 Review Articles

Maximum Recommended Doses of Local

Anesthetics: A Multifactorial Concept

Per H. Rosenberg, M.D., Ph.D, Bernadette Th. Veering, M.D., Ph.D.,

and William F. Urmey, M.D.

The current recommendations regarding maximum doses of local anesthetics presented in textbooks, or by the
responsible pharmaceutical companies, are not evidence based (ie, determined by randomized and controlled
studies). Rather, decisions on recommending certain maximum local anesthetic doses have been made in part
by extrapolations from animal experiments, clinical experiences from the use of various doses and measurement
of blood concentrations, case reports of local anesthetic toxicity, and pharmacokinetic results. The common
occurrence of central nervous system toxicity symptoms when large lidocaine doses were used in infiltration
anesthesia led to the recommendation of just 200 mg as the maximum dose, which has remained unchanged
for more than 50 years. In most cases, there is no scientific justification for presenting exact milligram doses or
mg/kg doses as maximum dose recommendations. Instead, only clinically adequate and safe doses (ranges) that
are block specific are justified, taking into consideration the site of local anesthetic injection and patient-related
factors such as age, organ dysfunctions, and pregnancy, which may influence the effect and the pharmacoki-
netics of the local anesthetic. Epinephrine in concentrations of 2.5 to 5 ␮g/mL should be added to the local
anesthetic solution when large doses are administered, providing there are no contraindications for the use of
epinephrine. As a rule, conditions (eg, end-stage pregnancy, high age in epidural, or spinal block) or diseases
(uremia) that may increase the rate of the initial uptake of the local anesthetic are indications to reduce the dose
in comparison to one normally used for young, healthy, and nonpregnant adults. On the other hand, the
reduced clearance of local anesthetics associated with renal, hepatic, and cardiac diseases is the most important
reason to reduce the dose for repeated or continuous administration. The magnitude of the reduction should be
related to the expected influence of the pharmacodynamic or pharmacokinetic change. Reg Anesth Pain Med 2004;
29:564-575.
Key Words: Local anesthetics, Maximum dose recommendation, Toxicity, Local anesthetic dose, Pharma-
cokinetics, Age, Renal disease, Hepatic disease, Regional anesthesia, Local anesthetic doses.

P resent recommendations for maximum doses

of local anesthetics are, in large part, not evi-
dence based. Most recommendations, if not all, are
published by the manufacturer. Presumably, the
purpose of stating maximum recommended doses
for local anesthetics has been to prevent the admin-
istration of excessive amounts of the drug, which
could result in systemic toxicity. Usually, recom-
mendations are in the form of a total amount of the
See Editorial page 524 drug, for example, 200 mg or 300 mg for lidocaine
in an adult. More recently, amounts of the drug per
body mass of the patient have been given in phy-
From the Department of Anesthesiology and Intensive Care
Medicine, Helsinki University Hospital, Helsinki, Finland sicians’ drug references. For example, in the case of
(P.H.R.); Department of Anesthesiology, Leiden University Med- bupivacaine, 2 mg/kg (FASS Sweden 2004, Phar-
ical Center, Leiden, The Netherlands (B.T.V.); and Department maca Phennica, Finland 2004).
of Anesthesiology, The Hospital for Special Surgery, New York,
NY. Recommendations for a single dose of local anes-
Reprint requests: Per H. Rosenberg, M.D., Ph.D., Department thetic that do not take into account the site of
of Anesthesiology and Intensive Care Medicine, Helsinki Univer-
sity Hospital, PB 340, Helsinki, FIN-00029 HUS, Finland. E-mail:
injection are of little value. There are no controlled
[email protected] data on this issue either. Some rough extrapolation
© 2004 by the American Society of Regional Anesthesia and can be made from various pharmacokinetic studies
Pain Medicine.
1098-7339/04/2906-0010$30.00/0 on lidocaine. Similar plasma concentrations of lido-
doi:10.1016/j.rapm.2004.08.003 caine are achieved after 300 mg in intercostal nerve

564 Regional Anesthesia and Pain Medicine, Vol 29, No 6 (November–December), 2004: pp 564 –575
 Maximum Recommended Doses of Local Anesthetics • Rosenberg et al. 565

Table 1. Officially Recommended Highest Doses of Local Anesthetics in Finland (Pharmaca Fennica 2004),
Germany (Rote Liste 2004), Japan (Drugs in Japan 2004, Japan Pharmaceutical Information Center), Sweden
(FASS 2004), and the United States (Physicians’ Desk Reference 2004)
Finland Germany Japan Sweden US

