Bupivacaine Toxicity Research Articles

Local Anesthetic Use in Tumescent Liposuction

INTRODUCTION: Current guidelines favor the use of lidocaine as the local anesthetic of choice in liposuction wetting solutions.1 The use of bupivacaine as an alternative remains controversial despite reports of its use with safe outcomes. The goals of this study were to determine the prevalence of bupivacaine use in wetting solutions, examine the liposuction practices of bupivacaine users, and elucidate opinions regarding bupivacaine use in tumescent liposuction. METHODS: An online survey was distributed to 2,500 randomly-selected members of the American Society of Plastic Surgery. Data was collected and analyzed with emphasis on comparing the liposuction practices and opinions of those who use bupivacaine and those who do not use bupivacaine. RESULTS: The response rate of the survey was 12.8% (n=320). Twenty-two respondents (7.2%) reported using bupivacaine in their wetting solutions (bupivacaine group) (Figure 1). Two hundred fifty-four respondents (83.5%) reported using either lidocaine or prilocaine (no-bupivacaine group). The demographic profile and liposuction practices of the bupivacaine group were comparable to those of the no-bupivacaine group. Although 36% of the no-bupivacaine group did not know or had no opinion on when it is appropriate to use bupivacaine in liposuction (Figure 2), 85% of this group use bupivacaine in other pain control modalities. There were no reports of bupivacaine toxicity in 2011. The only cases of toxicity reported were associated with lidocaine use in wetting solutions.Figure 1: Percentage of respondents by local anesthetic used in wetting solution.Figure 2: Comparison of the opinions of bupivacaine use in respondents who do not use bupivacaine and respondents who use bupivacaine.CONCLUSION: A review of 320 plastic surgeons’ experiences revealed that 7% of respondents are using bupivacaine in their liposuction wetting solutions with no reported cases of toxicity. Bupivacaine users differed dramatically only in their opinion regarding the safety of bupivacaine in tumescent liposuction. Our data support the contention that bupivacaine is no more dangerous than lidocaine when used appropriately. As the field of plastic surgery continues to evolve into an evidence-based field, a rigorous clinical trial documenting the safety and efficacy of bupivacaine in tumescent liposuction with direct comparison to lidocaine would be warranted.

Intra-articular Morphine Versus Bupivacaine for Postoperative Pain Management

The purpose of this study was to determine whether morphine would be as effective as bupivacaine for postoperative pain control after knee arthroscopy with no worsening of the side effect profile. Eighty-two patients who underwent partial meniscectomy, chondral debridement, or both were prospectively randomized to receive 10 mg of morphine (10-cc volume) or 10 cc of .5% bupivacaine immediately postoperatively. Visual analog scale scores and side effect profiles were recorded in the postanesthesia care unit, in the transitional care unit, and then every 4 hours postoperatively until 24 hours. In-hospital data were available for all 82 patients, but postdischarge data were available for only 64 patients. Visual analog scale scores in the postanesthesia care unit decreased from 3.4 on admission to 2.4 on discharge for the morphine group and from 2.6 to 2.4 for the bupivacaine group (P>.217, all time points). Medication use was the same for both groups in the hospital (62% and 78%, respectively) with no statistical difference. Visual analog scale scores decreased from 3.0 to 1.5 for the morphine group and from 2.8 to 1.8 for the bupivacaine group between 4 and 24 hours postoperatively (P>.376, all time points). Medication use decreased between 4 and 24 hours postoperatively for both groups, from 71.7% to 52.9%, respectively, with no statistical difference at all time points. Four patients in the morphine group and 1 patient in the bupivacaine group experienced side effects. This study indicates that 10 mg of intra-articular morphine is as effective as 10 cc of .5% bupivacaine for postoperative pain control for partial meniscectomy and chondral debridement of the knee. It minimally increases side effects initially and circumvents the issue of chondral toxicity of bupivacaine.

