ESRA19-0707 Use of intralipid to limit side effects of excessively high blocks or unwanted excessive duration of action?

Background Dentists who use an alpha-blocker to increase regional blood flow and thereby shorten nerve conduction block in the oro-pharynx provide proof-of-principle that nerve blocks can be shortened. Can infusing lipid emulsion be applied for this same purpose? Shortly after the first clinical descriptions of successful lipid resuscitation from severe local anesthetic systemic toxicity people began experimental studies in earnest to identify the underlying mechanisms. Once it was shown that perfusing an isolated heart with 1% lipid emulsion could accelerate the decline of myocardial bupivacaine concentrations, clinicians began to ask if it might be possible to take advantage of the same effect to ‘extract’ local anesthetic from nerves and accelerate the resolution of blocks, including spinal anesthesia. When would this be helpful? Patients with an inordinately prolonged block or high spinal with complications (hypotension, urinary retention) or just waiting for resolution of a spinal before going home would benefit from reversal of a block. Similarly, any problem confused or masked by a block might be easier to diagnose if the block were reversed. Unfortunately, clinical experience involving LAST is not helpful in this regard. That is, one might initially consider interrogating instances of LAST to determine whether nerve blocks resolve more quickly after LRT than without. However, the mere fact of a LAST event implies there’s no way to quantify or compare among patients the amount of drug in the perineural tissue versus the amount that was entrained or injected into the vascular space; also, it would be unethical now to create a control population of patients experiencing LAST who are not given lipid. None the less, it is not uncommon to hear of patients given lipid to treat LAST who still have sufficient sensorimotor blockade to have the planned operation. Clearly, if there is an effect following lipid infusion in LAST, it might not be easily or reliably ascertained and certainly not easy to study…except in the lab or possibly volunteers. None the less, it is useful to review the physiological effects of infusing lipid emulsion to understand how it might contribute to hastening resolution of nerve blocks. Mechanisms of LAST Reversal The most important mechanism underlying the benefit of lipid resuscitation in treating LAST is the acceleration of redistribution of local anesthetic away from molecular targets of toxicity to reservoir organs (e.g., liver and skeletal muscle) where they are relatively innocuous, metabolized and excreted. This dynamic, pharmacokinetic result is a consequence of the combined inotropic and partitioning effects of infusing lipid emulsion. the topic was recently reviewed in Fettiplace and Weinberg (2018). Partitioning of local anesthetic into lipid was first shown by Weinberg et al (1998) using a test tube experiment where radiolabeled bupivacaine was added to plasma with and without lipid emulsion. the plasma concentration was lowered by the addition of lipid emulsion and the calculated partition coefficient was 11.9. a much more refined in vitro result was reported by Mazoit et al (2009) who showed in a series of shaken flask experiments that emulsion containing either long-chain or mixed long and medium-chain length fatty acids had very high binding capacity for bupivacaine, levo-bupivacaine and ropivacaine. the distribution coefficient (expressed as mole ratio) was ∼1,870 and 1,240 for bupivacaine and ropivacaine, respectively, at 500mg/L in the long chain fatty acid emulsion. Equally important, they showed that the free concentration of local anesthetic dropped quickly, reaching equilibrium in less than three minutes. Clearly, lipid emulsion has a very high in vitro binding capacity for local anesthetic. How about its action in vivo? Shi et al (2013) showed in a rat model of bupivacaine overdose that infusing a lipid emulsion had dramatic effects on the pharmacokinetics of bupivacaine and lowered concentrations of bupivacaine in brain and heart while elevating them in the liver. They found that the bupivacaine alpha half-life was lengthened and beta-half life shortened by lipid infusion. This is a result of acutely increasing whole blood bupivacaine content following lipid infusion and provided early confirmation of a rapid, in vivo partitioning effect. Similarly, a volunteer study by Litonius et al (2012) showed that lipid infusion shortened the context-sensitive half-life of bupivacaine from 45 to 25 minutes (44% reduction). Both of these studies suggest that lipid infusion accelerates the redistribution of bupivacaine. a similar volunteer study by Dureau et al (2016) showed that lipid