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Ju-tae Sohn - One of the best experts on this subject based on the ideXlab platform.
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Lipid Emulsion inhibits the vasodilation induced by a toxic dose of amlodipine in isolated rat aortae.
International Journal of Medical Sciences, 2019Co-Authors: Soo Hee Lee, Yeran Hwang, Ji-yoon Kim, Hyun-jin Kim, Sung Il Bae, Seongyeong Tak, Ju-tae SohnAbstract:The goal of this study was to examine the effect of Lipid Emulsion on the vasodilation induced in isolated endothelium-denuded rat aortae by a toxic dose of amlodipine. We examined the effects of Lipid Emulsion and verapamil on amlodipine-induced vasodilation. We also examined the effects of a mixture of Lipid Emulsion and amlodipine, as well as the centrifuged aqueous extract (CAE) obtained by ultracentrifuging such a mixture and then removing the upper Lipid layer, on amlodipine-induced vasodilation. The effect of Lipid Emulsion on the amlodipine concentration was examined. Lipid Emulsion attenuated amlodipine-induced vasodilation in isolated aortae. Both CAE and Lipid Emulsion containing amlodipine inhibited amlodipine-induced vasodilation. However, there was no significant difference in amlodipine-induced vasodilation between aortae treated with CAE and those treated with Lipid Emulsion containing amlodipine. Verapamil inhibited amlodipine-induced vasodilation. Lipid Emulsion decreased the concentration of amlodipine. Lipid Emulsion attenuated the vasodilation induced by a toxic amlodipine dose in NaF-precontracted aortae. The data show that Lipid Emulsion inhibited the vasodilation induced by a toxic amlodipine dose in isolated rat aortae by reducing the concentration of amlodipine. Amlodipine-induced vasodilation seems to be mediated mainly by blockade of L-type calcium channels and partially by inhibition of the Rho-kinase pathway.
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Lipid Emulsion attenuates the vasodilation induced by a toxic dose of a calcium channel blocker through its partitioning into the Lipid phase.
General Physiology and Biophysics, 2019Co-Authors: Soo Hee Lee, Jeong-min Hong, Ji-yoon Kim, Hyun-jin Kim, Sung Il Bae, Yunsik Shin, Ju-tae SohnAbstract:The present in vitro study examined whether Lipid Emulsion attenuates the vasodilation evoked by toxic doses of calcium channel blockers (bepridil, verapamil, nifedipine and diltiazem) via their partitioning into the Lipid phase. The effects of the calcium channel blockers alone, the Lipid Emulsion and calcium channel blocker mixture, and the centrifuged aqueous extract (CAE) obtained from ultracentrifugation of the Lipid Emulsion and calcium channel blocker mixture on isolated endothelium-denuded rat aortas precontracted with phenylephrine were observed. The effects of Lipid Emulsion on calcium channel blocker concentration in the Krebs solution were examined using ultraperformance liquid chromatography. A mixture of Lipid Emulsion with either bepridil or verapamil and the corresponding CAE more effectively attenuated vasodilation than either bepridil or verapamil alone, whereas the vasodilation induced by the mixture of Lipid Emulsion and either bepridil or verapamil was not significantly different from that induced by the corresponding CAE. The magnitude of the Lipid Emulsion-mediated reduction in vasodilation and calcium channel blocker concentration was as follows: bepridil > verapamil > nifedipine or diltiazem. These results suggest that Lipid Emulsion attenuates vasodilation induced by a toxic dose of bepridil and verapamil, seemingly through partitioning of the calcium channel blocker into the Lipid phase.
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Lipid Emulsion Inhibits the Late Apoptosis/Cardiotoxicity Induced by Doxorubicin in Rat Cardiomyoblasts.
