Bupivacaine-induced Cardiac Arrest Research Articles

Intralipid fails to rescue bupivacaine-induced cardiotoxicity in late-pregnant rats.

BackgroundFemales routinely receive bupivacaine for obstetric and regional anesthesia. An accidental overdose of bupivacaine can result in cardiotoxicity and cardiac arrest. Intralipid (ILP) rescues bupivacaine-induced cardiotoxicity in male rats. However, bupivacaine cardiotoxicity and ILP rescue have not been studied in non-pregnant and late-pregnant female rats. Here, we tested the hypothesis that an appropriate dose of ILP would rescue non-pregnant and late-pregnant rats from bupivacaine-induced cardiotoxicity.MethodsNon-pregnant (n = 6) and late-pregnant (n = 7) female rats received intravenous bupivacaine (10-mg/kg bolus) to induce asystole. Resuscitation with 20% ILP (5-ml/kg actual body weight, single bolus, and 0.5-ml/kg/min maintenance) and chest compressions were continued for 10-min. Serial heart rate (HR), left ventricular ejection-fraction (LVEF%), and LV-fractional shortening (LVFS%) were recorded at baseline and 10-min after bupivacaine-induced cardiac arrest. Data are mean ± SD followed by 95% CI. P-values < 0.05 were considered statistically significant.ResultsAll rats developed cardiac arrest within a few seconds after bupivacaine. All non-pregnant rats were successfully rescued by ILP, with a HR of 280 ± 32 bpm at baseline vs. 212 ± 18 bpm at 10-min post ILP (p < 0.01), LVEF of 70 ± 6% vs. 68 ± 5% (p = ns), and LVFS of 41 ± 5% vs. 39 ± 4% (p = ns). Interestingly, 6 out of 7 late-pregnant rats did not recover with ILP. Baseline HR, LVEF and LVFS for late-pregnant rats were 330 ± 40 bpm, 66 ± 5% and 38 ± 4%, respectively. At 10-min post ILP, the HR, LVEF, and LVFS were 39 ± 102 bpm (p < 0.0001), 8 ± 22% (p < 0.0001), and 5 ± 12% (p < 0.001), respectively.ConclusionsILP successfully rescued bupivacaine-induced cardiac arrest in non-pregnant rats, but failed to rescue late-pregnant rats.

Dexmedetomidine enhances tolerance to bupivacaine cardiotoxicity in the isolated rat hearts: alpha 2 adrenoceptors were not involved

BackgroundDexmedetomidine was proved to mitigate bupivacaine-induced cardiotoxicity but mechanism of this ability is still unclear. This study was designed to investigate the direct effects of dexmedetomidine on cardiotoxicity induced by bupivacaine on Langendorff rat heart preparation and the role of alpha 2 adrenoceptors in this process was explored.MethodsHearts of rat were isolated, mounted on a Langendorff system. Five experimental groups were assessed after 10 min Krebs-Henseleit buffer (KHB) infusions as follow: (1) Group Con, only KHB was perfused; (2) Group Dex, KHB was perfused for 5 min, then dexmedetomidine (10 nmol/L) was added; (3) Group Bupi, KHB was perfused for 25 min, then bupivacaine (50 μmol/L) was added; (4) Group Bupi + Dex, KHB was perfused for 5 min, then the dexmedetomidine (10 nmol/L) was added for 20 min, at last a mixture of KHB + dexmedetomidine + bupivacaine were perfused; (5) Group Bupi + Dex + Yoh, a combination of KHB + yohimbine (alpha 2 adrenoceptor antagonists, 1 μmol/L) was perfusion for 5 min, then dexmedetomidine (10 nmol/L) was added for 20 min, at last a mixture of KHB + yohimbine + dexmedetomidine + bupivacaine was perfused. The experimental perfusion was maintained for 35 min in group Con and group Dex, and the experimental perfusion was sustained until asystole in the other three groups.ResultsCompared with group Bupi, dexmedetomidine significantly increased the time to first arrhythmia (P < 0.001) and time to asystole (P < 0.001) in group Bupi + Dex. In addition, dexmedetomidine also significantly increased the time to 25, 50 and 75% reductions in heart rate (P < 0.001) and the time to 25, 50 and 75% reductions in rate-pressure product (P < 0.001) in group Bupi + Dex. Dexmedetomidine increased the cardiac tissue bupivacaine content when asystole (Bupi + Dex vs. Bupi, 58.5 ± 6.3 vs. 46.8 ± 5.6 nmol/g, P = 0.003). The benefit of dexmedetomidine on bupivacaine-induced cardiotoxicity were not eliminated by yohimbine.ConclusionsDexmedetomidine could delay the occurrence of bupivacaine-induced arrhythmia and asystole in the isolated rat hearts, but the alpha 2 adrenoceptors were not involved in this process.