2-Chloroprocaine — — — — 800 mg
With epinephrine — — 1,000 mg — 1,000 mg
Procaine — 500 mg 600 mg (epidural) — 500 mg
With epinephrine — 600 mg — — —
Articaine 7 mg/kg 4 mg/kg — — —
With epinephrine 7 mg/kg 4 mg/kg — — —
Bupivacaine 175 mg (200 mg*) 150 mg 100 mg (epidural) 150 mg 175 mg
(400 mg/24 h)
With epinephrine 175 mg 150 mg — 150 mg 225 mg
Levobupivacaine 150 mg (400 mg/24 h) 150 mg — 150 mg 150 mg
With epinephrine — — — — —
Lidocaine 200 mg 200 mg 200 mg 200 mg 300 mg
With epinephrine 500 mg 500 mg — 500 mg 500 mg
Mepivacaine — 300 mg 400 mg (epidural) 350 mg 400 mg
With epinephrine — 500 mg — 350 mg 550 mg
Prilocaine 400 mg — — 400 mg —
With epinephrine 600 mg — — 600 mg —
Ropivacaine 225 mg (300 mg*) No mention 200 mg (epidural) 225 mg 225 mg (300 mg*)
(800 mg/24 h) 300 mg (infiltr.)
With epinephrine 225 mg No mention — 225 mg 225 mg (300 mg*)

*For brachial plexus block in adults.

block, after 500 mg in epidural block, after 600 mg It is presently common practice to administer a
in brachial plexus block, and after 1,000 mg in local anesthetic as a continuous infusion for several
subcutaneous infiltration of the skin of the legs.1,2 days to provide postoperative analgesia, after an
To complicate the matter, use of epinephrine and initial single large dose for surgical anesthesia. This
other additive vasoconstrictors may reduce the has boosted pharmacokinetic research, and knowl-
peak concentrations of local anesthetics in plasma. edge has been gathered regarding plasma concen-
This also seems to vary from block to block, as well trations of bupivacaine and ropivacaine during con-
as from agent to agent. For example, epinephrine 5 tinuous infusions. In fact, recommendations of 24-
␮g/mL (1:200,000) reduces the peak plasma con- hour doses of 3 local anesthetics have been issued
centration of lidocaine after subcutaneous infiltra- mainly based on experience rather than controlled
tion by approximately 50%, whereas after intercos- evidence (Table 1). More importantly, controlled
tal, epidural, and brachial plexus block, the research data are now available regarding the influ-
reduction is only about 20% to 30%.3-5 ence of certain disease states and drug interactions
The maximum recommended dose for lidocaine on plasma concentrations of the potent local
in the European countries is 200 mg without epi- anesthetics, bupivacaine,10-12 and ropivacaine.13-15
nephrine (European Pharmacopoeia) and in the These influences have been shown to be significant.
United States it is 300 mg. This dose of plain lido- The purpose of this review is to convince the anes-
caine may not be sufficient for many regional an- thesiologist that standard maximum dose recommen-
esthetic procedures in adults. In both Europe and dations of local anesthetics as exact milligram
the United States, 500 mg of lidocaine is allowed if amounts are inappropriate. As in all medicinal ther-
epinephrine (5 ␮g/mL) is added, and this assumes apy, the dose of a drug should be individualized as
that epinephrine reduces the peak plasma concen- clinically indicated. Therefore, this review deals with
trations by 60%. There is no evidence for this rec- the factors that must be considered as the basis for
ommendation. clinically necessary modifications of local anesthetic
It is illogical that a maximum dose of lidocaine of dosing, especially when large quantities of the drug
200 to 300 mg has been advocated, whereas an are administered. Appropriate general recommenda-
allowable dose of bupivacaine is 150 to 175 mg, tions that consider these factors are made.
despite data that in frog sciatic nerve bupivacaine is
4 times more potent.6,7 A recent extension of this
Background: Current Recommendations
irrational recommendation for bupivacaine is the
published maximum dose of 150 mg for levobupi- The current recommendations of maximum local
vacaine, although levobupivacaine is clearly less anesthetic doses in Finland, Germany, Japan, Swe-
toxic than bupivacaine (racemic bupivacaine).8,9 den, and the United States are presented in Table 1.
566 Regional Anesthesia and Pain Medicine Vol. 29 No. 6 November–December 2004

Table 2. Pharmacokinetic Parameters* of Local Anesthetics in Adults.

