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The Third American Society of Regional Anesthesia and Pain Medicine Practice Advisory on Local Anesthetic Systemic Toxicity: Executive Summary 2017

Neal, Joseph, M., MD*; Barrington, Michael, J., MBBS, FANZCA, PhD; Fettiplace, Michael, R., MD, PhD‡§; Gitman, Marina, MD§; Memtsoudis, Stavros, G., MD, PhD; Mörwald, Eva, E., MD; Rubin, Daniel, S., MD**; Weinberg, Guy, MD§††

Regional Anesthesia and Pain Medicine: February 2018 - Volume 43 - Issue 2 - p 113–123
doi: 10.1097/AAP.0000000000000720
REGIONAL ANESTHESIA AND ACUTE PAIN: SPECIAL ARTICLES

The American Society of Regional Anesthesia and Pain Medicine's Third Practice Advisory on local anesthetic systemic toxicity is an interim update from its 2010 advisory. The advisory focuses on new information regarding the mechanisms of lipid resuscitation, updated frequency estimates, the preventative role of ultrasound guidance, changes to case presentation patterns, and limited information related to local infiltration anesthesia and liposomal bupivacaine. In addition to emerging information, the advisory updates recommendations pertaining to prevention, recognition, and treatment of local anesthetic systemic toxicity.

What’s New in This Update? This interim update summarizes recent scientific findings that have enhanced our understanding of the mechanisms that lead to lipid emulsion reversal of LAST, including rapid partitioning, direct inotropy, and post-conditioning. Since the previous practice advisory, epidemiological data have emerged that suggest a lower frequency of LAST as reported by single institutions and some registries, nevertheless a considerable number of events still occur within the general community. Contemporary case reports suggest a trend toward delayed presentation, which may mirror the increased use of ultrasound guidance (fewer intravascular injections), local infiltration techniques (slower systemic uptake), and continuous local anesthetic infusions. Small patient size and sarcopenia are additional factors that increase potential risk for LAST. An increasing number of reported events occur outside of the traditional hospital setting and involve non-anesthesiologists.

From the *Virginia Mason Medical Center, Seattle, WA; †St Vincent's Hospital, University of Melbourne, Melbourne, Australia; ‡Massachusetts General Hospital, Boston, MA; §College of Medicine, University of Illinois, Chicago; ∥Hospital for Special Surgery, Weill Cornell Medical College, New York, NY; **University of Chicago; and ††Jesse Brown VA Medical Center, Chicago, IL.

Accepted for publication November 15, 2017.

Address correspondence to: Joseph M. Neal, MD, 1100 Ninth Ave (B2-AN), Seattle, WA 98111 (e-mail: Joseph.Neal@virginiamason.org).

G.W. is an officer, director, shareholder and paid consultant of ResQ Pharma, Inc. He also created and maintains www.lipidrescue.org, an educational web site. The authors otherwise declare no potential conflict of interest.

This article discusses an off-label use of lipid emulsion (eg, Intralipid) for treatment of local anesthetic systemic toxicity.

Interventions involving local anesthetics are ubiquitous throughout medicine and are performed by anesthesiologists, other physicians, dentists, and paramedical personnel. Local anesthetic systemic toxicity (LAST) remains a serious adverse event despite advances in prevention, detection, and treatment. Such events range across a continuum from mild subjective prodromal symptoms to seizure, cardiac arrest, and/or death. As noted in our previous practice advisory, “a variety of factors influence the likelihood and severity of LAST, including individual patient risk factors, concurrent medications, location and technique of block, specific local anesthetic compound, total local anesthetic dose (the product of concentration x volume), timeliness of detection, and adequacy of treatment.”1 The overall rarity of LAST and the fact that episodes can occur despite proper technique argue strongly for education and preparedness among all professionals who administer local anesthetics to their patients.

The American Society of Regional Anesthesia and Pain Medicine (ASRA) convened its first Conference on Local Anesthetic Toxicity in 2001 coinciding with initial clinical experience after release of the levo-enantiomers ropivacaine and l-bupivacaine, plus emerging laboratory observations on the effectiveness of lipid emulsion as an antidote for LAST. In 2008, a second advisory panel met to develop a rational approach for treatment2 and to assimilate information on the history, mechanisms, prevention, and detection of LAST.1,3–7 Consistent with ASRA's commitment to update its practice advisories as new knowledge emerges, in 2015, the board of directors commissioned a small group of current researchers to develop this third advisory. In compliance with calls from medical journal editors to focus practice advisory updates on new information,8 we herein present developing knowledge on the mechanisms of lipid resuscitation, new insights into incidence and epidemiology, evolving patterns of case presentation, and revised treatment protocols.

