Pharmacology of Local Anesthetics for Continuous Nerve Blocks in Children

Local anesthetics are tertiary amines and are divided into esters and amides. Esters
are metabolized by plasma cholinesterases, and neonates and infants up
to 6 months of age have one-half of the adult levels of this enzyme. Amides
are metabolized by the liver and are bound by plasma proteins, and
neonates and infants up to 3 months of age have a reduced hepatic blood
flow and immature degradation pathways. Consequently, a larger amount
of the drug remains unmetabolized and active in children than it does
in adults. Neonates and infants also are at greater risk of toxic
effects due to lower levels of albumin and α1-glycoprotein. In
addition, because the pediatric nerve fibers are small and the degree
of myelination is not complete, the minimum concentration necessary to
obtain nerve block may be reduced, and lower concentrations of local
anesthetic are required. The toxic effects of local anesthetics are
dependent on the total dose of drug administered and on the rapidity of
absorption into the bloodstream.

Although bupivacaine has been the local anesthetic of
choice for continuous infusion techniques, its toxicity, especially in
the case of continuous infusions, represents an increased concern that
has led to the introduction of ropivacaine and levobupivacaine, which
have less cardiotoxicity and neurotoxicity and produce a preferential
sensory block (children may be emotionally affected by the inability to
move their limbs). In children, most of the guidelines of continuous
local anesthetic infusion techniques are still largely

based
on experience developed with neuroaxial techniques. As in adult
patients, continuous nerve blocks are mostly indicated for controlling
pain of moderate to severe intensity that is expected to last at least
24 hours prior to or after upper or lower extremity surgery.

Lidocaine is an amide local anesthetic with a fast onset and an intermediate duration of action. It has a favorable toxicity profile.

Mepivacaine is an amide
local anesthetic, rapidly metabolized into the liver and excreted
through the kidneys. Mepivacaine has a short to intermediate action. It
is mostly indicated for single blocks and is rarely used for continuous
blocks.

Bupivacaine is a
long-lasting local anesthetic whose efficacy is well documented. Its
duration of action has made bupivacaine the drug of choice in
postoperative pain control for years, but its cardiotoxicity
(ventricular arrhythmias, myocardial depression) or neurotoxicity
(convulsions) represents an important limitation, especially for
continuous blocks. It is well established that prolonged infusions of
bupivacaine in children represent a major risk for the development of
toxic plasma levels (≥2 mg/mL). This is accentuated in newborns and
infants less than 4 months old because of their low serum albumin and
α1-glycoprotein levels. Pharmacokinetic studies as well as clinical use
of bupivacaine in children have led to guidelines for central block
loading doses of 0.25% bupivacaine 2.0 to 2.5 mg/kg, followed by a
continuous infusion of 0.125% bupivacaine 0.4 to 0.5 mg/kg/hour in
children and 0.2 mg/kg/hour in newborns and infants for 24 to 48 hours.

The plasma concentrations of bupivacaine and its main
metabolite after continuous fascia iliaca compartment block in children
are as follows: 0.25% bupivacaine 1.56 mg/kg with epinephrine followed
by 0.1% bupivacaine 0.135 mg/kg/hour for 48 hours. This technique
provides adequate analgesia in most cases and shows no severe adverse
effects.

For continuous infusion in brachial plexus, the maximum
recommended dose of bupivacaine is 0.3 to 0.4 mg/kg/hour in children
and 0.20 to 0.25 mg/kg/hour in infants and neonates.

Continuous femoral blocks are indicated for
postoperative pain management of femoral shaft fractures (0.2%
bupivacaine 0.15 mL/kg/hour).

Ropivacaine is a pure
S-enantiomer local anesthetic that has rapidly gained widespread
acceptance not only for adults but also for regional anesthesia in
children. The main reason for its increased use, even for continuous
infusion techniques, is its better safety profile, with a wider
therapeutic window and reduced risks for central nervous system
toxicity and cardiotoxicity. Furthermore, ropivacaine has shown a
preferential sensory/motor block discrimination compared with
bupivacaine in adults as well as in children.

Studies comparing the use of 0.2% ropivacaine or 0.25%
ropivacaine with 0.125% bupivacaine plus morphine at an infusion rate
of 0.1 to 0.3 mL/kg/hour showed the same analgesic efficacy but a
greater incidence of side effects associated with the bupivacaine and
morphine mixture. Even 0.1% and 0.08% of ropivacaine plus 0.12
mg/kg/hour clonidine has been shown to be effective.

