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.

Currently, lipid emulsion (LE) is widely used to treat local anesthetic systemic toxicity (LAST). LE also ameliorates intractable cardiovascular collapse caused by lipid-soluble non-local anesthetic drug toxicity. This review aims to provide the underlying mechanism of LE resuscitation in drug toxicity (including LAST) and a detailed description of LE treatment and to discuss further research directions. We searched for relevant articles using the following keywords: “local anesthetic systemic toxicity or LAST or toxicity or intoxication or poisoning” and “Intralipid or lipid emulsion”. The underlying mechanisms of LE treatment can be classified into indirect and direct effects. One indirect effect known as the lipid shuttle is a commonly accepted mechanism of LE treatment. The lipid shuttle involves the absorption of highly lipid-soluble drugs (e.g., bupivacaine) from the heart and brain through the lipid phase, which are then delivered to the muscle, adipose tissue, and liver for storage and detoxification. The direct effects include inotropic effects, fatty acid supply, attenuation of mitochondrial dysfunction, glycogen synthase kinase-3β phosphorylation, and inhibition of nitric oxide. These mechanisms appear to act synergistically to treat drug toxicity. The recommended protocol for LE treatment of LAST is as follows: a bolus administration of 20% LE at 1.5 ml/kg over 2–3 min followed by 20% LE at 0.25 ml/kg/min. LAST most commonly occurs after intravenous administration of local anesthetics. However, non-local anesthetic drugs that cause drug toxicity are orally administered. Further studies are needed to determine the optimal dosing schedule of LE treatment for non-local anesthetic drug toxicity.

A high neutrophil-lymphocyte ratio (N/L ratio) was associated with the development of acute kidney injury (AKI) in patients with severe sepsis. We sought to investigate the association between the perioperative N/L ratios and postoperative AKI in patients undergoing high-risk cardiovascular surgery.A retrospective medical chart review was performed of 590 patients who underwent cardiovascular surgeries, including coronary artery bypass, valve replacement, patch closure for atrial or ventricular septal defect and surgery on the thoracic aorta with cardiopulmonary bypass (CPB). Baseline perioperative clinical parameters, including N/L ratios measured before surgery, immediately after surgery, and on postoperative day (POD) one were obtained. Multivariate logistic regression analysis was used to evaluate risk factors.A total of 166 patients (28.1%) developed AKI defined by the KDIGO (kidney disease improving global outcomes) criteria in the first 7 PODs. Independent risk factors for AKI included old age, decreased left ventricular systolic function, preoperative high serum creatinine, low serum albumin and high uric acid levels, intraoperative large transfusion amount, oliguria, hyperglycemia, and elevated N/L ratio measured immediately after surgery and on POD one. The quartiles of immediately postoperative N/L ratio were associated with graded increase in risk of AKI development (fourth quartile [N/L ratio≥10] multivariate odds ratio 5.90, 95% confidence interval [CI] 2.74-12.73; P < 0.001), a longer hospital stay, and a higher in-hospital and 1-year mortality rate (fourth quartile [N/L ratio≥10] adjusted hazard ratio for 1-year mortality [8.40, 95% CI 2.50-28.17]; P < 0.001).In patients undergoing cardiovascular surgery with CPB, elevated N/L ratios in the immediately postoperative period and on POD one were associated with an increased risk of postoperative AKI and 1-year mortality. The N/L ratio, which is easily calculable from routine work-up, can therefore assist with risk stratification of AKI and mortality in high-risk surgical patients.