This executive summary condenses information and recommendations from supporting articles that have been published recently9 or concurrently as part of this practice advisory.10–13 Practitioners are encouraged to read these articles to understand the basis underlying our recommendations.

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METHODS

Individual supporting articles provide details relevant to the sources accessed to derive their analysis and recommendations. In general, standard medical literature search engines and article cross-referencing were used to identify animal and human studies, case reports and series, and epidemiologic information. The focus was on new publications and developments since our 2010 advisory.

The panel consisted of recognized experts in LAST and/or guideline development and includes the authors of this article. The ASRA provided standard travel reimbursement for members of the advisory group who met in Chicago on March 26, 2016. No panelist was paid for their participation, nor did ASRA receive external funds to support the advisory process.

The second ASRA practice advisory sought input from external sources including other anesthesiologists with expertise in LAST, professional organizations representing physicians and dentists who commonly use local anesthetics, and open forum discussion of our recommendations.1 Because the current practice advisory represents an interim update and does not recommend major changes to treatment, external input was solicited only at open forum presentations coinciding with the ASRA 2015 and 2016 spring meetings.

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Strength of Recommendations

As stated in our 2010 advisory: “There are no randomized clinical trials (RCTs) evaluating serious human LAST; future RCTs are unlikely because of the rarity of these complications and the associated difficulty of obtaining informed consent for medical interventions in critical illness. Common strength-of-evidence schemas that are based on RCT-level evidence are therefore inappropriate for the topic of human LAST, but may be appropriate for animal studies. Hence, the panel's recommendations are based on a modified Classification of Recommendations and Levels of Evidence schema that was developed by the American College of Cardiology/American Heart Association14 (Table 1). The panel wishes to emphasize that assigning a level of evidence B or C should not be construed as implying that the associated recommendation is supported by conflicting data or is limited by conflicting interpretations of the available data. Rather, such recommendations reflect our recognition of the importance of the particular question as it relates to LAST and to the reality that the specific question is either yet to be addressed by an RCT or does not lend itself to experimental inquiry in humans.”1

TABLE 1

TABLE 1

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Limitations

As with previous ASRA advisories, “readers of this manuscript are reminded that practice advisories are created when data on a subject are limited or non-existent. Advisories rely on limited clinical and animal data and, as such, the synthesis and interpretation of data by one group of experts may differ from conclusions by another set of equally qualified experts. Thus, practice advisories represent a level of recommendation less than that offered by standards or clinical practice guidelines. The recommendations contained herein do not define standard of care. They are not intended to replace clinical judgment as applied to a specific patient scenario. These recommendations are intended to encourage optimal patient care, but cannot ensure the avoidance of adverse outcomes. As with any practice advisory recommendation, these are subject to revision as knowledge of specific complications advances.”15,16

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DISCUSSION

Mechanisms Underlying Lipid Resuscitation

The most important recent advances in our knowledge of LAST relate to the basic science of lipid emulsion resuscitation, within both anesthesiology and other disciplines that involve medical toxicology. New to this practice advisory, Fettiplace and Weinberg10 provide an in depth discussion of the mechanisms that underlie the therapeutic reversal of LAST by lipid emulsion. Henceforth, we summarize the most salient points of this topic, the complexity of which necessitates reading the accompanying supporting article to move beyond basic understanding.

Lipid emulsion reversal of LAST is ultimately linked to cellular mechanisms that are affected by local anesthetics. Under normal circumstances, local anesthetics block nerve conduction by inhibiting transduction of sodium, calcium, and potassium through voltage-gated ionotropic channels located in the cell membrane. Acute local anesthetic cardiotoxicity negatively impacts myocardial contractility, cardiac conduction, and systemic vascular resistance through a complex and widespread set of events that involve channel blockade, metabolic signaling, and intracellular energy production, that is, inhibition of oxidative phosphorylation. The clinical effects of these cellular events manifest initially as hypertension and tachydysrhythmias that progress to depressed cardiac conduction and performance (reduced cardiac output), bradycardia, and hypotension. Similarly, local anesthetic toxic effects on central nervous system (CNS) ionic channels manifest initially as altered mental status and/or mild prodromal symptoms such as paresthesias, tinnitus, and agitation and progress to seizure and possible coma.