Levosimendan is superior to epinephrine on coronary flow for lipid-base resuscitation of bupivacaine-induced asystole in the isolated rat heart

BackgroundSuccessful resuscitation from asystole induced by bupivacaine requires the reestablishment of a sufficient coronary flow (CF) quickly. This study was designed to test whether levosimendan was superior to epinephrine in the reestablishment of crucial coronary flows after bupivacaine-induced asystole.MethodsThe isolated, perfused, nonrecirculating, Langendorff rat heart preparation was used. Bupivacaine 100 μmol/L was perfused into rat hearts to induce asystole, and then for 3 min thereafter. Three experimental groups were assessed after asystole with infusions as follow: (1) a mixture of 2% lipid emulsion and 40 μmol/L bupivacaine (control group), (2) a mixture of 0.15 μg/mL epinephrine combined with 2% lipid emulsion and 40 μmol/L bupivacaine (epinephrine group), and (3) a mixture of 5 μmol/L levosimendan combined with a 2% lipid emulsion and 40 μmol/L bupivacaine mixture (levosimendan group). Coronary flow (CF), the time to recovery (Trecovery), the number of ventricular arrhythmias, and cardiac function parameters were recorded for 40 min after heartbeat recovery.ResultsAll hearts in the control, epinephrine and levosimendan groups had heartbeat recovery. The rank order of the mean CF from highest to lowest was the levosimendan group > the epinepgrine group > the control group (P < 0.05). The rank order of Trecovery from shortest to longest was the levosimendan group < the epinephrine group < the control group (P < 0.01). During the recovery phase, isolated rat hearts developed more ventricular arrhythmias in the epinephrine group than in the levosimendan group (P = 0.01).ConclusionLevosimendan is superior to epinephrine in producing higher CFs and faster recovery when reversing bupivacaine-induced asystole in the isolated rat hearts.

Abstract 21323: Intralipid Fails to Rescue Bupivacaine-Induced Cardiac Arrest in Pregnant Rats

Background: Pregnant patients routinely get neuraxial anesthesia. Bupivacaine is one of the most commonly used local anesthetics in obstetric anesthesia. Studies have suggested that pregnancy increases Bupivacaine cardiotoxicity. We and others have previously shown that Intralipid (ILP) rescues the heart from Bupivacaine cardiotoxicity in male rats. ILP mediates its cardioprotective effects via glycogen synthase kinase-3b (GSK-3b) phosphorylation. We aimed to investigate Bupivacaine cardiotoxicity and potential for ILP’s rescue in pregnant rats, that has not been studied before. Methods: Late pregnant rats (200-300 g, n=12) at day 20 of pregnancy were used for the study. A group of pregnant rats received Bupivacaine bolus (10 mg/kg, IV over ~20 seconds, n=7) to induce asystole under anesthesia. Resuscitation with ILP 20% (5 ml/kg bolus, and 0.5 ml/kg/min maintenance, n=7) and chest compressions were initiated. The ejection-fraction (EF%), and heart rate (HR) were calculated from echocardiography and EKG at baseline and at 1, 5, and 10 min after ILP treatment. A group of pregnant rats that did not undergo Bupivacaine-induced cardiac arrest and ILP rescue served as sham controls (n=5). Hearts were collected and Western blot was performed to assess GSK-3b phosphorylation. Results: All 7 late pregnant rats developed cardiac arrest a few seconds after Bupivacaine. Interestingly, 6 out of the 7 rats were not rescued with ILP using the same dose as in male rats. In these 6 rats, the average baseline EF and HR were 67.344.47% and 34130.44 bpm. One, five and ten minutes after ILP administration, the EF and HR were 0. Western blots showed that pregnant rats which were not rescued by ILP failed to have GSK-3b activation (pGSK/GSK=0.80±0.51 vs. 1.00±0.56 in late pregnant sham controls; p=0.578). In the late pregnant rat that recovered with ILP, baseline EF and HR (66.302.99% and 31034 bpm), were not different than the rats that did not recover. Conclusions: ILP failed to rescue Bupivacaine-induced cardiac arrest in pregnant rats. This failure of rescue is most likely attributed to the inability of ILP to activate GSK-3b, a known mediator of ILP’s cardioprotection.

