Improved regional anesthesia techniques and less

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1 Local Anesthetic-Induced Cardiac Toxicity: A Survey of Contemporary Practice Strategies Among Academic Anesthesiology Departments William Corcoran, MD* John Butterworth, MD Robert S. Weller, MD* Jonathan C. Beck, MD* J. C. Gerancher, MD* Timothy T. Houle, PhD* Leanne Groban, MD Though new local anesthetics (LA), effective test-dosing, and new regional anesthetic techniques may have improved the safety of regional anesthesia, the optimal management plan for LA-induced cardiac toxicity remains uncertain. Accordingly, we evaluated current approaches to LA cardiotoxicity among academic anesthesiology departments in the United States. A 19-question survey regarding regional anesthesia practices and approaches to LA cardiac toxicity was sent to the 135 academic anesthesiology departments listed by the Society of Academic Anesthesiology Chairs-Association of Anesthesiology Program Directors. Ninety-one anonymously completed questionnaires were returned, at a response rate of 67%. The respondents were categorized into groups according to the number of peripheral nerve blocks (PNBs) performed each month: 7 PNBs (38%), 51 7 PNBs (13%), 31 5 PNBs (2%), 11 3 PNBs (23%), and 1 PNBs (6%). Anesthesia practices administering 7 PNBs were 1.7-times more likely to use ropivacaine (NS), 3.9-times more likely to consider lipid emulsion infusions for resuscitation (P.8), and equally as likely to have an established plan for use of invasive mechanical cardiopulmonary support in the event of LA cardiotoxicity (NS) than low-pnb volume. We conclude that there are differences in the management and preparedness for treatment of LA toxicity among institutions, but the safety implications of these differences are undetermined. (Anesth Analg 26;13: ) Improved regional anesthesia techniques and less toxic local anesthetics (LA) appear to be associated with a declining number of reported episodes of severe LA toxicity over the past quarter century. The current incidence of clinically important LA toxicity in adults may be subject to under-reporting, but estimates range from 7.5 to 2 per 1, peripheral nerve blocks (PNBs) and about 4 per 1, epidurals (1). Before the reports of cardiac arrest from labor epidurals with.75% bupivacaine and etidocaine (2) and the black box warning in the package insert (for the United States) of bupivacaine in 1983 (3), the rate of LA systemic toxicity with epidurals ranged from 2 to 32 per 1, (4 7). Although rare, LA toxicity may be lethal, and clinicians should formulate provisions From the *Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina; and Department of Anesthesia, Indiana University School of Medicine, Indianapolis, Indiana. Accepted for publication August 3, 26. Presented in part at the 26 Annual Meeting of the International Anesthesia Research Society, San Francisco, CA. Address correspondence to Leanne Groban, MD, Department of Anesthesiology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC Address to lgroban@wfubmc.edu. Reprints will not be available from the author. Copyright 26 International Anesthesia Research Society DOI: /1.ane bb 1322 for a rapid and educated response to such events. Unfortunately, despite more than 2 yr of animal research and case reports of potentially effective treatments, there appears to be no consensus for optimum management of catastrophic LA toxicity. The primary aim of this survey was to determine how U.S. academic anesthesiology departments prepare for and treat LA cardiotoxic events, and secondarily, to assess variation in practice patterns in PNB performance. We hypothesized that we would encounter a wide range of practice patterns and preparation for treatment of toxicity, and that departments where larger numbers of PNBs are performed would have responses more in line with current literature. METHODS The 19-question survey with return envelope was mailed to the chairs of the 135 academic anesthesiology departments listed by the Society of Academic Anesthesiology Chairs-Association of Anesthesiology Program Directors. Questions were designed to identify preferred LAs and typical dosage, monitoring during PNB, level of training of those performing PNBs, location where PNBs were performed, volume of PNBs performed, and choice of pharmacologic resuscitation used in the event of a cardiac complication (Fig. 1). We also asked whether lipid emulsion infusions and/or mechanical cardiopulmonary support would be Vol. 13, No. 5, November 26