Cells, 2018Co-Authors: Raghavendra Baregundi Subbarao, Soo Hee Lee, Ji-yoon Kim, Dawon Kang, Eun-jin Kim, Ju-tae SohnAbstract:This study aimed to examine the effect of Lipid Emulsion on the cardiotoxicity induced by doxorubicin in H9c2 rat cardiomyoblasts and elucidates the associated cellular mechanism. The effects of Lipid Emulsion on cell viability, Bax, cleaved caspase-8, cleaved capase-3, Bcl-XL, apoptosis, reactive oxygen species (ROS), malondialdehyde, superoxide dismutase (SOD), catalase and mitochondrial membrane potential induced by doxorubicin were examined. Treatment with doxorubicin decreased cell viability, whereas pretreatment with Lipid Emulsion reduced the effect of doxorubicin by increasing cell viability. Lipid Emulsion also suppressed the increased expression of cleaved caspase-3, cleaved caspase-8, and Bax induced by doxorubicin. Moreover, pretreatment with Lipid Emulsion decreased the increased Bax/Bcl-XL ratio induced by doxorubicin. Doxorubicin-induced late apoptosis was reduced by treatment with Lipid Emulsion. In addition, pretreatment with Lipid Emulsion prior to doxorubicin enhanced glycogen synthase kinase-3β phosphorylation. The increased malondialdehyde and ROS levels by doxorubicin were reduced by Lipid Emulsion pretreatment. Furthermore, Lipid Emulsion attenuated the reduced SOD and catalase activity and the decreased mitochondrial membrane potential induced by doxorubicin. Taken together, these results suggest that Lipid Emulsion attenuates doxorubicin-induced late apoptosis, which appears to be associated with the inhibition of oxidative stress induced by doxorubicin.
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Lipid Emulsion for Treating Local Anesthetic Systemic Toxicity.
International journal of medical sciences, 2018Co-Authors: Jeong-min Hong, Soo Hee Lee, Ju-tae SohnAbstract:Lipid Emulsion has been shown to be an effective treatment for systemic toxicity induced by local anesthetics, which is reflected in case reports. A systemic review and meta-analysis confirm the efficacy of this treatment. Investigators have suggested mechanisms associated with the Lipid Emulsion-mediated recovery of cardiovascular collapse caused by local anesthetic systemic toxicity; these mechanisms include Lipid sink, a widely accepted theory in which highly soluble local anesthetics (particularly bupivacaine) are absorbed into the Lipid phase of plasma from tissues (e.g., the heart) affected by local-anesthetic-induced toxicity; enhanced redistribution (Lipid shuttle); fatty acid supply; reversal of mitochondrial dysfunction; inotropic effects; glycogen synthase kinase-3β phosphorylation associated with inhibition of the mitochondrial permeability transition pore opening; inhibition of nitric oxide release; and reversal of cardiac sodium channel blockade. The current review includes the following: 1) an introduction, 2) a list of the proposed mechanisms, 3) a discussion of the best Lipid Emulsion treatment for reversal of local anesthetic toxicity, 4) a description of the effect of epinephrine on Lipid Emulsion-mediated resuscitation, 5) a description of the recommended Lipid Emulsion treatment, and 6) a conclusion.
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A Lipid Emulsion Reverses Toxic-Dose Bupivacaine-Induced Vasodilation during Tyrosine Phosphorylation-Evoked Contraction in Isolated Rat Aortae.