Protective Effect of Emulsified Isoflurane Preconditioning on Cardiac Toxicity Induced by Bupivacaine in Rats

Background: Lipid emulsion has been identified as a potent rescuing agent for cardiac arrest caused by local anesthetic overdose. In this animal study, we investigated whether prophylactic infusion of emulsified isoflurane, a mixture of lipid emulsion and isoflurane, could increase the tolerability for bupivacaine-induced cardiac toxicity.Methods: Rats were randomly assigned to receive one of the following treatments: saline, 30% Intralipid, 4% Emulsified Isoflurane (4% EISO), 2% EISO, 0.5% propofol, 0.25% propofol, inhaled isoflurane plus 30% Intralipid, or inhaled isoflurane plus saline, for 15 minutes. Then 0.75% bupivacaine was infused at the rate of 8 ml/kg/min (n=10 in each group). The time needed to induce cardiac arrest was recorded and the bupivacaine dose was calculated. Another set of rats were intubated for mechanical ventilation and catheterized for invasive arterial pressure monitoring while receiving one of the following sedative pretreatments for 15 minutes: 4% EISO, 0.5% propofol, inhaled isoflurane plus saline, or inhaled isoflurane plus 30% Intralipid (n=10 in each group). Then bupivacaine was infused at the rate of 8 ml/kg/min for 120 seconds (sublethal dose). The hemodynamic parameters were recorded till circulation fully recovered.Results: Pretreatment with 4% EISO significantly increased the dose of bupivacaine required to induce cardiac arrest (68.69±7.57 mg/kg vs. 26.61±5.13 mg/kg for saline, P<0.01). Prophylactic infusion of Intralipid alone also increased the bupivacaine tolerability (51.41±9.68 mg/kg, P<0.05 vs. saline), but less efficient than 4% EISO (P<0.05 vs. 4% EISO). Pretreatments with 4% EISO provided best preservation of hemodynamic parameters in the face of circulatory fluctuation caused by sublethal dose of bupivacaine.Conclusions: The 4% emulsified isoflurane preconditioning significantly increases the threshold of bupivacaine-induced cardiac arrest in rats and prevents circulatory instability caused by sublethal dose of bupivacaine. Our results implicate the potential application of emulsified isoflurane as an adjuvant agent in local anesthesia. Citation: Can-Sheng Gong, Xiao-Jia Wang, Jin Liu, Da-Qing Liao, Ru-Rong Wang, Han Huang, et al. Protective effect of emulsified isoflurane preconditioning on cardiac toxicity induced by bupivacaine in rats. J Anesth Perioper Med 2017; 4: 199-204. doi:10.24015/JAPM.2017.0014This is an open-access article, published by Evidence Based Communications (EBC). This work is licensed under the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium or format for any lawful purpose. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Levosimendan combined with epinephrine improves rescue outcomes in a rat model of lipid-based resuscitation from bupivacaine-induced cardiac arrest

BackgroundThe effectiveness of a combination of a lipid emulsion with epinephrine in reversing local anesthetic-induced cardiac arrest has been confirmed. The combination of a lipid emulsion with levosimendan, was shown to be superior to administration of a lipid emulsion alone with regard to successful resuscitation. In this study, we compared the reversal effects of levosimendan, epinephrine, and a combination of the two agents in lipid-based resuscitation in a rat model of bupivacaine-induced cardiac arrest.MethodsFifty-four adult male Sprague-Dawley rats were subjected to bupivacaine (15 mg·kg−1) –induced asystole and were then randomly divided into 3 groups. A lipid emulsion was used as the basic treatment, and administration of drug combinations varied in each group as follows: (1) levosimendan combined with epinephrine (LiEL); (2) epinephrine (LiE); and (3) levosimendan (LiL). The resuscitation outcomes were recorded and included the rate of return of spontaneous circulation (ROSC) and survival at 40 min, time to first heartbeat, time to ROSC, and cumulative dose of epinephrine. We calculated the wet-to-dry ratio of the lung, blood gas values at 40 min and bupivacaine concentration of cardiac tissue and plasma.ResultsThe rates of ROSC in LiEL and LiE groups were higher than LiL group (P < 0.001; LiEL vs LiL, P = 0.001; LiE vs LiL, P = 0.007). The survival rate in LiEL group was higher than LiE group (P = 0.003; LiEL vs LiE, P = 0.008; LiEL vs LiL, P = 0.001). The time to first heart beat in LiEL group was shorter than LiE, LiL groups. (P < 0.001; LiE vs LiEL, P = 0.001; LiL vs LiEL, P < 0.001). The time to ROSC in LiEL group was shorter than LiE, LiL groups (P < 0.001; LiEL vs LiE, P < 0.001; LiEL vs LiL, P < 0.001). The result was similar for the bupivacaine concentration of cardiac tissue and plasma (cardiac tissue: P = 0.002; plasma: P = 0.011). Furthermore, there were significant differences in the blood-gas values at 40 min, wet-to-dry lung weight ratio, and ratio of damaged alveoli among groups. The LiEL group had the best result for all parameters (P < 0.01, P = 0.008, P < 0.001, respectively). Additionally, significantly less epinephrine was used in the LiEL group (P < 0.001).ConclusionsLevosimendan combined with epinephrine may be superior to either drug alone for lipid-based resuscitation in a rat model of bupivacaine-induced cardiac arrest. The drug combination was associated with a higher survival rate as well as decreased epinephrine consumption and lung damage.

