Inotropic effect of lipid emulsion: a new perspective*.

August 2013 • Volume 41 • Number 8 It is not every day that the medical and scientific communities come across a medicine with so many potentials and therapeutic indications. Lipid emulsion, which was used for several decades mainly as parenteral nutrition, has recently emerged as a promising cardioprotective agent. Dr. Weinberg’s group discovered for the first time in 1998 that lipid emulsion can also be very effective in rescuing acute and deadly cardiotoxicity of local anesthetics, such as bupivacaine, in an experimental rat model (1). Later, lipid emulsion has also been used to resuscitate patients from toxicities caused by a wide range of factors, such as calcium channel blockers, β-blockers, and psycho-active agents (2–9). However, the underlying mechanisms involved in lipid rescue are complex and so far partitioning (10), and metabolic effects through the fatty acid oxidation pathway (11) and modulation of cardiac sodium channels (12) seem to be the major mechanisms. The article by Fettiplace et al (13) from Dr. Weinberg’s group, a pioneer in this field, investigated the fast inotropic effect (within a few minutes) of lipid emulsion in the absence of a pathologic insult. They found that one bolus of lipid emulsion infusion increases the arterial pressure and aortic flow and improves cardiac hemodynamics in the rat. Therefore, they speculated that rapid inotropic effect of lipid emulsion could also contribute to its resuscitative effect. The inotropic effect of lipid emulsion on cardiac contractility reported by Fettiplace et al could be due to increased intracellular calcium (14, 15). Application of both saturated and unsaturated long-chain-free fatty acids has been demonstrated to rapidly activate voltage-gated calcium channels (mainly L type) in isolated cardiomyocytes (16). Direct activation of the calcium current by fatty acids could partly explain the early effects of lipid emulsions on resuscitation of myocardial toxicity triggered by local anesthetics. In this issue of Critical Care Medicine, Fettiplace et al (13) observed the fast beneficial effect of a bolus infusion of lipid emulsion on systemic hemodynamics. The inotropy and increased aortic flow offered by lipid emulsion in the study conducted by Fettiplace et al is only sustained for several minutes after lipid emulsion withdrawal. However, in the context of cardiac pharmacotoxicity, a bolus infusion of lipid emulsion is sufficient to fully restore cardiac function both in experimental and in clinical settings. These data seem to make the rapid inotropic effect of lipid emulsion a less likely contributor to the long-term effect of lipid emulsion on resuscitation. In light of these findings, it can be concluded that either the effect of lipid emulsion on cardiac hemodynamics is transient under physiologic conditions or the fast inotropic benefit contributes only to the initial phase of the resuscitation. Future studies are needed to explore whether lipid emulsion can also exert rapid inotropic action in the pathologic setting. Both human and animal studies have shown that lipid emulsion is able to improve blood pressure mainly by increasing vascular resistance (17, 18). In contrast to these studies, Fettiplace et al (13) did not observe any change in peripheral vascular resistance following lipid emulsion infusion and claimed that the positive flow and rapid inotropic effects of lipid infusion are not caused by changes in peripheral resistance. The metabolic changes (increasing the cardiac utilization of glucose and fatty acid) result in appreciable alterations on myocardial contractile function (19). Thus, Fettiplace et al speculated that the improved hemodynamic performance offered by lipid emulsion infusion could be in part due to a metabolic benefit. In agreement with the metabolic effect of lipid emulsion, a recent study from our group showed that inhibition of fatty acid oxidation with CVT-4325 completely abolishes lipid-induced rescue of bupivacaine overdose (11). Taken together, lipidbased oxidative phosphorylation plays a role in maintaining the cardiac mechanical function, and the effect of lipid emulsion on contractile properties of the myocardium is actually the consequence of metabolic changes induced by lipid emulsion. Some of the cardioprotective action of lipid emulsion in the acute setting, such as ischemia-reperfusion injury, could be mediated via activation of the well-known signaling pathways. Our group has shown that lipid emulsion activates protein kinase B (AKT)/extracellular signal-regulated kinase/glycogen synthase kinase signaling pathways to restore cardiac hemodynamics and contractility in ischemia-reperfusion injury (20, 21). Our group has also highlighted the involvement of G protein–coupled receptors in mediating the rescue action of lipid emulsion in resuscitating the heart, as in the presence of opioid receptor antagonists, lipid emulsion failed to rescue bupivacaine-induced cardiac arrest (22). Fettiplace et al (13) speculate that activation of some of the known protective pathways could underlie the rapid inotropic effect of lipid emulsion observed under physiologic conditions. We should, however, keep in mind Inotropic Effect of Lipid Emulsion: A New Perspective*