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Guy L Weinberg - One of the best experts on this subject based on the ideXlab platform.
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Prolonged Pulseless Electrical Activity Cardiac Arrest After Intranasal Injection of Lidocaine With Epinephrine: A Case Report.
A&A practice, 2019Co-Authors: Frank Weber, Guy L Weinberg, Rahul Guha, Frank Steinbach, Marina GitmanAbstract:Local Anesthetic Toxicity is a rare but serious complication of Local Anesthetic administration. Although lidocaine has a safety profile superior to other amide Local Anesthetics, we report a case of cardiac arrest after intranasal injection of lidocaine. The case involves a 22-year-old healthy woma
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the mechanisms underlying lipid resuscitation therapy
Regional Anesthesia and Pain Medicine, 2018Co-Authors: Michael R. Fettiplace, Guy L WeinbergAbstract:Abstract The experimental use of lipid emulsion for Local Anesthetic Toxicity was originally identified in 1998. It was then translated to clinical practice in 2006 and expanded to drugs other than Local Anesthetics in 2008. Our understanding of lipid resuscitation therapy has progressed considerably since the previous update from the American Society of Regional Anesthesia and Pain Medicine, and the scientific evidence has coalesced around specific discrete mechanisms. Intravenous lipid emulsion therapy provides a multimodal resuscitation benefit that includes both scavenging (eg, the lipid shuttle) and nonscavenging components. The intravascular lipid compartment scavenges drug from organs susceptible to Toxicity and accelerates redistribution to organs where drug (eg, bupivacaine) is stored, detoxified, and later excreted. In addition, lipid exerts nonscavenging effects that include postconditioning (via activation of prosurvival kinases) along with cardiotonic and vasoconstrictive benefits. These effects protect tissue from ischemic damage and increase tissue perfusion during recovery from Toxicity. Other mechanisms have diminished in favor based on lack of evidence; these include direct effects on channel currents (eg, calcium) and mass-effect overpowering a block in mitochondrial metabolism. In this narrative review, we discuss these proposed mechanisms and address questions left to answer in the field. Further work is needed, but the field has made considerable strides towards understanding the mechanisms.
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insulin signaling in bupivacaine induced cardiac Toxicity sensitization during recovery and potentiation by lipid emulsion
Anesthesiology, 2016Co-Authors: Michael R. Fettiplace, Richard Ripper, Katarzyna Kowal, Alexandria N Young, Kinga Lis, Israel Rubinstein, Marcelo G Bonini, Richard D Minshall, Guy L WeinbergAbstract:Background The impact of Local Anesthetics on the regulation of glucose homeostasis by protein kinase B (Akt) and 5'-adenosine monophosphate-activated protein kinase (AMPK) is unclear but important because of the implications for both Local Anesthetic Toxicity and its reversal by IV lipid emulsion (ILE). Methods Sprague-Dawley rats received 10 mg/kg bupivacaine over 20 s followed by nothing or 10 ml/kg ILE (or ILE without bupivacaine). At key time points, heart and kidney were excised. Glycogen content and phosphorylation levels of Akt, p70 s6 kinase, s6, insulin receptor substrate-1, glycogen synthase kinase-3β, AMPK, acetyl-CoA carboxylase, and tuberous sclerosis 2 were quantified. Three animals received Wortmannin to irreversibly inhibit phosphoinositide-3-kinase (Pi3k) signaling. Isolated heart studies were conducted with bupivacaine and LY294002-a reversible Pi3K inhibitor. Results Bupivacaine cardioToxicity rapidly dephosphorylated Akt at S473 to 63 ± 5% of baseline and phosphorylated AMPK to 151 ± 19%. AMPK activation inhibited targets downstream of mammalian target of rapamycin complex 1 via tuberous sclerosis 2. Feedback dephosphorylation of IRS1 to 31 ± 8% of baseline sensitized Akt signaling in hearts resulting in hyperphosphorylation of Akt at T308 and glycogen synthase kinase-3β to 390 ± 64% and 293 ± 50% of baseline, respectively. Glycogen accumulated to 142 ± 7% of baseline. Irreversible inhibition of Pi3k upstream of Akt exacerbated bupivacaine cardioToxicity, whereas pretreating with a reversible inhibitor delayed the onset of Toxicity. ILE rapidly phosphorylated Akt at S473 and T308 to 150 ± 23% and 167 ± 10% of baseline, respectively, but did not interfere with AMPK or targets of mammalian target of rapamycin complex 1. Conclusion Glucose handling by Akt and AMPK is integral to recovery from bupivacaine cardioToxicity and modulation of these pathways by ILE contributes to lipid resuscitation.