Vdss (L/kg) CL (L/kg/h) t1/2 (h)

2-Chloroprocaine 0.50 2.96 0.1

Procaine 0.93 5.62 0.1
Articaine approximately 0.7 approximately 7 0.2–0.320
Bupivacaine 1.02 0.41 3.5
Levobupivacaine 0.9 0.3 3.512
Lidocaine 1.30 0.85 1.6
Mepivacaine 1.2 0.67 1.0
Prilocaine 2.73 2.03 1.6
Ropivacaine 0.84 0.63 1.9

*All parameters are from Denson et al.,19 except those of Palkama et al.12 and Oertel et al.20

Such doses have usually been determined by ex- site of injection), distribution (spread in the body
trapolating data obtained from laboratory animals fluids and tissues according to lipid solubility and
to man, followed by clinical investigations in man protein binding characteristics), and elimination
using these extrapolated doses for peripheral nerve (metabolism and excretion) of the drug. In the case
blocks and epidural block. Published case reports of of ester-linked local anesthetic molecules (eg, pro-
systemic toxicity in patients are also referred to caine and 2-chloroprocaine) the metabolism starts
when recommendations have been given. mainly in the blood by esterases before the distri-
The problems with recommendations of maxi- bution phase. Thus, from the toxicity point of view,
mum doses have been dealt with repeatedly. Mile- ester-linked local anesthetics are quite safe and rel-
stone publications in this respect include the paper atively high doses may be used. On the other hand,
by Moore et al.16 in 1977 and the editorial by Scott2 their breakdown into molecules similar to para-
in 1989. Both of them question the validity and the aminobenzoic acid18 is the reason for a relatively
logic of maximum dose recommendations because high frequency of anaphylactic reaction related to
they do not take into consideration factors such as their use.
the varying absorption at different sites or patient The important pharmacokinetic parameters of
characteristics (eg, age, disease). In addition, the the amide-linked local anesthetics are presented in
rather conservative dose recommendations, or Table 2. As mentioned earlier, the absorption of the
modifications given by the pharmaceutical compa- local anesthetic into the circulation depends pri-
nies, probably reflect an economic interest and pro- marily on the vascularity of the site of deposition
tection of the product. These companies are cer- (injection) as well as on the structure composition
tainly not without bias. of the surrounding tissues (eg, presence of lipid).
The background for the most conservative max- Because of the huge interindividual and interblock
imum dose recommendation (ie, that of lidocaine variations and the fact that systemic toxicity of the
[200 mg in Europe]) relates back to the first clinical amide-linked local anesthetics is caused by the un-
testing of lidocaine in the 1940s and 1950s. At the bound (free) local anesthetic in plasma, the magni-
Karolinska Hospital in Stockholm, Gordh17 per- tude of a safe dose of the local anesthetic should not
formed clinical tests on patients with lidocaine be based on the total plasma concentrations of the
doses up to, or even exceeding, 1,000 mg, occasion- drug.
ally accompanied by systemic toxicity. His own The volumes of drug distribution at steady state
maximum dose recommendation to the Astra phar- (Vdss) of local anesthetics (when uptake by less-
maceutical company was 300 mg (T. Gorgh, per- perfused organs, together with simultaneous bio-
sonal communication, 2002). However, despite this transformation, are matched by drug release from
recommendation, the company decided on 200 mg, well-perfused organs) clearly exceed the total body
which has remained unchanged to this day in most volume. This is because local anesthetics are more
European countries. Whoever was responsible in
soluble in fat, liver, and brain and other organs than
the United States for having suggested, or having
in water. The low degree of central nervous system
made the decision, that 300 mg is a maximum
toxicity symptoms with prilocaine has been consid-
recommended dose of lidocaine cannot be tracked.
ered to be caused by its relatively great Vdss (Table
2), its rapid uptake into the lungs,21 and its rapid
Pharmacokinetics of Local Anesthetics
metabolism.22 The difference in Vdss between race-
The pharmacokinetic parameters of local anes- mic bupivacaine and its S(⫺)-enantiomer seems to
thetics depend on the uptake (absorption from the be because of enantioselectivity in plasma protein
 Maximum Recommended Doses of Local Anesthetics • Rosenberg et al. 567

