Lipid emulsion for intoxication by local anaesthetic: sunken sink?

Understanding the working principles of anaesthetic equipment and drugs helps us compensate when they don't work as expected. It is presumed to be a foundation of safety, and has therefore become a fundamental part of the postgraduate syllabus. Yet, there are exceptions. The most baffling, perhaps, are the very notions of consciousness and its loss 1. But that, practical clinicians would say, is philosophy. So, how about lipid emulsion as an antidote to local anaesthetic systemic toxicity (LAST)? Nothing is philosophical about fat – and, at first glance, its use might seem amenable to hard empirical graft. Yet, life-threatening LAST is unpredictable, potentially lethal and rare. This makes it impossible to study prospectively and ethically in humans. And so, in 2007, when the AAGBI first recommended the use of lipid in LAST - as a last resort- its mechanism had not been studied in our species. Indeed, it wasn't clear to what degree it worked at all. It just seemed not to do harm, and to have saved some lives in extremis 2, 3. Since then, two putative mechanisms have attracted most speculation. The first has a confusing array of labels: ‘physical’; ‘partitioning’; ‘pharmacokinetic’; and ‘the lipid sink’- they all suggest that the hydrophobic local anaesthetic settles in the suddenly increased lipid phase of the circulating volume, and the concentration in the aqueous phase falls safely away. The second possible set of mechanisms is more biological, or pharmacodynamic: lipid may have direct effects on pertinent tissues, above all the heart and brain. Studied in isolation, in the simplest of models, evidence has accrued for both mechanisms. For example, lipophilic drugs such as bupivacaine will indeed partition into lipid added to a phial of plasma, and work with dyes provides visually striking support for this mechanism 4-6. Similarly, isolated intoxicated hearts are given a fillip when lipid is added to their perfusate 7. But, of course, the price of such simplicity in the laboratory is potential clinical irrelevance. An intoxicated patient dying fast is a far cry from a dangling heart in Langendorff preparation. So, investigators have tackled more complex models, making different compromises. In some work, toxic doses have been studied in animal models; in other work, smaller doses have been studied in humans 8-13. There has also been more work done in vitro and also, more recently, in silico- that is, with computer modelling 14. Over time, lipid's action as an antidote has become somewhat clearer. One group of studies on whole animals is particularly instructive. In the first work on lipid's beneficial effect in LAST, rats were studied 8. From there, investigators scaled up to dogs and rabbits 9, 11. Again, lipid seemed beneficial in LAST. But work on lipid in LAST conducted in pigs has been equivocal 10, 12. These mixed results have sustained sceptics. In the UK, lipid's contribution to resuscitation in LAST is currently accepted. But in Finland, for example, there is no national guideline, and protocols for treatment of LAST include lipid emulsion in only 47% of hospitals 15. It transpires that pigs have an idiosyncratic reaction to lipid emulsion infusion: increases in systolic and pulmonary artery pressures correlate with dose, while heart rate falls. Exactly what mediates the reaction is unclear, though thromboxane is implicated 16. But whatever the reason, the reaction makes pigs a poor model for any studies of lipid as an antidote, and provides a salutary lesson in the dangers of presuming one species approximates another. Researchers studying sub-toxic doses of local anaesthetic in humans have taken another tack. Professor Rosenberg's group, for example, studied healthy male volunteers who were administered a low dose of bupivacaine, and then either saline or lipid 13. Blood samples taken five minutes later yielded fascinating results. If the lipid functions as a sink, it should absorb lipophilic bupivacaine, and this in turn should reduce the concentration of bupivacaine in the aqueous phase of plasma. Amongst Professor Rosenberg's volunteers, those given lipid should have had, in the aqueous phase of their plasma, lower concentrations of bupivacaine. And yet they didn't. Between the two groups, there was little difference five minutes after lipid administration. The only discrepancy will be relevant in a moment: the total bupivacaine concentration in circulating blood decayed faster in the volunteers who got lipid; there was a statistically significant difference 20 and 30 minutes after the lipid was given. So, is the pharmacokinetic hypothesis debunked? Or, if you'll forgive it, is the sink sunk? In short, the answer is ‘yes’. But the damage hasn't been done only by Rosenberg et al.; Professor Weinberg's group has also contributed 14. Looking at rats, Weinberg's group zoomed in on the first minutes after lipid was administered. In