Neonates and infants are more prone to developing systemic toxicity to local anesthetics (LAs), particularly amide LAs, compared with older children and adults. This is due to reduced plasma concentration of α 1 -acid glycoprotein with higher unbound fraction and decreased clearance of amide LAs.
Higher baseline heart rates in neonates and infants predispose them to increased sensitivity for bupivacaine-induced cardiotoxicity compared with adults. This is due to the strong affinity of bupivacaine for the fast sodium channels, resulting in prolonged blockade of these channels in the cardiac conduction system and a profound decrease in ventricular conduction velocity.
Chloroprocaine is the LA of choice for epidural infusion in neonates and small infants due to its very low risk of systemic toxicity and accumulation compared with amide LAs in this age group as well as easier dosing and pump programming.
Regional anesthesia is usually performed under general anesthesia, which may mask the earliest signs of systemic toxicity, particularly central nervous system (CNS) signs. Therefore refractory cardiovascular collapse may be the first and only sign in pediatric patients.
It is recommended that an epinephrine-containing test dose be used in all regional blocks before giving the full bolus dose. Order of sensitivity for detection of unintentional intravascular injection in pediatric patients when a test dose of LAs mixed with epinephrine is given, from most to least sensitive, is:
Increase T wave amplitude and ST segment changes > increase in systolic blood pressure more than 10% > increase in heart rate 10% to 15% above baseline heart rate before administration of test dose.
Total doses of LAs should not exceed the maximum allowable dose under any circumstances. The dose should be based on the lean body weight rather than the actual body weight, particularly in obese patients.
Introduction
LAs are divided into two main chemical compounds: the amides and the esters.
Amide LAs are metabolized exclusively in the liver by cytochrome P450 enzymes. These enzymes reach adult activity level by 9 months to 1 year of age. Therefore neonates and infants have a decreased clearance of amide LAs. Amide LAs bind to serum proteins. α 1 -acid glycoprotein is the major serum protein that binds amide LAs. Albumin has a very low affinity to bind amide LAs. However, being the most abundant protein in serum, albumin binding capacity to amide LAs is not insignificant.
Infants have a decreased level of α 1 -acid glycoprotein and albumin. Adult levels of protein binding are reached at about 1 year of age. Therefore neonates and infants are more prone to developing toxicity from amide LAs due to a higher serum-free fraction and lower clearance rate. The susceptibility to cardiac toxicity is amplified by increased heart rates. Due to their higher baseline heart rates neonates and infants are more sensitive than adults to amide LA-induced cardiotoxicity.
Neonates and infants have a relatively larger volume of distribution (VD) of amide LAs compared with adults. Toxicity will be more likely to occur following repeated doses and/or continuous infusion. This can be explained by the fact that larger VD prevents high serum drug concentrations from occurring after a slow incremental injection of a single dose of amide LAs.
Commonly used amide LAs in children include lidocaine, ropivacaine, bupivacaine, its L-enantiomer levobupivacaine, and eutectic mixture of local anesthetics (EMLA) cream.
Ester LAs are degraded in plasma by cholinesterases. Although neonates and infants have a lower level of cholinesterases, this has not been shown to be of clinical significance. Commonly used ester LAs in children include tetracaine and 2% to 3% chloroprocaine. Chloroprocaine use for continuous epidural analgesia in neonates and infants has been on the rise due to its rare incidence of systemic toxicity.
Amide local anesthetics
Bupivacaine
This is the most commonly used amide LA for regional blockade in pediatric anesthesia. Its long duration of action is related to its high binding to plasma proteins. Adding epinephrine will not result in further prolongation of the duration of action. However, epinephrine will reduce the rate of systemic absorption and the peak plasma concentration of bupivacaine. Its relatively slow onset of action is due to its high pKa of 8.1. It is a racemic mixture of levorotatory (L) and dextrorotatory (D) enantiomers; the L-enantiomer is the bioactive form, and the D-enantiomer is responsible for its toxicity. Toxicity from bupivacaine can be serious, ranging from CNS excitation to cardiovascular collapse. Direct cardiac toxicity is due to prolonged blockade of the sodium channels in the cardiac conduction system, resulting in a profound decrease in ventricular conduction velocity. This phenomenon is markedly amplified by tachycardia due to the strong affinity of bupivacaine for the fast sodium channels. Stereoselectivity of the sodium channel in the open state, however, has not been demonstrated.