binding.23,24 Perhaps the most important parameter

is the elimination half-life (t1/2), which indicates
how soon another dose or at which rate a contin-
uous infusion of the local anesthetic can be admin-
istered safely. As a rule, 5 half-lives are required for
a decline of the plasma concentration to near zero
(in practice, a fall to about 3% of the peak concen-
tration). It may be prudent to give some clinical
examples with regards to the most toxic of the
presently used local anesthetic (ie, bupivacaine
with an elimination half-life of about 3 hours).
When the administration of a similar dose (2 mg/
kg) of bupivacaine with epinephrine for intercostal
nerve blocks was repeated after 6 hours, the second
peak plasma concentration was, on average, 10%
higher than the first one.25 In continuous inter-
scalene brachial plexus block with 0.25% bupiva-
caine at a rate of 6 to 10 mL/h, after an initial block
for surgery with 150 to 200 mg bupivacaine, the
total plasma concentration rose clearly and statisti- Fig 1. Collection of data of local anesthetic blood levels
cally significantly by about 20%, on average, during (mainly plasma concentrations) from various sources,34-39
the second postoperative day.26 indicating the pattern of order of peak concentrations asso-
The clearance (CL) is the overall efficiency of ciated with various regional anesthetic blocks.40
drug elimination from the body. Because only a
very small fraction of nonmetabolized amide-linked
local anesthetics is excreted by the kidneys and sorption of local anesthetics into the blood occurs
their biotransformation occurs mainly in the liver, rapidly and high early peak concentration may
CL of amide-linked local anesthetics is essentially result.
synonymous with hepatic clearance (Table 2). It Absorption from richly vascularized regions such
should be noted that there is an enantioselectivity as the pleura, the bronchial mucosa, and the scalp
in clearance also and the CL of S(⫹)-mepivacaine is occurs rapidly and high peak concentrations are
clearly lower than that of racemic mepivacaine and seen in the blood. Very slow absorption of local
R(⫺)-mepivacaine.27 There are also some differ- anesthetics occurs from the urinary bladder,31 and
ences in the CL for bupivacaine enantiomers. In intact skin is almost impermeable to regular con-
humans, the CL of R(⫹)-bupivacaine is greater centrations of amide-linked local anesthetics as hy-
than that of S(⫺)-bupivacaine, but the CL of un- drochlorides.32,33
bound R(⫹)-bupivacaine is less than that of S(⫺)- Several studies have shown that the blood level
bupivacaine.23 In single-dose regional anesthetic of the local anesthetic depends on the total dose and
techniques, CL does not play a great role with re- is independent of the the concentration of local
gards to toxicity or maximum dose. In case of renal anesthetic in the injected solution.34,35 It is thought
or hepatic insufficiency (see later), the CL will de- that a smaller absorption surface counterbalances a
crease accompanied by a retention of the local an- greater concentration so that no alteration in ab-
esthetic and certain metabolites in the body, which sorbed blood levels occurs.
assumes great importance in continuous regional Studies on peak plasma concentrations of a fixed
anesthetic techniques. dose of certain local anesthetics used in various
Site of Injection Affects the Absorption of blocks have been performed to a limited extent. A
Local Anesthetics. The vascularity (density of particular pattern of order of peak concentrations
capillaries)28 and the binding of the local anes- has been shown for a number of amide-linked local
thetic to the tissues1,29 will influence the initial anesthetics (Fig 1) with the highest after intercostal
rate of absorption into the circulating blood. Ad- block and higher after epidural than after brachial
ditionally, the vasoactive properties (dilatation or plexus block.35-40 The fact that all studies show that
constriction) may play a role in further rate of the highest peak concentrations occur after inter-
absorption (see later). During end-stage pregnan- costal nerve block independent of the local anes-
cy30 and in uremia,14 when the blood perfusion of thetic used is thought to be caused by the fact that
the site of local anesthetic injection is enhanced several injections are made and the absorption area
because of a hyperdynamic circulation, the ab- is large. More recently, it has become obvious that
568 Regional Anesthesia and Pain Medicine Vol. 29 No. 6 November–December 2004

