Cardiac Arrest and Seizures Caused by Local AnestheticSystemic Toxicity After Peripheral Nerve Blocks
Should We Still Fear the Reaper?
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Spencer S. Liu, MD,*† Sarah Ortolan, MS,* Miguel Vizarreta Sandoval, BS,* Jodie Curren, RN,*Kara G. Fields, MS,* Stavros G. Memtsoudis, MD, PhD,*† and Jacques T. YaDeau, MD, PhD*†
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Regional anesthesia (RA) and analgesia have enjoyed resur-gence in recent years. Benefits in outcomes,1 increased em-
phasis on regional anesthesia/analgesia in training requirements,enhanced availability of guidelines for training in ultrasoundguidance,2 and proliferation of RA fellowships3 have likely allimproved access. Although the application of and skill levelsin regional techniques have increased, potential serious risks re-main poorly defined and may hamper full acceptance of RA.Major local anesthetic systemic toxicity (LAST), defined as car-diac arrest or seizures, is a potentially life-threatening risk ofRA. Peripheral nerve blocks (PNBs) in particular may requirelarge doses of local anesthetic, with a concomitant risk of LAST,and previous surveys report a perhaps 4- to 5-fold greater risk ofLAST after PNBs compared with epidural blocks.4 The severityof injury after LAST may be high because an analysis of theAmerican Society of Anesthesiologists (ASA) closed claims data-base (cases from 1980 to 2000) reported that LAST after PNBswas associated with 7 of 19 claims resulting in death or brain dam-age.5 However, since these reported cases, multiple clinical safetysteps have been recommended and implemented.6 Several recentprospective and retrospective surveys have attempted to definethe incidence and risk factors for LASTafter PNBs, but precisedefinitions are hampered by the rarity of major LAST and therelatively modest sizes of the surveys (7000–25,000 PNBs).7
Estimated incidence of seizures was approximately 0.6 to0.9/1000 PNBs, with a large 95% confidence interval (95% CI)of 0.3 to 1.3/1000. No incidence for the more severe complicationof cardiac arrest was determinable because of a lack of indexcases. Correspondingly, the American Society of Regional Anes-thesia and Pain Medicine (ASRA) practice advisory on LASTnoted that epidemiologic studies on LAST report statistics thatvary widely depending on how toxicity is defined.8 Regardlessof the exact risk of LASTafter PNBs, the ASRA practice advisoryemphasized the primacy of prevention in reducing the frequencyand severity of LAST. The first recommendation for risk reduc-tion is the use of the least dose of local anesthetic necessary.This is certainly a prudent suggestion, yet large doses of local
From the *Department of Anesthesiology, Hospital for Special Surgery; and†Weil Cornell Medical College, New York, NY.Accepted for publication September 16, 2015.Address correspondence to: Spencer Liu, MD, Department of Anesthesiology,
Hospital for Special Surgery, 535 E 70th St, New York, NY 10021(e‐mail: [email protected]).
The authors declare no conflict of interest.Funding was provided by the Department of Anesthesiology, Hospital for
Special Surgery, New York, NY.Work should be attributed to the Department of Anesthesiology, Hospital for
anesthetic may sometimes be necessary to ensure the desiredefficacy, and information on the clinical safety margin of localanesthetic dose and LAST after PNBs would be useful.
Thus, there remains a gap in our current understanding of therisk of major LAST and the potential safety margin of modernclinical practice. Here at the Hospital for Special Surgery (HSS),we perform approximately 13,000 to 15,000 PNBs per year andhave maintained various quality assurance (QA) databases since2009. Our QA databases represent a potential analysis of nearly90,000 PNBs for LAST; thus, this retrospective QA analysis ofour clinical use of PNBs at HSS during the past 6 years will aidin addressing our current knowledge gap in LAST after PNBs.