Aminoamide local anesthetics induce vasoconstrictionin vivoandin vitro. The goals of thisin vitrostudy were to investigate the potency of local anesthetic-induced vasoconstriction and to identify the physicochemical property (octanol/buffer partition coefficient, pKa, molecular weight, or potency) of local anesthetics that determines their potency in inducing isolated rat aortic ring contraction. Cumulative concentration-response curves to local anesthetics (levobupivacaine, ropivacaine, lidocaine, and mepivacaine) were obtained from isolated rat aorta. Regression analyses were performed to determine the relationship between the reported physicochemical properties of local anesthetics and the local anesthetic concentration that produced 50% (ED₅₀) of the local anesthetic-induced maximum vasoconstriction. We determined the order of potency (ED₅₀) of vasoconstriction among local anesthetics to be levobupivacaine > ropivacaine > lidocaine > mepivacaine. The relative importance of the independent variables that affect the vasoconstriction potency is octanol/buffer partition coefficient > potency > pKa > molecular weight. The ED₅₀in endothelium-denuded aorta negatively correlated with the octanol/buffer partition coefficient of local anesthetics (r2=0.9563;P<0.001). The potency of the vasoconstriction in the endothelium-denuded aorta induced by local anesthetics is determined primarily by lipid solubility and, in part, by other physicochemical properties including potency and pKa.

This study examined the possible upstream cellular signaling pathway associated with nitric oxide (NO)-mediated inhibition of phenylephrine-induced contraction in isolated rat aortae in response to mild hypothermia, with a particular focus on endothelial Rho-kinase. We examined the effects of mild hypothermia (33°C), wortmannin, N^ω-nitro-L-arginine methyl ester (L-NAME), Y-27632, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and methylene blue, alone and combined, on phenylephrine-induced contraction in isolated rat aortae. Finally, we examined the effects of mild hypothermia, wortmannin, Y-27632 and L-NAME, alone and combined, on endothelial nitric oxide synthase (eNOS) and endothelial Rho-kinase membrane translocation induced by phenylephrine. Mild hypothermia attenuated phenylephrine-induced contraction only in endothelium-intact aortae. L-NAME, wortmannin, ODQ and methylene blue increased phenylephrine-induced contraction of endothelium-intact aortae pretreated at 33°C. Wortmannin did not significantly alter the L-NAME-induced enhancement of phenylephrine-induced maximal contraction of endothelium-intact aortae pretreated at 33°C. Wortmannin abolished the ability of Y-27632 to magnify the hypothermic inhibition of maximal phenylephrine-induced contraction. Wortmannin and L-NAME inhibited the enhancing effect of mild hypothermia on phenylephrine-induced eNOS phosphorylation. Y-27632 and L-NAME attenuated the enhancing effect of hypothermia on phenylephrine-induced endothelial Rho-kinase membrane translocation. The results suggest that hypothermia-induced, NO-dependent inhibition of phenylephrine-induced contraction is mediated by phosphoinositide 3-kinase and inhibited by endothelial Rho-kinase activation.

Intravenous lipid emulsions (LEs) are effective in the treatment of toxicity associated with various drugs such as local anesthetics and other lipid soluble agents. The goals of this study were to examine the effect of LE on left ventricular hemodynamic variables and systemic blood pressure in an in vivo rat model, and to determine the associated cellular mechanism with a particular focus on nitric oxide. Two LEs (Intralipid^® 20% and Lipofundin^® MCT/LCT 20%) or normal saline were administered intravenously in an in vivo rat model following induction of anesthesia by intramuscular injection of tiletamine/zolazepam and xylazine. Left ventricular systolic pressure (LVSP), blood pressure, heart rate, maximum rate of intraventricular pressure increase, and maximum rate of intraventricular pressure decrease were measured before and after intravenous administration of various doses of LEs or normal saline to an in vivo rat with or without pretreatment with the non-specific nitric oxide synthase inhibitor N^ω-nitro-L-arginine-methyl ester (L-NAME). Administration of Intralipid^® (3 and 10 ml/kg) increased LVSP and decreased heart rate. Pretreatment with L-NAME (10 mg/kg) increased LSVP and decreased heart rate, whereas subsequent treatment with Intralipid^® did not significantly alter LVSP. Intralipid^® (10 ml/kg) increased mean blood pressure and decreased heart rate. The increase in LVSP induced by Lipofundin^® MCT/LCT was greater than that induced by Intralipid^®. Intralipid^® (1%) did not significantly alter nitric oxide donor sodium nitroprusside-induced relaxation in endothelium-denuded rat aorta. Taken together, systemic blockage of nitric oxide synthase by L-NAME increases LVSP, which is not augmented further by intralipid^®.