Intralipid Restoration of Myocardial Contractions Following Bupivacaine-Induced Asystole: Concentration- and Time-Dependence In Vitro.

The concentration- and time-response relationships of lipid emulsion (LE; Intralipid) on the recovery of myocardial contractility following bupivacaine (BPV)-induced asystole are poorly defined. After achieving asystole by 500-μM BPV, varied concentrations of LE were applied to determine the recovery of stimulated contractile responses and contractions in the cardiac tissues of guinea pigs at a 1.2-Hz stimulation rate. These experiments were performed with LE in either a recirculating (2%-16%) or washout (nonrecirculating) condition (0.05%-12%) for 60 minutes. The effect of LE itself (0.05%-12%) was examined. Oxfenicine was used to evaluate the metabolic action of LE to reverse asystole. BPV concentrations in solution and myocardial tissues were measured. In the recirculation condition, partial recovery of contractile forces was observed for 60 minutes at 4%, 8%, and 12% LE. A contracture followed after exposure to 16% LE in some asystolic muscles. In the washout experiments, following asystole, LE (0.05%-12%) had no effect on the recovery time of the first and regular contractile responses. LE (0.1%-8%) restored contractility to baseline levels after 45 minutes; partial recovery was shown with lower (0.05%) and higher (12%) concentrations. Oxfenicine did not alter the recovery of contractile forces. Contractile depression was observed with 12% LE alone. Concentration-related reduction of tissue BPV concentration by LE was observed in both circulating conditions. LE induced time- and concentration-dependent recovery of stimulated myocardial contractions from BPV-induced asystole. The lipid uptake effect, along with other undefined mechanisms of LE, seems to contribute to the recovery of contractile function; however, the LE effect on myocardial metabolism is less likely involved at this concentration (500 μM) of BPV.

The protective effect of lipid emulsion in preventing bupivacaine-induced mitochondrial injury and apoptosis of H9C2 cardiomyocytes

Lipid emulsion (LE) has been shown to be effective in the resuscitation of bupivacaine-induced cardiac arrest, but the precise mechanism of this action has not been fully elucidated. Pursuant to this lack of information on the mechanism in which LE protects the myocardium during bupivacaine-induced toxicity, we explored mitochondrial function and cell apoptosis. H9C2 cardiomyocytes were used in study. Cells were randomly divided in different groups and were cultivated 6 h, 12 h, and 24 h. The mitochondria were extracted and mitochondrial ATP content was measured, as was mitochondrial membrane potential, the concentration of calcium ion (Ca2+), and the activity of Ca2+-ATP enzyme (Ca2+-ATPase). Cells from groups Bup1000, LE group, and Bup1000LE were collected to determine cell viability, cell apoptosis, and electron microscopy scanning of mitochondrial ultrastructure (after 24 h). We found that LE can reverse the inhibition of the mitochondrial function induced by bupivacaine, regulate the concentration of calcium ion in mitochondria, resulting in the protection of myocardial cells from toxicity induced by bupivacaine.

L-carnitine reduces susceptibility to bupivacaine-induced cardiotoxicity: an experimental study in rats.