peak concentrations as high as after intercostal the same dose of bupivacaine in epidural anes-
nerve blocks may result from a similar dose used for thesia,53 and both concentrations are reduced to
interpleural (intrapleural) regional block.41,42 This the same extent if the solution contains 5 ␮g/mL
presumably results from the ⬙sheeting” distribution epinephrine.
of the drug in the interpleural space, an anatomic Epinephrine. Epinephrine slows the absorp-
potential space with a comparatively large surface tion of local anesthetic and thereby prolongs the
area. anesthetic action and also increases the intensity of
After deflation of an arm tourniquet cuff in the block. With medium-duration local anesthetics
intravenous regional anesthesia, approximately such as lidocaine and mepivacaine, a suitable epi-
30% of the dose is released into the systemic nephrine concentration appears to be 5 ␮g/mL,35
circulation by the first flush of blood.43 Therefore, but both lower and higher concentrations have
the peak concentration is usually not encoun-
been used. Particularly in dentistry, concentrations
tered immediately after the cuff release.44,45 De-
up to 12.5 ␮g/mL are used, the aim being a blood-
spite that, mild central nervous system toxicity
less field (ischemia) for minor surgery in addition to
symptoms often occur soon after the cuff defla-
the prolongation of the duration of the anesthetic
tion before attaining the peak concentration, in
effect.
particular by lidocaine.46 This effective but mech-
anistically and technically rather complicated It has also been speculated that the ␣2-adrenergic
technique depends strongly on the awareness of action of epinephrine could provide analgesia, at
safety precautions regarding cuff functioning and least at the spinal level.54 Epinephrine is of no sig-
timing of deflation. Ischemia makes up a signifi- nificant value in prolonging the effect of long-acting
cant part of the mechanisms of action of intrave- local anesthetics such as bupivacaine and ropiva-
nous regional anesthesia,47 and, therefore, a caine because the epinephrine effect is exceeded by
lower dose of a local anesthetic with low toxicity the local anesthetic effect. However, acutely, epi-
potential should always be considered. nephrine diminishes the peak concentration of both
Intrinsic Vasoactivity of Various Local An- bupivacaine and ropivacaine, and this has been
esthetics. Although local anesthetics have intrin- found useful when large doses are used, as with
sic vasoactive effects on blood vessels, the resulting interpleural regional analgesia.42,55
systemic absorption may be difficult to predict. Va- Clinically available injectable concentrations of
soactivity is both dose dependent (usually high con- lidocaine may decrease neural blood flow. Labo-
centrations cause dilatation and low concentrations ratory studies have shown that whereas epineph-
cause constriction) and organ specific. It should also rine 5 ␮g/mL decreased sciatic nerve blood flow
be kept in mind that the needle stick produces in the rat by 20%, the addition of lidocaine 20
vasodilatation, whereas injection of a large bulk of mg/mL synergistically lowered flow by 60%.49 In
fluid may cause temporary compression of even another experimental series, this decrease was as
large blood vessels. great as 78%.48 Intact nerve can tolerate such
Clearly, clinically injected anesthetic solutions of intense vasoconstriction, at least temporarily,
bupivacaine and lidocaine cause vasodilation of without any complications. To what extent a con-
skin blood vessels while neural blood flow is re- tinuous infusion of epinephrine-containing local
duced.48,49 Lower concentrations may cause vaso-
anesthetic solution could reduce nerve blood flow
constriction in certain tissues and reduce, for exam-
is unknown, and such a situation may be re-
ple, muscle blood flow. In man, injection of
garded as theoretical.
bupivacaine (0.25%-0.5%) in the skin increases
Large doses of epinephrine injected within a
capillary blood flow substantially, whereas ropiva-
caine (0.25%-0.75%) decreases the flow, as com- short time interval may cause tachycardia and se-
pared with control values.50 vere dysrhythmias. Based on clinical experience,
The vasoactivity of mepivacaine lies in between Raj et al.56 recommend that in infiltration for inci-
that of bupivacaine and ropivacaine (ie, in man sional analgesia of the skin, the amount of epineph-
mepivacaine does not increase skin blood flow rine should not exceed 1.5 ␮g/kg/10 minutes or 8
beyond that of saline alone, suggesting a mild ␮g/kg/h. If large amounts of local anesthetic are
vasoconstrictive action).51 This intrinsic vasoac- needed, both the local anesthetic solution and the
tivity of the local anesthetic does not have any epinephrine solution should be diluted. In fact, a
significant clinical role in influencing its own ab- similar reduction in lidocaine uptake from the epi-
sorption; for example, plasma concentrations of dural space was shown when the epinephrine con-
ropivacaine (assumed to cause vasoconstriction) centration was reduced from 5 ␮g/mL to 1.7 ␮g/mL
in epidural anesthesia52 are similar to those after (1:600,000).57
 Maximum Recommended Doses of Local Anesthetics • Rosenberg et al. 569

