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: 70 PNBs
(38%), 5170 PNBs (13%), 3150 PNBs (20%), 1130 PNBs (23%), and 10 PNBs
(6%). Anesthesia practices administering 70 PNBs were 1.7-times more likely to
use ropivacaine (NS), 3.9-times more likely to consider lipid emulsion infusions for
resuscitation (P 0.008), 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 centers. 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 2006;103:132226)

mproved 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 20 per 10,000 peripheral nerve
blocks (PNBs) and about 4 per 10,000 epidurals (1).
Before the reports of cardiac arrest from labor epidurals with 0.75% 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 20 to
320 per 10,000 (4 7). Although rare, LA toxicity may
be lethal, and clinicians should formulate provisions

for a rapid and educated response to such events.

Unfortunately, despite more than 20 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
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, 2006.
Presented in part at the 2006 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 27157-1009. Address
e-mail to lgroban@wfubmc.edu. Reprints will not be available from
the author.
Copyright 2006 International Anesthesia Research Society
DOI: 10.1213/01.ane.0000242515.03653.bb

1322

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. 103, No. 5, November 2006

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 centers as those performing 70
per month, and low-volume as 70 month. Responses
were analyzed relative to the number of procedures
performed in a responders 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 0.05. All
analyses were conducted using SPSS 13.0 (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: 70 PNBs (38%), 5170 PNBs
(13%), 3150 PNBs (20%), 1130 PNBs (23%), and 10
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 (50%), a dedicated regional anesthesia induction area (30%), and the operating room
Vol. 103, No. 5, November 2006

(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 0.26) (Fig. 2A). Though most centers preferred
bupivacaine, there was a slight trend for high-volume
institutions to choose ropivacaine, odds ratio 1.7 (95%
CI 0.70 3.9, P 0.24).
The choice of intermediate-acting LAs reflected
similar variability. The two most cited single drugs
were mepivacaine (50%) and lidocaine (32%), with a
trend for centers to prefer mepivacaine, 2 3.46, P
0.06 (Fig. 2B).
When performing an infraclavicular or axillary block
with bupivacaine, most institutions chose doses of
125200 mg (71%). Few centers used 200 mg (10%) or
125 mg (19%). High-volume centers were 7.5-times
more likely to use 200 mg (95% CI 1.4 40.3, P 0.02).
When performing infraclavicular or axillary blocks with
ropivacaine, most institutions chose 125200 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
2006 International Anesthesia Research Society

1323

Use of Lipid Emulsion

Preferred Long-acting Local Anesthetic

60
50
40

100

no

75

yes

% 30

50

20

25

10

0
High volume Low volume
centers
centers

0
Levo

Bup

Rop

Mixtures

Other

Preferred Intermediate-acting Local Anesthetic

B
50
40

Figure 3. Preferences for lipid emulsion use in the event of

local anesthetic-induced cardiac toxicity. High-volume centers are more likely to use lipid emulsion for the treatment of
bupivacaine toxicity than low-volume centers, 2(1) 7.52,
P 0.008. Data represent percentage of respondents by
category.

30
%

100

20
10
0
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 0.24). 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 0.06).

the practitioner performing the block. Standard monitoring consisted of pulse oximetry, noninvasive arterial blood pressure (BP), and electrocardiogram (ECG)
for 69% of centers, 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 centers, defined as 30 PNBs for this
analysis only, were 3.6-times (95% CI 1.310.3) more
likely to choose bretylium for bupivacaine-induced ventricular tachycardia than high-volume centers (40% vs
16%, P 0.016).
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
1324

LA-Induced Toxicity: Contemporary Practice Strategies

80

No CP Support

60

CP Support

40
20
0

High volume
centers

Low volume
centers

Figure 4. Presence of an established plan for mechanical

cardiopulmonary (CP) support in the event of failed resuscitation. High- and low-volume centers were similarly unlikely to have an established plan for CP support, 2(1)
2.74, P 0.098. Data represent percentage of respondents by
category.

choose epinephrine, 20% 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 centers
would not use it, and 26% would consider its use.
High-volume centers were 3.9-times more likely (95%
CI 1.4 10.6) than low-volume centers to use lipid
infusion for bupivacaine toxicity (44% vs 17%, P
0.008) (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 10 min for 59%,
10 30 min for 26%, and 30 min for 15% of the
centers.

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
ANESTHESIA & ANALGESIA

included cardiopulmonary bypass (CPB) (89%), intraaortic balloon pump counterpulsation (22%), and
extracorporeal membrane oxygenation (14%). Cardiothoracic surgeons could respond in 10 min for
33%, 10 30 min for 51%, and 30 min for 15% of
respondents.