Lipid emulsion resuscitation was first proposed as a treatment for LAST in 1998 and translated into clinical practice 8 years later.10 Over this timeframe, a number of potential mechanisms of action were proposed, the most prominent of which involved the hypothesis that lipid emulsion infusion effectively created an intravascular lipophilic “sink” into which lipid soluble local anesthetics such as bupivacaine partitioned and were ultimately removed from the body.17 Twenty years later, lipid emulsion therapy is believed to involve multiple mechanisms that involve active shuttling of local anesthetic away from the heart and brain, cardiotonic effects that involve the heart and/or vasculature, and postconditioning cardioprotective effects.10

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Shuttling Effects

Rather than acting as a static lipid sink, current research supports the concept that lipid emulsion works as a dynamic carrier to scavenge local anesthetic away from high blood flow organs that are most sensitive to LAST (ie, the heart and brain) and redistribute it to organs that store and detoxify the drug (ie, muscle and liver, respectively)18 (Fig. 1). The precise mechanisms of local anesthetic binding to lipid droplets are not understood fully but are believed to combine thermodynamic effects, for example, electrostatic attraction and physicochemical characteristics such as lipophilicity and acid-base ionization, as positively charged, fat-soluble local anesthetic molecules bind to negatively charged lipid particles. These observations appear to support lipid emulsion having greater efficacy in shuttling the more lipophilic local anesthetics such as bupivacaine. Nevertheless, even the less lipophilic local anesthetics such as lidocaine or mepivacaine are highly lipid soluble and carry a positive charge at physiologic pH. Therefore, lipid emulsion should be effective at reversing toxicity after overdose with lidocaine19 or mepivacaine. Further evidence suggests that together these pharmacokinetic attributes work to accelerate redistribution of local anesthetics by increasing the α half-life in whole blood, while decreasing the concentration of local anesthetic in the nonlipid fraction. The net effect shortens local anesthetic elimination half-life.20–22 Lipid emulsion also has nonscavenging effects that manifest as cardiotonic and postconditioning effects.

FIGURE 1

FIGURE 1

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Cardiotonic Effects

Several lines of evidence support the concept that lipid increases cardiac performance, which enhances the shuttling effect. The direct cardiotonic effects of lipid emulsion increase cardiac contractility, which increases cardiac output and blood flow through affected organs. Volume loads associated with lipid resuscitation improve cardiac function by a simple preload effect, although this effect is significantly less than the positive inotropy seen in both intact rat and isolated heart models during infusion of lipid. Lipid infusion also increases blood pressure via poorly understood effects on the peripheral vasculature. Together, these mechanisms serve to improve both cardiac output and blood pressure.23,24

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Postconditioning Effects

Recent laboratory experiments support the concept that adverse cellular effects of LAST overlap with mechanisms of cardiac ischemia-reperfusion injury.25 Coupled with the observation that infused lipid emulsion activates cardioprotective pathways, this provides an additional mechanism of postconditioning benefit to the local anesthetic-toxic heart.26,27 The explanations behind these purported benefits are discussed in detail in the supporting article.10

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Incidence and Epidemiology

Since publication of our 2010 practice advisory, new evidence has furthered our understanding of LAST epidemiology. This information is derived from analysis of administrative databases, registries, and case reports/case series. Of particular importance is publication of several studies that suggest the incidence of LAST associated with epidural28 and peripheral nerve blocks (PNBs) is decreasing,29 which has led some experts29,30 to debate whether or not LAST remains a clinically relevant complication.

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Administrative Databases

One avenue to assess the frequency of LAST in the general community population is to query large administrative databases such as the Premier Perspective Database (PPD).31 As part of the current advisory series, Mörwald et al9 recently presented data from over 400 hospitals on nearly 238,500 patients who received a PNB for total joint arthroplasty between 2006 and 2014. This methodology's weakness is that it lacks clinical details beyond those revealed by diagnostic or billing codes, and because no specific coding for LAST could be identified in the hospital reports, the methodology relies on surrogate markers such as seizure, cardiac arrest, or administration of lipid emulsion. Although the occurrence of seizure or cardiac arrest may overestimate the frequency of LAST, the increased use of lipid emulsion on the day of surgery is likely specific to the true diagnosis. In Mörwald et al's9 study, the cumulative rate of LAST was 0.18%, that is, the rate of patients receiving a PNB and experiencing at least one LAST-associated outcome was 1.8/1000. During the 9-year study period, the overall adverse outcome rate trended downward without the trend reaching statistical significance, whereas the use of lipid emulsion increased significantly. The investigators concluded that, although this population-based frequency of LAST is low, it should be considered clinically meaningful.

