Download Maximum recommended doses of local anaesthetics

Kirjeitä toimitukselle
Per H. Rosenberg
Department of Anaesthesiology and Intensive Care Medicine
Helsinki University Hospital
Helsinki, Finland
Maximum recommended doses of
local anaesthetics
T
he recommendations regarding maximum
doses of local anaesthetics presented in
physicians’ pharmaceutical reference
books or in anaesthesiology text books are
not evidence based. As a matter of fact, most
of the recommendations are published by the
manufacturer and are often very conservative.
Usually, the recommendation of a maximum
dose is expressed as the total amount of the local
anaesthetic, e.g. 200 mg for lidocaine in an adult.
The site of administration, size and age of the
patient, concomitant diseases and medications
are not taken into account. This controversy has
been pointed out several times, and most strongly
by Daniel C. Moore and co-workers 1 and by Bruce
Scott 2. They questioned the validity of maximum
dose recommendations because of the completely
ignored consideration of the various factors known
or suspected, to affect absorption, metabolism and
elimination of the drug.
Drug-related factors
Influence of site injection
The vascularity and the binding of the local
anaesthetic to the tissues will influence the rate of
absorption into the circulating blood. Absorption
from richly vascularized regions such as the
pleura, the bronchial mucosa, and the scalp occurs
rapidly 3.
Intrinsic vasoactivity of the local anaesthetics
The vasoactive potency of the clinically used
amide-linked local anaesthetics varies. The effect is
dose-dependent and as a rule, high concentrations
cause dilatation and low concentrations cause
constriction. The intrinsic vasoactivity of the
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local anaesthetic does not play any greater role in
influencing its absorption. Ropivacaine has been
found to produce less vasodilatation than other
commonly used amide-linked local anaesthetics 4,
or even vasoconstriction, but whether this has any
clinically beneficial consequences remains open. As
an example, plasma concentrations of ropivacaine
in epidural anaesthesia are similar to those
measured after a similar dose of bupivacaine 5, 6.
Adrenaline
Adrenaline slows the absorption of local anaesthetic
and prolongs the anaesthetic action and increases
the duration of the block. A suitable adrenaline
concentration is 5 µg/ml which reduces the peak
plasma concentration of the local anaesthetic,
depending on the local anaesthetic, by 30–60 %.
Higher adrenaline concentrations are commonly
used in dentistry, but if one aims primarily at
reducing the uptake of the local anaesthetic into
blood, as low adrenaline concentration as 1.7 µg/
ml (1 : 600,000) has been shown to be effective with
lidocaine 8.
Patient-related factors
Age
Deterioration in morphology and nerve
conduction by aging may increase the sensitivity
to local anaesthetic block 8. In addition, because of
reduced clearance, the doses of local anaesthetics
need to be reduced in adults, age-dependently
between 10–20 % 9.
In the newborn less than 4 months old, the low
plasma concentrations of α1-acid glycoprotein
(AAG), the local anaesthetic-binding acute phase
protein, is related to an enhanced risk of toxicity.
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When large doses of local anaesthetic are used
in this group of patients, the dose per kilogram
should be about 15 % lower than in older infants 9.
Size
Extremes in size need to be considered when
regional anaesthetic blocks are used, both
from the performance point of view and the
pharmacokinetic/toxicity point of view. There is
no evidence based recommendation or rule for
proportional reduction of doses according to the
weight but, obviously, dosing on milligram-perkilogram basis would be dangerous 10.
Renal dysfunction
In renal dysfunction, the clearance of local
anaesthetics has been found to be lower than in
nonuraemic patients 11. The concentration of AAG
is usually increased in uraemic patients 12 and this
offers an important protection against toxicity.
The initial absorption of local anaesthetic in
uraemic patients is rapid 11 and the dose of a local
anaesthetic should de reduced by 10–20 % when
large doses are planned to be used. Furthermore,
due to reduced elimination of the local anaesthetic
and its metabolites, the doses used for continuous
infusions should also be reduced by 10–20 %,
according to the degree of renal dysfunction 9.