DISCUSSION
Our results show a wide range of current practice
patterns for PNB in U.S. academic centers, 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 centers
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 centers (30
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. (10), 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
(50% mortality) and ropivacaine-treated dogs (10% 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
(www.asahq.org/publicationsAndServices/standards/
02.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
Vol. 103, No. 5, November 2006

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 centers 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 centers 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 0% in the control group to
100% 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 centers are significantly more receptive to the use of lipid emulsion for refractory LA
cardiotoxicity than the low-volume centers. 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 (2325). In the
event of failed pharmacologic resuscitation, our results show that only 41% of centers have a plan for
mechanical cardiopulmonary support (Fig. 4). Most
institutions report that cardiothoracic surgeons could
arrive in 30 min or less, although the most important
variable, time from identification of the need until
onset of bypass, was not ascertained. There are no
2006 International Anesthesia Research Society

1325

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
centers 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. Systemic toxicity and cardiotoxicity from local
anesthetics: incidence and preventive measures. Reg Anesth
Pain Med 2002;27:556 61.
2. Albright GA. Cardiac arrest following regional anesthesia with
etidocaine or bupivacaine. Anesthesiology 1979;51:2857.
3. Horlocker TT, Wedel DJ. Local anesthetic toxicity does product
labeling reflect actual risk? Reg Anesth Pain Med 2002;27:5627.
4. Blundell AE, Bodell B, Andorko JE, et al. Clinical evaluation of
drugs used in obtaining lumbar epidural anesthesia. Anesthesiology 1955;16:386 93.
5. Bonica JJ, Backup PH, Anderson CE, et al. Peridural block: analysis
of 3,637 cases and a review. Anesthesiology 1957;18:723 84.

1326

LA-Induced Toxicity: Contemporary Practice Strategies

6. Moore DC. Toxic effects of local anesthetics. JAMA 1978;240:434.

7. Kenepp NB, Gutsche BB. Inadvertent intravascular injections
during lumbar epidural anesthesia. Anesthesiology 1981;54:1723.
8. Shewhart WA. Statistical methods from the viewpoint of quality
control. Mineola, NY: Dover, 1986.
9. Aberg G. Toxicological and local anaesthetic effects of optically
active isomers of two local anaesthetic compounds. Acta Pharmacol Toxicol (Copenh) 1972;31:273 86.
10. Akerman B, Hellberg IB, Trossvik C. Primary evaluation of the
local anaesthetic properties of the amino amide agent ropivacaine (LEA 103). Acta Anaesthesiol Scand 1988;32:571 8.
11. Mather LE, Chang DH. Cardiotoxicity with modern local anaesthetics: is there a safer choice? Drugs 2001;61:333 42.
12. Groban L. Central nervous system and cardiac effects from
long-acting amide local anesthetic toxicity in the intact animal
model. Reg Anesth Pain Med 2003;28:311.
13. Groban L, Deal DD, Vernon JC, et al. Cardiac resuscitation after
incremental overdosage with lidocaine, bupivacaine, levobupivacaine, and ropivacaine in anesthetized dogs. Anesth Analg
2001;92:37 43.
14. Chazalon P, Tourtier JP, Villevielle T, et al. Ropivacaine-induced
cardiac arrest after peripheral nerve block: successful resuscitation. Anesthesiology 2003;99:1449 51.
15. Huet O, Eyrolle LJ, Mazoit JX, Ozier YM. Cardiac arrest after
injection of ropivacaine for posterior lumbar plexus blockade.
Anesthesiology 2003;99:14513.
16. Klein SM, Pierce T, Rubin Y, et al. Successful resuscitation after
ropivacaine-induced ventricular fibrillation. Anesth Analg
2003;97:9013.
17. Polley LS, Santos AC. Cardiac arrest following regional anesthesia
with ropivacaine: here we go again. Anesthesiology 2003;99:
1253 4.
18. Takahashi S, Tanaka M, Toyooka H. The efficacy of hemodynamic and T-wave criteria for detecting intravascular injection
of epinephrine test dose in propofol-anesthetized adults. Anesth
Analg 2002;94:71722.
19. Weinberg GL. Current concepts in resuscitation of patients with
local anesthetic cardiac toxicity. Reg Anesth Pain Med 2002;27:
568 75.
20. Weinberg G, Ripper R, Feinstein DL, Hoffman W. Lipid emulsion infusion rescues dogs from bupivacaine-induced cardiac
toxicity. Reg Anesth Pain Med 2003;28:198 202.
21. Weinberg GL, VadeBoncouer T, Ramaraju GA, et al. Pretreatment
or resuscitation with a lipid infusion shifts the dose-response to
bupivacaine-induced asystole in rats. Anesthesiology 1998;88:10715.
22. Rosenblatt MA, Abel M, Fischer GW, et al. Successful use of a
20% lipid emulsion to resuscitate a patient after a presumed
bupivacaine-related cardiac arrest. Anesthesiology 2006;105:217 8.
23. Soltesz EG, van Pelt F, Byrne JG. Emergent cardiopulmonary
bypass for bupivacaine cardiotoxicity. J Cardiothorac Vasc
Anesth 2003;17:357 8.
24. Tsai MH, Tseng CK, Wong KC. Successful resuscitation of a
bupivacaine-induced cardiac arrest using cardiopulmonary bypass and mitral valve replacement. J Cardiothorac Anesth
1987;1:454 6.
25. Long WB, Rosenblum S, Grady IP. Successful resuscitation of
bupivacaine-induced cardiac arrest using cardiopulmonary bypass. Anesth Analg 1989;69:403 6.
26. Cohen JC. Statistical power analysis for the behavioral sciences,
2nd ed. Hillsdale, NJ: Lawrence Erlbaum Associates, 1988.
27. Halliday NJ. Malignant hyperthermia. J Craniofac Surg 2003;14:
800 2.

ANESTHESIA & ANALGESIA