International Journal of Molecular Sciences, 2017Co-Authors: Soo Hee Lee, Seong-chun Kwon, Mun Hwan Choi, Il-woo Shin, Sebin Kang, Miyeong Park, Jeong-min Hong, Ju-tae SohnAbstract:The goal of this in vitro study was to examine the effect of a Lipid Emulsion on toxic-dose bupivacaine-induced vasodilation in a model of tyrosine phosphatase inhibitor sodium orthovanadate-induced contraction in endothelium-denuded rat aortae and to elucidate the associated cellular mechanism. The effect of a Lipid Emulsion on vasodilation induced by a toxic dose of a local anesthetic during sodium orthovanadate-induced contraction was examined. In addition, the effects of various inhibitors, either bupivacaine alone or a Lipid Emulsion plus bupivacaine, on protein kinase phosphorylation induced by sodium orthovanadate in rat aortic vascular smooth muscle cells was examined. A Lipid Emulsion reversed the vasodilation induced by bupivacaine during sodium orthovanadate-induced contraction. The Lipid Emulsion attenuated the bupivacaine-mediated inhibition of the sodium orthovanadate-induced phosphorylation of protein tyrosine, c-Jun NH₂-terminal kinase (JNK), myosin phosphatase target subunit 1 (MYPT1), phospholipase C (PLC) γ-1 and extracellular signal-regulated kinase (ERK). These results suggest that a Lipid Emulsion reverses toxic-dose bupivacaine-induced vasodilation during sodium orthovanadate-induced contraction via the activation of a pathway involving either tyrosine kinase, JNK, Rho-kinase and MYPT1 or tyrosine kinase, PLC γ-1 and ERK, and this reversal is associated with the Lipid solubility of the local anesthetic and the induction of calcium sensitization.
Guy L Weinberg - One of the best experts on this subject based on the ideXlab platform.
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confusion about infusion rational volume limits for intravenous Lipid Emulsion during treatment of oral overdoses
Annals of Emergency Medicine, 2015Co-Authors: Michael R. Fettiplace, Israel Rubinstein, Belinda S Akpa, Guy L WeinbergAbstract:After the initial report of treatment of bupropion and lamotrigine overdose by intravenous Lipid Emulsion, additional case reports have asserted the usefulness of Lipid Emulsion for enteral poisonings. In accordance with these and other reports, the American College of Medical Toxicology offered interim guidelines on Lipid resuscitation therapy; they recommended a bolus of 1.5 mL/kg, followed by an infusion of 0.25 mL/kg/min of intravenous Lipid Emulsion if toxicity persists. This recommendation was based on guidelines for treatment of local anesthetic toxicity, in which absorption is quick and toxicity short lived. In contrast to local anesthetic toxicity, prolonged absorption during enteral overdose can result in extended toxicity, with a need for continuing medical support, including a protracted infusion of Lipid Emulsion. Guidelines for Lipid resuscitation therapy in local anesthetic toxicity set an upper limit of 10 to 12 mL/kg during the first half hour, but because of the aforementioned nature of oral overdoses, the American College of Medical Toxicology did not provide a limit on total Lipid infusion volume or duration of infusion. In the absence of limits, an increasing number of cases have reported the use of large volumes of Lipid to treat oral overdose. However, until definitive studies can be conducted, there is a need for rational volume limits to prevent undisciplined use of intravenous Lipid Emulsion. With the increased adoption of Lipid resuscitation therapy, several case reports have identified the potential usefulness of prolonged Lipid infusions for enteral toxicity. In the largest aggregation of cases, Cave et al reported that intravenous Lipid Emulsion improved Glasgow Coma Scale ratings and increased systolic blood pressure during treatment of nonlocal anesthetic overdose in 38 patients. The average dose of Lipid used in these cases was 531 mL (SD 22 mL), which is within ranges recommended by professional societies. With these doses, there were no significant adverse effects except interference with laboratory tests because of lipemia
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Lipid Emulsion rapidly restores contractility in stunned mouse cardiomyocytes: A comparison with therapeutic hypothermia