The primary aim of this study was to evaluate the effect of acute administration of L-carnitine 100 mg·kg-1 iv on susceptibility to bupivacaine-induced cardiotoxicity in rats. In the first of two experiments, L-carnitine 100 mg·kg-1 iv (n = 10) or saline iv (n = 10) was administered to anesthetized and mechanically ventilated Sprague-Dawley rats following which an infusion of bupivacaine 2.0 mg·kg-1·min-1 iv was given until asystole occurred. The primary outcome was the probability of survival. Secondary outcomes included times to asystole, first dysrhythmia, and to 50% reductions in heart rate (HR) and mean arterial pressure (MAP). To determine whether the same dose of L-carnitine is effective in treating established bupivacaine cardiotoxicity, we also conducted a second experiment in which bupivacaine 20 mg·kg-1 iv was infused over 20 sec. Animals (n = 10 per group) received one of four iv treatments: 30% lipid emulsion 4.0 mL·kg-1, L-carnitine 100 mg·kg-1, 30% lipid emulsion plus L-carnitine, or saline. The primary outcome was the return of spontaneous circulation (ROSC) during resuscitation. In the first study, L-carnitine 100 mg·kg-1 increased the probability of survival during bupivacaine infusion (hazard ratio, 12.0; 95% confidence interval, 3.5 to 41.5; P < 0.001). In L-carnitine-treated animals, the times to asystole, first dysrhythmia, and to 50% reductions in HR and MAP increased by 33% (P < 0.001), 65% (P < 0.001), 71% (P < 0.001), and 63% (P < 0.001), respectively. In the second study, no animal in the control or L-carnitine alone groups achieved ROSC when compared with the lipid emulsion groups (P < 0.01). These findings suggest that acute administration of L-carnitine 100 mg·kg-1 decreases susceptibility to bupivacaine cardiotoxicity, but is ineffective during resuscitation from bupivacaine-induced cardiac arrest.

The effect of epinephrine on reversing bupivacaine-induced asystole in isolated rat heart

Objective To study the influence of epinephrine on reversing bupivacaine-induced asystole in isolated rat heart. Methods Twenty-four adult male SD rats were randomly divided into four groups according to the table of random number(n=6): group B40, EB40, B50 and EB50. Langendorff isolated heart perfusion model was used. Continuous infusion with 100 μmol/L bupivacaine until asystole had been induced for 3 min, then the model was completed. Group B40, perfused with K-H solution containing 40 μmol/L bupivacaine for 20 min. Group EB40, perfused with K-H solution containing 0.15 mg/L epinephrine and 40 μmol/L bupivacaine for 20 min. Group B50, perfused with K-H solution containing 50 μmol/L bupivacaine for 20 min. Group EB50, perfused with K-H solution containing 0.15 mg/L epinephrine and 50 μmol/L bupivacaine for 10 min, then epinephrine was increased to 0.3 mg/L for 10 min. The situation of recovery of heart beat was recorded and the following cardiac functional parameters were monitored during 20 min perfusion: HR, heart rate-pressure product (RPP) and coronary flow (CF). Results The recovery rate of heart beat(100%) in the group EB40 was higher than which in other groups(0)(P<0.01). The recovery time of heart beat in the group EB40 was (35±9) s and the asystole time after recovery of heart beat was (568±182) s. The CF in the groups EB40 and EB50 were higher compared with the groups B40 and B50 (P<0.01). Conclusions The ability of epinephrine on reversing asystole induced by bupivacaine in isolated rat heart is related to the concentration of bupivacaine. When drug concentration of bupivacaine was 40-50 μmol/L, the ability of epinephrine could not be displayed. Key words: Epinephrine; Bupivacaine; Asystole; Resuscitation

Electroacupuncture pretreatment induces rapid tolerance to bupivacaine cardiotoxicity in rats.

Evidence suggests that electroacupuncture (EA) protects against arrhythmia and myocardial injury induced by myocardial ischaemia-reperfusion. However, to our knowledge, it remains unknown whether EA could alleviate bupivacaine-induced cardiotoxicity. Therefore, we aimed to explore the effect of EA pretreatment on bupivacaine-induced cardiac arrest and outcomes of cardiopulmonary resuscitation (CPR) in rats. 24 adult male Sprague-Dawley rats were randomly divided into two groups: EA (n=12), and minimal acupuncture (MA) (n=12). Rats in both groups were needled at bilateral PC6, ST36, and ST40. Needles in the EA group were electrically stimulated for 60 min. ECG and invasive arterial blood pressure measurements were recorded. Two hours after EA or MA, 10 mg/kg bupivacaine was infused intravenously at a rate of 5 mg/kg/min in all rats. Rats suffering cardiac arrest were immediately subjected to CPR. At the end of the experiment, arterial blood samples were taken from surviving rats for blood gas analysis. The time from bupivacaine infusion until 20% prolongation of the QRS and QT interval, and the time to cardiac arrest, were notably increased among the rats pretreated with EA. Moreover, EA pretreatment significantly improved mean arterial pressure and heart rate at all monitored points after bupivacaine infusion. The proportion of animals surviving was higher in the EA group (9/12) than the MA group (3/12) at the end of experiment (p=0.039). Tolerance to bupivacaine-induced cardiotoxicity appeared to be increased following EA pre-treatment. The mechanism of action underlying the effects of EA on bupivacaine-induced cardiotoxicity requires further investigation.

