DMED), an alpha-2 adrenoreceptor agonist, has been widely used in regional anesthesia procedures. However, the effect of DMED on local anesthetic cardiotoxicity has not been well delineated. This study consisted of two experiments. In experiment A, 42 Sprague-Dawley (SD) rats were randomly divided into 6 groups (n = 7), each group was pretreated with DMED 0 μg kg-1 (D0 group), 1 μg kg-1 (D1 group), 3 μg kg-1 (D3 group), 6 μg kg-1 (D6 group), 12 μg kg-1 (D12 group), and 24 μg kg-1 (D24 group), administered through the right femoral vein. In experiment B, 20 SD rats were randomly divided into 4 groups (n = 5), such as control group, DMED group, yohimbine (YOH) group, and DMED + YOH group. Each subgroup in experiment B was also pretreated similarly as in experiment A. After pretreatment of rats as described above (in experiments A and B), bupivacaine 2.5 mg kg-1 min-1 was infused to induce cardiac arrest. In experiment A, the lethal dose threshold of bupivacaine and plasma bupivacaine concentration in D3 and D6 group were higher than the other groups. In experiment B, there was no interaction between DMED and YOH in lethal dose threshold, arrhythmia time, plasma concentration of bupivacaine, and myocardial content of bupivacaine. DMED doses of 3-6 μg kg-1 elevated the lethal dose threshold of bupivacaine without involvement of the alpha-2 adrenoceptors.

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.

Patient-controlled analgesia with and without transverse abdominis plane and rectus sheath space block in cirrhotic patients undergoing liver resection

Background and Aims:Optimal pain control can be a challenge in cirrhotic patients. The aim was to compare the analgesic efficacy and side effects of intravenous fentanyl patient-controlled analgesia (PCA) with and without bupivacaine boluses in transversus abdominis plane (TAP) and rectus sheath space (RSB) in cirrhotics undergoing liver surgery.Material and Methods:A double-blinded randomized controlled trial (n = 55, child's A) was conducted. Catheters were inserted surgically in TAP and rectal sheath space during surgical closure. Fentanyl PCA + TAP + RSB group (gp) (n = 30): (0.2 ml/kg of 0.25% bupivacaine, 8 hourly) was compared with fentanyl PCA gp (n = 25): [0.2 ml/kg of saline (placebo) injected in catheters 8 hourly] for 48 h postoperatively. Plasma bupivacaine was measured with an enzyme-linked immunosorbent assay at 10 min, 30 min, 1 h, 2 h, and 4 h after each injection and 30 min before next injection.Results:Fentanyl consumption was reduced in (PCA + TAP + RSB) gp compared to PCA gp (Day 1: 325.4 ± 169.1 vs. 1034 ± 231.7, Day 2: 204.44 ± 62.9 vs. 481.6 ± 158.3 μg, P < 0.05). Both groups demonstrated effective pain control at rest [Visual Analog Scales (VAS) <3), but on movement pain control with bupivacaine was better (P < 0.05). Increased demand for rescue opioids was observed prior to next scheduled bupivacaine injection in 10/30 patients on Day 1 and 2/30 on Day 2, in association with a reduced bupivacaine serum levels compared to 10 min after injection (47.6 ± 22.7 vs. 93.6 ± 61.0 ng/ml, respectively, P < 0.05). Bupivacaine did not exceed referred toxic levels.Conclusion:Repeated bupivacaine TAP and RSB with PCA fentanyl improved pain control, reduced opioids demand with no toxicity. Time interval between injections needs to be reduced to avoid breakthrough pain.

Effects of different administration routes of lipid emulsion on bupivacaine-induced cardiotoxicity in rats

Objective To evaluate the effects of different administration routes of lipid emulsion on bupivacaine-induced cardiotoxicity in rats. Methods Forty-eight clean healthy adult male Sprague-Dawley rats, weighing 300-350 g, were divided into 6 groups (n=8 each) using a random number table: IV infusion of normal saline (NS) group (group VN), IV infusion of lipid emulsion group (group VL), duodenal infusion of NS group (group DN), duodenal infusion of lipid emulsion group (group DL), intraperitoneal infusion of NS group (group PN) and intraperitoneal infusion of lipid emulsion group (group PL). In VN and VL groups, preheated NS and 20% lipid emulsion 3 ml·kg-1·min-1 were infused via the femoral vein for 5 min, respectively, and then 0.75% bupivacaine was infused at the rate of 2 mg·kg-1·min-1 until cardiac arrest happened.Preheated NS and 20% lipid emulsion 15 ml/kg were infused via the duodenum (over 1 min, at a constant rate) in DN and DL groups, respectively, and were intraperitoneally infused in PN and PL groups, respectively, followed by an infusion of 0.2 ml/min for 15 min in DN, DL, PN and PL groups.Then 0.75% bupivacaine was infused via the left femoral vein at a rate of 2 mg·kg-1·min-1 until cardiac arrest happened.The time to ventricular arrhythmia, mean arterial pressure (MAP) decreasing to 50% of the baseline and cardiac arrest was recorded.The amount of bupivacaine consumed was calculated immediately after ventricular arrhythmia occurred (T0), immediately after MAP decreased to 50% of the baseline (T1) and immediately after occurrence of cardiac arrest (T2). Arterial blood samples were collected at T0-2 for determination of the concentration of bupivacaine in plasma by high-performance liquid chromatography. Results Compared with group VN, the time to ventricular arrhythmia, MAP decreasing to 50% of the baseline and cardiac arrest was significantly prolonged, and the amount of bupivacaine consumed was increased at T0-2 in group VL (P 0.05). Compared with group VL, the time to ventricular arrhythmia, MAP decreasing to 50% of the baseline and cardiac arrest was significantly shortened, and the amount of bupivacaine consumed was decreased at T0-2 in DL and PL groups (P 0.05). Conclusion IV infusion of lipid emulsion can decrease bupivacaine-induced cardiotoxicity when compared with duodenal and intraperitoneal infusion in rats. Key words: Lipid emulsions, intravenous; Bupivacaine; Drug toxicity