Critical care medicine, 2014Co-Authors: Michael R. Fettiplace, Guy L Weinberg, Sy Jou Chen, Benjamin Steinhorn, Zuo-hui Shao, Xiangdong Zhu, Shaun Harty, Terry L. Vanden HoekAbstract:OBJECTIVES Cooling following cardiac arrest can improve survival significantly. However, delays in achieving target temperature may decrease the overall benefits of cooling. Here, we test whether Lipid Emulsion, a clinically approved drug reported to exert cardioprotection, can rescue heart contractility in the setting of delayed cooling in stunned mouse cardiomyocytes. DESIGN Cell culture study. SETTING Academic research laboratory. SUBJECTS Cardiomyocytes isolated from 1- to 2-day-old C57BL6 mice. INTERVENTIONS Cardiomyocytes were exposed to 30 minutes of ischemia followed by 90 minutes of reperfusion and 10 minutes of isoproterenol with nine interventions: 1) no additional treatment; 2) intraischemic cooling at 32 °C initiated 10 minutes prior to reperfusion; 3) delayed cooling started 20 minutes after reperfusion; 4) Lipid Emulsion + delayed cooling; 5) Lipid Emulsion (0.25%) administered at reperfusion; 6) Lipid Emulsion + intraischemic cooling; 7) delayed Lipid Emulsion; 8) Lipid Emulsion + delayed cooling + Akt inhibitor (API-2, 10 µM); and 9) Lipid Emulsion + delayed cooling + Erk inhibitor (U0126, 10 µM). Inhibitors were given to cells 1 hour prior to ischemia. MEASUREMENTS AND MAIN RESULTS Contractility was recorded by real-time phase-contrast imaging and analyzed with pulse image velocimetry in MATLAB (Mathworks, Natick, MA). Ischemia diminished cell contraction. The cardioprotective effect of cooling was diminished when delayed but was rescued by Lipid Emulsion. Further, Lipid Emulsion on its own improved recovery of the contractility to a greater extent as intraischemic cooling. However, cotreatment of Lipid Emulsion and intraischemic cooling did not further improve the recovery compared to either treatment alone. Furthermore, Akt and Erk inhibitors blocked Lipid Emulsion-induced protection. CONCLUSIONS Lipid Emulsion improved contractility and rescued contractility in the context of delayed cooling. This protective effect required Akt and Erk signaling. Lipid Emulsion might serve as a treatment or adjunct to cooling in ameliorating myocardial ischemia/reperfusion injury.
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Intraosseous Lipid Emulsion: an effective alternative to IV delivery in emergency situations.
Critical care medicine, 2014Co-Authors: Michael R. Fettiplace, Richard Ripper, Kinga Lis, Israel Rubinstein, Douglas L. Feinstein, Guy L WeinbergAbstract:OBJECTIVE To determine whether intraosseous infusion of a Lipid Emulsion reverses cardiac pharmacotoxicity in anaesthetized rats. DESIGN Prospective, randomized animal study. SETTING Academic research laboratory. SUBJECTS Adult, male Sprague-Dawley rats. INTERVENTIONS We assigned 25 male Sprague-Dawley rats into four groups: intraosseous Lipid Emulsion, intraosseous saline, IV Lipid Emulsion, and sham/null. Rats were anesthetized with 1.5% isoflurane and 95% oxygen. The left internal carotid artery and both internal jugular veins were cannulated and a flow probe was placed on the right carotid artery. Subsequently, in animals assigned to the intraosseous groups, the greater trochanter of the left proximal femur was exposed and the intraosseous space was cannulated. After surgical recovery, bupivacaine (10 mg/kg) was injected IV over 20 seconds followed 10 seconds later by treatment with one of the following: intraosseous Lipid-Emulsion (10 mL/kg over 180 s), intraosseous saline (10 mL/kg over 180 s), IV Lipid-Emulsion (10 mL/kg over 90 s), or no treatment (sham/null). MEASUREMENTS AND MAIN RESULTS Electrocardiogram, aortic blood pressure, and carotid blood flow were recorded continuously. Rats treated with intraosseous Lipid Emulsion experienced a significantly faster recovery of hemodynamic variables (return of 50% flow; median [CI]: 160 s [105-263 s]) than did rats treated with saline (471 s [283-611 s]; p < 0.05) or animals with no treatment (415 s [340-539 s], p < 0.05), but at a similar rate to animals treated with IV Lipid Emulsion (176 s [152-217 s], p = not significant). All groups experienced persistent negative chronotropic effects. A compensatory increase in systemic arterial pressure was observed in rats treated with Lipid Emulsion. CONCLUSION These proof-of-principle data indicate that intraosseous infusion of Lipid Emulsion rapidly reverses bupivacaine-induced cardiac toxicity in rats. Further studies are warranted to optimize this novel route of Lipid Emulsion injection in emergency situations when intravascular access is not secured.