Chondrotoxic effect of intraarticular bupivacaine administration

We read the article ‘‘The comparison of intraarticular morphine-bupivacaine and tramadol-bupivacaine in postoperative analgesia after arthroscopic anterior cruciate ligament reconstruction’’ by Hosseini et al. [5] recently published in this journal with great interest. The article describes a randomised, double blind, controlled trial study of ASA I–II patients undergoing arthroscopic ACL reconstruction performed under general anaesthesia who were given a combination of drugs intraarticularly for postoperative analgesia and pain control. Study was approved by the research ethics committees in Shahid Sadoughi University of Medical Sciences, and written informed consents were obtained from 60 male patients. Patients were randomly allocated into three groups. The MB group (n = 20) received 10 mg morphine and 0.5 % bupivacaine, the TB group (n = 20) received 100 mg tramadol and 0.5 % bupivacaine and the control group (n = 20) received 20 ml of isotonic saline intraarticularly at the end of the operation. The authors concluded that intraarticular morphine–bupivacaine combination provides more effective pain relief, longer analgesic duration, less supplemental analgesic postoperative requirements, shorter unassisted ambulation and discharge time when compared to intraarticular tramadol–bupivacaine injection and isotonic saline after ACL reconstruction arthroscopy. In side effects assesment, none of the patients had respiratory depression, and there was no significant difference between the groups in terms of nausea and vomiting. It is interesting that there was no mention or even concern of chondrotoxic effect of bupivacaine in this article. Chu et al. [4] have shown in 2006 that 0.5 % bupivacaine solution is cytotoxic to bovine articular chondrocytes and articular cartilage in vitro after only 15–30 min exposure. The authors suggested caution in the intraarticular use of 0.5 % bupivacaine. Toxicity of bupivacaine was demonstrated on human articular chondrocytes too [6]. Piper et al. compared the in vitro viability after exposure of full-thickness knee cartilage explants and cultured chondrocytes to 0.9 % normal saline solution, 0.5 % ropivacaine and 0.5 % bupivacaine, respectively, after 30 min. Chondrocyte viability in cartilage explants and the viability of cultured chondrocytes were significantly lower after treatment with bupivacaine as compared to ropivacaine. A few years later, in vivo animal study was conducted to determine whether a single intraarticular injection of 0.5 % bupivacaine results in chondrocyte morbidity and rapid chondrolysis [3]. Reduced chondrocyte density without cartilage tissue loss 6 months after a single intraarticular injection of 0.5 % bupivacaine suggested bupivacaine toxicity. The effects of bupivacaine were milder than those of an injection of 0.6 % monoiodoacetate (positive control), which resulted in chondrolysis over the same time period. As the risk of chondrotoxic effect of bupivacaine clearly exists, we would like to know why the adverse effect of bupivacaine was completely ignored in the article. Unfortunately, period of time when the study has been conducted was not specified in the Hosseini et al. [5] article. We are curious if the authors were aware of the adverse chondrotoxic effect of bupivacaine and if it was mentioned in the N. V. Filipcic (&) Department of Anaesthesiology and Intensive Care, University Hospital Merkur, Zagreb University, Zajceva 19, 10000 Zagreb, Croatia e-mail: natashav7@gmail.com

Bupivacaine Induces Short-Term Alterations and Impairment in Rat Tendons

Background: Toxicity of the local anesthetic bupivacaine (BV) has been a matter of debate across medical fields. Numerous in vitro studies demonstrate considerable toxicity of BV on various cell types. Purpose: This study addresses the question of how tendon tissue responds to BV in vivo and in vitro. Study Design: Controlled laboratory study. Methods: In vitro studies on cultured rat Achilles tendon–derived cells were performed with cell viability assays and cleaved caspase 3 immunocytochemistry. Quantitative reverse transcription–polymerase chain reaction, Western blotting, gelatin zymography, and a biomechanical testing routine were applied on rat Achilles tendons at 1 and 4 weeks after a single unilateral peritendinous injection of 0.5% BV. The BV-mediated cell death in tendons was estimated with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and immunohistochemical detection of cleaved caspase 3. Results: Treatment of rat tendon–derived cells with 0.5% bupivacaine for 10 minutes had detrimental effects on cell viability, which can be reduced by N-acetyl-L-cysteine or reduction of extracellular calcium. In vivo, single peritendinous injections of BV caused apoptosis in endotenon cells and an increase of pro–matrix metalloproteinase-9 after 6 hours. The collagen ratio shifted toward collagen type III after 6 hours and 2 days; scleraxis messenger RNA (mRNA) expression was reduced by 87%. Maximum tensile load was reduced by 17.6% after 1 week. Conclusion: Bupivacaine exerts a severe, reactive oxygen species–mediated effect on tendon cell viability in vitro in a time- and dose-dependent manner, depending on extracellular calcium concentration. Culture conditions need to be taken into account when in vitro data are translated into the in vivo situation. In vivo, administration of BV elicits a marked but temporary functional damage. Clinical Relevance: Local anesthetics cause short-term alterations in rat tendons, which, if occurring in humans to a similar extent, may be relevant regarding decreased biomechanical properties and increased vulnerability to tendon overload or injury.

