Pasquale De Negri
Pediatric regional anesthesia entered the new millennium with widespread approval for perioperative pain control in children. An increasing number of continuous peripheral nerve blocks are now used in clinical practice to provide anesthesia and acute postoperative pain control following upper and lower extremity orthopedic surgery. Although the placement of perineural catheters in children requires a particular expertise, it is important to recognize the specific pediatric pharmacology of local anesthetics indicated for continuous infusions as well as the rationale for their use.
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.
Table 56-1. Suggested Infusion Rates of Local Anesthetics for Continuous Axillary, Femoral, Lumbar Plexus, and Sciatic Continuous Peripheral Nerve Blocks in Children
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.
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