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Rapid cardiotonic effects of Lipid Emulsion infusion
Critical care medicine, 2013Co-Authors: Michael R. Fettiplace, Jing Wang, Richard Ripper, Kinga Lis, Bocheng Lin, Jason Lang, Brian Zider, Israel Rubinstein, Guy L WeinbergAbstract:Objectives:Bolus infusion of Lipid Emulsion can reverse cardiac pharmacotoxicity caused by local anesthetics and other lipophilic drugs. The mechanisms of this effect are not completely elucidated. The authors test the hypothesis that Lipid Emulsion infusion exerts direct, positive inotropic effects
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Availability of Lipid Emulsion in United States Obstetric Units
Anesthesia and analgesia, 2012Co-Authors: Paloma Toledo, Heather C. Nixon, Jill M. Mhyre, Cynthia A. Wong, Guy L WeinbergAbstract:BACKGROUND:Lipid Emulsion is recommended in the guidelines for the management of local anesthetic systemic toxicity. In this study, we sought to identify the current level of Lipid Emulsion availability in U.S. obstetric units.METHODS:A survey was developed addressing Lipid Emulsion availability and
Susan J. Skledar - One of the best experts on this subject based on the ideXlab platform.
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use of Lipid Emulsion to reverse local anesthetic induced toxicity
Annals of Pharmacotherapy, 2007Co-Authors: Shelby L. Corman, Susan J. SkledarAbstract:Objective:To evaluate the use of Lipid Emulsion for reversal of local anesthetic–induced toxicity.Data Sources:Literature was accessed through PubMed and OVID (1966–May 2007) using the search terms Lipid Emulsion and local anesthetic. Reference lists were consulted to identify additional publications.Study Selection and Data Extraction:All articles published in English were evaluated for inclusion. Publications describing the use of Lipid Emulsion for reversal of local anesthetic in either humans or animals were included.Data Synthesis:It has been suggested that Lipid Emulsion (IntraLipid) may reverse local anesthetic toxicity by extracting lipophilic local anesthetics from aqueous plasma or tissues or by counteracting local anesthetic inhibition of myocardial fatty acid oxygenation. Studies in rats and dogs have shown that Lipid Emulsion is effective in resuscitating animals who are asystolic after the administration of intravenous bupivacaine. Three case reports support the use of Lipid Emulsion to reve...
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Use of Lipid Emulsion to Reverse Local Anesthetic–Induced Toxicity
The Annals of pharmacotherapy, 2007Co-Authors: Shelby L. Corman, Susan J. SkledarAbstract:Objective:To evaluate the use of Lipid Emulsion for reversal of local anesthetic–induced toxicity.Data Sources:Literature was accessed through PubMed and OVID (1966–May 2007) using the search terms Lipid Emulsion and local anesthetic. Reference lists were consulted to identify additional publications.Study Selection and Data Extraction:All articles published in English were evaluated for inclusion. Publications describing the use of Lipid Emulsion for reversal of local anesthetic in either humans or animals were included.Data Synthesis:It has been suggested that Lipid Emulsion (IntraLipid) may reverse local anesthetic toxicity by extracting lipophilic local anesthetics from aqueous plasma or tissues or by counteracting local anesthetic inhibition of myocardial fatty acid oxygenation. Studies in rats and dogs have shown that Lipid Emulsion is effective in resuscitating animals who are asystolic after the administration of intravenous bupivacaine. Three case reports support the use of Lipid Emulsion to reve...
Mark Puder - One of the best experts on this subject based on the ideXlab platform.