Patient-Related Factors to Be Considered increase the sensitivity of nerve axons to local an-
When Large Doses of Local Anesthetics esthetics blockade.70,71 This, in addition to reduced
Are Used CL,61,62 is the main reason for the need to reduce
the dose in the elderly (C). In repeat dosing and
In the recommendations, we apply the “Grades of during continuous infusions, the lower CL of
Recommendation” published by the Oxford Uni- amide-linked local anesthetics easily results in ac-
versity Centre for Evidence Based Medicine (avail- cumulation of the local anesthetic and some of its
able at: http://www.cebm.net/index.asp): A ⫽ sys- metabolites, with concomitant rise of the free
tematic reviews of randomized controlled trials or plasma concentration and an increased risk of tox-
prospective good-quality cohort studies with good icity. In nerve blocks, in which large amounts are
follow-up; B ⫽ systematic reviews of cohort studies, commonly used (epidural block, brachial plexus
individual cohort studies, low-quality randomized block, lower extremity combined bocks, interpleu-
controlled trials, outcomes research; C ⫽ case se- ral block) followed by continuous infusion, or as
ries, poor-quality cohort studies, extrapolations repeated dosing in middle-aged adults with normal
from studies of grade B; and D ⫽ evidence from organ functions, the doses should be reduced by
inconsistent or inconclusive studies at any level, 10% to 20% age dependently over the age of 70
expert opinion. years (D), mainly because of age-dependent phar-
Age. At birth, the plasma concentration of ␣1- macodynamic and anatomic changes rather than of
acid glycoprotein (AAG, orosomucoid) is about half pharmacokinetic reasons.
the adult concentration,58 suggesting that the risk of In the newborn (⬍4 months), the low AAG con-
systemic local anesthetic toxicity would be in- centration in plasma is related to an enhanced risk
creased. Probably, because large doses of local an- of local anesthetic toxicity. When using regional
esthetics are not used in obstetric epidural analgesia anesthetic blocks with large doses in this age group,
or for postoperative analgesia in the newborn, toxic the dose per kilogram should be approximately
reactions are quite rare. 15% lower than in older infants58,60 (C).
A single caudal injection of ropivacaine in infants Renal Dysfunction. In renal dysfunction, the
resulted in higher free ropivacaine plasma concen- CL of lidocaine has been found to be lower73 or
trations in infants aged 0 to 3 months compared similar74 to that of subjects with normal kidney
with older infants.59 In that particular study, how- function. Bupivacaine CL10 and ropivacaine CL14 in
ever, both the free and the total ropivacaine con- uremia, on the other hand, have been shown to be
centrations were within the levels reported in lower than in nonuremic patients. The elimination
adults and in children. In addition to a low AAG half-life of local anesthetics does not seem to
level in plasma of the newborn, they seem to have change in uremia.10,14,73,74 The CL of the main me-
a low intrinsic CL of bupivacaine.60 Based on stud- tabolites of ropivacaine, 2,6-pipecoloxylidide (PPX)
ies on continuous caudal bupivacaine infusion in and 3-OH-ropivacaine, is also decreased in uremic
the newborn, Meunier et al.60 recommend restrict- patients. Plasma concentrations of bupivacaine and
ing the dosage to less than 0.25 mg/kg/h in infants ropivacaine have been shown to rise rapidly in
younger than 4 months and to a maximum of 0.3 brachial plexus block in uremic patients,10,14 prob-
mg/kg/h in older infants. ably because a hyperdynamic circulation75 pro-
Deteriorating blood flow and organ functions de- motes absorption of the drugs into the blood. The
crease the CL of local anesthetics in the elderly.61,62 concentration of the acute phase protein, AAG, is
Peak plasma concentrations and plasma protein increased in uremic patients76 and this may offer
binding of local anesthetics are similar in elderly important protection against local anesthetic
people and young adults.63,64 However, the nerve toxicity.
axon function deteriorates,65,66 nerve morphology Toxicity may become a real risk in uremic pa-
changes,66 and the surrounding fatty tissue disap- tients when long-term continuous infusions of bu-
pears68 in the elderly who become more sensitive to pivacaine or ropivacaine are administered because
the blocking action and, therefore, smaller doses of of the accumulation of both the parent drug and its
local anesthetics are required in elderly patients, a metabolites. The PPX metabolite, the cardiotoxicity
phenomenon observed in epidural block69,70 and of which in anesthetized rats seems to be about half
brachial plexus block.71 The isolated vagus nerve in that of bupivacaine,77 is increasing continuously in
young and old rabbits has been found to be more plasma during continuous brachial plexus block in-
sensitive to local anesthetic–induced nerve conduc- fusions.26 Again, the surgery-stimulated increase in
tion blockade than that in adult rabbits.72 the production of AAG78 functions as a buffer, ef-
Recommendation. Deterioration in morphol- fectively binding local anesthetic in blood, and that
ogy and nerve conduction by aging is assumed to is likely the reason why systemic toxicity is ex-
570 Regional Anesthesia and Pain Medicine Vol. 29 No. 6 November–December 2004