Pharmacokinetics of bupivacaine after bilateral ultrasound-guided transversus abdominis plane block following cesarean delivery under spinal anesthesia

BackgroundTransversus abdominis plane block is an effective method of post-cesarean analgesia. There are no data available about plasma bupivacaine levels after this block in adults. This study aimed to assess bupivacaine pharmacokinetic parameters after ultrasound-guided transversus abdominis plane blocks following cesarean delivery under spinal anesthesia. MethodsA prospective observational study in parturients undergoing elective cesarean delivery under hyperbaric bupivacaine spinal anesthesia was conducted. After surgery, patients received bilateral transversus abdominis plane block (50mg bupivacaine each side). Venous blood samples were collected immediately before performing the block and at 10, 20, 30, 45, 60, 90, 120, 180, 240, 720 and 1440minutes. High performance liquid chromatography was used to measure total plasma bupivacaine concentrations. Mean bupivacaine area under the curve (AUC) was calculated from 0 to 24hours. ResultsData were collected from 17 parturients. Mean age and body mass index were 31±6y and 30±4kg/m2 respectively. Mean plasma bupivacaine concentration before the block was 171ng/mL. Mean peak concentration was 802.36ng/mL (range 231.8 to 3504.5ng/mL). Mean time to peak concentration was 30min and mean area-under-the-curve (0–24h) was 4505.4h.ng/mL. Mean elimination half-life was 8.75h. Three subjects had concentrations above the quoted toxic threshold and mild symptoms suggestive of neurotoxicity were reported by two subjects, but no treatment was required. ConclusionSingle-dose bilateral transversus abdominis plane block using 100mg of bupivacaine, after spinal anesthesia for cesarean delivery, can result in toxic plasma bupivacaine concentrations.

Plasma bupivacaine concentrations following orbital injections in cats

ObjectiveTo determine plasma bupivacaine concentrations after retrobulbar or peribulbar injection of bupivacaine in cats. Study designRandomized, crossover, experimental trial with a 2 week washout period. AnimalsSix adult healthy cats, aged 1–2 years, weighing 4.6 ± 0.7 kg. MethodsCats 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. ResultsThe 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 relevanceIn 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.

The safety of liposome bupivacaine following various routes of administration in animals.

BackgroundThis report presents results from four preclinical studies evaluating safety and pharmacokinetics (PKs) of liposome bupivacaine following intravascular (intravenous [IV], intra-arterial [IA]), epidural, and intrathecal administration in dogs.MethodsIntravascular administration was initially tested in a pilot study to determine maximum tolerated doses, and then in an expanded study of systemic adverse effects and PKs. An epidural study compared properties of liposome bupivacaine alone and in combination with lidocaine/epinephrine vs bupivacaine HCl. Another study assessed effects after intrathecal administration.ResultsIn the initial intravascular studies, maximum doses at which no meaningful adverse events were observed with liposome bupivacaine were higher than for bupivacaine HCl (4.5 mg/kg IV vs 0.75 mg/kg IV, and 1.5 mg/kg IA vs 0.1 mg/kg IA, respectively). In the expanded intravascular study, there was no mortality or changes in pathology; adverse clinical signs included convulsions, lying on side, and decreased muscle tone (all were transient). In the epidural study, liposome bupivacaine was well tolerated at doses up to the highest dose tested (40 mg), with no evidence of spinal cord damage and with less motor blockade than bupivacaine HCl 15 mg. Intrathecal administration of liposome bupivacaine 40 mg was not associated with meaningful safety concerns and resulted in less motor blockade than bupivacaine HCl 15 mg. PK analyses showed that maximum plasma bupivacaine levels following administration of liposome bupivacaine (4.5 mg/kg IV and 40 mg epidural) were similar to maximum plasma bupivacaine levels following a threefold lower dose of bupivacaine HCl (1.5 mg/kg IV and 15 mg epidural).ConclusionLiposome bupivacaine has a favorable safety profile compared with bupivacaine HCl when administered to dogs via intravascular, epidural, and intrathecal routes. This favorable safety profile is likely related to the liposome-bound nature of bupivacaine in the liposome bupivacaine formulation.