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essential fatty acid status in surgical infants receiving parenteral nutrition with a composite Lipid Emulsion a case series
Journal of Parenteral and Enteral Nutrition, 2019Co-Authors: Kathleen M. Gura, Mark Puder, Alexandra N Carey, Coral Rudie, Paul Mitchell, Bram P RaphaelAbstract:: Infants requiring prolonged parenteral nutrition (PN) may receive intravenous (IV) Lipid in the form of soybean oil, fish oil, or a composite Lipid Emulsion (CLE) (i.e., SMOFLipid®). Soybean oil Lipid-dose restriction is a popular method of treating and reducing the risk of intestinal failure-associated liver disease (IFALD) that may influence dosing strategies of other IV fat Emulsions. Here we present 4 infants receiving PN with SMOFLipid® as their IV Lipid source and examine trends in essential fatty-acid status, triglycerides, and dosing strategy. The infants on restricted doses of CLE developed biochemical essential fatty-acid deficiency (EFAD) that resolved with a dosage increase or by transition to a pure fish-oil Lipid Emulsion. Three of the 4 infants originally prescribed CLE were diagnosed with IFALD and started a pure fish-oil Lipid Emulsion after treatable causes of cholestasis were excluded. One of the 4 infants presented with hypertriglyceridemia that resolved upon transition to pure fish-oil Lipid Emulsion. Misapplication of Lipid restriction protocols to CLE regimens render infants at risk for EFAD. CLE should be dosed within recommended ranges to prevent EFAD. Restricted protocols warrant close monitoring of essential fatty-acid status in infants receiving prolonged PN, particularly in those with minimal or no enteral intake. Hypertriglyceridemia and cholestasis are known adverse effects of CLE and require monitoring.
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intravenous fish oil Lipid Emulsion promotes a shift toward anti inflammatory proresolving Lipid mediators
American Journal of Physiology-gastrointestinal and Liver Physiology, 2013Co-Authors: Brian T Kalish, Kathleen M. Gura, Jonathan M Fitzgerald, Samantha Wang, Kyle J Seamon, Karsten Gronert, Mark PuderAbstract:Parenteral nutrition (PN)-associated liver disease (PNALD) is a life-threatening complication of the administration of PN. The development of PNALD may be partly due to the composition of the Lipid Emulsion administered with PN: soybean oil-based Lipid Emulsions (SOLE) are associated with liver disease, while fish oil-based Lipid Emulsions (FOLE) are associated with prevention and improvement of liver disease. The objective of this study was to determine how the choice of Lipid Emulsion modified the production of bioactive Lipid mediators (LMs). We utilized a mouse model of steatosis to study the differential effect of FOLE and SOLE. We subsequently validated these results in serum samples from a small cohort of human infants transitioning from SOLE to FOLE. In mice, FOLE was associated with production of anti-inflammatory, proresolving LMs; SOLE was associated with increased production of inflammatory LMs. In human infants, the transition from SOLE to FOLE was associated with a shift toward a proresolving Lipidome. Together, these results demonstrate that the composition of the Lipid Emulsion directly modifies inflammatory homeostasis.
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provision of a soy based intravenous Lipid Emulsion at 1 g kg d does not prevent cholestasis in neonates
Journal of Parenteral and Enteral Nutrition, 2013Co-Authors: Deepika Nehra, Kathleen M. Gura, Paul Mitchell, Erica M Fallon, Sarah J Carlson, Alexis K Potemkin, Nathanael D Hevelone, Mark PuderAbstract:Background: One of the most common and severe complications of long-term parenteral nutrition (PN) is PN-associated cholestasis. The soybean oil–based Lipid Emulsion administered with PN has been associated with cholestasis, leading to an interest in Lipid reduction strategies. The purpose of this study was to determine whether the provision of a soybean oil–based Lipid Emulsion at 1 g/kg/d compared with 2–3 g/kg/d is associated with a reduced incidence of cholestasis. Methods: Retrospective review of neonates admitted between 2007 and 2011 with a gastrointestinal condition necessitating ≥21 days of PN support. Neonates were divided into 2 groups based on the intravenous Lipid Emulsion dose: 1-g group (1 g/kg/d) and 2- to 3-g group (2–3 g/kg/d). The primary outcome measure was the incidence of cholestasis. Results: Sixty-one patients met inclusion criteria (n = 29, 1-g group; n = 32, 2- to 3-g group). The 2 groups did not differ in any baseline characteristics other than associated comorbidities that were...