METHODSThis was a retrospective QA analysis of our QA, pharmacy,
code, and anesthesiology databases from 2009 to 2014. Institu-tional review board approval was granted, and the requirementfor individual informed consent was waived. Primary outcomewas defined as cardiac arrest caused by LAST (use of lipid rescuewithin 60 minutes after PNB injection).8,9 Per HSS OR Pharmacy,lipid rescue has been available since 2004 to treat LAST. Second-ary outcome was defined as seizure caused by LAST (60 secondsor more of tonic clonic activity within 60 minutes of PNB in-jection).10 Among other data, the QA database contains summarydata on all PNBs and intraoperative complications for the oper-ating rooms since 2009. Summary data for PNBs are generatedfrom daily review of all anesthesia records by the QA department.Intraoperative complications in the QA database consist of datacollected from multiple sources: 1) Staff anesthesiologists areexpected to self-report all major intraoperative complications;2) Any perioperative staff member can report potential compli-cations in real time via RL Solution Occurrence Reporting Sys-tem (RL Solutions, Cambridge, Massachusetts), which is usedto report any adverse events throughout the hospital. All entriesfor potential intraoperative complications are automatically sentto the QA department; 3) A staff member of the QA departmentindependently reviews all anesthesia records daily for potentialcomplications with subsequent referral for formal peer and multi-specialty review; 4) Hospital Quality and Risk Management de-partments also independently review all hospital admissions withreferral to QA for potential intraoperative complications. Phar-macy database contains data on use of drugs during codes includinglipid emulsion (eg, Intralipid). Code database includes standard-ized information on all cardiac arrest situations in the institution,and we participate in the American Heart Association Get-With-the-Guidelines:Resuscitation (http://www.heart.org/HEARTORG/HealthcareResearch/GetWithTheGuidelines-Resuscitation/Get-With-The-Guidelines-Resuscitation_UCM_314496_SubHomePage.jsp)registry for in-hospital cardiac arrests. Individual anesthesia recordsare stored in the anesthesiology database for all procedures but arescanned as a PDF file and are not searchable. Potential index casesper the defined primary and secondary outcomes from the QA,pharmacy, and code databases were then independently reviewed
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by 3 authors (S.S.L., J.T.Y., S.G.M.) to achieve consensus on prob-able LASTafter PNBs. Summary statistics on PNBs were collectedfrom the QA database. Individual patient and PNB characteristicswere systematically collected from a random sample of 600 casesreceiving PNBs from 2009 to 2014 from the anesthesiology data-base. Randomization was blocked by dates (each block was 1 datefrom 2009, 2010, 2011, 2012, 2013, and 2014) from a random dategenerator.11 The randomizer was set to January 1 to December 31,Monday to Friday only for eachyear. Data collectorsmoved throughthe blocks and dates systematically (2009, 2010, 2011, 2012, 2013,2014, then next block 2009, 2010, 2011, 2012, 2013, 2014, etc),looking at the scanned files in the online anesthesiology archivesystem for all adult patients (aged 18–99 years) on the OR sched-ule for PNBs (defined as the presence of a completed PNB record)for that date. Individual patientsmissing anesthesia records orwithillegible data on forms were excluded, and the next date in theblock was examined. For example, if the 2010 date did not haveany files, data collection moved on to the 2011 date.
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Statistical Analysis
Patient and PNB characteristics are presented as means andstandard deviations for continuous variables and as counts andpercentages for binary variables. Adverse events of major LASTare reported as number of events per 1000 PNBs with 95% CIscalculated as exact Poisson confidence limits. Statistical analyseswere performed with SAS Version 9.3 (SAS Institute, Cary, NorthCarolina), and the “exactci” package implemented in R software(R Foundation for Statistical Computing, Vienna, Austria).
TABLE 1. Summary of All Peripheral Nerve Blocks Performed From
RESULTSThere were a total of 80,661 PNBs from 2009 to 2014. There
were 0 cases of cardiac arrest (0/1000 PNBs [95% CI, 0–0.05/1000]) and 3 cases of seizures (0.04/1000 PNBs [95% CI, 0.01–0.11/1000]) caused by LAST identified via the QA, pharmacy,and code databases. There were 9 cases of intraoperative cardiacarrest during the study period, and none received lipid rescue.Six cases did not receive a PNB and were excluded. Two casesof ankle surgery received an ultrasound-guided (USG) poplitealsciatic nerve block followed by spinal anesthesia with 15 mgbupivacaine. Both then developed bradycardia and hypotension,and peer, multispecialty, and study authors' reviews all agreed thatspinal anesthesia was the likely root cause. The last case was atotal knee replacement that received a USG saphenous nerveblock followed by combined spinal epidural anesthesia. The thightourniquet was deflated approximately 75 minutes after inductionof anesthesia, with subsequent hypotension and tachycardia thatprogressed to pulseless electrical activity. Transesophageal echoexamination during resuscitation noted empty and hyperdynamicright and left ventricles suggestive of hypovolemia, and peer,multispecialty, and study authors' reviews all agreed that hypovo-lemia with possible embolic event was the likely root cause.