Hepatic dysfunction
The parmacokinetics of the majority of local
anaesthetics is affected by a poorly functioning
liver associated with concomitant alterations in
circulation and body fluids. In end-stage liver
dysfunction, the clearance of ropivacaine has been
found to be about 60 % lower than in healthy
volunteers 13.
Patients with severe liver dysfunction often have
other concomitant diseases (renal and cardiac),
which may be even more important indications to
reduce the dose of the local anaesthetic. In mild
liver dysfunction due to alcoholism, there is only
minor alteration in the clearance of lidocaine 14.
Single-dose local anaesthetic blocks can
be performed without dose reduction in liver
dysfunction. However, in repeat blocks (within
short interval) and during continuous infusion
blocks, the dose needs to be reduced by 10–50 %,
depending on the stage of liver dysfunction 9.
Heart failure
In mild cardiac disease, there may be no reason
to reduce the local anaesthetic dose in single-
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dose blocks. Due to decreased liver and kidney
blood flow in advanced heart failure, causing slow
elimination of drugs and metabolites, the dose of
the local anaesthetic should be reduced at least in
continuous infusion blocks, e.g., by 10–20 % 9.
Large doses of adrenaline should be avoided
in patients with cardiac disease with arrhythmias
or hypokalaemia. Obviously, lidocaine should
not be used to treat local anaesthetic-provoked
ventricular dysrhythmia because cardiac toxicity
of local anaesthetic is additive 15.
Pregnancy
Regional anaesthetic blocks requiring large
doses (e.g., brachial plexus block, epidural block)
should be avoided during the first trimester of
pregnancy.
Dose reduction in epidural or spinal anaesthesia
for caesarean section is necessary because of
anatomical and physiological changes in the late
stages of pregnancy and the enhanced sensitivity of
nerves to local anaesthetics. Continuous infusion
blocks are rarely used during pregnancy but, in
principle, low doses for short periods could be used
postoperatively, with the aim to reduce the need
for analgesics such as opioid and cyclooxygenase
inhibitors 9.
Drug interactions
The cytochrome P450 (CYP) isoenzymes primarily
involved in the metabolism of local anaesthetics
are CYP 3A4, CYP 2D6 and CYP 1A2 16, 17. In
single dose blocks the impact of drug interactions
(CYP enzymes) for toxicity of local anaesthetics
is theoretical. In continuous infusions, however,
the decreased clearance of bupivacaine by strong
CYP3A4 inhibitors (e.g., itraconazole and other
conazole antimycotics) and of ropivacaine by strong
CYP1A2 inhibitors (e.g., fluvoxamine, which also
inhibits CYP 3A4) needs to be considered. If the
patient receives such medication the continuous
infusion doses of bupivacaine or ropivacaine needs
to be reduced by 10–20 % 9.
Conclusion
None of the above mentioned recommendation
is based on evidence classified higher than
grade C (case series or poor quality cohort
studies) 9. Therefore, exact recommendations
regarding highest allowable dose of the local
anaesthetics cannot be given. Recommendations
regarding which factors need to be considered
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for the reduction of the dose are given in this
presentation.
The choice of a suitable (sufficient) dose for
a particular type of regional anaesthetic block
can be made with the guidance of modern highquality textbooks of regional anaesthesia. When
large doses are needed, the addition of low
concentrations (1.7–5 µg/ml) of adrenaline is
most useful in reducing the absorption of the local
anaesthetic.
The local anaesthetics are potentially toxic agents
and, therefore, everyone who uses them must
know which a suitable dose for a particular block
in normal conditions is. In order to adjust the local
anaesthetic dose properly one must also know how
the drug-related factors and the patient-related
factors can influence the absorption, distribution,
metabolism and elimination.
Finally, the maximum milligram dose
recommendations for local anaesthetics by the
pharmaceutical companies are illogical and
needless.

References
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determining dosages of amide-type local anesthetic drugs.
Anesthesiology 1977; 47: 263–268.
2. Scott DB. Maximum recommended doses of local anaesthetic
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3. Covino BG, Vassallo H. Local Anesthetics. Mechanisms of Action
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