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American Society of Regional Anesthesia and Pain Medicine checklist for managing Local Anesthetic systemic Toxicity: 2012 version.
Regional anesthesia and pain medicine, 2012Co-Authors: Joseph M. Neal, Michael F. Mulroy, Guy L WeinbergAbstract:The American Society of Regional Anesthesia and Pain Medicine (ASRA) periodically revises and updates its checklist for the management of Local Anesthetic systemic Toxicity. The 2017 update replaces the 2012 version and reflects new information contained in the third ASRA Practice Advisory on Local Anesthetic Systemic Toxicity. Electronic copies of the ASRA checklist can be downloaded from the ASRA Web site (www.asra.com) for inclusion in Local Anesthetic Toxicity rescue kits or perioperative checklist repositories.
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Lipid resuscitation: a life-saving antidote for Local Anesthetic Toxicity.
Current pharmaceutical biotechnology, 2011Co-Authors: S. Bern, Belinda S Akpa, I. Kuo, Guy L WeinbergAbstract:Local Anesthetic Toxicity is a rare, but potentially lethal, complication of regional anesthesia that cannot be prevented by any single measure. It is associated with CNS excitation and can lead to refractory cardiac dysfunction and collapse. The development of lipid emulsion for the treatment of Anesthetic-induced Toxicity resulted from a set of observations during a study on the potent, lipophilic drug bupivacaine and its associated clinical risk of intransigent cardiac Toxicity in otherwise healthy individuals. Subsequent laboratory studies and clinical reports have shown that infusion of lipid can reliably reverse Toxicity from potent Local Anesthetics as well as other drugs. The underlying mechanisms of lipid resuscitation may be a combination of a 'lipid sink' and metabolic effect. Lipid rescue has led to a reduction in fatalities associated with severe systemic Toxicity, but continued research is necessary for a better mechanistic understanding. Increased physician awareness and education, as well as optimized treatment protocols, will significantly reduce the rate of morbidity and mortality from Local Anesthetic Toxicity.
Michael R. Fettiplace - One of the best experts on this subject based on the ideXlab platform.
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heterogeneity and bias in animal models of lipid emulsion therapy a systematic review and meta analysis
Clinical Toxicology, 2020Co-Authors: Michael R. Fettiplace, Adrian B PichurkoAbstract:Clinicians utilize lipid emulsion to treat Local Anesthetic Toxicity and non-Local Anesthetic toxicities, a practice supported by animal experimentation and clinical experience. Prior meta-analysis...
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the mechanisms underlying lipid resuscitation therapy
Regional Anesthesia and Pain Medicine, 2018Co-Authors: Michael R. Fettiplace, Guy L WeinbergAbstract:Abstract The experimental use of lipid emulsion for Local Anesthetic Toxicity was originally identified in 1998. It was then translated to clinical practice in 2006 and expanded to drugs other than Local Anesthetics in 2008. Our understanding of lipid resuscitation therapy has progressed considerably since the previous update from the American Society of Regional Anesthesia and Pain Medicine, and the scientific evidence has coalesced around specific discrete mechanisms. Intravenous lipid emulsion therapy provides a multimodal resuscitation benefit that includes both scavenging (eg, the lipid shuttle) and nonscavenging components. The intravascular lipid compartment scavenges drug from organs susceptible to Toxicity and accelerates redistribution to organs where drug (eg, bupivacaine) is stored, detoxified, and later excreted. In addition, lipid exerts nonscavenging effects that include postconditioning (via activation of prosurvival kinases) along with cardiotonic and vasoconstrictive benefits. These effects protect tissue from ischemic damage and increase tissue perfusion during recovery from Toxicity. Other mechanisms have diminished in favor based on lack of evidence; these include direct effects on channel currents (eg, calcium) and mass-effect overpowering a block in mitochondrial metabolism. In this narrative review, we discuss these proposed mechanisms and address questions left to answer in the field. Further work is needed, but the field has made considerable strides towards understanding the mechanisms.