The National Inpatient Sample (NIS) contains a diagnostic code specific to LAST, although it remains uncertain how specific the coding is for LAST events, because errors in coding can occur as a result of physician documentation or data abstraction. In the current practice advisory series, Rubin et al12 report an incidence of LAST intermediate between that of the PPD and those of single institutions and specialized registries. Their database query of over 710,000 PNBs placed for total joint arthroplasties revealed an average adjusted incidence of 1.04 (confidence interval [CI], 0.49–1.80) LAST events per 1000 PNBs over the 15-year period 1998 to 2013. Of these events, 1 in 5 was considered major, that is, involved a seizure (8.1%) or a major cardiac complication (6.8%). Contrary to observations from case reports,4 there were no deaths and multivariable analysis found no correlation between LAST and age or comorbidity. Total shoulder arthroplasty was associated with LAST more often than knee or hip operations (odds ratio [OR], 4.35; CI, 1.96–9.65), as was being cared for in a large to medium-sized hospital. Over the 15-year study period, and similar to Mörwald et al's9 findings, the odds of a LAST event trended downward by 10% per year (OR, 0.90; CI, 0.84–0.96) despite increased PNB use.

The PPD's 1.8/1000 cumulative rate and the NIS 1.04/1000 incidence, while similar, are considerably higher than the 0.04/1000 to 0.8/1000 LAST incidences reported contemporaneously from various registries,32 national surveys,33 and single institutions.29,34 Variations in the incidence may reflect differing definitions of LAST. For example, studies that include generalized CNS excitation35 or minor cardiac complications12 in addition to seizure and cardiac arrest report a higher incidence of LAST (0.87/1000 to 1.04/1000) than studies29 that only include seizure or cardiac arrest (0.04/1000). With regard to expertise and caseload, PPD data suggest that LAST events within the community, where case volumes may be low and ultrasound use not universal, may be more common than those reported from registry instruments or single institutions that manifest expertise in regional anesthesia. Conversely, the NIS study found no difference between teaching and nonteaching hospitals. In summary, although administrative databases have specific weaknesses related to the lack of relevant clinical information on individual LAST events, they do demonstrate that LAST remains a rare yet relevant issue in the community at large.

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Registries

A wealth of registry and observational study data have been published since 2010. These works range from extensions of previously published quality assurance data sets,36,37 national databases33,38 and international registries,35,39 to specific registries that focus on pediatric practice,40–42 single-center data,29,32 and data specific to interscalene brachial plexus block.34

The most important new finding from the Australian and New Zealand Registry of Regional Anaesthesia (now the International Registry of Regional Anaesthesia) is that ultrasound guidance reduces the risk of LAST throughout its continuum by 60% to 65% (propensity analysis OR, 0.35–0.36) as compared with peripheral nerve stimulation alone.35 This observation is supported by the Dartmouth registry, which reported only 1 seizure in 12,668 ultrasound-guided blocks.32 The International Registry of Regional Anaesthesia registry also reported a surprisingly higher risk of LAST with lidocaine than with ropivacaine, which the authors speculated may reflect a practitioner's false sense of security when using relatively less toxic lidocaine.35

National survey data from Italy38 reveal an incidence of LAST during PNB of 0.34/1000 blocks, and Finnish data33 document a similar 0.37 per 1000 PNBs. Of note, the Finnish incidence is lower if all LAST events (including epidural, but not spinal, anesthetics) are included (0.07 per 1000). This observation is consistent with previous knowledge that LAST is 4 to 5 times more common with PNBs than with epidurals.1 If one were to combine LAST events reported since 2010 from 11 registries and observational studies, the population frequency is 0.27/1000 (95% CI, 0.21–0.35) (69 events per 251,325 PNBs).11

Data from observational studies offer some insights into whether or not experience and expertise affect the rate of LAST. The Finnish study33 noted a 3.3 relative risk of having a LAST event in a nonuniversity hospital as compared with a university hospital. Similarly, the Hospital for Special Surgery in New York, which represents a specialized high-volume regional anesthesia practice, reported 0.04 seizures per 1000 blocks, which is lower than other reports and may not apply to the community at large.29

Pediatric anesthetics captured in registries40,42 and single-center41 observational studies confirm a very low overall rate of LAST in children. Data from the 2012 Pediatric Regional Anesthesia Network documented no LAST episodes in 14,917 procedures,42 although its most recent analysis of over 100,000 regional anesthetics will report 7 severe LAST episodes (cardiac arrest or seizure)—0.076/1000, 95% CI, 0.029 to 0.14/1000 (J.M. Neal, MD, and D.M. Polaner, MD, personal written communication September 19, 2017). The French-Language Society of Pediatric Anaesthesiologists' registry40 reported rates of 0.16/1000 for PNBs and 1.3/1000 neuraxial blocks (excluding spinal anesthesia). The frequency of LAST associated with pediatric continuous catheter techniques is higher, 1.53 per 1000.41 When compared with the overall population frequency of 0.27/1000 (95% CI, 0.21–0.35),11 it can be argued that the rate of LAST in pediatric populations is less than that in adults. This in part may be because most regional anesthesia in children is performed under general anesthesia (which raises seizure threshold) using smaller local anesthetic volumes, and children likely have a lower comorbidity burden.

