Validity of the Lipid Sink as a Mechanism for the Reversal of Local Anesthetic Systemic Toxicity

Kuo, I‐Lin; Akpa, Belinda S.

doi:10.1097/aln.0b013e31828ce74d

Cited by 70 publications

(55 citation statements)

References 33 publications

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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: Mechanismsupporting

confidence: 55%

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

Oda

2013

J Anesth

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Section: Mechanismsupporting

confidence: 55%

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

Oda

2013

J Anesth

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“…While the mechanism of ILE action is debatable, case reports support ILE efficacy in acute verapamil poisoning [19]. A number of mechanisms have been proposed: simple serum volume expansion, ILE particles sequestering the lipophilic drug akin to a Blipid sink^, enhanced drug distribution, increased hepatic drug metabolism, inotropic action due to increased cardiac fat metabolism, and increase of L-type Ca 2+ current by direct action of free fatty acids [21][22][23]. Our in vitro studies are most consistent with ILE acting as a lipid sink: 0.5 % ILE rapidly reversed verapamil-induced Ca 2+ channel block and restored myocyte contractility despite the continued presence of verapamil in the experimental solutions (Fig.…”

Section: Discussionmentioning

confidence: 99%

In Vitro Studies Indicate Intravenous Lipid Emulsion Acts as Lipid Sink in Verapamil Poisoning

et al. 2015

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Intravenous lipid emulsion (ILE), a component of parenteral nutrition, consists of a fat emulsion of soy bean oil, egg phospholipids, and glycerin. Case reports suggest that ILE may reverse hypotension caused by acute poisoning with lipophilic drugs such as verapamil, but the mechanism remains unclear. The methods used are the following: (1) measurement of ILE concentration in serum samples from a patient with verapamil poisoning treated with ILE, (2) measurement of free verapamil concentrations in human serum mixed in vitro with increasing concentrations of ILE, and (3) measurement of murine ventricular cardiomyocyte L-type Ca 2+ currents, intracellular Ca 2+ , and contractility in response to verapamil and/or ILE. Maximum patient serum ILE concentration after infusion of 1 L ILE over 1 h was approximately 1.6 vol%. In vitro GC/ MS verapamil assays showed that addition of ILE (0.03-5.0 vol%) dose-dependently decreased the free verapamil concentration in human serum. In voltage-clamped myocytes, adding ILE to Tyrode's solution containing 5 μM verapamil recovered L-type Ca 2+ currents (I Ca ). Recovery was concentration dependent, with significant I Ca recovery at ILE concentrations as low as 0.03 vol%. ILE had no effect on I Ca in the absence of verapamil. In field-stimulated intact ventricular myocytes exposed to verapamil, adding ILE (0.5 %) resulted in a rapid and nearly complete recovery of myocyte contractility and intracellular Ca 2+ . Our in vitro studies indicate that ILE acts as a lipid sink that rapidly reverses impaired cardiomyocyte contractility in the continued presence of verapamil.

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“…In a series of follow-up studies, the protective effect of emulsion against cardiotoxicity caused by local anesthetics has been confirmed in various animal models. The proposed mechanisms included "lipid sink" theory (12,13) and improved metabolic status (14).…”

Section: Discussionmentioning

confidence: 99%

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

Gong¹,

Wang²,

Liu³

et al. 2017

J Anesth Perioper Med

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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.

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Validity of the Lipid Sink as a Mechanism for the Reversal of Local Anesthetic Systemic Toxicity

Abstract: Results suggest that the timescale on which tissue content is reduced varies from organ to organ, with the concentration in the heart falling by 11% within 3 min. This initial study suggests that, in isolation, the lipid sink is insufficient to guarantee a reversal of systemic toxicity.

Cited by 70 publications

References 33 publications

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

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

In Vitro Studies Indicate Intravenous Lipid Emulsion Acts as Lipid Sink in Verapamil Poisoning

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

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