Table 1 displays descriptive summary of types, numbers, anduse of ultrasound guidance. Use of ultrasound guidance increasedfrom 48% in 2009 to 90% of PNBs by 2014. Table 2 displayspatient and PNB characteristics from our random sample of600 PNBs. Seven hundred fifty-six records were eligible for in-clusion (patient age between 18 and 99 years with a documentedPNB). The data collection tool is included as an Appendix andcontains data fields not pertinent to this article. Nonetheless,
0.5% bupivacaine 30 mL Foot surgery Seizure after injection ofPNB and after patientrepositioned supine.“Vital signs stable”during seizure. Sinusrhythm 117 beats per min.Blood pressure160/82 mm Hg.Treated with midazolam2 mg and airway support.Duration of seizure <60 s.Patient became responsiveand procedure canceled
Seizure immediately aftercompletion of injection.Heart rate98–118 beats per min.Treated with propofol100 mg and airway support.Unknown duration ofseizure. Patient becameresponsive and procedurecontinued. Patient wasdischarged home on thesame day.
All cases were seizures that occurred after completion of the PNB.
NSG indicates nerve stimulator guidance; PMH, past medical history.
Liu et al Regional Anesthesia and Pain Medicine • Volume 41, Number 1, January-February 2016
Regional Anesthesia and Pain Medicine • Volume 41, Number 1, January-February 2016 Incidence of LAST After PNBs
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any incomplete/illegible data fields resulted in exclusion. Ninerecords were excluded because of missing anesthesia record.Fifty-four records were excluded because of any incomplete/illegible data on the anesthesia record, and 93 were excludedbecause of any incomplete/illegible data from the PNB record.All staff anesthesiologists perform PNBs because there is nospecialized RA team. During the study period, there were upto 48 attending anesthesiologists. Type of block, type and doseof local anesthetic, addition of epinephrine, and guidance tech-nique were selected by the individual anesthesiologist and istypically guided by specific block requirements. Fractional in-jection of local anesthetic and frequent aspiration are standardsafety steps during injection of PNBs.
Table 3 displays clinical characteristics of the 3 index casesidentified in the QA database of seizures after PNBs caused byLAST as extracted from the original records.
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DISCUSSIONOur QA analysis confirms previous studies that major com-
plications from LAST after PNBs are rare.7,10,12,13 This survey isthe largest single-institution survey to date and provides the mostaccurate estimate with homogeneous definition of major LAST.Consistent definitions of outcomes are necessary to provide accu-rate estimates of incidence. For example, the ASA NACOR data-base recently examined the incidence and risk for perioperativecardiac arrest in 11,478,920 cases but could only use 1,691,472cases because of heterogeneity of definition of perioperativecardiac arrest.14
The ASRA LAST practice advisory stresses the primacy ofprevention for LAST after PNBs. Our increasing use of ultra-sound guidance at HSS across time may have decreased the riskof LAST.12 Whether use of ultrasound guidance reduces therisk of major LAST has been an enduring controversy in RA.Use of ultrasound guidance was initially reported to reduce therisk of vascular puncture but with unknown effect on the risk ofLAST after PNBs. Initial reports from the prospective AURORARA survey and from a retrospective survey from the Universityof Pittsburgh did not note a difference in the incidence of LASTbetween nerve stimulator and ultrasound guidance,7 and theASRA 2010 evidence-based analysis of USG RA concludedthat the effect of ultrasound guidance on LASTwas uncertain.15
However, follow-up reports from both sources later reported a re-duction in the incidence of seizures with the use of ultrasoundguidance for PNBs.10,13 Because of rarity, no survey has been ableto determine the effect of ultrasound guidance on cardiac arrestfrom LAST after PNBs.