In summary, clinical registries have the capability of identifying infrequent events that occur in large populations, but often at the expense of detailed analysis. Of recent events that were reported in sufficient detail, 72% were considered major: 42 seizures and 8 cardiovascular (CV) presentations.11 Expectedly, minor events are less likely to be reported at all. These data support the assertion that LAST, while rare, remains a serious complication of local anesthetic use. Ultrasound guidance reduces the likelihood of any LAST event, yet seizure and/or cardiac arrest still occur at an estimated rate of 0.26/1000 ultrasound-guided blocks.43

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Case Reports and Series

Voluminous case reports published over the past decade emphasize the need to educate anesthesiologists and especially nonanesthesiologists in the prevention, recognition, and treatment of LAST. Case reports and case series allow in-depth analysis of individual incidents of LAST, but without the ability to gain insight into population-based frequency. The power of case report analysis is the ability to discern patient comorbidities, technique details, and treatment effectiveness, together with the ability to appreciate evolving trends in LAST presentation. The latter is important in assessing the impact of newer local anesthetic agents, nerve localization techniques (ultrasound guidance), and/or treatment modalities such as lipid emulsion therapy. Insights from case report analysis will be presented in Recognition section.

In summarizing knowledge related to the incidence or frequency of LAST, we wish to emphasize that regardless of reporting mechanism, administrative data, registries, or case reports, the true frequency of LAST in the anesthesiology community is very likely underreported. This stems from a number of factors including misdiagnosis, publication bias, and individual practitioner underreporting, especially because it relates to nonanesthesiologists. The panel opines that, even if the rates of LAST are decreasing, the complication should not be trivialized. When placed into the perspective of other rare anesthetic complications, serious LAST occurs more frequently than epidural hematoma and at least as often as peripheral nerve injury, and is unique to both in its potential for mortality.

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Prevention

Prevention is the primary and preferred mechanism for reducing the frequency and severity of LAST; meticulous attention to detail is the most important aspect of prevention. Optimal prevention is a multifactorial process, because no single intervention eliminates risk. Prevention involves 3 facets: avoidance and/or recognition of direct intravascular injection of local anesthetic, mitigating systemic uptake of local anesthetic from soft tissues, and awareness of patients at increased risk for LAST. The latter topic will be discussed in Recognition section.

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Limiting Local Anesthetic Uptake

Table 2 reviews key prevention strategies. Avoidance of intravascular injection is best accomplished by ultrasound guidance, judicious use of an intravascular marker, and incremental injection of local anesthetic through needles and catheters based on an appropriate circulation time between injections (longer for lower extremity blocks and at-risk patients, such as those with slower circulation). Systemic uptake of local anesthetic is best mitigated by awareness of those regional techniques most associated with delayed systemic uptake, by prolonging drug clearance through the use of epinephrine,44 and by using the lowest effective local anesthetic dose, which can be facilitated by low volume ultrasound-guided techniques.43 The panel wishes to emphasize awareness that local anesthetic toxicity is additive—whether by subsequent redosing of the same or a different local anesthetic and whether administration of the drug is by the same or a different member of the perioperative team. The latter scenario may occur when anesthesiologist and surgeon both administer local anesthetic during the care of a patient.

TABLE 2

TABLE 2

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LAST and the Newer Regional Anesthetic Techniques

New regional anesthetic techniques have expanded into anesthesiologists' practice. These include a variety of fascial plane-based truncal blocks, local infiltration anesthesia (LIA), and extended release liposomal bupivacaine (LB). Published information on these topics is limited, which impacts the panel's ability to offer definitive recommendations.

Within the anesthesiology community, the largest growth in new techniques involves truncal blocks that target fascial planes (eg, transversus abdominis plane, rectus sheath, quadratus lumborum, pectoral blocks).45 Within the surgical community, LIA has expanded, particularly in total joint arthroplasty practice. Case reports document LAST occurrences in both truncal block46 and LIA47 patients. The former may be at particularly high risk for LAST because targeted tissue planes are very vascular, local anesthetic volumes are high, and the blocks are often used in at-risk patient populations, that is, children and parturients. The advisory panel agrees with the recommendations put forth by Chin et al48 in their recent review of abdominal wall blocks. Their recommended strategies to reduce the likelihood of LAST include using epinephrine to reduce local anesthetic bioavailability,49 using dilute concentrations of less cardiotoxic local anesthetics, basing dose calculations on lean body weight, and 30- to 45-minute monitoring periods to account for the prolonged time to local anesthetic peak plasma concentration that is inherent to truncal blocks.48 (IIa; B)

