Effect of lipid emulsion on acute clozapine poisoning-induced QT prolongation

The article “Intravenous lipid emulsion as an adjuvant therapy of acute clozapine poisoning,” recently published in Human and Experimental Toxicology, is interesting. ¹ Elgazzar et al. reported that lipid emulsion (SMOFlipid) increased the Glasgow Coma Scale (GCS) and reduced the incidence of QT prolongation and hospital stay in the acute clozapine (an antipsychotic drug) toxicity. ¹ Such randomized clinical studies using lipid emulsions as an antidote in non-local anesthetic toxicity are rare and important in clinical toxicology, which should be complimented. Although there were some problems in the statistical analysis of a previous randomized controlled clinical study, lipid emulsion treatment as an antidote in acute non-local anesthetic toxicity only slightly increased the GCS (calculated Cohen’s effect size: 0.63, 95% confidence interval: −0.101 to 1.366). ² However, in the study of Elgazzar et al., lipid emulsion treatment significantly improved the GCS (Cohen’s effect size: 2.65, 95% confidence interval: 1.808–3.509) in acute clozapine poisoning. ¹ Acute toxicity of clozapine, which is used to treat schizophrenia, can prolong the QT interval, leading to Torsade de pointes, ventricular fibrillation, and sudden cardiac arrest.^3,4 Additionally, toxicity of other antipsychotic drugs, including risperidone, quetiapine, haloperidol, and droperidol, can cause Torsade de pointes. ⁴ Repolarization of phase 3 of action potential in cardiac myocytes normally occurs when calcium channels are inactivated and conductance through potassium channels is increased, which include mainly rapid delayed rectifier potassium current, slow delayed rectifier potassium current, and inward rectifying potassium current. ⁴ QT prolongation of phase 3 of action potential in the cardiac myocytes, associated with Torsade de pointes, may be induced in decreased outward potassium current or increased inward calcium or sodium current. The following discussion may help understand the potential mechanisms underlying the lipid emulsion-mediated inhibition of QT prolongation induced by clozapine poisoning. ¹ Drug-induced prolonged QT interval causing Torsade de Pointes is due to the inhibition of human Ether-à-go-go-Related Gene (hERG)-encoded rapid delayed rectifier potassium channels, leading to the inhibition of potassium efflux. ⁴ Local anesthetics including bupivacaine, ropivacaine, and mepivacaine inhibit hERG potassium channel encoding rapid delayed rectifier potassium channels, which is correlated with the lipid solubility of local anesthetics. ⁵ Bupivacaine toxicity induces transmural dispersion of repolarization, which is responsible for QT prolongation. ⁶ However, lipid emulsion treatment reduces Tpeak-to-Tend interval, indicating transmural dispersion of repolarization induced by bupivacaine toxicity, leading to the restoration of sinus rhythm and recovery from cardiac arrest. ⁶ Additionally, clozapine reportedly inhibits hERG potassium channel and rapidly activating delayed rectifier potassium current in guinea-pig cardiomyocytes. ⁷ The underlying mechanism of lipid emulsion treatment of local anesthetic systemic toxicity involves lipid shuttle. ⁸ That is, the lipid phase of lipid emulsion absorbs highly lipid-soluble drugs (Log [octanol/water partition coefficient]: >2) such as bupivacaine (Log [octanol/water partition coefficient]: 3.41), and then lipid emulsion containing lipid-soluble drugs is transported to the liver and muscle for detoxification and storage, leading to enhanced redistribution.^8,9 Clozapine (Log [octanol/water partition coefficient]: 3.23) is highly lipid-soluble and is similar to bupivacaine (3.41).^9,10 The magnitude of reduction of lipid-soluble drug concentration by lipid emulsion greatly correlates with lipid solubility and partially correlates with the volume of distribution. ¹¹ It has been reported that lipid emulsion reduced the amount of clozapine in the brain compared with normal saline. ¹² The volume of distribution of clozapine has been reported to be 1.6–7.3 L/kg, which is large.^13,14 Furthermore, lipid emulsion alone increased left ventricular systolic pressure and maximum rate of intraventricular pressure change (increase or decrease: ±dP/dt_Max), suggesting a positive inotropic effect. ¹⁵ On the basis of these findings, lipid emulsion might decrease the prolonged QT interval induced by clozapine at toxic doses via the inhibition of hERG-encoded rapid delayed rectifier potassium channels. This appears to be mediated by the absorption of the highly lipid-soluble antipsychotic drug clozapine by lipid emulsion. Thus, lipid emulsions might increase the GCS in clozapine toxicity. However, further studies are needed to examine the relationship between lipid emulsion-mediated changes in clozapine concentration and lipid emulsion-mediated improvement of QT prolongation or decreased consciousness caused by clozapine at toxic doses. In addition, toxicity by non-local anesthetic drugs, including clozapine, is induced by oral administration, whereas local anesthetic systemic toxicity is mostly induced by intravenous administration. Thus, further studies are needed to determine the optimal dosage of lipid emulsions as an adjuvant therapy and the optimal timing of lipid emulsion administration in toxicity induced by non-local anesthetic drugs, including clozapine.