tremely rare during continuous postoperative anal- dysfunction, single-dose blocks can usually be per-
gesic infusions. formed safely with normal doses of the local anes-
Because the initial absorption of local anesthetic thetics15,73 (C). However, patients with severe liver
is rapid in uremic patients, there is an obvious need disease often have renal dysfunction, which also
for dose reduction in single-injection blocks in requires dose reduction. The doses for repeat blocks
which large doses are applied (eg, brachial plexus within a short time period (⬍5 half-lives), and the
block, multi-injection paravertebral blocks, inter- doses for continuous infusion blocks need to be
pleural blocks, epidural surgical blocks, and com- reduced markedly (10%-50%) (D) in patients with
bined lower-extremity blocks). liver dysfunction, mainly because of a significantly
Recommendation. The hyperdynamic circu- reduced CL15,73 and accumulation of the local an-
lation in uremic patients results in enhanced ab- esthetic and its metabolites in the blood15,26 (C).
sorption of the local anesthetic from the site of Heart Failure. In heart failure, deterioration of
deposition. High peak plasma concentrations may the circulation may cause changes in the body
occur early after injection, and the concentrations clearance of drugs such as lidocaine73 by reducing
may remain higher than in nonuremic patients for blood flow to the liver and kidneys. Indeed, similar
an extended time10,14 (C). A small reduction of plasma concentrations of lidocaine were found in
doses (10%-20%), relative to the degree of renal patients with heart failure after injecting 0.5 mg/kg
dysfunction, in those regional anesthetic tech- intravenously as after 1 mg/kg in patients without
niques in which large doses are normally used (eg, heart failure.81 Although about three fourths of
brachial plexus block and epidural block) is recom- lidocaine entering the liver via the hepatic artery
mended (D). will be extracted from the circulation, less than half
The decreased renal function causes a reduction of bupivacaine and ropivacaine will be cleared by
in CL of local anesthetics and some of their metab- the liver per pass.19 Therefore, lower cardiac output
olites10,14 (C), and this is the primary reason for the may not greatly affect the blood levels of the
need to reduce the amount of repeat doses admin- strongly protein-bound local anesthetics, bupiva-
istered within the time span of less than 5 half-lives caine, and ropivacaine to any greater extent.
and the doses for the continuous regional anes- Because of the autoregulation of cerebral blood
thetic techniques by 10% to 20%, according to the flow, the proportion of a local anesthetic in the
degree of dysfunction (D). blood that reaches the brain is increased in severe
Hepatic Dysfunction. The pharmacokinetics heart failure (low cardiac output), thereby predis-
of the majority of local anesthetics are affected by a posing to acute central nervous system toxicity
poorly functioning liver associated with alterations when a substantial amount of the drug has entered
in circulation and body fluids. In end-stage liver the circulation. On the other hand, because of the
dysfunction (patients being evaluated for liver low cardiac output perfusion to the site of local
transplantation), the CL of ropivacaine was found anesthetic injection (eg, epidural space) is de-
to be about 60% lower than in healthy volun- creased, which may decrease the rate of further
teers,15 but, interestingly, plasma concentrations absorption.
were similar. The latter finding may depend on an Recommendation. In mild and well-con-
increased Vdss of ropivacaine. The Vdss of other trolled cardiac disease, there may not be any reason
drugs, such as rocuronium79 and propofol,80 is also to reduce the local anesthetic dose (D). However,
increased in patients with hepatic dysfunction. the substantially lowered total body CL because of
When repeated doses25 or continuous infusions are reduced blood flow to the liver and kidneys occur-
used, the accumulation of both bupivacaine and ring in advanced heart failure is a clear indication
ropivacaine and of their metabolites needs to be for a reduction of local anesthetic dose73 (C). This
considered, and doses should be reduced accord- should be done also for the intravenous lidocaine
ingly. Even in end-stage liver dysfunction, AAG is dose used for the treatment and prevention of ven-
synthesized15 and thus provides some protection tricular arrhythmias. Lidocaine must not be used
against local anesthetic toxicity. for the treatment of local anesthetic–induced ven-
It should be kept in mind that patients with se- tricular arrhythmias because the toxicity of the
vere liver dysfunction may also have other diseases amide-linked local anesthetics is additive.82 Epi-
(eg, nephropathy and cardiac disease), which may nephrine should be avoided in patients with cardiac
be even more important indications to reduce the diseases involving hypokalemia,83 and its dose
dose of a drug. Conversely, in mild hepatic dysfunc- should be kept low in other types of cardiac disease
tion related to alcoholism, there seems to be almost (D). Because of reduced CL of local anesthetics73
no alteration in the clearance of lidocaine.73 (C) and because the metabolites of both bupiva-
Recommendations. In patients with hepatic caine and ropivacaine will be eliminated slowly15,26
 Maximum Recommended Doses of Local Anesthetics • Rosenberg et al. 571