Data pertinent to LB and LAST are limited, which is both reassuring and worthy of conservative interpretation. Ilfeld et al's50 retrospective review of 6 published RCTs of LB use for 335 PNBs reported no incident of identifiable LAST. Incidents of dose-related bradycardia (2%–14%) were conceivably consistent with limited LAST, but by no means diagnostic. To our knowledge, there are no published case reports of LAST associated with LB (possibly indicating negative reporting bias for adverse events); however, 130 cases (January 2012 to June 2016) are present in the US Food and Drug Administration's (FDA's) Adverse Event Reporting System. This voluntary self-reporting system, which does not have a code specific to LAST, is non–peer reviewed and is open to reports from medical professionals, industry, and private individuals. Using the statistical technique of disproportionality analysis, Aggarwal51 reports an association between LB and LAST based on the FDA's Adverse Event Reporting System data.

The corpus of published human studies on LB totals only a few thousand patients, the drug has been clinically available in the United States for only 5 years, and the pharmacologic and chemical dynamics of liposomal formulations are dramatically different from standard local anesthetics. Based on such limited information, our recommendation is that patients receiving LB be afforded the same level of vigilance as would be given to any patient receiving a local anesthetic (IIb; C).

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Prevention Strategies

In the interval since our second practice advisory, 2 new findings related to prevention deserve emphasis. First is the evolving role of ultrasound guidance. Meta-analysis had shown that ultrasound reduced the incidence of vascular puncture associated with PNB compared with peripheral nerve stimulation,52 yet previous institutional32,36 and registry39 data did not link this surrogate outcome to a definitive reduction in seizure or cardiac arrest. In the intervening years, Barrington and Kluger35 have confirmed that ultrasound guidance reduces the incidence of LAST episodes spanning the continuum from mild subjective symptoms of toxicity to seizure and cardiac arrest. As compared with landmark techniques, ultrasound reduced the risk of LAST by 65% in their study of over 25,000 PNBs. These findings are consistent with those reported by Orebaugh et al.37 The second new finding related to prevention involves the changing patterns of LAST presentation, as discussed below.

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Recognition: The Changing Patterns of LAST Presentation

Our 2010 advisory was accompanied by DiGregorio et al's4 analysis of 93 LAST cases reported over the 30-year period, 1979 to 2009.4 In the interim, Vasques et al53 presented 67 additional cases from 2010 to March 2014. Accompanying the current advisory, Gitman and Barrington11 present 47 more cases reported between April 2014 and November 2016. These case series span nearly 4 decades and serve to confirm some expected patterns of LAST clinical presentation while revealing changing patterns in others. First, all 3 case series reinforce the concept that LAST events are skewed toward the extremes of age. The recent finding that large amounts of absorbed local anesthetic are stored in skeletal muscle suggests that patients with low muscle mass are at higher risk for LAST. The most recent Pediatric Regional Anesthesia Network data confirm similar observations in infants under 6 months old, whose rate of serious LAST is 6-fold higher than that for other children (J.M. Neal, MD, and D.M. Polaner, MD, personal written communication on September 19, 2017). In addition to lower muscle mass, infants and neonates manifest a higher unbound fraction of local anesthetic. Second, although bupivacaine is the most toxic local anesthetic and the most difficult overdose to resuscitate when LAST occurs, all local anesthetics are capable of causing toxicity, including “safer” agents such as lidocaine and ropivacaine (26% and 21%, respectively, of total events in the latest case series).11 The advisory panel and others35,54 speculate that practitioners may be less vigilant with regard to dosing and safety steps when administering these purportedly less toxic local anesthetics. Furthermore, the panel opines that, when viewed on an equipotent basis, ropivacaine as administered in most clinical settings is likely similar in toxicity to bupivacaine. Third, about 15% of LAST events involve continuous local anesthetic infusions and most episodes present 1 to 4 days after initiation of the infusion, often with subtle prodromes or hemodynamic changes.

The combined case series4,11,53 also reveal shifting patterns in LAST's clinical presentation. First, an increasing number of events (about 20%) occur outside of the traditional hospital environment and half involve a nonanesthesiologist. The occurrence of LAST after simple tissue infiltration of local anesthetic in 20% of events is consistent with nonanesthesia-trained practitioners administering the drug and/or an increase in LIA techniques. Similar events involve topical anesthesia of the airway or transcutaneous absorption of local anesthetics. Second, a new signal from the current case series11 involves a preponderance of pediatric LAST events associated with penile block, which accounted for a quarter of case reports during that series' 2.5-year period. Some of these cases required chest compression.55 Encouragingly, after implementing policy, dosing, and technique changes, the involved institution reports no further LAST events associated with penile block (G. Weinberg, MD and R. Yu, MD, personal verbal communication May 2017).