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insulin signaling in bupivacaine induced cardiac Toxicity sensitization during recovery and potentiation by lipid emulsion
Anesthesiology, 2016Co-Authors: Michael R. Fettiplace, Richard Ripper, Katarzyna Kowal, Alexandria N Young, Kinga Lis, Israel Rubinstein, Marcelo G Bonini, Richard D Minshall, Guy L WeinbergAbstract:Background The impact of Local Anesthetics on the regulation of glucose homeostasis by protein kinase B (Akt) and 5'-adenosine monophosphate-activated protein kinase (AMPK) is unclear but important because of the implications for both Local Anesthetic Toxicity and its reversal by IV lipid emulsion (ILE). Methods Sprague-Dawley rats received 10 mg/kg bupivacaine over 20 s followed by nothing or 10 ml/kg ILE (or ILE without bupivacaine). At key time points, heart and kidney were excised. Glycogen content and phosphorylation levels of Akt, p70 s6 kinase, s6, insulin receptor substrate-1, glycogen synthase kinase-3β, AMPK, acetyl-CoA carboxylase, and tuberous sclerosis 2 were quantified. Three animals received Wortmannin to irreversibly inhibit phosphoinositide-3-kinase (Pi3k) signaling. Isolated heart studies were conducted with bupivacaine and LY294002-a reversible Pi3K inhibitor. Results Bupivacaine cardioToxicity rapidly dephosphorylated Akt at S473 to 63 ± 5% of baseline and phosphorylated AMPK to 151 ± 19%. AMPK activation inhibited targets downstream of mammalian target of rapamycin complex 1 via tuberous sclerosis 2. Feedback dephosphorylation of IRS1 to 31 ± 8% of baseline sensitized Akt signaling in hearts resulting in hyperphosphorylation of Akt at T308 and glycogen synthase kinase-3β to 390 ± 64% and 293 ± 50% of baseline, respectively. Glycogen accumulated to 142 ± 7% of baseline. Irreversible inhibition of Pi3k upstream of Akt exacerbated bupivacaine cardioToxicity, whereas pretreating with a reversible inhibitor delayed the onset of Toxicity. ILE rapidly phosphorylated Akt at S473 and T308 to 150 ± 23% and 167 ± 10% of baseline, respectively, but did not interfere with AMPK or targets of mammalian target of rapamycin complex 1. Conclusion Glucose handling by Akt and AMPK is integral to recovery from bupivacaine cardioToxicity and modulation of these pathways by ILE contributes to lipid resuscitation.
