From local to global: lipid emulsion (intralipid) makes a move.

I N clinical practice, lipid emulsion is used commonly as a component of parenteral nutrition. Lipid emulsion also is used as therapy for severe cardiotoxicity secondary to accidental overdose of local anesthetics, an effect that has been confirmed in animals and humans. Because patients with local anesthetic-induced cardiac arrest are considered to be less responsive for standard resuscitation methods, this finding is striking, and currently infusion of lipid emulsion is considered the primary treatment for local anesthetic toxicity. In this issue of ANESTHESIOLOGY, Rahman et al. report a new and potentially clinically relevant benefit of lipid emulsion therapy. Classic preconditioning produces in the heart a state profoundly protected from ischemia–reperfusion injury; however, the prerequisite for knowing when the ischemic injury will occur has limited the clinical translation and relevance of preconditioning. Recently, a potentially more clinically relevant form of cardiac protection, termed postconditioning, has been described. Postconditioning involves the application of protective interventions (e.g., brief ischemia–reperfusion, volatile anesthetics, opioids, and other classic cardioprotective agents) after ischemia but before reperfusion. Rahman et al. extend the list of postconditioning agents to include Intralipid (Sigma, St. Louis, MO). They show that lipid emulsion infusion just before reperfusion (i.e., postconditioning) protects from myocardial ischemia–reperfusion injury. Subsequent mechanistic studies define a role for glycogen synthase kinase-3 and the mitochondrial permeability transition pore (mPTP) in this response. Mitochondria, a source of cellular adenosine triphosphate, are increasingly implicated in cell survival and death signaling in the heart. In particular, the mPTP has been suggested as the final effector in cardiac myocyte protection. The mPTP opening in response to stress leads to an increase in mitochondrial membrane permeability to small molecules, resulting in cellular apoptosis and necrosis. Thus, regulating the mPTP opening has been considered to be a promising target for cardiac protection, and others have suggested the involvement of mPTP in postconditioning. Postconditioning is mediated via a complex molecular signaling cascade involving the reperfusion injury salvage kinase and the survivor activating factor enhancement pathways. Rahman et al. implicate common survival pathways, such as PI3K-Akt and ERK, in lipid emulsion-induced protection. In addition, they link these upstream survival kinases to downstream regulation of glycogen synthase kinase-3 . Recent work has shown that increased phosphorylation of glycogen synthase kinase-3 reduces the affinity of the adenine nucleotide translocase for cyclophilin D, suggesting that assembly of the complex is targeted by protective signals to limit mPTP opening. Thus, there appears to be a direct link between survival kinase regulation and mPTP end effector function. These intriguing findings by Rahman et al. leave us with some important questions to be addressed in future investigation. First, how does lipid emulsion activate survival kinases—via a direct effect or secondary to receptor stimulation? General protective interventions appear to signal through G-protein–coupled receptor pathways, including preconditioning and postconditioning via opioids, volatile anesthetics, and other cardioprotective agents. It would be important to determine whether lipid emulsion is sensitive to Illustration: J. P. Rathmell/A. Johnson.