The 2010 practice advisory noted that 40% of reported cases did not present in a manner consistent with the classic textbook description of LAST. Rather than an initial complex of CNS excitement, for example, metallic taste or auditory changes, followed by seizure and then CV collapse, nearly half of the presentations were considered “atypical,” presenting with CV signs alone (no evidence of CNS toxicity) and/or having a delayed presentation (more than 5 minutes after injection of local anesthetic). Although the occurrence rates vary slightly, the interim analyses from 2010 to 201611,53 conform to previous observations that about one third of patients present with combined CNS/CV signs and symptoms (mostly seizures, hypertension or hypotension, and electrocardiographic changes). Fewer patients exhibit isolated CV symptoms as compared with isolated CNS symptoms (Figs. 2, 3). Another change to clinical presentation is a shift in timing from signs and symptoms appearing coincident with or within a minute of local anesthetic administration (intravascular injection) to presentations that are delayed from several minutes to 30 or even 60 minutes after injection11,53 (Fig. 4). We speculate that this shift toward delayed presentation involves fewer intravascular injections as a consequence of ultrasound guidance, the increasing use of local tissue infiltration techniques, and/or increasing use of continuous local anesthetic infusion. This shift strengthens our previous advice to observe patients for at least 30 minutes after injecting potentially toxic doses of local anesthetic.

FIGURE 2

FIGURE 2

FIGURE 3

FIGURE 3

FIGURE 4

FIGURE 4

Despite changing patterns in LAST presentation, our recommendations remain consistent. Local anesthetic systemic toxicity is a masquerader, and its detection requires persistent open-minded vigilance. To emphasize reasonable local anesthetic dosing and to highlight those patients most at risk for LAST, we recommend including a discussion of local anesthetic use during the preincisional surgical pause. Doing so facilitates awareness among all perioperative team members of maximal local anesthetic dosing and the issue of additive toxicity, particularly because it pertains to local anesthetic administration by different team members, including nonanesthesiologists. The surgical pause is also an opportunity to highlight at-risk patients and how they might present with LAST. Classic presentation patterns that involve subjective signs, seizure, or cardiac arrest in close proximity to local anesthetic dosing do not always occur. When patients receive a local anesthetic and manifest a delayed presentation of agitation or CNS depression, or unexplained signs of cardiac compromise such as progressive hypotension or bradycardia, LAST should be considered in the differential diagnosis. Table 3 outlines factors believed to heighten the risk of LAST. Table 4 reviews recommendations for diagnosing LAST.

TABLE 3

TABLE 3

TABLE 4

TABLE 4

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Treatment: Evolving Paradigms

The treatment of severe LAST is fundamentally different from conventional cardiopulmonary resuscitation (CPR) insofar as toxic cardiomyopathy differs pathophysiologically from other causes of CV collapse. First, unlike contemporary CPR paradigms that eschew early respiratory interventions in favor of cardiac support, successful treatment of LAST hinges on the primacy of airway management to prevent the hypoxia, hypercapnia, and acidosis that potentiate LAST and negatively impact resuscitative efforts. The mechanism of potentiation may be related to increased free fraction of local anesthetic and/or worsening of cardiac function. Second, while CPR and Advanced Cardiac Life Support (ACLS) symptomatically treat hemodynamic perturbations consequent to ischemic cardiac injury, usually with the goal of improving coronary perfusion, successful treatment of LAST seeks to effectively moderate or reverse the mechanisms underlying the local anesthetic toxicity. Recent evidence indicates that the inotropic benefit of lipid only occurs when myocardial local anesthetic content is reduced below a threshold that corresponds to ion channel blocking concentrations. This underlines the importance of effective CPR to ensure that coronary perfusion is sufficient to reduce local anesthetic tissue levels to attain the maximum benefit of lipid infusion. Third, recent data from rat models reinforce the admonition that epinephrine, when necessary, be administered initially in small doses (1 μg/kg or less) to avoid impaired pulmonary gas exchange56 and increased afterload. Fourth, simulated LAST scenarios have demonstrated the usefulness of the ASRA Checklist57 as a cognitive aid during LAST treatment58 and the value of a reader to prompt adherence to recommendations.59 An updated version of the ASRA Checklist is part of this practice advisory series.13 The ASRA LAST smart phone app (iOS and Android) has been updated coincident with this practice advisory.