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cardiac depression induced by cocaine or cocaethylene is alleviated by lipid emulsion more effectively than by sulfobutylether β cyclodextrin
Academic Emergency Medicine, 2015Co-Authors: Michael R. Fettiplace, Adrian B Pichurko, Richard Ripper, Bocheng Lin, Katarzyna KowalAbstract:Objectives Cocaine intoxication leads to over 500,000 emergency department visits annually in the United States and ethanol cointoxication occurs in 34% of those cases. CardioToxicity is an ominous complication of cocaine and cocaethylene overdose for which no specific antidote exists. Because infusion of lipid emulsion (Intralipid) can treat lipophilic Local Anesthetic Toxicity and cocaine is an amphipathic Local Anesthetic, the authors tested whether lipid emulsion could attenuate cocaine cardioToxicity in vivo. The effects of lipid emulsion were compared with the metabolically inert sulfobutylether-β-cyclodextrin (SBE-β-CD; Captisol) in an isolated heart model of cocaine and cocaethylene Toxicity to determine if capture alone could exert similar benefit as lipid emulsion, which exhibits multimodal effects. The authors then tested if cocaine and cocaethylene, like bupivacaine, inhibit lipid-based metabolism in isolated cardiac mitochondria. Methods For whole animal experiments, Sprague-Dawley rats were anesthetized, instrumented, and pretreated with lipid emulsion followed by a continuous infusion of cocaine to assess time of onset of cocaine Toxicity. For ex vivo experiments, rat hearts were placed onto a nonrecirculating Langendorff system perfused with Krebs-Henseleit solution. Heart rate, left ventricle maximum developed pressure (LVdevP), left ventricle diastolic pressure, maximum rate of contraction (+dP/dtmax), maximum rate of relaxation (–dP/dtmax), rate-pressure product (RPP = heart rate × LVdevP), and line pressure were monitored continuously during the experiment. A dose response to cocaine (10, 30, 50, and 100 μmol/L) and cocaethylene (10, 30, and 50 μmol/L) was generated in the absence or presence of either 0.25% lipid emulsion or SBE-β-CD. Substrate-specific rates of oxygen consumption were measured in interfibrillar cardiac mitochondria in the presence of cocaine, cocaethylene, ecgonine, and benzoylecgonine. Results Treatment with lipid emulsion delayed onset of hypotension (140 seconds vs. 279 seconds; p = 0.008) and asystole (369 seconds vs. 607 seconds; p = 0.02) in whole animals. Cocaine and cocaethylene induced dose-dependent decreases in RPP, +dP/dtmax, and –dP/dtmaxabs (p < 0.0001) in Langendorff hearts; line pressure was increased by cocaine and cocaethylene infusion, but not altered by treatment. Lipid emulsion attenuated cocaine- and cocaethylene-induced cardiac depression. SBE-β-CD alone evoked a mild cardiodepressant effect (p < 0.0001) but attenuated further cocaine- and cocaethylene-induced decrements in cardiac contractility at high concentrations of drug (100 μmol/L; p < 0.001). Finally, both cocaine and cocaethylene, but not ecgonine and benzoylecgonine, inhibited lipid-dependent mitochondrial respiration by blocking carnitine exchange (p < 0.05). Conclusions A commercially available lipid emulsion was able to delay progression of cocaine cardiac Toxicity in vivo. Further, it improved acute cocaine- and cocaethylene-induced cardiac Toxicity in rat isolated heart while SBE-β-CD was effective only at the highest cocaine concentration. Further, both cocaine and cocaethylene inhibited lipid-dependent mitochondrial respiration. Collectively, this suggests that scavenging-independent effects of lipid emulsion may contribute to reversal of acute cocaine and cocaethylene cardioToxicity, and the beneficial effects may involve mitochondrial lipid processing.
Adrian B Pichurko - One of the best experts on this subject based on the ideXlab platform.
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heterogeneity and bias in animal models of lipid emulsion therapy a systematic review and meta analysis
Clinical Toxicology, 2020Co-Authors: Michael R. Fettiplace, Adrian B PichurkoAbstract:Clinicians utilize lipid emulsion to treat Local Anesthetic Toxicity and non-Local Anesthetic toxicities, a practice supported by animal experimentation and clinical experience. Prior meta-analysis...
