I read with great interest the excellent article titled, “Local anesthetic systemic toxicity: awareness, recognition, and risk mitigation in the emergency department,” recently published in Clinical and Experimental Emergency Medicine [1]. Lipid emulsions are widely used to treat local anesthetic systemic toxicity (LAST) [2]. Furthermore, they have been reported to mitigate cardiovascular collapse induced by toxic doses of nonlocal anesthetics with high lipid solubility (log P = log [octanol/water partition coefficient], >2), when such collapse is unresponsive to supportive treatments [2]. In this context, I would like to comment on the direct effects of lipid emulsion treatment on LAST. The underlying mechanisms of lipid emulsion therapy for LAST involve both indirect and direct effects [2]. The indirect effect, known as the lipid shuttle, involves absorption of highly lipid-soluble drugs (e.g., bupivacaine, with a log P of 3.41) from the brain and heart into the lipid phase of the emulsion. These lipid emulsions are then transported to the liver, muscles, and adipose tissues for detoxification and storage [2]. Additionally, the direct effects of lipid emulsion therapy include enhanced heart contractility, provision of fatty acids, reduction of mitochondrial dysfunction, phosphorylation of glycogen synthase kinase-3β (GSK-3β), and suppression of nitric oxide (NO) [2]. A summary of the direct effects of lipid emulsions is provided below.

First, lipid emulsion alone enhances the maximum rates of increase and decrease in left ventricular pressure, resulting in both positive inotropic and lusitropic effects [3]. Pretreatment with lipid emulsion alone induces an increase in left ventricular systolic pressure, seemingly mediated by the inhibition of NO release [4]. Toxic doses of local anesthetics such as bupivacaine and ropivacaine induce negative inotropic and lusitropic effects, ultimately leading to cardiac arrest [5]. Therefore, the direct inotropic and lusitropic effects of lipid emulsions contribute to the attenuation of myocardial depression induced by toxic doses of local anesthetics.

Second, lipid emulsions containing either long-chain fatty acids alone or a combination of long- and medium-chain fatty acids provide fatty acid supply and inhibit mitochondrial dysfunction [2]. Long-chain fatty acids, which supply 60% to 90% of the energy utilized by the adult fasting heart, generate adenosine triphosphate (ATP) through the following steps [6]:

• Delivery of long-chain fatty acids to the cytoplasm through fatty acid transport proteins in the plasma membrane.

• Conversion to long-chain fatty acyl CoA from long-chain fatty acids by long-chain fatty acid CoA synthase.

• Formation of long-chain fatty acylcarnitine from long-chain fatty acyl CoA and carnitine by carnitine palmitoyltransferase I, followed by transport to the mitochondrial intermembrane space.

• Transportation of long-chain fatty acylcarnitine to the mitochondrial matrix by carnitine acylcarnitine translocase.

• Splitting of long-chain fatty acylcarnitine into long-chain fatty acyl CoA and carnitine by carnitine palmitoyltransferase II.

• Return of carnitine to the cytoplasm by carnitine acylcarnitine translocase.

• Production of ATP from long-chain fatty acyl CoA through fatty acid β-oxidation, the tricarboxylic acid cycle, and the electron transport chain.

However, toxic doses of bupivacaine inhibit carnitine acylcarnitine translocase, leading to impaired ATP production [7] and complex I of the mitochondrial respiratory chain [8]. Conversely, lipid emulsion enhances carnitine acylcarnitine translocase activity and reverses bupivacaine-induced mitochondrial membrane depolarization by inhibiting reactive oxygen species [9]. Additionally, pretreatment with ATP restores the bupivacaine-induced decrease in inotropic function [10]. These findings suggest that fatty acid supply and the attenuation of mitochondrial dysfunction contribute to lipid emulsion-mediated recovery from bupivacaine-induced myocardial depression.

Third, lipid emulsion induces cardiac protection from ischemic injury through GSK-3β phosphorylation and subsequent inhibition of mitochondrial permeability transition pore opening [11]. This process is mediated by pathways involving phosphoinositide-3 kinase, Akt, and extracellular signal-regulated kinase [11]. Furthermore, lipid emulsion inhibits toxic doses of bupivacaine-induced apoptotic cell death in rat cardiomyoblasts by preventing mitochondrial permeability transition pore opening through the same signaling pathways [12].

Finally, lipid emulsions alone increase blood pressure, decrease arterial compliance, increase vascular resistance, and reduce flow-mediated vasodilation, possibly due to inhibition of NO release [13,14]. As previously noted, amino amide local anesthetics cause vasoconstriction at low concentrations and vasodilation at high concentrations [1,15]. Lipid emulsions inhibit acetylcholine-induced NO-mediated vasodilation [16]. Toxic doses of bupivacaine and ropivacaine induce vasodilation (attenuated vasoconstriction), partially mediated by endothelial NO [17,18]. Additionally, lipid emulsions containing long-chain fatty acids alone or a 50:50 mixture of long- and medium-chain fatty acids reverse levobupivacaine-induced vasodilation by inhibiting NO release [19,20]. Toxic doses of levobupivacaine increase endothelial NO synthase (Ser1177) phosphorylation, whereas lipid emulsion attenuates this increase [19,20]. These results suggest that the lipid emulsion-mediated inhibition of NO release partially contributes to reversing levobupivacaine-induced vasodilation.

The widely accepted mechanism underlying lipid emulsion treatment for LAST is the indirect lipid shuttling effect. Additionally, lipid emulsions exert the direct effects mentioned above. Therefore, it is challenging to fully distinguish between lipid shuttling and other direct effects, as they often overlap. For example, lipid emulsions alleviate myocardial depression caused by toxic doses of bupivacaine through two mechanisms: (1) the lipid shuttle scavenges bupivacaine from the heart, contributing to recovery from cardiac depression; and (2) the direct inotropic effect of the lipid emulsion itself aids in the recovery from cardiac depression induced by the toxic dose of bupivacaine.

Therefore, to obtain clearer results from laboratory and clinical experiments, I suggest employing an experimental method that includes a lipid emulsion-only group and using high-performance liquid chromatography to measure the local anesthetic concentration in the aqueous phase of the lipid emulsion. This approach would facilitate a more accurate interpretation of the results.