Lipid Emulsion Increases the Fast Na⁺ Current and Reverses the Bupivacaine-induced Block: A New Aspect of Lipid Resuscitation?

We read with great interest the article by Wagner et al.,¹  in which the authors evaluated the effects of lipid emulsion with bupivacaine on cardiac action potential and fast Na⁺ current (I_Na) in native rat cardiomyocytes. Because lipid emulsion is becoming a standard rescue treatment for intractable fatal arrhythmias resulting from local anesthetic systemic toxicity, it is of great significance to assess the effects of lipid emulsion on cardiac electrophysiology. Of special interest was the result showing a “direct lipid effect” in the presence and absence of local anesthetics on sodium channels, separating a “lipid sink” by ultracentrifugation. In the presence of local anesthetics, a direct lipid effect was clearly shown by subtracting the effect of centrifuged from uncentrifuged lipid solutions. However, we had some concerns in interpreting these results. In our recent study, we also evaluated the lipid sink effect using lipid emulsions and their centrifuged solutions in voltage-gated proton channels.²  Use of these solutions in proton channels was unimportant because lipid emulsions did not affect proton currents. However, we thought some care should be taken when using these solutions in voltage-gated sodium channels.

Our first concern is in regard to a small amount of sodium ions contained in lipid emulsions. Wagner et al. used Lipovenös^® MCT 20% (medium-chain triglycerides) (Fresenius Kabi AG, Bad Homburg, Germany), which contains sodium hydrate and sodium oleate, that is, up to 5 mM sodium ions in total.^* These concentrations are low but can slightly increase the driving force of sodium currents. In addition, as the authors described in detail, sodium currents in cardiomyocytes can easily lead to voltage errors. Therefore, the low concentration of sodium in lipid emulsions may increase the I_Na. Indeed, Wagner et al.¹  showed that 10% Lipovenös^®-containing solutions without local anesthetics increased the I_Na by approximately 20% compared with the control solutions. Lipovenös^® MCT 20% consists of 50% long-chain triglycerides and 50% MCTs. Some long-chain triglycerides (linolenic acid, linoleic acid, and oleic acid) and caprylic acid in MCT have been shown to reduce I_Na, whereas other monounsaturated or saturated fatty acids did not.^3,4  Indeed, recent report by Nadrowitz et al.⁵  indicated that 15% Lipofundin^® (B. Braun Melsungen AG, Melsungen, Germany) (50/50 long-chain triglyceride/MCT) significantly reduced I_Na by 42 ± 4% in human embryonic kidney cells expressing human Nav 1.5. In contrast, Wagner et al. first showed the increase of I_Na by lipid emulsion in native rat cardiomyocytes, which could be the new important mechanism of lipid resuscitation. However, we are concerned about the effects of low sodium concentration on this increase and would like to know how the authors think about their results of lipid emulsion different from that of previous reports. How did they adjust Na⁺ content of 10% lipid-containing solution (“approximately 2 mM”)?

Our second concern is regarding the residual triglyceride after removal of lipid emulsion by centrifugation. In our preliminary trial, we centrifuged 10% lipid-containing solution using Lipofundin^® 20%, which consists of the similar contents with Lipovenös^® MCT 20%. We made the same solution as Wagner et al. and centrifuged it similarly at 110,000g for 2 h at 4°C (CP-100α; Hitachi Koki Co., Ltd., Tokyo, Japan) and measured the triglyceride concentrations (Cholestest^®TG; Sekisui Medical Co., Ltd., Tokyo, Japan). The centrifuged solutions of 10% Lipofundin^® contained 9.6 ± 1.5 mg/dl residual triglyceride (n = 5). Although these residual triglycerides are low, Nadrowitz et al.⁵  showed that even 0.05% Lipofundin^®, containing 10 mg/dl triglyceride, slightly reduced the peak current amplitude of I_Na in human embryonic kidney cells. Thus, the direct lipid effect on sodium channels may not be shown by simply subtracting the effects of centrifuged from uncentrifuged lipid solutions.

We cannot estimate the effects of these two concerns on their results. However, as the sodium contents and residual triglyceride of lipid emulsion can directly affect the I_Na, we have to carefully analyze the data obtained with lipid emulsions and their centrifuged solutions in experiments using voltage-gated sodium channels. Aside from these concerns, we thank the authors for presenting these very interesting results, providing a new aspect of lipid resuscitation.

The experiment in this letter was supported by a grant-in-aid for scientific research from the Japan Society for the Promotion of Science (24791619), Tokyo, Japan.

The authors declare no competing interests.