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cardiac depression induced by cocaine or cocaethylene is alleviated by lipid emulsion more effectively than by sulfobutylether β cyclodextrin
Academic Emergency Medicine, 2015Co-Authors: Michael R. Fettiplace, Adrian B Pichurko, Richard Ripper, Bocheng Lin, Katarzyna KowalAbstract:Objectives Cocaine intoxication leads to over 500,000 emergency department visits annually in the United States and ethanol cointoxication occurs in 34% of those cases. CardioToxicity is an ominous complication of cocaine and cocaethylene overdose for which no specific antidote exists. Because infusion of lipid emulsion (Intralipid) can treat lipophilic Local Anesthetic Toxicity and cocaine is an amphipathic Local Anesthetic, the authors tested whether lipid emulsion could attenuate cocaine cardioToxicity in vivo. The effects of lipid emulsion were compared with the metabolically inert sulfobutylether-β-cyclodextrin (SBE-β-CD; Captisol) in an isolated heart model of cocaine and cocaethylene Toxicity to determine if capture alone could exert similar benefit as lipid emulsion, which exhibits multimodal effects. The authors then tested if cocaine and cocaethylene, like bupivacaine, inhibit lipid-based metabolism in isolated cardiac mitochondria. Methods For whole animal experiments, Sprague-Dawley rats were anesthetized, instrumented, and pretreated with lipid emulsion followed by a continuous infusion of cocaine to assess time of onset of cocaine Toxicity. For ex vivo experiments, rat hearts were placed onto a nonrecirculating Langendorff system perfused with Krebs-Henseleit solution. Heart rate, left ventricle maximum developed pressure (LVdevP), left ventricle diastolic pressure, maximum rate of contraction (+dP/dtmax), maximum rate of relaxation (–dP/dtmax), rate-pressure product (RPP = heart rate × LVdevP), and line pressure were monitored continuously during the experiment. A dose response to cocaine (10, 30, 50, and 100 μmol/L) and cocaethylene (10, 30, and 50 μmol/L) was generated in the absence or presence of either 0.25% lipid emulsion or SBE-β-CD. Substrate-specific rates of oxygen consumption were measured in interfibrillar cardiac mitochondria in the presence of cocaine, cocaethylene, ecgonine, and benzoylecgonine. Results Treatment with lipid emulsion delayed onset of hypotension (140 seconds vs. 279 seconds; p = 0.008) and asystole (369 seconds vs. 607 seconds; p = 0.02) in whole animals. Cocaine and cocaethylene induced dose-dependent decreases in RPP, +dP/dtmax, and –dP/dtmaxabs (p < 0.0001) in Langendorff hearts; line pressure was increased by cocaine and cocaethylene infusion, but not altered by treatment. Lipid emulsion attenuated cocaine- and cocaethylene-induced cardiac depression. SBE-β-CD alone evoked a mild cardiodepressant effect (p < 0.0001) but attenuated further cocaine- and cocaethylene-induced decrements in cardiac contractility at high concentrations of drug (100 μmol/L; p < 0.001). Finally, both cocaine and cocaethylene, but not ecgonine and benzoylecgonine, inhibited lipid-dependent mitochondrial respiration by blocking carnitine exchange (p < 0.05). Conclusions A commercially available lipid emulsion was able to delay progression of cocaine cardiac Toxicity in vivo. Further, it improved acute cocaine- and cocaethylene-induced cardiac Toxicity in rat isolated heart while SBE-β-CD was effective only at the highest cocaine concentration. Further, both cocaine and cocaethylene inhibited lipid-dependent mitochondrial respiration. Collectively, this suggests that scavenging-independent effects of lipid emulsion may contribute to reversal of acute cocaine and cocaethylene cardioToxicity, and the beneficial effects may involve mitochondrial lipid processing.
A Kohli - One of the best experts on this subject based on the ideXlab platform.