Effect of lipid emulsion on the central nervous system and cardiac toxicity of bupivacaine and levobupivacaine in awake rats

Despite numerous studies examining the effect of lipid emulsion on bupivacaine-induced cardiac toxicity, few studies have examined its effect on central nervous system (CNS) toxicity of local anesthetics. We investigated the effect of lipid emulsion on the CNS and cardiac toxicity of bupivacaine and levobupivacaine in awake, spontaneously breathing rats. Male Sprague-Dawley rats were randomly allocated to control-bupivacaine (CB), control-levobupivacaine (CL), lipid-bupivacaine (LB), and lipid-levobupivacaine (LL) groups (n = 8 in each group). After infusion of saline (CB and CL groups) or 20 % lipid emulsion (LB and LL groups) for 5 min, bupivacaine (CB and LB groups) or levobupivacaine (CL and LL groups) was administered IV at 1 mg/kg/min. Cumulative dose of anesthetics and their plasma concentrations at the onset of convulsions and cardiac arrest were measured. The doses of bupivacaine for inducing convulsions and cardiac arrest in the LB group (8.8 ± 1.7 and 10.2 ± 1.5 mg/kg, respectively) were significantly larger than those in the CB group (5.9 ± 1.1 and 7.1 ± 1.3 mg/kg, respectively, p < 0.001 for both). The doses of levobupivacaine for inducing convulsions and cardiac arrest in the LL group (10.0 ± 2.0 and 13.7 ± 3.6 mg/kg, respectively) were significantly larger than those in the CL group (7.7 ± 1.6 and 9.4 ± 2.4 mg/kg, p = 0.03 and p = 0.02, respectively). Plasma concentrations of bupivacaine at the onset of convulsions and cardiac arrest in the LB group (12.9 ± 2.9 and 41.4 ± 5.2 μg/ml, respectively) were significantly higher than those in the CB group (7.9 ± 1.2 and 21.6 ± 3.3 μg/ml, respectively, p < 0.001 for both). Plasma concentrations of levobupivacaine at the onset of convulsions and cardiac arrest in the LL group (17.5 ± 1.5 and 47.6 ± 6.1 μg/ml, respectively) were significantly higher than in the CL group (10.9 ± 2.2 and 29.2 ± 3.5 μg/ml, respectively, p < 0.001 for both). Lipid emulsion decreased CNS and cardiac toxicity of both bupivacaine and levobupivacaine.

The Effect of Lipid Emulsion on Pharmacokinetics and Tissue Distribution of Bupivacaine in Rats