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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Lipid Emulsion improves survival in animal models of local anesthetic toxicity a meta analysis
Clinical Toxicology, 2017Co-Authors: Michael R. Fettiplace, Daniel J MccabeAbstract:AbstractIntroduction: The Lipid Emulsion Therapy workgroup, organized by the American Academy of Clinical Toxicology, recently conducted a systematic review, which subjectively evaluated Lipid Emulsion as a treatment for local anesthetic toxicity. We re-extracted data and conducted a meta-analysis of survival in animal models.Methods: We extracted survival data from 26 publications and conducted a random-effect meta-analysis based on odds ratio weighted by inverse variance. We assessed the benefit of Lipid Emulsion as an independent variable in resuscitative models (16 studies). We measured Cochran’s Q for heterogeneity and I2 to determine variance contributed by heterogeneity. Finally, we conducted a funnel plot analysis and Egger’s test to assess for publication bias in studies.Results: Lipid Emulsion reduced the odds of death in resuscitative models (OR =0.24; 95%CI: 0.1–0.56, p = .0012). Heterogeneity analysis indicated a homogenous distribution. Funnel plot analysis did not indicate publication bias ...
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confusion about infusion rational volume limits for intravenous Lipid Emulsion during treatment of oral overdoses
Annals of Emergency Medicine, 2015Co-Authors: Michael R. Fettiplace, Israel Rubinstein, Belinda S Akpa, Guy L WeinbergAbstract:After the initial report of treatment of bupropion and lamotrigine overdose by intravenous Lipid Emulsion, additional case reports have asserted the usefulness of Lipid Emulsion for enteral poisonings. In accordance with these and other reports, the American College of Medical Toxicology offered interim guidelines on Lipid resuscitation therapy; they recommended a bolus of 1.5 mL/kg, followed by an infusion of 0.25 mL/kg/min of intravenous Lipid Emulsion if toxicity persists. This recommendation was based on guidelines for treatment of local anesthetic toxicity, in which absorption is quick and toxicity short lived. In contrast to local anesthetic toxicity, prolonged absorption during enteral overdose can result in extended toxicity, with a need for continuing medical support, including a protracted infusion of Lipid Emulsion. Guidelines for Lipid resuscitation therapy in local anesthetic toxicity set an upper limit of 10 to 12 mL/kg during the first half hour, but because of the aforementioned nature of oral overdoses, the American College of Medical Toxicology did not provide a limit on total Lipid infusion volume or duration of infusion. In the absence of limits, an increasing number of cases have reported the use of large volumes of Lipid to treat oral overdose. However, until definitive studies can be conducted, there is a need for rational volume limits to prevent undisciplined use of intravenous Lipid Emulsion. With the increased adoption of Lipid resuscitation therapy, several case reports have identified the potential usefulness of prolonged Lipid infusions for enteral toxicity. In the largest aggregation of cases, Cave et al reported that intravenous Lipid Emulsion improved Glasgow Coma Scale ratings and increased systolic blood pressure during treatment of nonlocal anesthetic overdose in 38 patients. The average dose of Lipid used in these cases was 531 mL (SD 22 mL), which is within ranges recommended by professional societies. With these doses, there were no significant adverse effects except interference with laboratory tests because of lipemia
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resuscitation with Lipid Emulsion dose dependent recovery from cardiac pharmacotoxicity requires a cardiotonic effect