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forearm ivra using 0 5 lidocaine in a dose of 1 5 mg kg with ketorolac 0 15 mg kg for hand and wrist surgeries
Minerva Anestesiologica, 2010Co-Authors: R Singh, A Bhagwat, P Bhadoria, A KohliAbstract:Aim. Local Anesthetic Toxicity remains one of the most dreaded complications of the intravenous regional anesthesia (IVRA) technique. It results from the sudden release of a large amount of Local Anesthetic (LA) into the systemic circulation. This release can occur when the tourniquet deflates accidentally during the procedure or when it is deflated intentionally at the end of the procedure to terminate the anesthesia. The forearm tourniquet IVRA technique may offer distinct advantages over the conventional upper arm tourniquet IVRA technique. Use of a forearm tourniquet allows the dosage of Local Anesthetic to be decreased to almost half of what is required with an upper arm tourniquet, and the incidence of tourniquet pain has been reported to be less with forearm tourniquet. In this study, authors assessed the clinical efficacy of administering IVRA with lidocaine plus ketorolac using either a forearm or upper arm tourniquet. Methods. Upper arm IVRA was established using 0.5% lidocaine at a dose of 3 mg/kg with ketorolac at 0.3 mg/kg. Forearm IVRA was established using 0.5 % lidocaine at a dose of 1.5 mg/kg with ketorolac at 0.15 mg/kg. Quality of surgical anesthesia, onset, duration of sensory block and postoperative surgical pain and analgesic use were recorded and assessed. The incidence of Local Anesthetic Toxicity and Local complications due to the tourniquet were also recorded. Results. Surgical anesthesia was assessed as excellent or good (grade 0/1) in all 20/20 patients who received IVRA using an upper arm tourniquet and in 19/20 patients who received IVRA using a forearm tourniquet (P= 1.00). Onset as well as regression of sensory block was similar in both the groups. Post operative VAS scores at 30 min and 60 min were statistically comparable between the two groups, as was the analgesic use in the first 24 h. Conclusion. In conclusion, forearm IVRA provides effective perioperative anesthesia and analgesia. The technique results in a similar clinical profile as upper arm IVRA while using half the dose of both lidocaine and ketorolac.
Richard Ripper - One of the best experts on this subject based on the ideXlab platform.
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insulin signaling in bupivacaine induced cardiac Toxicity sensitization during recovery and potentiation by lipid emulsion
Anesthesiology, 2016Co-Authors: Michael R. Fettiplace, Richard Ripper, Katarzyna Kowal, Alexandria N Young, Kinga Lis, Israel Rubinstein, Marcelo G Bonini, Richard D Minshall, Guy L WeinbergAbstract:Background The impact of Local Anesthetics on the regulation of glucose homeostasis by protein kinase B (Akt) and 5'-adenosine monophosphate-activated protein kinase (AMPK) is unclear but important because of the implications for both Local Anesthetic Toxicity and its reversal by IV lipid emulsion (ILE). Methods Sprague-Dawley rats received 10 mg/kg bupivacaine over 20 s followed by nothing or 10 ml/kg ILE (or ILE without bupivacaine). At key time points, heart and kidney were excised. Glycogen content and phosphorylation levels of Akt, p70 s6 kinase, s6, insulin receptor substrate-1, glycogen synthase kinase-3β, AMPK, acetyl-CoA carboxylase, and tuberous sclerosis 2 were quantified. Three animals received Wortmannin to irreversibly inhibit phosphoinositide-3-kinase (Pi3k) signaling. Isolated heart studies were conducted with bupivacaine and LY294002-a reversible Pi3K inhibitor. Results Bupivacaine cardioToxicity rapidly dephosphorylated Akt at S473 to 63 ± 5% of baseline and phosphorylated AMPK to 151 ± 19%. AMPK activation inhibited targets downstream of mammalian target of rapamycin complex 1 via tuberous sclerosis 2. Feedback dephosphorylation of IRS1 to 31 ± 8% of baseline sensitized Akt signaling in hearts resulting in hyperphosphorylation of Akt at T308 and glycogen synthase kinase-3β to 390 ± 64% and 293 ± 50% of baseline, respectively. Glycogen accumulated to 142 ± 7% of baseline. Irreversible inhibition of Pi3k upstream of Akt exacerbated bupivacaine cardioToxicity, whereas pretreating with a reversible inhibitor delayed the onset of Toxicity. ILE rapidly phosphorylated Akt at S473 and T308 to 150 ± 23% and 167 ± 10% of baseline, respectively, but did not interfere with AMPK or targets of mammalian target of rapamycin complex 1. Conclusion Glucose handling by Akt and AMPK is integral to recovery from bupivacaine cardioToxicity and modulation of these pathways by ILE contributes to lipid resuscitation.