(C), the dosages used for repeat or continuous dos- cytochrome P450 enzymes (CYP). Several of the
ing of local anesthetics need to be reduced by 10% isoforms of CYP are involved in the metabolism of
to 20% (D). local anesthetics. Lidocaine is N-de-ethylated in
Pregnancy. During pregnancy, hormonal (pro- liver to monoethylglycine xylidide by CYP1A2 and
gesterone) mechanisms may increase the sensitivity CYP3A4.89 The metabolism of bupivacaine has been
of nerve axons to neural blockade.84,85 There seems shown indirectly to depend on both CYP2D6 and
also to be an enhanced risk of cardiotoxicity by bu- CYP3A4. Propranolol and cimetidine, inhibitors of
pivacaine and ropivacaine in pregnancy induced by CYP2D6, have been found to reduce plasma clear-
progesterone.86 The protein binding of bupivacaine in ance of bupivacaine by 30% to 35%.90,91 These
blood (but not of mepivacaine) is significantly re- drugs also decrease liver blood flow and may there-
duced in pregnancy, which also may enhance the risk fore have some influence on the clearance of bu-
of toxicity.87 Therefore, at any stage of pregnancy, it is pivacaine, which has a low-moderate hepatic ex-
indicated to reduce the dose in blocks in which large traction ratio.23 Itraconazole, the inhibitor of
doses would normally be used, such as in brachial CYP3A4, decreases the elimination of bupivacaine
plexus block because of an enhanced risk of local enantiomers by 20% to 25%.12
anesthetic toxicity. Ropivacaine is metabolized to 3-OH-ropivacaine
When pregnancy progresses to the stage in which by CYP1A2 and to 2=,6=-PPX by CYP 3A4.92,93 Cip-
cardiac output is increased, blood perfusion to the rofloxacin, an inhibitor of CYP1A2,94 slightly de-
site of local anesthetic injection will increase and creased the clearance of ropivacaine,95 and at the
the absorption of local anesthetic into the circula- same time the CYP3A4-mediated formation of PPX
tion is rapid.30 This constitutes an independent rea- was increased. On the other hand, fluvoxamine, a
son to further reduce the dose of the local anes-
strong inhibitor of CYP1A2,96 reduces the clearance
thetic in blocks with large doses. In cesarean
of ropivacaine by approximately 70%.13,96 Evidence
delivery, both hormonal effects84,85 and the me-
for less significance of the CYP3A4 pathway in ropi-
chanical effect of uterus compression are assumed
vacaine metabolism was shown in studies with
to have a significant impact on speed and spread of
strong CYP3A4 inhibitors (eg, chlarithromycin, itra-
spinal and epidural blocks and therefore markedly
conazole, ketoconazole), which only slightly re-
reduced doses can be used.
duced the CL of ropivacaine.96,97
Recommendations. Regional anesthetic blocks
Recommendations. The impact of drug (CYP)
in which usually large doses are required (eg, brachial
plexus block, epidural block) should be avoided dur- interactions for toxicity of local anesthetics is theo-
ing the first trimester of pregnancy (D). Regional an- retical concerning single-dose nerve blocks. On the
esthetic blocks where usually small doses are needed other hand, in continuous infusions, the decreased
(eg, spinal anesthesia, infiltration blocks), the doses CL of bupivacaine by the CYP3A4 inhibitor itracon-
can be still reduced because of a hormonally induced azole (and possibly other azole antimycotics) and of
increased sensitivity of the nerve axons to sodium ropivacaine by the CYP1A2 inhibitors may play a
channel block84,85 (C) and can be performed without role in increasing the risk of systemic toxicity. In
risk to the mother and the fetus (D). Special precau- particular, fluvoxamine is a risky drug in this re-
tions need to be taken to avoid unintentional intra- spect because in addition to its major inhibition of
vascular injection of the local anesthetic because of CYP1A2, it also causes some inhibition on CYP2D6
danger to the fetus and maternal heart. The use of and CYP3A4,98,99 which are involved in the metab-
epinephrine in the local anesthetic solutions is not olism of ropivacaine and other amide-linked local
contraindicated in obstetric patients.88 anesthetics. Patients’ use of itraconazole or fluvox-
Dose reduction in epidural or spinal anesthesia amine should be an indication to reduce the dose
for cesarean delivery is necessary because of ana- (10%-20%) (D) in repeat administration of a large
tomic (narrowed spaces) and physiologic changes amount within a short interval of bupivacaine
(greater pressure at the site of injection and en- and ropivacaine, respectively, and to reduce their
hanced sensitivity of nerves to local anesthetics) in doses in long-term continuous regional anesthetic
the later stages of pregnancy84,85,88 (C). In principle, blocks12,98,99 (C).
continuous regional anesthetic blocks, with low
doses of local anesthetics, may be used for short
Conclusion
periods in pregnant patients (D), the aim being to
reduce the need for analgesics such as opioids or None of the recommendations presented in this
cyclooxygenase inhibitors. review is based directly on evidence classified
Drug Interaction. Amide-linked local anes- higher than grade C (case series or poor quality
thetics are metabolized mainly in the liver by the cohort studies). Therefore, exact recommendations
572 Regional Anesthesia and Pain Medicine Vol. 29 No. 6 November–December 2004

regarding highest allowable dose of the local anes- Tryba for the assistance and discussions when col-
thetics cannot be given. lecting data for the present work.
The choice of a suitable dose range for a particu-
lar type of block can be made with the guidance of
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