While lipid emulsion may reverse the systemic toxicity of bupivacaine, the pharmacokinetics and tissue distribution of bupivacaine after lipid emulsion infusion are not clear. In this study, we assessed the influence of lipid emulsion administration on the pharmacokinetics and tissue distribution of bupivacaine. Rats in the lipid group were administered IV bupivacaine at the rate of 2 mg·kg(-1)·min(-1) for 4 minutes, and then were treated with an infusion of 30% lipid emulsion at the rate of 3 mL·kg(-1)·min(-1) for 5 minutes; saline was substituted in the control group (n = 6 for pharmacokinetics). We then randomly assigned 100 rats into the lipid group and control group (n = 50 for distribution). The toxicity model and treatment were the same as the pharmacokinetic portion. Plasma and tissues including brain, heart, liver, spleen, lung, kidney, omentum, and muscle were collected. The plasma concentration and tissue content of bupivacaine were measured by a liquid chromatography-tandem mass spectrometric method. A 2-compartmental analysis was performed to calculate the pharmacokinetics of bupivacaine. All data are shown as mean ± SD. After treatment with the lipid emulsion, t1/2β of bupivacaine in the lipid group was significantly shorter (110 ± 25 minutes vs 199 ± 38 minutes, P = 0.001), the clearance was higher (14 ± 4 mL·mg(-1)·kg(-1) vs 9 ± 4 mL·mg(-1)·kg(-1), P = 0.038), and the t1/2α was longer than that of the control group (4 ± 1 minutes vs 2 ± 1 minutes, P = 0.014); the K12 in the lipid group was less than that of the control group (0.13 ± 0.04 vs 0.32 ± 0.13, P = 0.011). In the lipid group, the bupivacaine content in heart, brain, lung, kidney, and spleen was lower than that in the control group, but higher in the liver at 20, 30, and 45 minutes. The lipid sink phenomenon was observed in this study. The use of a lipid emulsion accelerated the elimination of bupivacaine.

Comparing Resuscitative Measures for Bupivacaine Toxicity Utilizing Lipid Emulsions in a swine model(Sus scrofa)

Comparing Resuscitative Measures for Bupivacaine Toxicity Utilizing Lipid Emulsions in a swine model(Sus scrofa) A toxic dose of bupivacaine causes cardiac arrhythmias and ultimately asystole. Resuscitation is difficult and almost always unsuccessful. Until recently, cardiopulmonary bypass was the only effective treatment. Anecdotal evidence suggests that infusion of lipid emulsion may be an effective treatment. No studies have determined the optimal combination of lipid rescue and traditional Advanced Cardiac Life Support (ACLS) therapy for a toxic dose of bupivacaine. The purpose was to determine the optimal combination of lipid rescue and traditional ACLS therapy for treatment overdose of bupivacaine.

Abstract 19275: T-type Calcium Channel Overexpression in Mice Attenuates Recovery from Bupivacaine-Induced Cardiac Arrest

Background _ The cardiotoxicity from the local anesthetic bupivacaine is predominantly a result of sodium channel blockade, though calcium channel inhibition has been implicated as well. Mechanisms of reversal of this cardiotoxicity are unclear. We investigated the toxicity of bupivacaine on FVB isolated mouse hearts that were either wild type (WT) or overexpressors for T-type calcium channel (TTCC). We subsequently attempted reversal of cardiotoxicity with a combination of intralipid and epinephrine. We hypothesized that the increased calcium metabolism of the transgenic hearts would augment the adverse effects of bupivacaine. Methods and Results _ Hearts from anesthetized WT and transgenic FVB mice aged 4 months were excised and placed on a Langendorff perfusion apparatus. The left atrial auricle was excised, the mitral valve was perforated, and a fluid-filled balloon was placed in the left ventricle to capture left ventricular pressure and heart rate data. After 10 min of baseline perfusion at an EDP of 10mmHg, bupivacaine was added at 100μM, causing arrest of cardiac activity for both mouse lines. After 3 min of cardiac arrest, the heart was perfused with a solution of bupivacaine (30μM), intralipid (0.2%) and epinephrine (0.15μg/ml) with cardiac recovery following. At baseline, there were no differences in left ventricle function between WT and transgenic mice. After recovery, the left ventricle end diastolic pressure in the transgenic mice was significantly higher (29.18 ± 4.05 mm Hg) than in the WT mice (17.15 ± 0.83 mmHg), P=0.02). Furthermore, the left ventricle developed pressure was significantly reduced (P=0.03) in the transgenic mice (28.61 ± 5.966 mmHg) when compared to WT (57.17 ± 8.052 mmHg). When incorporating heart rate, the Rate Pressure Product (HR x LVESP) was significantly decreased (P=0.03) in the transgenic mice (6455 ± 748.3) versus the WT (11396 ± 1646). Electrophysiological analysis revealed significantly increased suppression of calcium current in the L Type Calcium Channel (P=0.03) Conclusions _ These data show that bupivacaine-induced cardiotoxicity is more difficult to reverse in hearts overexpressing TTCC, possibly reflecting a stronger inhibition of Calcium release from the Sarcoplasmic Reticulum in them.

