Background Acute, systemic toxicity associated with the use local anesthetics (LAST) has been recognized as an important clinical problem since their introduction into clinical practice in the late 19th Century. It is no surprise that small (MW∼300Da), amphipathic molecules rapidly access and interfere with a wide range of molecular targets. the initial search for molecular targets of toxicity naturally fell to voltage-gated sodium channel given their clinical importance in the beneficial nerve block effect. However, many other ionotropic and metabotropic systems are now known to be equally affected. Impairment of oxidative phosphorylation now takes on particular relevance when one considers the key organ dysfunction in LAST (viz., heart and brain) reflect organs that are intolerant of anaerobic metabolism and as an explanation for the difficulty in resuscitating severe LAST with conventional methods. New treatment strategies reflect this improved understanding of toxicity. More important, recognizing the contribution of specific systems and patient-related issues to LAST will lead to improvements in preventing this potentially fatal complication of regional anesthesia.

Incidence LAST is a rare event and therefore, like all such problems, is discounted until experienced firsthand. Paradoxically, the potential damage isn’t limited to the patient since most often the physician delivers the drug and the event is therefore iatrogenic – such an event can especially devastate an early career. More important, the patient harm can be severe and substantial and extends to a circle of family and friends; this is also all the more catastrophic in a young patient. So how common is LAST? Analysis of large administrative databases generates a rate of 1:1000 peripheral nerve blocks; this number comports with the rate estimate made by Mulroy et al almost 20 years ago. However, two important caveats extend to such results. First, there is considerable clinical heterogeneity among sites suggesting an average of 1:1000 might include and fail to distinguish among hospitals with either much higher or much lower rates. For instance, Liu et al estimated rates an order of magnitude less than 1:1000 at HHS, a facility with a very high volume of regional anesthesia. Second, it is likely that LAST is generally under-diagnosed and under-reported. Consider whether a case of LAST you have observed was reported. Moreover, it is possible that potentially severe LAST is averted with early recognition and intervention, making it unnecessary to report the event. Therefore, LAST is considered a rare event but is perhaps not as rare as the numbers suggest. Nevertheless, several studies suggest and Barrington et al later confirmed that use of ultrasound guidance reduces the risk of LAST – an important advance in the safe practice of regional anesthesia. Interestingly, the same study also indicated that small patient size should be added to the list of co-morbidities that increase the risk of LAST; these include pre-existing heart disease (especially ischemia, conduction block, low output state and arrhythmias), extremes of age, frailty and certain metabolic diseases (e.g., carnitine deficiency).

Clinical picture The clinical phenotype of LAST has evolved over the past decade, with a trend to longer latency to the occurrence of symptoms and an increased frequency of mild prodromal symptoms as the first indication of a problem. These changes represent a transition from of intravascular injection to the absorption of local anesthetic from the tissue depot as the predominant mechanism of attaining toxic blood levels of anesthetic. This change likely resulted from the advent of ultrasound guidance in regional anesthesia over the past decade. Insofar as the use of USGRA has decreased the prevalence of abrupt onset of LAST this should also provide a wider window to intervene before toxicity overwhelms the patient. on the obverse, delayed onset of symptoms can obscure the correct diagnosis if the connection between injecting local anesthetic and patient instability isn’t temporally obvious. This becomes more of an issue as the interval increases. Very long latent intervals are particularly concerning with catheter infusion of local anesthetic where LAST has occurred more than 12 hours post-operatively. In any case, it is important to consider the diagnosis of LAST in any patient with any atypical symptoms following regional anesthesia since there is effective treatment that can prevent or slow progression to severe toxicity.

Treatment Rosenblatt et al¹ first reported the infusion of a 20% lipid emulsion (ILE) in successful treatment of severe local anesthetic cardiac toxicity in 2006. This re-purposing of a total parenteral nutrition solution has subsequently been widely adopted by the anesthesia community as an effective treatment for a potentially fatal complication of regional anesthesia – one that had traditionally been viewed as exceptionally difficult to treat. a number of professional societies in the Eu, US and elsewhere now include lipid emulsion in their recommendations for treating LAST and such solutions are routinely stocked for rapid access at anesthetizing locations in hospitals and outpatient facilities.

Initial case reports of ILE treatment of severe cardiac local anesthetic toxicity recapitulate the laboratory experience: combining good CPR with ILE leads to very rapid recovery of heart rate and blood pressure and normalization of rhythm. Moreover, neurologic signs of local anesthetic toxicity are also reported to abate with ILE; this appears to apply to prodromal symptoms and altered mental status as well as seizure activity. the ASRA, AAGBI and AHA recommendations for treating local anesthetic systemic toxicity provide specific recommendations for administering ILE which is typically given as a large bolus (∼100 mL for an adult) followed by a continuous infusion (∼0.25 mL/kg/min lean body mass; max dose, 12 mL/kg) usually given several minutes past a full recovery. These will be revised in the future to improve both efficacy and safety of ILE. Potential recurrence of toxicity requires us to monitor the patient for some time after and event and to keep materials for ILE at the ready.