Epinephrine Administration in Lipid-based Resuscitation in a Rat Model of Bupivacaine-induced Cardiac Arrest

(Reg Anesth Pain Med. 2015;40(3):223–231) The use of lipid emulsion combined with epinephrine is commonly administered during cardiac arrest from local anesthetic overdose. However, the most effective time to administer epinephrine in relation to the lipid emulsion is unknown. Currently, there are no studies that have explored this issue. The authors conducted this study to investigate the effects of epinephrine when administered before, immediately following, and 1 minute after a lipid emulsion bolus.

Abstract 15968: Rescue of Bupivacaine-induced Cardiac Arrest by Lipid Emulsion is Prevented by Inhibition of Free Fatty Acid Receptor GPR40

Introduction: Bupivacaine overdose leads to lethal arrhythmias and cardiac arrest. Lipid emulsion (LE) is cardioprotective and rescues Bupivacaine toxicity. Although both lipid sink and metabolic theories have been proposed, yet the exact molecular mechanism is not known. G protein-coupled receptor 40 (GPR40), also known as free fatty acid receptor-1 is activated by medium and long chain fatty acids. Among free fatty acid receptors, GPR40 expression is one of the highest in heart. Hypothesis: As GPR40 is activated by medium and long chain fatty acids, we hypothesized that GPR40 may mediate LE’s rescue of Bupivacaine cardiotoxicity. Methods: Male Sprague-Dawley rats were used. Continuous Echocardiography and ECG were done. In protocol-1 (n=6), rats received Bupivacaine bolus (10mg/kg, IV) to induce asystole. Resuscitation with LE 20% (5ml/kg bolus, and 0.5ml/kg/min maintenance) and chest compressions were initiated. In Protocol-2 (n=6) rats were pre-treated with GPR40-antagonist GW1100 (200uM, IV) 30-min before inducing asystole. Heart rate (HR) and ejection-fraction (EF) were measured before and 30-min after GW1100. In both protocols, HR, EF and fractional shortening (FS) were measured before asystole (baseline) and at 1, 5 and 10-min after LE. Means±SEM are reported. Results: In protocol-1, baseline HR and EF were 321±21 beats/min and 72.3±4.6%. Bupivacaine resulted in asystole. LE improved HR gradually within 10min; HR was 86±13 at 1min (27% recovery), 216±10 at 5min (67% recovery), and 228±14 at 10min (71% recovery). LV function fully recovered within 5 min of LE treatment as EF and FS were similar to baseline (EF=72±5%, FS=42±4%). To test our hypothesis, rats were pretreated with GW1100, 30-min before inducing asystole. There were no significant differences between HR and EF before (HR=316.6±3.3, EF=68.0±2.3%) and 30-min after GW1100 (HR=330±5.7, EF=71.6±1.5%) excluding GW1100 effects on hemodynamics. GW1100 pre-treatment however prevented LE rescue, with no recovery of cardiac function even after 10min of LE. Conclusions: This is the first report of involvement of GPR40 in rescue of Bupivacaine-induced cardiac arrest by LE. Discovery of GPR40 as a potential receptor for effects of LE may help us understand LE-induced cardioprotection.

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 …

Epinephrine administration in lipid-based resuscitation in a rat model of bupivacaine-induced cardiac arrest: optimal timing.