Lipid Emulsion Infusion

It seems implausible that an injection of a simple, off-the-shelf, intravenous nutritional solution could be acutely life-saving for a patient with severe drug overdose. Yet, dozens of published case reports support this observation, first made more than a decade ago in a rodent model of bupivacaine toxicity. It is even more surprising that such a simple formulation can rapidly reverse severe clinical toxicity from a variety of vastly disparate medications with distinct pharmacodynamics and mechanisms of action. This review will focus on the clinical application of lipid emulsion therapy in resuscitation from drug-related toxicity and provide an introduction to the development of the method, guidelines for its use and insights into potential controversies and future applications.

Thermal Stress Potentiates Bupivacaine Chondrotoxicity

The primary objective of this study was to determine whether thermal stress potentiates the chondrotoxic effect of bupivacaine, resulting in decreased articular chondrocyte viability compared with exposure to bupivacaine alone. Bovine articular cartilage explants and cultured chondrocytes were treated with a range of thermal exposures (10 to 20 minutes at 37°C to 65°C) to create time/temperature viability curves and to determine threshold conditions for cell death. A second set of experiments was performed to determine whether subthreshold thermal stress potentiates bupivacaine toxicity. Explants were exposed to 37°C or 55°C for 10 or 20 minutes, and cultured chondrocytes were exposed to 37°C or 45°C for 10 or 20 minutes. Thirty minutes later, the explants and chondrocytes were treated with either 0.9% normal saline solution or 0.5% bupivacaine for 30 minutes. Chondrocyte viability was quantified 24 hours after treatment. There was a temperature- and time-dependent decrease in chondrocyte viability above the thermo-toxicity threshold in both intact cartilage explants and cultured chondrocytes (55°C and 45°C, respectively; P < .05). Chondrocyte viability in cartilage explants was significantly lower after treatment with thermal stress for 10 or 20 minutes followed by bupivacaine for 30 minutes compared with treatment with bupivacaine at 37°C (bupivacaine and 55°C for 10 minutes, 0.09% ± 0%; bupivacaine and 55°C for 20 minutes, 0.08% ± 0%; bupivacaine and 37°C for 10 minutes, 37.4% ± 1.2% [P < .001]; and bupivacaine and 37°C for 20 minutes, 47.1% ± 0.8% [P < .001]). A similar trend was seen in cultured chondrocytes, although it was not statistically significant (P > .05). Thermal stress potentiates the chondrotoxic effects of bupivacaine in intact cartilage, leading to decreased chondrocyte viability compared with exposure to bupivacaine alone. Intra-articular injection of bupivacaine after arthroscopic procedures during which cartilage is exposed to elevated temperatures, such as with prolonged use of radiofrequency probes, may increase the risk of chondrocyte toxicity.

Hemodynamic changes in lipid emulsion therapy (SMOFlipid) for bupivacaine toxicity in swines

To evaluate the hemodynamic changes following SMOFlipid emulsion therapy with after bupivacaine intoxication in swines. Large White pigs were anesthetized with thiopental, tracheal intubation was performed and mechanical ventilation was instituted. Hemodynamic variables were recorded with invasive pressure monitoring and pulmonary artery catheterization (Swan-Ganz catheter). After a 30-minute resting period, 5 mg.kg(-1) of bupivacaine by intravenous injection was administered and new hemodynamic measures were performed 1 minute later; the animals were than randomly divided into two groups and received 4 ml.kg(-1) of saline solution or 4 ml.kg(-1) of SMOFlipid emulsion 20%. Hemodynamic changes were then re-evaluated at 5, 10, 15, 20 and 30 minutes. Bupivacaine intoxication caused fall in arterial blood pressure, cardiac index, ventricular systolic work index mainly and no important changes in vascular resistances. SMOFlipid emulsion therapy was able to improve blood pressure mainly by increasing vascular resistance since the cardiac index had no significant improvement in our study. Hemodynamic results of the use of lipid emulsion in bupivacaine intoxication were better than the control group. The SMOFlipid emulsion is a option for reversing hypotension in cases of intoxication by bupivacaine.