their model, action was very fast; five minutes after the lipid had been given as an antidote to intoxication by local anaesthetic, much of relevance was over. In the first minutes after intoxicated rats were given lipid, the antidote made a substantial difference to the distribution of the local anaesthetic through the rats’ bodies; after two minutes, the rats who got lipid had more bupivacaine in their blood, but less in their cardiac tissue and less in their cerebellum. Bupivacaine also washed faster out of the lungs and kidneys of rats treated with lipid. In other words, lipid didn't seem to act as a lipid sink; instead, lipid appeared to serve first as a vehicle. It appeared to scavenge local anaesthetic from the heart, brain and other well-perfused organs, carrying it to other more poorly perfused tissues. Five minutes after lipid had been given to the rats, it scarcely affected the concentration of bupivacaine in whole blood. All this is consistent with Rosenberg et al's results: no evidence for a long-lasting sink, but acceleration of the clearance of local anaesthetic. Weinberg et al's results also add detail to a pharmacodynamic effect. They imply that lipid has little effect on cardiac function while concentrations of local anaesthetic are high. But as the lipid vehicle relieves cardiac tissue of its local anaesthetic burden, then, as a threshold is passed, the lipid begins to boost cardiac output. So the whole process may be summarised thus: lipid carries local anaesthetic from heart and brain to less well-perfused organs, and then, as the concentration of local anaesthetic falls far enough, lipid also acts as a tonic to the depressed hear. One reasonable response to all this is to ask: ‘does it matter’? Three strands braid together to form the predictable answer: ‘yes, with reservations’. First, a better understanding of lipid's action as an antidote will guide design of therapeutic emulsions. After all, Intralipid® has been widely used and studied largely because, in many countries, it is more familiar than alternatives as a foundation for total parenteral nutrition. However, it may not be optimal as an antidote. In the past, researchers have compared different emulsions to identify those which bind more local anaesthetic when mixed up with local anaesthetic and something like plasma 4, 6. Others have gone further to engineer pegylated liposomes, all intended especially to absorb toxins 17. Tinkering further to acidify the liposomes’ interior significantly boosts the nano-carriers’ capacity to capture local anaesthetic 18. But, now it seems that such absorption into circulating lipid may not be what the intoxicated patient needs. Just as haemoglobin is an excellent transport molecule because it not only binds blood gases, but also releases them appropriately, so the affinity of lipid for local anaesthetic may not be the ultimate test. What may matter more is how effective a shuttle an antidote is. Second, the armamentarium of the resuscitator may change. In the latest UK Resuscitation Council Guidelines, epinephrine and amiodarone hold their places, confounding the winds of change, despite a remarkably shallow evidence base 19. Resuscitation in LAST was notoriously difficult before the use of lipid, and nothing has changed in this regard. But it might: levosimendan has its proponents, for example 20. Used in LAST, it may simply complement lipid emulsion;(the sole published study was underpowered 21). But, in the more distant future, some drug may so surpass lipid as to render it redundant. Third, LAST's incidence may be falling, though the causes of this welcome development are unclear. Changes in training, staffing and in the presentation and storage of local anaesthetic may have contributed. Changes in anaesthetic technique may also have played a part. Recognition of the danger of single-shot epidural injections of large volumes of local anaesthetic led to wider adoption of catheters, incremental and test doses. In addition, wider use of ultrasound to guide perineural and fascial blocks may be leading to smaller doses of local anaesthetic, and above all, to operators moving the needle as the dose is delivered 22. A moving needle may cause more physical trauma, but intravascular injections should be smaller. Some have suggested that the danger of LAST is now more ghost than bogeyman 23. Local anaesthetic systemic toxicity lies between the two extremes: it still happens, but not so frequently as to be familiar. So it behoves us to beware, and to incur the small costs of remaining ready to treat it. Complacency is dangerous to all; at least in some settings, the risk of being sued for malpractice rises with the anaesthetist's age. Perhaps the delusion of safety and supranormal ability gathers with success through time, until the very worst occurs 24. No external funding or conflicts of interest declared.

Topic: Anesthesia and Pain Management
Subfield: Surgery
Field: Medicine
Domain: Health Sciences