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

Shi, Kenrin; Xia, Yun; Wang, Quanguang; Wu, Yiquan; Dong, Xiaoxi; Chen, Chanjuan; Tang, Wan Yee; Zhang, Yujian; Luo, Mengxu; Wang, Xianqin; Papadimos, Thomas J.; Xu, Xuzhong

doi:10.1213/ane.0b013e318284123e

Cited by 80 publications

(65 citation statements)

References 23 publications

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“…The median individual increase per patient in GCS was 2 points. This effect is consistent with animal models demonstrating decreased brain drug levels when ILE is administered after initial drug distribution [28,29]. While promising, these observations do not hold direct clinical utility.…”

Section: Discussionsupporting

confidence: 74%

LIPAEMIC Report: Results of Clinical Use of Intravenous Lipid Emulsion in Drug Toxicity Reported to an Online Lipid Registry

et al. 2014

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The use of intravenous lipid emulsion (ILE) as an antidote has prompted significant academic and clinical interest. Between August 2009 and August 2012, data from cases of ILE use in intoxicated patients in different hospitals on different continents were voluntarily entered into a registry based on the world wide web (www.lipidregistry.org). Here, we report data from this project. Participating centers were given access to the registry following institutional subscription. Specifically sought were details of the individual patients' presenting condition, indications for ILE use, ILE administration regimen, potential complications, and of clinical outcome. Forty-eight uses of ILE were reported from 61 participating centers. Ten cases of local anesthetic systemic toxicity were reported; all (10/10) survived. Thirtyeight cases of intoxication by other agents were reported [30 decreased conscious state, 8 cardiovascular collapse (3 deaths)]. There was an elevation in GCS (p<0.0001) and increased systolic blood pressure (p=0.012) from immediately prior to ILE administration to 30 min after use. One serious and two minor adverse effects of ILE use were recorded in 48 reported cases (one case of bronchospastic reaction, one case of hyperamylasemia and one case of interference with laboratory testing). In this series of cases reported to the registry, improvements were seen for GCS in patients with central nervous system toxicity and in systolic blood pressure in shocked patients over a short time frame after the injection of ILE. Few adverse effects were recorded. Clinical trials and the reporting of drug concentrations after ILE use are necessary to further elucidate the role of ILE in clinical toxicology.

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Section: Discussionsupporting

confidence: 74%

LIPAEMIC Report: Results of Clinical Use of Intravenous Lipid Emulsion in Drug Toxicity Reported to an Online Lipid Registry

et al. 2014

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“…Shi et al 11 have shown decreased target organ bupivacaine concentrations, in addition to increased hepatic bupivacaine concentrations following ILE infusion in intact rats. Measured elimination half-life decreased and clearance rate increased, consistent with the forwarded hypothesis of augmented redistribution.…”

Section: Discussionmentioning

confidence: 99%

Comparison of Intravenous Lipid Emulsion, Bicarbonate, and Tailored Liposomes in Rabbit Clomipramine Toxicity

Cave

Harvey

Shaw

et al. 2013

Academic Emergency Medicine

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Objectives: Liposome (LIP)-like lipid dispersions have emerged as useful detoxification vehicles in vitro. The authors compare resuscitation with tailored LIPs, 20% intravenous lipid emulsion (ILE), and sodium bicarbonate (BIC), in a rabbit model of clomipramine toxicity.Methods: Sedated, instrumented New Zealand white rabbits underwent clomipramine infusion at 3.2 mg/kg/min to 50% baseline mean arterial pressure (MAP) and then at 1.6 mg/kg/min for 30 minutes. BIC (3 mL/kg 8.4%), ILE (3 mL/kg 20%), or LIP (24 mg/kg) were infused as rescue treatments at toxicity and were repeated at 10 minutes (n = 5 in each group). remains a difficult therapeutic challenge. Mainstays of therapy include aggressive supportive care and sodium bicarbonate (BIC)-initiated systemic alkalinization. 1 More recently, intravenous lipid emulsion (ILE) preparations have been forwarded as adjuncts to standard management of TCA toxicity with successful reports of use in animal models 2 and human subjects. 3 Both pharmacokinetic and pharmacodynamic mechanisms have been forwarded to explain the beneficial effects of ILE. The widely held lipid sink theory is that lipid sequesters certain xenobiotics (such as TCAs) and reduces toxicity by decreasing the free serum concentration of the offending toxin. 4,5 Liposomes are spherical vesicles of phospholipids and effectively sequester amitriptyline and imipramine in vitro. 6,7 Specific advantages afforded by liposomes (LIPs) include increased surface area:volume ratios, the ability to modulate surface charge and internal pH, and the inherent lipid bilayer structure. To date, however, there are limited data on the antidotal efficacy of liposomal formulations in intact animal models.We examined the effect of LIPs in an established animal model of TCA toxicity. Specifically, in this study we compare resuscitation with bicarbonate (BIC), ILE, and LIPs in a previously studied rabbit model of clomipramineinduced shock. METHODS Study DesignThis was a laboratory study of clomipramine-induced cardiotoxicity in a rabbit model. The study was approved by the institutional ethics committee of the

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“…Lipid emulsion also substantially reduced methemoglobin production caused by the three most lipid soluble drugs tested, but not by the other less lipid soluble ones in vitro [19]. Recently, enhanced decrease of the concentration of bupivacaine in multiple organs including the brain and heart by lipid emulsion was shown in rats and in a physiologically based pharmacokinetic model [13,20]. Taken together, these studies support the role of partitioning in lipid resuscitation in treating bupivacaine toxicity and overdose of other lipophilic drugs.…”

Section: Mechanismmentioning

confidence: 58%

“…The primary objective of these animal studies was to elucidate the mechanisms of reversal of the toxic effects of local anesthetics, apart from merely examining the effect of lipid emulsion on their toxicity [11][12][13][14][15]. Two distinct effects, partitioning and enhanced metabolism, have been suggested as possible mechanisms of the antidote effect of lipid emulsion, although the effects are complicated and cannot be explained simply [8].…”

Section: Mechanismmentioning

confidence: 99%

“…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][12][13][14]. In contrast, awake, spontaneously breathing animals are needed to observe its effect on the central nervous system toxicity [15].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Oda

2013

J Anesth

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

Abstract: The lipid sink phenomenon was observed in this study. The use of a lipid emulsion accelerated the elimination of bupivacaine.

Cited by 80 publications

References 23 publications

LIPAEMIC Report: Results of Clinical Use of Intravenous Lipid Emulsion in Drug Toxicity Reported to an Online Lipid Registry

LIPAEMIC Report: Results of Clinical Use of Intravenous Lipid Emulsion in Drug Toxicity Reported to an Online Lipid Registry

Comparison of Intravenous Lipid Emulsion, Bicarbonate, and Tailored Liposomes in Rabbit Clomipramine Toxicity

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

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