Fatality Involving Complications of Bupivacaine Toxicity and Hypersensitivity Reaction*

This case represents unusual findings of elevated bupivacaine and tryptase concentrations following local anesthetic, bupivacaine, administered as a scalene nerve block for elective rotator cuff repair surgery. Following bupivacaine injection, the patient exhibited almost immediate seizure activity, bradycardia, and cardiac arrest. Resuscitative efforts including cardiopulmonary bypass restored a cardiac rhythm. However, the clinical medical status of the patient progressively declined and he died 7 h following administration of the local anesthetic. Autopsy revealed several abnormalities of the heart including cardiomegaly, myocardial bridging, and lipomatous hypertrophy of the intraatrial septum, which may have contributed to bradycardia and arrhythmia. Postmortem toxicology results revealed elevated bupivacaine and tryptase concentrations. Elevated postmortem bupivacaine concentrations 7 h following administration and abrupt onset of seizures indicate unintentional intravascular injection instead of nerve and tissue infiltration. An elevated postmortem tryptase concentration points to the possibility of a hypersensitivity reaction to bupivacaine.

Cauda equina syndrome following combined spinal and epidural anesthesia: a case report

To describe a case of complete neurological recovery from cauda equina syndrome lasting ten months following spinal anesthesia with 0.5% hyperbaric bupivacaine and epidural anesthesia with ropivacaine, and to discuss the possible mechanisms involved. A 79-yr-old man with Paget's disease was scheduled for surgery to remove a skin tumour below his scrotum. He had no history of radicular pain or back pain and no pre-existing neurologic disorder. Surgery was performed with the patient in the supine position. He received 0.5% hyperbaric bupivacaine intrathecally for the procedure and ropivacaine through an epidural catheter for postoperative pain management. After catheter removal, the patient developed urinary retention, fecal incontinence, and perianal hypoesthesia. A lumbosacral magnetic resonance imaging (MRI) revealed no tumour, infarction, degeneration, spinal stenosis, or compression on the cauda equina nerve roots. A diagnosis of cauda equina syndrome was made, and the etiology was thought to be toxicity of bupivacaine either alone or in combination with ropivacaine. After three months, the patient reported some return of sensation at the perianal area, with complete resolution at four months. At the ten-month follow-up visit, the patient had recovered from his urinary retention and fecal incontinence. This case suggests that spinal anesthesia, even with an ordinary dose of hyperbaric 0.5% bupivacaine, might induce cauda equina syndrome in older patients.

Successful reversal of bupivacaine and lidocaine-induced severe junctional bradycardia by lipid emulsion following infraclavicular brachial plexus block in a uremic patient

Cardiac toxicity of bupivacaine has long been documented and it could be potentiated in certain circumstances, such as preexisting cardiac conduction abnormality or uremic status. The concept that lipid emulsion acts as a rescue of bupivacaine’s toxicity has prevailed pending universal recognition. Herein, we report the successful use of lipid to resuscitate a female uremic patient who sustained junctional bradycardia while she was receiving ultrasound-guided infraclavicular brachial plexus block with the dose of local anesthetics far below the currently recommended maximum one. The possible mechanisms for the occurrence of cardiotoxicity in this case are discussed and the role of lipid emulsion as a treatment is reviewed.

Temporal changes in bupivacaine kinetics.