infusion during a challenge with a lipid soluble local anesthetic (levo-bupivacaine or ropivacaine) reduced the peak local anesthetic concentrations by 26–30%. Finally, a rat study by Fettiplace et al (2015) confirmed the strong partitioning effect of infusing a lipid emulsion by showing that after lipid infusion, compared to controls, a dramatic increase in the total blood bupivacaine concentration was required to achieve a given bupivacaine tissue content for virtually every organ studied. This difference did not hold for the ‘clear plasma’ (non-lipid bound) bupivacaine concentration; hence the increase in individual organ partition coefficients was entirely dependent on the presence of lipid. Interestingly, the shift in blood concentration occurred early (2 min) and was evanescent. Studies looking at later time points (e.g. 5 min) would not find a difference. Furthermore, the slope of the lipid:bupivacaine in vivo binding matched almost exactly that found in the shaken flask study of Mazoit et al, indicating, like simulations of Dureau et al, that partitioning is greatest at higher local anesthetic concentrations. Taken together, these studies confirm that the benefit of lipid resuscitation is likely to be greatest when higher local anesthetic concentrations are high, that is, early in a LAST event. Moreover, rats infused with lipid emulsion showed increased bupivacaine content at later time points in the skeletal muscle and liver compared to controls. Clearly, lipid acts as a drug shuttle for local anesthetics. Fettiplace et al (2016) showed that lipid infusion also activates the cellular insulin-signaling pathway that includes components of the cyto-protective kinase cascade (e.g., Akt). This important effect might underlie the inotropic effect of lipid infusion given that insulin is also an inotrope. Notably, Kim et al (2019) recently reported that insulin accelerates recovery from either lidocaine or bupivacaine sciatic nerve block, suggesting that insulinergic signaling is at play. It is therefore interesting to consider that any mimic of insulin signaling could also exert the same effect. Taken together, lipid as drug shuttle, and insulin mimic lends support to the idea that lipid could potentially hasten resolution of nerve block. An Informative Volunteer Study Chen et al (2019) reported the pharmacokinetic effects of infusing lipid emulsion before regional anesthesia in patients with lower leg fracture. They infused 1.5mL/kg of either saline (control) or 20% lipid emulsion over 10 minutes then immediately performed the blocks using a total of 2.5mg/kg of levo-bupivacaine divided equally between femoral and sciatic nerves. They found that both the apparent volume of distribution (∼211 v 170L) and the clearance (35 v 26 L/hour) of anesthetic were greater in patients with lipid than those receiving saline. More important, the maximum plasma concentration was reduced by lipid pretreatment (e.g., 57 vs 78ug/L for free, non-protein, non-lipid bound levo-bupivacaine). So, did lipid treatment reduce the duration of block? No! the durations were nearly identical for both blocks in control and lipid treated patients: 22/18 hours for femoral/sciatic in controls and 21/17 in the lipid group. Why is there no difference? Without having a solid, experimentally-confirmed explanation, I can easily think of at least two reasons. First, the nerves are sufficiently sensitive to local anesthetic conduction blockade and concentrations needed to block the voltage-gated sodium channels so low, that lipid partitioning cannot be effective – at equilibrium, local anesthetic concentrations might be lowered with lipid, but still high enough to bind the sodium channel. Also, the connective tissue surrounding the nerve tissue could further impede local anesthetic binding or transport to the lipid particles. So, at this stage, in answer to the question posed in this session, ‘CAN LIPID LIMIT SIDE EFFECTS OF EXCESSIVELY HIGH BLOCKS OR UNWANTED EXCESSIVE DURATION OF ACTION?’, the answer at this stage is, ‘Probably not’. Future Possibilities More detailed experimental study of the reversal of local anesthetic blockade to answer the question raised in this session requires a rigorous animal model of the phenomenon. This could use conduction velocity as in Kim et al or evoked potentials as used by Vadeboncouer et al (1990) or any appropriate and objective criteria to monitor resolution of sensory and motor nerves in treated versus controls groups. Such a model would provide useful information to support the clinical application of any such intervention: lipid, insulin, phentolamine, or other as yet to be discovered agents. We look forward to someone picking up the issue and finding an acceptable solution to the issue of excessively high spinals or prolonged blocks.