Continuous lumbar plexus block with 0.2% ropivacaine at
a rate of 4 mL/hour provides effective postoperative analgesia in young
children following knee surgery.

Infusion of 0.2% ropivacaine through interscalene
catheter has been effective for pain treatment in a 3-year-old child
after amputation of upper extremity.

Ropivacaine 0.2% (0.02 mL kg-1 hr-1) has been used for
postoperative pain control with patient-controlled regional analgesia
(PCRA) following lower limb surgery with perineural catheters inserted
for popliteal and fascia iliaca compartment block

Continuous psoas compartment blocks with 0.2%
ropivacaine (0.2 mg kg-1 h-1) provided optimal pain relief in children
after major orthopedic surgery without major adverse events.

After a fascia iliaca compartment block with ropivacaine
0.375% or 0.5% (0.7 mL kg-1) in children aged 5 to 15 years, although
no signs of toxicity had been observed, high maximal plasma
concentrations (C(max) 4.33–5.6 µg/mL-1) resulted in three of four
patients in the ropivacaine 0.5% group. Consequently, the
administration of ropivacaine 3.5 mg kg-1 could be associated with high
plasma concentrations of ropivacaine, outside the tolerable range.

In a 3-year-old boy the continuous infusion of
ropivacaine 0.2% (0.4 mg kg-1 h-1) plus clonidine (0.12 µg kg-1 h-1)
for 21 days resulted in a complete pain relief without any adverse
effect.

Because the cardiotoxicity of bupivacaine has been shown
to be enantioselective and mainly related to the R(+)-enantiomer, the
S(-)-enantiomer (levobupivacaine) has been developed for clinical use.
Levobupivacaine has similar potency to bupivacaine with a supposedly
lower risk of cardiovascular and central nervous system toxicity than
bupivacaine in animal studies and in human volunteers. Clinical studies
have established that the anesthetic and analgesic effects of
levobupivacaine are similar to those of bupivacaine at the same dose,
but sensory block tended to be longer with levobupivacaine than with
bupivacaine. Pharmacokinetic studies of levobupivacaine in children
showed that size and postnatal age are the major contributors to
clearance variability in children. Reduced clearance and slower
absorption half-time contribute to delayed T(max) in neonates and young
infants. The onset of action for levobupivacaine is about 15 minutes.

Very few studies have been performed thus far on
levobupivacaine in the pediatric population. Continuous infusion of
0.0625% levobupivacaine with or without fentanyl seems to be optimum.
Continuous infusion of 0.125% levobupivacaine provides similar
analgesia as 0.125% bupivacaine, but the use of bupivacaine is
associated with more of a block, which confirms that either ropivacaine
or levobupivacaine should be preferred. Indeed, in the pediatric
population, any impairment of motor function can increase anxiety and
stress for both children and parents (Table 56-1).

Children can greatly benefit from the use of continuous
nerve blocks. Such techniques minimize the requirement of opioids and
consequently decrease the risk of associated side effects (nausea,
itching, urinary retention), facilitate functional recovery, and
decrease hospital length of stay. Because of the increased risk of
emotional stress associated with motor block and the increased risk of
local anesthetic accumulation, it is important in this patient
population to select a drug with the highest safety profile known to
induce a preferential sensory block. For postoperative analgesia, a
bolus of 0.4 to 0.6 mL/kg of 0.2% ropivacaine can precede the infusion
(a higher concentration, such as 0.5% ropivacaine, is used when an
intraoperative pain control is also required). Also, a combination of
1.5% lidocaine and 0.2% ropivacaine can be used for the initial bolus.

Our recommendation is to start with a bolus of 0.5 mL/kg
of 0.2% ropivacaine plus clonidine 2 µg/kg. The length of the
continuous infusion is 48 to 72 hours, but for infants less than 6
months of age the doses should be reduced by 25% to 30% because of the
risk of toxicity linked to their anatomy and physiology. The local
anesthetic solution for continuous infusion is 0.2% ropivacaine 0.1 to
0.3 mL/kg/hour usually ranging from 0.2 to 0.4 mg/kg/hour plus
clonidine 3 µg/kg per 24 hours.