The chronokinetics of bupivacaine have been examined in the mouse. Different groups of adult male NMRI mice maintained under controlled environmental conditions received a single intraperitoneal injection of bupivacaine (20 mg kg-1) at one of four different fixed time points in a 24 h period i.e. 10:00, 16:00, 22:00 and 04:00 h. Blood samples were taken 0.25, 0.5, 0.75, 1, 1.5, 3, 4 and 6 h after drug administration and total serum levels of bupivacaine were determined by a gas-liquid chromatography with a flame ionization detector. Statistically significant temporal changes were found in the following pharmacokinetic parameters: highest Cmax value = 0.900 +/- 0.080 micrograms mL-1 at 22:00 h (amplitude, maximum-minimum/mean X 100, is 64%); highest Cmax/Tmax ratio = 3.596 +/- 0.339 at 22:00 h (amplitude = 85%); highest beta elimination half-life, T1/2 beta, = 3.950 +/- 0.246 h at 22:00 h (amplitude = 35%); area under concentration curve (AUC infinity 0) was not found to be significantly different among the hours of administration. The temporal kinetic changes demonstrated suggest a possible circadian difference in bupivacaine efficacy and/or toxicity.

Systemic dextromethorphan and dextrorphan are less toxic in rats than bupivacaine at equianesthetic doses

Dextrorphan, a major metabolite of dextromethorphan, produces the duration of spinal and cutaneous anesthesia similar to bupivacaine. The purpose of this study was to test the central nervous system and cardiovascular toxicity of bupivacaine, dextromethorphan, and dextrorphan. First, dose-response curves for dextromethorphan, dextrorphan, and bupivacaine (n = 8 at each testing point) were determined for cutaneous analgesia on the rat back, and equipotent doses were calculated. Next, during continuous intravenous infusion of equipotent doses of bupivacaine, dextromethorphan, and dextrorphan (n = 8 in each group), we observed the time to seizure, apnea, and complete cardiac arrest. A saline group (n = 7) was used for comparison. Mean arterial blood pressure (MAP), heart rate (HR), stroke volume (SV), and cardiac output (CO) were also monitored. Bupivacaine, dextromethorphan, and dextrorphan produced dose-dependent cutaneous anesthesia. A longer duration of equipotent infusion doses was required to produce seizures in the dextromethorphan group (10.6 ± 1.3 min) than in the bupivacaine group (7.6 ± 2.1 min) (P = 0.005). Dextrorphan did not produce any seizures. Compared with bupivacaine, time to apnea and complete cardiac arrest was longer with dextrorphan (P < 0.001) and with dextromethorphan (P = 0.001). Cardiovascular collapse, defined as a decline in MAP, HR, CO, and SV, was slower in the dextromethorphan and dextrorphan groups than in the bupivacaine group (P < 0.001 for both comparisons). At equipotent doses for local anesthesia, dextromethorphan and dextrorphan were less likely than bupivacaine to induce central nervous system and cardiovascular toxicity.

Effect of hypertonic saline on electrocardiography QRS duration in rabbit model of bupivacaine toxicity resuscitated by intravenous lipid

Intravenous lipid emulsion is established therapy for bupivacaine induced cardiotoxicity. The benefit of combined hypertonic saline and lipid treatment is unexplored. In this experiment, sedated rabbits were resuscitated from bupivacaine-induced asystole with intravenous lipid according to the Association of Anaesthetists of Great Britain and Ireland's guideline, or by identical lipid dosing with hypertonic saline: 6 mEq x kg(-1) 21% sodium chloride. Early electrocardiography QRS prolongation was less with lipid plus hypertonic saline (mean (SD) QRS 0.19 (0.07) s lipid only vs 0.09 (0.01) s lipid plus hypertonic saline; p = 0.003) at 9 min though not different from the lipid only group at 20 min. No difference was observed in rates of circulatory return (7/10 lipid only and 9/10 lipid plus hypertonic saline; p = 0.58) or survival (5/10 lipid only and 6/10 lipid plus hypertonic saline; p = 1.00). Some benefit to cardiac conduction may be afforded by hypertonic saline co-administered with lipid emulsion in bupivacaine-induced cardiotoxicity.