The medical community commonly uses lipid emulsion combined with epinephrine in local anesthetic-induced cardiac arrest, but the optimal timing of epinephrine administration relative to lipid emulsion is currently unknown and needs to be determined. Thirty adult male Sprague-Dawley rats were subjected to bupivacaine-induced asystole and were then randomly divided into 3 groups. The temporal administration of epinephrine varied in each group: (1) immediately after the completion of the initial bolus of lipid emulsion therapy (postILE0); (2) immediately after cardiac arrest before the initial bolus of lipid emulsion (preILE); or (3) 1 minute after the completion of the initial bolus of lipid emulsion (postILE1). External chest compression was administered until the return of spontaneous circulation or the end of a 20-minute resuscitation period. The postILE0, preILE, and postILE1 groups displayed different survival rates (100%, 30%, and 40%; P = 0.003). After return of spontaneous circulation, the rate-pressure product of the postILE0 group was higher than that of the postILE1 group (P < 0.001). Wet-to-dry lung weight ratio of preILE and postILE1 groups was higher than that of the postILE0 group (P < 0.05). The rate of damaged alveoli of the postILE0 group was lower than those of the preILE (P = 0.001) and postILE1 (P < 0.001) groups. Concentrations of bupivacaine in the cardiac tissues of the postILE0 group were lower than that of the postILE1 group (P = 0.01). In the rat model of bupivacaine-induced cardiac arrest, the optimal timing for the administration of epinephrine to produce best outcomes of successful cardiopulmonary resuscitation is immediately after the completion of the lipid emulsion bolus. This optimal timing/therapeutic window is of paramount importance.

The effect of levosimendan combined with 20% lipid emulsion treatment on survival from bupivacaine induced toxicity in experiment.

Recent reports demonstrated that levosimendan improved post-resuscitation myocardial function in rat and pig models. Rabbits were randomized into 4 groups as 12 rabbits in each group. Bupivacaine 10 mg/kg was injected as an intravenous bolus to all groups. Basic life support was performed by mechanical ventilation and manual external chest compressions. After 1 min, animals in the group 1 received 1.5 ml/ kg saline 0.9% solution, and animals in the groups 2 and 4 received 5 ml/kg 20% lipid emulsion for 1 min through the ear vein followed by continuous infusion at 0.25 ml/kg/min. Three additional boluses of 1.5 ml/ kg lipid emulsion were repeated at 5-min intervals. The group 3 received fluid resuscitation plus levosimendan (3 µg/kg/min) 1 min after asystole and the group 4 received both levosimendan and lipid emulsion treatment. Return of spontaneous circulation and hemodynamic metrics were obtained in 20 minutes. The number of rabbits that survived after cardiac resuscitation was lower in the Groups 1 (0%) and 3 (33.3%) than in the Group 4 (91.7%) with a statistically significant difference (p < 0.001). The number of rabbits that survived resuscitation was higher in the Group 4 than in the Group 2 (66.7%), though not with a statistically significant difference (p = 0.317). The median duration of cardiac arrest in the Group 4 was significantly shorter than that in the other three groups (p < 0.001). In this rabbit model of bupivacaine-induced cardiac arrest, resuscitation with combined iv lipid emulsion and levosimendan was more efficacious than lipid alone (Tab. 3, Ref. 24).

Lipid resuscitation: development in basic research and application to clinical practice

It has been nearly 15 years since the effectiveness of intravenous lipid emulsion in resuscitation from bupivacaine-induced cardiac arrest was reported by Weinberg et al. [1]. Despite the outstanding novelty and originality of this finding, it was not until a 2006 case report of a patient resuscitated with lipid emulsion after bupivacaine-induced refractory dysrhythmia and cardiac arrest that its clinical effectiveness was acknowledged [2]. This event was followed by a large number of case reports that showed the effectiveness of lipid emulsion for treating the central nervous system as well as cardiac toxicity induced by various kinds of local anesthetics [3–8]. Treatment with intravenous lipid emulsion has been incorporated into practice advisories of the Association of Anesthesiologists of Great Britain and Ireland, the American Society of Regional Anesthesia and Pain Medicine [9], and endorsed by the American Heart Association Advanced Cardiac Life Support (ACLS) guidelines [10] (Table 1). In response to widespread interest, numerous studies have been undertaken using various animal models [8]. Notably, most of the animal experiments have been focused on examining the effect of lipid on local anesthetic-induced cardiac toxicity, not central nervous system toxicity, probably because of the primary concern of resuscitation and the entirely different animal models required for studying these two types of toxicity. Animals under mechanical ventilation with oxygen are needed to examine the effect of lipid emulsion on cardiac toxicity of local anesthetics while eliminating the influence of hypoxia induced by sedation and convulsions preceding circulatory collapse [11–14]. In contrast, awake, spontaneously breathing animals are needed to observe its effect on the central nervous system toxicity [15]. Randomized clinical trials are no longer ethically defensible for studying local anesthetic toxicity. Moreover, clinical data from healthy volunteers given nontoxic doses of bupivacaine would not precisely reflect the condition at the onset of the toxic effects [16].