2 Figure 1. The questionnaire. used if initial attempts at pharmacologic resuscitation failed. We asked that the department chair, the director of regional anesthesia, or the director of acute pain management complete the survey. No follow-up survey was sent to nonresponders. Institutions were categorized by the number of PNBs performed per month, and we arbitrarily defined high-volume as those performing 7 per month, and low-volume as 7 month. Responses were analyzed relative to the number of procedures performed in a responder s medical setting using 2. Care was taken to artificially dichotomize the procedure volume categories so that 5 responses were expected in each cell. Odds ratios with 95% confidence intervals (CI) were used to index the effect size of the observed differences. The -value was set at.5. All analyses were conducted using SPSS 13. (SPSS, Chicago, IL). RESULTS Survey Response and PNB Volume Sixty-seven percent of surveys were completed and returned. The distribution of the number of PNBs performed monthly was: 7 PNBs (38%), 51 7 PNBs (13%), 31 5 PNBs (2%), 11 3 PNBs (23%), and 1 PNBs (6%). PNBs were performed by trainees (residents or fellows) 88% of the time. At 9% of the programs, only staff anesthesiologists performed PNBs. The location of block administration and supervision included the preoperative holding area (5%), a dedicated regional anesthesia induction area (3%), and the operating room (24%). Some programs reported that PNBs were performed in multiple locations. LA Choice and Dosage A substantial variation was observed in preferred long-acting LAs. Although 19% of respondents selected multiple drugs, the preferred long-acting LA was either bupivacaine (55% of respondents) or ropivacaine (43%) (P.26) (Fig. 2A). Though most preferred bupivacaine, there was a slight trend for high-volume institutions to choose ropivacaine, odds ratio 1.7 (95% CI.7 3.9, P.24). The choice of intermediate-acting LAs reflected similar variability. The two most cited single drugs were mepivacaine (5%) and lidocaine (32%), with a trend for to prefer mepivacaine, , P.6 (Fig. 2B). When performing an infraclavicular or axillary block with bupivacaine, most institutions chose doses of mg (71%). Few used 2 mg (1%) or 125 mg (19%). High-volume were 7.5-times more likely to use 2 mg (95% CI , P.2). When performing infraclavicular or axillary blocks with ropivacaine, most institutions chose mg (66%). Monitoring During Block Placement Standard monitoring during PNB varied among institutions. There was no apparent relationship between monitoring procedures and the number of PNBs performed per month or the level of training of Vol. 13, No. 5, November International Anesthesia Research Society 1323

3 A % B % 2 1 Preferred Long-acting Local Anesthetic Levo Bup Rop Mixtures Other Preferred Intermediate-acting Local Anesthetic Lid Mep Mixtures Other Figure 2. (A) The preferred long-acting local anesthetic. The long-acting drug of choice is bupivacaine, although there is a trend for high-volume institutions to choose ropivacaine versus low-volume institutions. Using logistical regression we found that high-volume institutions are 1.7-times more likely to choose ropivacaine (P.24). Levo levobupivacaine; Bup bupivacaine, Rop ropivacaine. (B) The preferred intermediate-acting local anesthetic. The preference for mepivacaine (Mep) over lidocaine (Lid) nearly reached statistical significance (P.6) Use of Lipid Emulsion High volume Low volume no yes Figure 3. Preferences for lipid emulsion use in the event of local anesthetic-induced cardiac toxicity. High-volume are more likely to use lipid emulsion for the treatment of bupivacaine toxicity than low-volume, 2 (1) 7.52, P.8. Data represent percentage of respondents by category High volume Low volume No CP Support CP Support Figure 4. Presence of an established plan for mechanical cardiopulmonary (CP) support in the event of failed resuscitation. High- and low-volume were similarly unlikely to have an established plan for CP support, 2 (1) 2.74, P.98. Data represent percentage of respondents by category. the practitioner performing the block. Standard monitoring consisted of pulse oximetry, noninvasive arterial blood pressure (BP), and electrocardiogram (ECG) for 69% of, while 15% used only pulse oximetry and BP, and 16% used only pulse oximetry while performing regional blocks. Resuscitation Practice Centers stored emergency drugs variously in a code blue cart (63%), designated regional anesthesia lock box (26%), or another location (11%) for emergency treatment of LA toxicity. In response to ventricular tachycardia from presumed bupivacaine toxicity, 59% would use amiodarone, while 19% would choose bretylium, 13% esmolol, and 2% would use lidocaine. Low-volume, defined as 3 PNBs for this analysis only, were 3.6-times (95% CI ) more likely to choose bretylium for bupivacaine-induced ventricular tachycardia than high-volume (4% vs 16%, P.16). For an episode of hypotension, 87% of respondents would choose ephedrine and/or phenylephrine followed by epinephrine (8%) or vasopressin (3%). For persistent hypotension 71% of programs would choose epinephrine, 2% ephedrine and/or phenylephrine, and 11% vasopressin. Lipid Emulsion: Choice and Availability With respect to the potential use of lipid emulsion infusion to treat bupivacaine toxicity, 74% of would not use it, and 26% would consider its use. High-volume were 3.9-times more likely (95% CI ) than low-volume to use lipid infusion for bupivacaine toxicity (44% vs 17%, P.8) (Fig. 3). Of those considering the use of lipid infusion, storage location was the operating room pharmacy (39%), the hospital pharmacy (35%), the code cart/lock box (22%), or a drug-dispensing machine (4%). It could be obtained in 1 min for 59%, 1 3 min for 26%, and 3 min for 15% of the. Mechanical Circulatory Support For failed resuscitation, 59% of respondents have no established plan for mechanical cardiopulmonary support, with no difference by PNB volume (Fig. 4). For those with an established plan, most often it 1324 LA-Induced Toxicity: Contemporary Practice Strategies ANESTHESIA & ANALGESIA

4 included cardiopulmonary bypass (CPB) (89%), intraaortic balloon pump counterpulsation (22%), and extracorporeal membrane oxygenation (14%). Cardiothoracic surgeons could respond in 1 min for 33%, 1 3 min for 51%, and 3 min for 15% of respondents. DISCUSSION Our results show a wide range of current practice patterns for PNB in U.S. academic, and variability in nearly all aspects of treatment strategies for managing severe LA toxicity. Much of the observed variability (PNB performance site, monitoring, preferred intermediate-duration LA, resuscitation drugs, and so forth) was independent of PNB volume. Conversely, the finding that high-pnb volume showed a trend to favor ropivacaine, and to be significantly more likely to consider lipid emulsion infusion and less likely to list bretylium as a treatment for severe LA toxicity than low-volume ( 3 PNBs) merits closer examination. It is possible that process variation could lead to poorer outcome from relatively rare, but catastrophic, toxic reactions (8). LA Choice The findings of Aberg (9) and Akerman et al. (1), that S-bupivacaine requires larger doses than R-bupivacaine to produce convulsions and mortality, led to the development of levobupivacaine and its S-enantiomer homologue ropivacaine (11,12). Subsequent animal studies have demonstrated differences in mortality or inability to resuscitate between racemic bupivacaine-treated dogs (5% mortality) and ropivacaine-treated dogs (1% mortality) after anesthetized dogs received continuous, escalating infusions of LA. (13) Still, severe toxicity in patients has been reported with ropivacaine (14 17), but ropivacaine toxicity may be more amenable to treatment than reactions to bupivacaine, and no ropivacaineinduced deaths have been reported. Despite the apparent increased safety margin with ropivacaine, our study demonstrates that bupivacaine is widely, and even exclusively, used in many institutions. Factors other than safety during rare toxic events, such as acquisition cost and perceived quality or duration of PNB, may influence LA choice, but these factors were not evaluated in our survey. Monitoring During PNB BP, three-lead ECG, and pulse-oximetry are among the standard monitors endorsed by the American Society of Anesthesiologists for use during all anesthetics ( 2.pdf), but only 69% of respondents used all three monitors during PNB. Although the American Society of Anesthesiologists Standards acknowledge that practitioners may circumvent standard monitoring when indicated (and documented), both BP and ECG monitoring may supplement pulse oximetry to demonstrate early signs of LA toxicity (18). Specifically, the ECG is necessary to characterize arrhythmias should severe toxicity occur. Treatment Strategies for LA Toxicity There is no consensus strategy for how best to treat severe LA