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cardiac depression induced by cocaine or cocaethylene is alleviated by lipid emulsion more effectively than by sulfobutylether β cyclodextrin
Academic Emergency Medicine, 2015Co-Authors: Michael R. Fettiplace, Adrian B Pichurko, Richard Ripper, Bocheng Lin, Katarzyna KowalAbstract:Objectives Cocaine intoxication leads to over 500,000 emergency department visits annually in the United States and ethanol cointoxication occurs in 34% of those cases. CardioToxicity is an ominous complication of cocaine and cocaethylene overdose for which no specific antidote exists. Because infusion of lipid emulsion (Intralipid) can treat lipophilic Local Anesthetic Toxicity and cocaine is an amphipathic Local Anesthetic, the authors tested whether lipid emulsion could attenuate cocaine cardioToxicity in vivo. The effects of lipid emulsion were compared with the metabolically inert sulfobutylether-β-cyclodextrin (SBE-β-CD; Captisol) in an isolated heart model of cocaine and cocaethylene Toxicity to determine if capture alone could exert similar benefit as lipid emulsion, which exhibits multimodal effects. The authors then tested if cocaine and cocaethylene, like bupivacaine, inhibit lipid-based metabolism in isolated cardiac mitochondria. Methods For whole animal experiments, Sprague-Dawley rats were anesthetized, instrumented, and pretreated with lipid emulsion followed by a continuous infusion of cocaine to assess time of onset of cocaine Toxicity. For ex vivo experiments, rat hearts were placed onto a nonrecirculating Langendorff system perfused with Krebs-Henseleit solution. Heart rate, left ventricle maximum developed pressure (LVdevP), left ventricle diastolic pressure, maximum rate of contraction (+dP/dtmax), maximum rate of relaxation (–dP/dtmax), rate-pressure product (RPP = heart rate × LVdevP), and line pressure were monitored continuously during the experiment. A dose response to cocaine (10, 30, 50, and 100 μmol/L) and cocaethylene (10, 30, and 50 μmol/L) was generated in the absence or presence of either 0.25% lipid emulsion or SBE-β-CD. Substrate-specific rates of oxygen consumption were measured in interfibrillar cardiac mitochondria in the presence of cocaine, cocaethylene, ecgonine, and benzoylecgonine. Results Treatment with lipid emulsion delayed onset of hypotension (140 seconds vs. 279 seconds; p = 0.008) and asystole (369 seconds vs. 607 seconds; p = 0.02) in whole animals. Cocaine and cocaethylene induced dose-dependent decreases in RPP, +dP/dtmax, and –dP/dtmaxabs (p < 0.0001) in Langendorff hearts; line pressure was increased by cocaine and cocaethylene infusion, but not altered by treatment. Lipid emulsion attenuated cocaine- and cocaethylene-induced cardiac depression. SBE-β-CD alone evoked a mild cardiodepressant effect (p < 0.0001) but attenuated further cocaine- and cocaethylene-induced decrements in cardiac contractility at high concentrations of drug (100 μmol/L; p < 0.001). Finally, both cocaine and cocaethylene, but not ecgonine and benzoylecgonine, inhibited lipid-dependent mitochondrial respiration by blocking carnitine exchange (p < 0.05). Conclusions A commercially available lipid emulsion was able to delay progression of cocaine cardiac Toxicity in vivo. Further, it improved acute cocaine- and cocaethylene-induced cardiac Toxicity in rat isolated heart while SBE-β-CD was effective only at the highest cocaine concentration. Further, both cocaine and cocaethylene inhibited lipid-dependent mitochondrial respiration. Collectively, this suggests that scavenging-independent effects of lipid emulsion may contribute to reversal of acute cocaine and cocaethylene cardioToxicity, and the beneficial effects may involve mitochondrial lipid processing.