Local anaesthetic systemic toxicity

Access the CPD MCQs for this issue online here ### Key points Well-placed local anaesthetics (LAs) can yield great clinical benefits. But systemic toxicity related to their use can be devastating. The highly publicized case in 2004 of Mayra Cabrera, a theatre nurse who died shortly after delivery of her baby boy when her epidural infusion of bupivacaine was mistakenly connected to her i.v. line, reminds us to be vigilant and to learn from such rare events. While prevention is clearly the most important element in avoiding morbidity and mortality associated with local anaesthetic systemic toxicity (LAST), such cases still occur despite best practice. Knowing how to manage these uncommon events is vital. In this review, we cover LA toxicity, its incidence, clinical features, risk factors, prevention, and management and examine i.v. lipid emulsion (ILE) therapy in more detail. LAST has been recognized for more than a hundred years, but the precise incidence is currently unknown. In 1928, the American Medical Association reported 40 deaths attributable to LAs.1 Cocaine was responsible for half of these deaths, but procaine was also implicated. These findings prompted the search for less toxic agents. Lidocaine, first synthesized in 1944, was the first amide LA to be used clinically. However, in 1979, the potentially fatal toxicity of amide LAs was highlighted by Albright.2 More recently, studies from 1993 …

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.

Is the pharmacokinetics of bupivacaine equivalent after lumbar epidural administration through a needle or a catheter in male and female adults?

We assessed possible pharmacokinetic modifications due to different epidural injection techniques using either a needle or a catheter. Adult patients (n=23) undergoing lower abdominal or lower extremity surgery were randomly assigned a single bupivacaine epidural injection anesthesia (0.5%, 15mL, 0.3mL/s) through needle or catheter device. Plasma bupivacaine concentration was quantified using a validated HPLC method and non-compartmental pharmacokinetic parameters estimated. CMAX and TMAX were similar in both groups: 952±346 ng/mL, 0.65±0.51h in the needle group; 810±307 ng/mL, 0.43±0.29h in the catheter group respectively. Plasma AUC0→∞ was also similar in both groups: 3868±1687 ngh/mL for needle versus 4096±1748 ngh/mL using catheter. The catheter group showed slower disposition than the needle group: t1/2=3.9±2.3h, MRT=6.0±3.1h versus 2.7±1.03h and 4.5±1.2h with needle administration respectively though it did not reach statistical significance, Cl/F and V/F were also similar. Lastly, female patients showed significant longer t1/2 after administration through catheter (5.7±2.0h) than needle (2.7±0.6h) group (P=0.0279). The device type does not affect the pharmacokinetics which is similar in both groups although sex-based differences might exist.

Bupivacaine administered intrathecally versus rectally in the management of intractable rectal cancer pain in palliative care.

BackgroundUnacceptable adverse effects, contraindications to and/or ineffectiveness of World Health Organization step III “pain ladder” drugs causes needless suffering among a population of cancer patients. Successful management of severe cancer pain may require invasive treatment. However, a patient’s refusal of an invasive procedure necessitates that clinicians consider alternative options.ObjectiveIntrathecal bupivacaine delivery as a viable treatment of intractable pain is well documented. There are no data on rectal bupivacaine use in cancer patients or in the treatment of cancer tenesmoid pain. This study aims to demonstrate that bupivacaine administered rectally could be a step in between the current treatment options for intractable cancer pain (conventional/conservative analgesia or invasive procedures), and to evaluate the effect of the mode of administration (intrathecal versus rectal) on the bupivacaine plasma concentration.CasesWe present two Caucasian, elderly inpatients admitted to hospice due to intractable rectal/tenesmoid pain. The first case is a female with vulvar cancer, and malignant infiltration of the rectum/vagina. Bupivacaine was used intrathecally (0.25–0.5%, 1–2 mL every 6 hours). The second case is a female with ovarian cancer and malignant rectal infiltration. Bupivacaine was adminstered rectally (0.05–0.1%, 100 mL every 4.5–11 hours).MethodsTotal bupivacaine plasma concentrations were determined using the high-performance liquid chromatography-ultraviolet method.ResultsEffective pain control was achieved with intrathecal bupivacaine (0.077–0.154 mg·kg−1) and bupivacaine in enema (1.820 mg·kg−1). Intrathecal bupivacaine (0.5%, 2 mL) caused a drop in blood pressure; other side effects were absent in both cases. Total plasma bupivacaine concentrations following intrathecal and rectal bupivacaine application did not exceed 317.2 ng·mL−1 and 235.7 ng·mL−1, respectively. Bupivacaine elimination was slower after rectal than after intrathecal administration (t½= 5.50 versus 2.02 hours, respectively).LimitationsThis study reports two cases only, and there could be inter-patient variation.ConclusionBupivacaine in boluses administered intrathecally (0.25%, 2 mL) provided effective, safe analgesia in advanced cancer patients. Bupivacaine enema (100 mg·100 mL−1) was shown to be a valuable option for control of end-of-life tenesmoid cancer pain.