Journal-related Activities and Other Special Activities at the 2012 American Society of Anesthesiologists Annual Meeting

Journal-related Activities and Other Special Activities at the 2012 American Society of Anesthesiologists Annual Meeting

Fatty-acid oxidation and calcium homeostasis are involved in the rescue of bupivacaine-induced cardiotoxicity by lipid emulsion in rats*

Lipid emulsion has been shown to be effective in resuscitating bupivacaine-induced cardiac arrest but its mechanism of action is not clear. Here we investigated whether fatty-acid oxidation is required for rescue of bupivacaine-induced cardiotoxicity by lipid emulsion in rats. We also compared the mitochondrial function and calcium threshold for triggering of mitochondrial permeability transition pore opening in bupivacaine-induced cardiac arrest before and after resuscitation with lipid emulsion. Prospective, randomized animal study. University research laboratory. Adult male Sprague-Dawley rats. Asystole was achieved with a single dose of bupivacaine (10 mg/kg over 20 secs, intravenously) and 20% lipid emulsion infusion (5 mL/kg bolus, and 0.5 mL/kg/min maintenance), and cardiac massage started immediately. The rats in CVT-4325 (CVT) group were pretreated with a single dose of fatty-acid oxidation inhibitor CVT (0.5, 0.25, 0.125, or 0.0625 mg/kg bolus intravenously) 5 mins prior to inducing asystole by bupivacaine overdose. Heart rate, ejection fraction, fractional shortening, the threshold for opening of mitochondrial permeability transition pore, oxygen consumption, and membrane potential were measured. The values are mean ± SEM. Administration of bupivacaine resulted in asystole. Lipid Emulsion infusion improved the cardiac function gradually as the ejection fraction was fully recovered within 5 mins (ejection fraction=64±4% and fractional shortening=36±3%, n=6) and heart rate increased to 239±9 beats/min (71% recovery, n=6) within 10 mins. Lipid emulsion was only able to rescue rats pretreated with low dose of CVT (0.0625 mg/kg; heart rate~181±11 beats/min at 10 mins, recovery of 56%; ejection fraction=50±1%; fractional shortening=26±0.6% at 5 mins, n=3), but was unable to resuscitate rats pretreated with higher doses of CVT (0.5, 0.25, or 0.125 mg/kg). The calcium-retention capacity in response to Ca²⁺ overload was significantly higher in cardiac mitochondria isolated from rats resuscitated with 20% lipid emulsion compared to the group that did not receive Lipid Emulsion after bupivacaine overdose (330±42 nmol/mg vs. 180±8.2 nmol/mg of mitochondrial protein, p<.05, n=3 in each group). The mitochondrial oxidative rate and membrane potential were similar in the bupivacaine group before and after resuscitation with lipid emulsion infusion. Fatty-acid oxidation is required for successful rescue of bupivacaine-induced cardiotoxicity by lipid emulsion. This rescue action is associated with inhibition of mitochondrial permeability transition pore opening.

Association of sustained cardiovascular recovery with epinephrine in the delayed lipid-based resuscitation from cardiac arrest induced by bupivacaine overdose in rats

The role of epinephrine combined with lipid emulsion in rescuing cardiovascular collapse induced by local anaesthetic overdose remains unclear. The objective of this study was to explore the effect of epinephrine on delayed lipid-based treatment for bupivacaine-induced cardiac arrest in rats. Thirty-two rats were subjected to bupivacaine to induce asystole. Basic life support was performed for 10 min before the rats received saline, epinephrine alone, or 20% lipid emulsion bolus with or without epinephrine pretreatment. ECG and invasive arterial pressure were monitored continuously. Arterial blood gas was analysed at 25 min; the right lungs and hearts of rats were harvested for measurement of dry-to-wet lung weight ratio and myocardial bupivacaine content, respectively. In the rats treated with epinephrine plus lipid emulsion, there was a marked improvement in haemodynamic parameters at 25 min compared with rats treated with lipid alone, P<0.05. The coronary perfusion pressure immediately after lipid rescue was higher in the epinephrine/lipid-treated rats when compared with rats given lipid only (70 and 24 mm Hg, respectively, P<0.05). The myocardial bupivacaine content was lower (8.34 nM g(-1)) in the epinephrine/lipid group relative to other groups (P<0.05). However, the rats treated with lipid alone which survived had higher PO(2), less severe acidosis, and better hypoxaemia relative to surviving rats given epinephrine plus lipid. Late intervention with epinephrine plus lipid emulsion contributed to sustained improvement in haemodynamic profile, but failed to alleviate deterioration of hypoxaemia and acidaemia in rats.