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safety of high volume lipid emulsion infusion a first approximation of ld50 in rats
Regional Anesthesia and Pain Medicine, 2010Co-Authors: David B Hiller, Richard Ripper, Guido Di Gregorio, Kemba Kelly, Lucas Edelman, Redouane Boumendjel, Kenneth Drasner, Guy L WeinbergAbstract:Background: Lipid infusion reverses systemic Local Anesthetic Toxicity. The acceptable upper limit for lipid administration is unknown and has direct bearing on clinical management. We hypothesize that high volumes of lipid could have undesirable effects and sought to identify the dose required to kill 50% of the animals (LD50) of large volume lipid administration. Methods: Intravenous lines and electrocardiogram electrodes were placed in anesthetized, male Sprague-Dawley rats. Twenty percent lipid emulsion (20, 40, 60, or 80 mL/kg) or saline (60 or 80 mL/kg), were administered over 30 mins; lipid dosing was assigned by the Dixon "up-and-down" method. Rats were recovered and observed for 48 hrs then euthanized for histologic analysis of major organs. Three additional rats were administered 60 mL/kg lipid emulsion and euthanized at 1, 4, and 24 hrs to identify progression of organ damage. Results: The maximum likelihood estimate for LD50 was 67.72 (SE, 10.69) mL/kg. Triglycerides were elevated immediately after infusion but returned to baseline by 48 hrs when laboratory abnormalities included elevated amylase, aspartate aminotransferase, and serum urea nitrogen for all lipid doses. Histologic diagnosis of myocardium, brain, pancreas, and kidneys was normal at all doses. Microscopic abnormalities in lung and liver were observed at 60 and 80 mL/kg; histopathology in the lung and liver was worse at 1 hr than at 4 and 24 hrs. Conclusions: The LD50 of rapid, high volume lipid infusion is an order of magnitude greater than doses typically used for lipid rescue in humans and supports the safety of lipid infusion at currently recommended doses for toxin-induced cardiac arrest. Lung and liver histopathology was observed at the highest infused volumes.
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resuscitation with lipid versus epinephrine in a rat model of bupivacaine overdose
Anesthesiology, 2008Co-Authors: Guy L Weinberg, Richard Ripper, Guido Di Gregorio, Kemba Kelly, Malek G Massad, Lucas Edelman, David E Schwartz, Nirali Shah, Sophie Zheng, Douglas L FeinsteinAbstract:Background: Lipid emulsion infusion reverses cardiovascular compromise due to Local Anesthetic overdose in laboratory and clinical settings. The authors compared resuscitation with lipid, epinephrine, and saline control in a rat model of bupivacaine-induced cardiac Toxicity to determine whether lipid provides a benefit over epinephrine. Methods: Bupivacaine, 20 mg/kg, was infused in rats anesthetized with isoflurane, producing asystole in all subjects. Ventilation with 100% oxygen and chest compressions were begun immediately, along with intravenous treatment with 30% lipid emulsion or saline (5-ml/kg bolus plus continuous infusion at 0.5 ml kg -1 ·min -1 ) or epinephrine (30 μg/kg). Chest compressions were continued and boluses were repeated at 2.5 and 5 min until the native rate-pressure product was greater than 20% baseline. Electrocardiogram and arterial pressure were monitored continuously and at 10 min, arterial blood gas, central venous oxygen saturation, and blood lactate were measured. Effect size (Cohen d) was determined for comparisons at 10 min. Results: Lipid infusion resulted in higher rate-pressure product (P < 0.001, d = 3.84), pH (P < 0.01, d = 3.78), arterial oxygen tension (P < 0.05, d = 2.8), and central venous oxygen saturation (P < 0.001, d = 4.9) at 10 min than did epinephrine. Epinephrine treatment caused higher lactate (P < 0.01, d = 1.48), persistent ventricular ectopy in all subjects, pulmonary edema in four of five rats, hypoxemia, and a mixed metabolic and respiratory acidosis by 10 min. Conclusions: Hemodynamic and metabolic metrics during resuscitation with lipid surpassed those with epinephrine, which were no better than those seen in the saline control group. Further studies are required to optimize the clinical management of systemic Local Anesthetic Toxicity.