toxicity. Indeed, there is no ethical way to conduct meaningful clinical trials in this area. Our survey showed, however, that high-pnb volume institutions are more likely to choose amiodarone (as opposed to lidocaine or bretylium) for ventricular tachycardia. The stated preference of some for bretylium is particularly alarming, since this drug is no longer available in North America or included in Advanced Cardiac Life Support Guidelines. Lipid Emulsion Infusion and Mechanical Circulatory Support for Severe LA Toxicity We presumed that all would institute ventilatory support and chest compression per Advanced Cardiac Life Support Guidelines for complete cardiopulmonary collapse after PNB, and we did not include survey questions for those interventions. Lipid emulsion infusion may be a consideration after institution of cardiopulmonary resuscitation in such severe toxic events. Animal studies by Weinberg and co-workers (19 21) have shown lipid emulsion infusions to be effective as a means of resuscitation from bupivacaine toxicity after chest compression (rat) or cardiac massage (dog) failed to resuscitate the animals. The mechanism of lipid resuscitation remains under investigation, but may be due to the migration of amphiphilic LA molecules from binding sites in the heart into the plasma-born lipid. Dog studies show that after circulatory collapse secondary to bupivacaine toxicity, lipid treatment increased the survival rate from % in the control group to 1% in the lipid-treated group (19). Enthusiasm for lipid treatment must be tempered by the absence of published reports of successful use of lipid to resuscitate humans with LA toxicity. Results of this survey show that the high-volume are significantly more receptive to the use of lipid emulsion for refractory LA cardiotoxicity than the low-volume. One case report documents the successful use of lipid for bupivacaine cardiac toxicity (22). CPB has resulted in survival in human cases of bupivacaine cardiovascular toxicity. Bupivacaine may have a prolonged duration of action in cases of cardiovascular collapse; thus, patients may require cardiopulmonary support for 45 min (23 25). In the event of failed pharmacologic resuscitation, our results show that only 41% of have a plan for mechanical cardiopulmonary support (Fig. 4). Most institutions report that cardiothoracic surgeons could arrive in 3 min or less, although the most important variable, time from identification of the need until onset of bypass, was not ascertained. There are no Vol. 13, No. 5, November International Anesthesia Research Society 1325

5 documented reports of the successful use of extracorporeal membrane oxygenation for LA toxicity; nevertheless, if available, it may be instituted more rapidly than CPB. Study Limitations This study has a number of limitations. The inability to show differences between high and low-volume can indicate that differences were not present or that there was simply a lack of statistical power to detect them. Although a response rate of 67% is good, our findings should be interpreted cautiously because of limited statistical power, which enabled us to detect only moderate to large effect sizes in the differences between categories (26). In addition, only academic anesthesiology departments were surveyed, and the results may not reflect the much broader practice of regional anesthesia in non-academic departments. Furthermore, there may be a range of practice within responding departments not reflected by the survey, and an assumption was made that a department chair would provide the same responses as the director of regional anesthesia in a given institution, which may not be accurate. This limitation, however, would most likely lead to our survey results under-estimating the variability in PNB practice and preparedness for LA toxicity. Our finding of wide variability in preparedness for LA toxicity and lack of consensus for treatment is noteworthy. Lessons learned from malignant hyperthermia show that well-established treatment guidelines could allow for early intervention to effectively save lives (27). LA cardiac toxicity is likely at least as common as malignant hyperthermia, and potentially as frequently fatal. Our survey results support efforts to determine and disseminate optimal treatment strategies for severe LA toxicity. REFERENCES 1. Mulroy MF. 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J Craniofac Surg 23;14: LA-Induced Toxicity: Contemporary Practice Strategies ANESTHESIA & ANALGESIA