Comparison of lipid with standard vasopressor drugs in treating rat models of bupivacaine overdose showed that ILE was superior to epinephrine alone or in combination with vasopressin. ILE-treated animals had better hemodynamic and metabolic parameters (pH, lactate and pO2) than animals given vasopressors. It is important to note that rats challenged with bupivacaine and treated with vasopressin alone did very poorly from the standpoint of both hemodynamic and metabolic recovery. It was also reported in the same model that epinephrine when given above a threshold dose of 10 mcg/kg epinephrine impaired the efficacy of ILE in treatment of bupivacaine overdose while lower doses of epinephrine accelerated recovery. Given the normal human dose (1 mg) is ∼15 mcg/kg, this suggests that much lower-than-usual doses of epinephrine might be more effective than the usual 1 mg in treating cardiac arrest secondary to LAST. These findings informed the current recommendations to reduce the dose of epinephrine and eliminate vasopressin for treating LAST. Li et al showed in a rat model that adding epinephrine to ILE improved coronary perfusion pressure but unlike ILE alone did not reduce cardiac bupivacaine concentrations. Moreover, they confirmed that adding epinephrine to ILE worsened pO2 and pH. These findings comport with mounting evidence that the standard (∼1 mg) dose of epinephrine does not contribute to improved survival in cardiac arrest generally; furthermore, they inform the current recommendations for treating local anesthetic toxicity that 1) vasopressin not be used at all and that 2) decreased epinephrine bolus doses (e.g. ∼1 mcg/kg) be used, especially when given with ILE.

Interestingly, a recent study by Liu et al in a rat model of bupivacaine indicated that repeat bolus dosing of lipid through a peripheral (viz., tail) intravenous line was superior to injecting lipid as a bolus plus infusion through the same line and was identical in efficacy to injecting through a central line using a bolus plus infusion regime. This could improve clinical treatment by simplifying the method of infusing lipid and thereby addressing the complexity of using lipid, an issue previously raised by Thompson.

Controversies and issues to resolve in improving future practice Whether and When to Use Lipid: the approach to deciding when to use ILE in treating local anesthetic toxicity has evolved over the past several years. the earliest recommendations were to use ILE only as a last resort. However, observations suggesting that ILE might slow or prevent progression to cardiac toxicity lead to earlier use following symptoms of toxicity. This and the difficulty predicting progression to cardiovascular compromise provide the rationale for early administration of lipid. It is worth noting that some patients appearing to have fully recovered from local anesthetic-induced seizures go on minutes later to full cardiac arrest. It seems reasonable to call for the materials necessary for injecting lipid as soon as the diagnosis of local anesthetic toxicity is considered; one can then decide whether to treat based on the patient’s clinical picture and physician judgment. This decision should also factor in the potential for adverse effects of lipid. While there are no commonly encountered scenarios where lipid should be given before regional anesthesia, a Bier block accidentally performed with bupivacaine is one situation where ‘pre-treatment’ makes sense – that is, lipid could be given before (incrementally) deflating the cuff.

Methods for Studying Lipid Resuscitation: Experimental models are context and species sensitive and findings in one scenario using a particular species don’t necessarily apply to another situation or other animals. There is further controversy over the best animal for studying lipid resuscitation. While porcine models are often used for studying CPR and ischemic arrest, pigs are hyper-sensitive to liposome infusions including lipid emulsion. Bedocs et al³ showed that standard ILE infusion induces the generalized cutaneous mottling and discoloration previously reported by others, as well as significant pulmonary hypertension. This systemic sensitivity should disqualify pigs as a useful model for ILE.

Practice Trends: the common use of LIA in joint replacement surgery, especially in combination with peripheral nerve block has led to the need for improved education of our surgical colleagues about the risks of LAST; this often requires considerable diplomacy to convey the message of a need for limiting total local anesthetic dose. Increased use of catheters and intravenous lidocaine infusion for post-operative analgesia add the need to inform personnel on surgical wards about the risks, diagnosis and treatment of LAST. the increased use of liposomal local anesthetic formulations also requires laboratory study of the best methods for treating LAST associated with their use.

Conclusion We’ve learned a great deal over the past 20 years about the mechanisms of local anesthetic toxicity, how to manage and reduce its overall morbidity and mortality. However, given the number of relevant contributing factors, including systems and physician errors and patient co-morbidities, there’s no way to completely eliminate this risk as long as local anesthetics are used. the increasing reliance on regional anesthesia and an aging population are two factors that suggest the potential for a future with increased occurrence of LAST. These risks demand we continually rise to the challenge of educating ourselves, surgical colleagues and others to improve patient safety and outcomes through better methods of prevention, diagnosis and treatment of LAST.