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Insights Regarding Contemporary LAST Treatment

The case report analysis presented with this practice advisory11 allows insights into the contemporary treatment of LAST. Treatment protocols developed by national organizations such as ASRA57 and the Association of Anaesthetists of Great Britain and Ireland60 are followed inconsistently. Less than half (47%) of patients with LAST were treated with lipid emulsion, and nearly 40% of those patients received the antidote 10 minutes or longer after symptom onset, occasionally at an incorrect dose. Nevertheless, and within the limits of case series comparison, the overall use of lipid emulsion has apparently increased from 34% to 47% as compared with our 2010 report.4 An ACLS was necessary in 21% of patients; duration ranged from 2 to 60 minutes. Two of the reported 47 patients died; one from a combination of delayed diagnosis and treatment, and the other self-administered over 4 g of topical lidocaine at home. As expected, all 11 unpublished cases submitted to lipidrescue.org from April 2014 to November 2016 received lipid emulsion immediately or within 5 minutes of symptom onset. Three of these patients required ACLS, but none died.

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New Treatment Recommendations

The use of lipid emulsion as an antidote for LAST is “off label,” as defined by the FDA. Our 2010 advisory suggested using lipid emulsion therapy at the first sign of arrhythmia, prolonged seizures, or rapid clinical deterioration of the patient. Based on evidence that lipid shuttling is most effective early in the toxic event10 when local anesthetic plasma concentrations are at their peak, we now unequivocally recommend lipid emulsion therapy soon after airway management in any LAST event that is judged to be potentially serious. Furthermore, because adverse effects from lipid administration specifically as an antidote for LAST appear to be minor and limited, we recommend erring on the early side of administration. The maximum lipid dose has been increased to ~12 mL/kg based on FDA recommendations.61 Nevertheless, total lipid doses used in resuscitation of LAST are usually much less (typically about half) of this limit. Thus, it is important to avoid delivering an excessive dose of lipid since dangerous fat overload can occur.62 Table 5 outlines treatment recommendations.

TABLE 5

TABLE 5

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Future Directions

If the previous decade is any indication, we expect continued progress in our understanding of LAST—its incidence, cellular mechanisms, prevention, and treatment. Much work remains with regard to understanding the cellular and systemic mechanisms inherent to local anesthetic poisoning. Advancement of this knowledge holds promise for improved resuscitation. Whether or not the overall incidence of LAST is truly diminishing remains open to debate, particularly because it pertains to the healthcare community at large, in nonhospital settings, and among nonanesthesiologist practitioners. Hopefully the future will see further development of local anesthetic alternatives such as neosaxitoxin, which blocks sensory conduction by binding to the external pores of noncardiac sodium channels and does not cross the blood-brain barrier.63 Neosaxitoxin thus prolongs anesthesia without the risk of local anesthetic-induced cardio- and CNS toxicity. Until such time as alternative drugs come into use, the burden is on anesthesiologists and LAST researchers to improve our knowledge of basic mechanisms, enhance early recognition, improve awareness, and build effective systems for prevention and treatment.

To reiterate our concluding comments from the 2010 practice advisory, “LAST remains a significant clinical problem. Considering 1) the extensive use of local anesthetics, 2) the frequent use of doses sufficient to cause significant morbidity or mortality, and 3) the imperfect nature of our ability to predict, prevent, detect, and treat these complications, it remains the responsibility of all clinicians using local anesthetics to understand their potential for causing severe systemic toxicity and to be prepared to respond immediately when these events occur.”1 Moreover, subtle or undetected patient comorbidities can significantly increase susceptibility to LAST. Practice patterns and system improvements may well reduce the likelihood of LAST and optimize patient safety. Nevertheless, although we contend that the frequency of LAST can be reduced, it is unlikely to be eliminated altogether—there will always be system errors, unrecognized patient comorbidities, and stochastic events that invariably arise in large populations. Although LAST is indeed a rare event, it still occurs despite proper technique used by competent professionals. When LAST happens, recognition and preparedness make it a treatable complication of regional anesthesia.

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ACKNOWLEDGMENTS

The authors thank the following colleagues who made substantial contributions to this project through authorship of the individual background articles from which this executive summary was drawn: Hospital for Special Surgery, Weill Cornell Medical College, New York, NY: Crispiana Cozowicz, MD; Mt. Sinai School of Medicine, New York, NY: Nicole Zubizarreta, MPH and Jashvant Poeran, MD, PhD; University of Illinois College of Medicine, Chicago, IL: Steven Roth, MD; Pritzker School of Medicine, University of Chicago, Chicago, IL: Monica Matsumoto, BA; Stanford University, Palo Alto, CA: T. Kyle Harrison, MD; and Virginia Mason Medical Center, Seattle, WA: Crystal M. Woodward, MD.

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