Bupivacaine causes cytotoxicity in mouse C2C12 myoblast cells: involvement of ERK and Akt signaling pathways

The adverse effects of local anesthetics (LAs) on wound healing at surgical sites have been suggested, and may be related to their cytotoxicity. This study was aimed to compare the cellular toxicity of bupivacaine and lidocaine (two well-known LAs), and to explore the molecular mechanism(s). Toxicity of bupivacaine and lidocaine was assessed in cultured mouse C2C12 myoblasts by cell viability and apoptosis assays. Effects of LAs on extracellular signal-regulated kinase (ERK) and protein kinase B (Akt) activation, which are essential for cell proliferation and survival, were evaluated by immunoblotting. Both LAs, especially bupivacaine, prevented cell growth and caused cell death in a dose-dependent manner. The half maximal inhibitory concentrations (IC(50)) for bupivacaine and lidocaine were 0.49+/-0.04 and 3.37+/-0.53 mmol/L, respectively. When applied at the same dilutions of commercially available preparations, the apoptotic effect induced by bupivacaine was more severe than that of lidocaine in C2C12 cells. Furthermore, bupivacaine significantly diminished the ERK activation, which may underlie its anti-proliferative actions. Both LAs suppressed Akt activation, which correlated with their effects on apoptosis. Our study demonstrated that, when used at the same dilutions from clinically relevant concentrations, bupivacaine is more cytotoxic than lidocaine in vitro. Anti-proliferation and cell death with concomitant apoptosis mediated by bupivacaine may offer an explanation for its adverse effects in vivo (eg slowing wound healing at the surgical sites). A less toxic, long-acting anesthetic may be needed.

In Vivo Effects of Single Intra-Articular Injection of 0.5% Bupivacaine on Articular Cartilage

Single intra-articular injections of local anesthetics are commonly used clinically. Recent in vitro studies have demonstrated chondrotoxic effects of local anesthetics, with the greatest emphasis on bupivacaine toxicity. This in vivo study was conducted to determine whether a single intra-articular injection of 0.5% bupivacaine results in chondrocyte morbidity and rapid chondrolysis. Forty-eight Sprague-Dawley rats received a 100-microL injection of sterile 0.9% saline solution (negative control) into one stifle joint and 100 microL of either preservative-free 0.5% bupivacaine (experimental group) or 0.6 mg/mL monoiodoacetate (positive control) into the contralateral joint. The rats were killed at one week, four weeks, twelve weeks, or six months. Live and dead cells were quantified with use of three-dimensional confocal reconstructions of fluorescent-stained tissues at standardized locations on the distal part of the femur. Histological findings were graded with use of a modified Mankin score, and cell density was quantified with use of custom image-analysis software. In the specimens injected with bupivacaine, the chondral surfaces remained intact as seen with gross and histological examination. No differences in superficial chondrocyte viability or modified Mankin scores were observed between the saline-solution and bupivacaine groups at any location or time point (p > 0.05). Quantitative histological analysis of the bupivacaine-treated knees at six months revealed an up to 50% reduction in chondrocyte density compared with that of the saline-solution-treated knees (p < or = 0.01). Monoiodoacetate injection resulted in death of up to 87% of the superficial chondrocyte cells at one week and chondrolysis at six months. Despite severe histological abnormalities by four weeks after monoiodoacetate injection, cartilage injury was not evident on gross inspection until six months. This in vivo study showing reduced chondrocyte density without cartilage tissue loss six months after a single intra-articular injection of 0.5% bupivacaine suggests bupivacaine toxicity. The effects of bupivacaine were milder than those of an injection of 0.6% monoiodoacetate, which resulted in chondrolysis over the same time period.

Lipid rescue for bupivacaine toxicity during cardiovascular procedures

Bupivacaine toxicity is a recognized complication of procedures done under local anesthetic infiltration. While local anesthetic toxicity is rare, it is potentially catastrophic and life-threatening.1 A 20% lipid emulsion has been used to resuscitate patients after bupivacaine overdose or inadvertent intravascular injection.2–7 While the use of lipid emulsion for local anesthetic toxicity has been reported extensively in the anesthesia literature,8 it has not yet been reported in the cardiology literature. We report a case of local anesthetic toxicity resulting in pulseless electrical activity during an electrophysiology procedure that was successfully treated by infusion of 20% lipid emulsion.