A second interesting finding comes from our PNB blockcharacteristics. We observed only 3 index cases of seizures likelycaused by LAST despite the use of relatively large volumes anddoses of local anesthetic. Our sample of PNBs reported a meanof 40 mL of local anesthetic for upper extremity blocks and26 mL for lower extremity blocks. We previously reported amean volume of 50 mL of local anesthetic in a prospective surveyof 1169 interscalene and supraclavicular blocks for ambulatoryshoulder surgery.16 Hospital for Special Surgery anesthesiologistshave traditionally used larger doses than typical,12 which may beuseful to describe safety margins for the dose of local anestheticfor PNBs. Our use of large doses of local anesthetic is likely re-lated to clinical necessity of performing all blocks in the oper-ating room immediately before surgery and for the PNB oftenserving as the primary anesthetic. Although minimizing the doseof local anesthetic is a primary preventive recommendation ofthe ASRA LAST guidelines, the exact required dose is often un-clear. The use of ultrasound guidance has led to a reduction in
recommended dose, and several studies have tried to establishthe minimum effective doses for different PNBs.17 However,exact individual dose requirements vary despite population esti-mates,18 and our study suggests that there is a safety margin inthe dose of local anesthetic tolerated by patients without de-veloping major LAST after PNBs. Pharmacokinetics of absorp-tion of local anesthetic after PNBs may also serve as a safetymargin. Typically, peak blood levels of local anesthetic aregreatest after intercostal block > epidural block > brachial plexusblock > femoral sciatic nerve block.19 Other potential safety fea-tures included that 91% of our sample of PNBs were performedwith the patients either awake or sedated with meaningful contactmaintained to allow early identification of LAST and that mid-azolam was used for sedation in 92% of our sample, whichmay have increased the potential seizure threshold.
There are several limitations to our QA analysis that are typ-ical for administrative database analyses. This is an observationalstudy, thus, exact contributing factors for the low incidence ofLAST cannot be determined. The QA database is not designedspecifically to study LAST events, thus, it is possible that minorLAST events may have never been reported or detected. It isunlikely that events conforming to our primary outcome of car-diac arrest requiring lipid rescue after PNBs would have beenundetected because of an overlapping review of medical recordsfrom different hospital departments and because of ongoingparticipation in the American Heart Association Get-With-the-Guidelines:Resuscitation registry. Our QA department dailyreviews every anesthesia record and records anesthesia tech-niques, but it is possible that some techniques were miscodedor lost. Finally, data are from a single institution specializingin orthopedic surgery with a high volume of RA, thus externalvalidity of incidences would need to be confirmed.
In conclusion, our QA analysis is the largest to date forLASTafter PNBs. Cardiac arrest and seizures are rare after PNBs.Increasing use of ultrasound guidance across time may haveimproved the safety of PNBs. Our practice of using relativelylarge doses of local anesthetic suggests a safety margin in dosingwhen a particular patient or PNB requires greater doses to achievethe desired clinical outcome. The absolute rarity of cardiac arrestcaused by LAST after PNBs reported in this and in all previousmodern registries deserves comment. The true incidence and riskfactors for cardiac arrest caused by LAST remain to be determinedand will likely require an enormous sample size with completeclinical data to identify the risk factors. A rule of thumb is that aminimum of 10 events per predictor variable are required foradequate multivariable logistic regression model performance.20
Thus, even if the incidence of cardiac arrest caused by LASTwas overestimated to be 0.05/1000 PNBs (the upper limit ofthe 95% CI of our observed incidence), an estimated minimumsample size of 2,000,000 PNBs would be needed to test 10 riskfactors. As noted, the ASA NACOR database analyzed nearly1.5 million cases to determine the incidence and risk factors forperioperative cardiac arrest after a variety of cases, anesthetictechniques, and perioperative settings.18 A similar accumulationof sufficient cases specifically pertaining to LAST after PNBswould be a formidable challenge. Alternatively, the rarity of car-diac arrest caused by LASTafter PNBs may suggest that the evo-lution of the safety steps of our current practice for performingPNBs has reduced this once-feared bogeyman to a ghost.
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