Anesthesiology, 2014Co-Authors: Michael R. Fettiplace, Richard Ripper, Jason Lang, Brian Zider, Israel Rubinstein, Belinda S Akpa, Guy WeinbergAbstract:Background Recent publications have questioned the validity of the "Lipid sink" theory of Lipid resuscitation while others have identified sink-independent effects and posed alternative mechanisms such as hemodilution. To address these issues, the authors tested the dose-dependent response to intravenous Lipid Emulsion during reversal of bupivacaine-induced cardiovascular toxicity in vivo. Subsequently, the authors modeled the relative contribution of volume resuscitation, drug sequestration, inotropy and combined drug sequestration, and inotropy to this response with the use of an in silico model. Methods Rats were surgically prepared to monitor cardiovascular metrics and deliver drugs. After catheterization and instrumentation, animals received a nonlethal dose of bupivacaine to produce transient cardiovascular toxicity, then were randomized to receive one of the four treatments: 30% intravenous Lipid Emulsion, 20% intravenous Lipid Emulsion, intravenous saline, or no treatment (n = 7 per condition; 28 total animals). Recovery responses were compared with the predictions of a pharmacokinetic-pharmacodynamic model parameterized using previously published laboratory data. Results Rats treated with Lipid Emulsions recovered faster than did rats treated with saline or no treatment. Intravenous Lipid Emulsion of 30% elicited the fastest hemodynamic recovery followed in order by 20% intravenous Lipid Emulsion, saline, and no treatment. An increase in arterial blood pressure underlay the recovery in both Lipid Emulsion-treated groups. Heart rates remained depressed in all four groups throughout the observation period. Model predictions mirrored the experimental recovery, and the model that combined volume, sequestration, and inotropy predicted in vivo results most accurately. Conclusion Intravenous Lipid Emulsion accelerates cardiovascular recovery from bupivacaine toxicity in a dose-dependent manner, which is driven by a cardiotonic response that complements the previously reported sequestration effect.
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Lipid Emulsion rapidly restores contractility in stunned mouse cardiomyocytes: A comparison with therapeutic hypothermia
Critical care medicine, 2014Co-Authors: Michael R. Fettiplace, Guy L Weinberg, Sy Jou Chen, Benjamin Steinhorn, Zuo-hui Shao, Xiangdong Zhu, Shaun Harty, Terry L. Vanden HoekAbstract:OBJECTIVES Cooling following cardiac arrest can improve survival significantly. However, delays in achieving target temperature may decrease the overall benefits of cooling. Here, we test whether Lipid Emulsion, a clinically approved drug reported to exert cardioprotection, can rescue heart contractility in the setting of delayed cooling in stunned mouse cardiomyocytes. DESIGN Cell culture study. SETTING Academic research laboratory. SUBJECTS Cardiomyocytes isolated from 1- to 2-day-old C57BL6 mice. INTERVENTIONS Cardiomyocytes were exposed to 30 minutes of ischemia followed by 90 minutes of reperfusion and 10 minutes of isoproterenol with nine interventions: 1) no additional treatment; 2) intraischemic cooling at 32 °C initiated 10 minutes prior to reperfusion; 3) delayed cooling started 20 minutes after reperfusion; 4) Lipid Emulsion + delayed cooling; 5) Lipid Emulsion (0.25%) administered at reperfusion; 6) Lipid Emulsion + intraischemic cooling; 7) delayed Lipid Emulsion; 8) Lipid Emulsion + delayed cooling + Akt inhibitor (API-2, 10 µM); and 9) Lipid Emulsion + delayed cooling + Erk inhibitor (U0126, 10 µM). Inhibitors were given to cells 1 hour prior to ischemia. MEASUREMENTS AND MAIN RESULTS Contractility was recorded by real-time phase-contrast imaging and analyzed with pulse image velocimetry in MATLAB (Mathworks, Natick, MA). Ischemia diminished cell contraction. The cardioprotective effect of cooling was diminished when delayed but was rescued by Lipid Emulsion. Further, Lipid Emulsion on its own improved recovery of the contractility to a greater extent as intraischemic cooling. However, cotreatment of Lipid Emulsion and intraischemic cooling did not further improve the recovery compared to either treatment alone. Furthermore, Akt and Erk inhibitors blocked Lipid Emulsion-induced protection. CONCLUSIONS Lipid Emulsion improved contractility and rescued contractility in the context of delayed cooling. This protective effect required Akt and Erk signaling. Lipid Emulsion might serve as a treatment or adjunct to cooling in ameliorating myocardial ischemia/reperfusion injury.