The threshold for toxicity occurs at a bupivacaine level of 2 to 4 µg/mL. The maximum dose of bupivacaine is 2.5 to 3 mg/kg. The most commonly used concentration for single-shot peripheral nerve block and caudal epidural is 0.25% ( Table 2.1 ). After a single administration, analgesia usually lasts for 3 to 4 hours. For an epidural catheter the loading dose is 0.05 mL/kg/spinal segment or between 0.5 and 1 mL/kg, not to exceed the maximum dose of 2.5 mg/kg. For continuous epidural infusion a concentration ranging from 0.0625% to 0.125% is used and usually runs at a dose of 0.2 to 0.4 mg/kg/h ( Table 2.2 ).
| Local anesthetic | Concentration | Dose (mg/kg) | Dose (mL/kg) |
|---|---|---|---|
| Bupivacaine | 0.25% (2.5 mg/mL) | 2.5 | 1 |
| Ropivacaine | 0.2% (2 mg/mL) | 2 | 1 |
| Local anesthetic | Maximum rate of infusion and suggested infusion concentration (conc.) | ||
|---|---|---|---|
| Neonates and infants up to 6 months | Infants (6 months to 1 year) | Children older than 1 year | |
| Chloroprocaine a | Conc. of 2%. Rate of 5 to 15 mg/kg/h. | N/A c | N/A c |
| Bupivacaine | Conc. of 0.0625%. Rate of 0.2 mg/kg/h for no more than 48 hours. | Conc. of 0.0625% to 0.125%. Rate of 0.3 to 0.4 mg/kg/h. Reduce the infusion rate 30% after 48 hours and discontinue after 72 hours. | Conc. of 0.0625% to 0.125%. Rate of 0.4 mg/kg/h. |
| Ropivacaine b | Conc. of 0.1%. Rate of 0.2 mg/kg/h for no more than 72 hours. Reduce the infusion rate 30% after 48 hours. | Conc. of 0.1% to 0.2%. Rate of 0.3 to 0.4 mg/kg/h. Reduce the infusion rate 30% after 48 hours. | Conc. of 0.1% to 0.2%. Rate of 0.4 mg/kg/h. |
a Chloroprocaine is the first choice for epidural infusion in neonates due to reduced risk of systemic toxicity compared with amide LAs.
b Ropivacaine is the second choice for epidural infusion in neonates due to its better toxicity profile compared with bupivacaine.
c N/A, nonapplicable. Chloroprocaine is not usually used in this age group and is replaced by amide LAs.
Liposomal bupivacaine
Recently, a liposome bupivacaine has been approved by the Food and Drug Administration (FDA) for use in adults as a local anesthetic injected into the surgical site for postsurgical pain relief. The liposome bupivacaine formulation incorporates liposome-encapsulated bupivacaine (DepoFoam) and a small amount of extraliposomal bupivacaine. The liposome-encapsulated component permits bupivacaine release over an extended period. The extraliposomal component allows for rapid release and relatively rapid onset of action. There are some recent studies evaluating its use in the epidural space in adults as an alternative to continuous bupivacaine infusion through an indwelling epidural catheter. Liposomal bupivacaine is not currently approved for use in children. If approved, it may offer an attractive alternative for children in whom an indwelling catheter is not an option, but in whom prolonged regional blockade provided by liposome bupivacaine formulation may be beneficial.
Levobupivacaine (L-enantiomer of bupivacaine)
Levobupivacaine has almost the same blocking properties and pharmacokinetics as its racemic counterpart bupivacaine. The effect on the cardiac conduction system is stereospecific, with the L-enantiomer having much less of an effect than the D-enantiomer present in the racemic mixture of bupivacaine. As a result, levobupivacaine carries a reduced risk of cardiac toxicity compared with bupivacaine. It is currently unavailable in the United States.
Ropivacaine
This exists as an L-enantiomer. It is chemically similar to bupivacaine, but differs from it structurally having a propyl (three-carbon) side chain rather than a butyl (four-carbon) side chain. In an equipotent dose it carries a lower risk of cardiac and neurological toxicities compared with bupivacaine. This makes ropivacaine an attractive alternative to bupivacaine in pediatric patients. The data available from studies on infants and children do not report greater sparing of motor function following ropivacaine blockade compared with bupivacaine. Adult studies are conflicting in this regard.
The most commonly used concentration for single-shot caudal and single-shot peripheral nerve block is 0.2% (see Table 2.1 ). For an epidural catheter, the loading dose is 0.05 mL/kg/spinal segment or between 0.5 and 1 mL/kg, not to exceed the maximum dose of 3 mg/kg. For continuous infusion, the concentration range is from 0.1% to 0.2% and usually runs at a dose of 0.2 to 0.5 mg/kg/h (see Table 2.2 ).
Lidocaine
Lidocaine is not commonly used in pediatrics due to its short duration of analgesia. The amides ropivacaine and bupivacaine are more commonly used instead.
Emla cream
This is a eutectic mixture of equal quantities of lidocaine 2.5% and prilocaine 2.5%. It is commonly used to provide transdermal local anesthesia in pediatric patients. Methemoglobinemia has been reported with the use of EMLA cream. Therefore the maximum total surface area to which the cream is applied should be calculated in advance, and the maximum allowable dose should never be exceeded ( Table 2.3 ). This is particularly important in neonates. However, close attention should also be paid to the dose used in infants and toddlers. EMLA cream should be applied only to intact skin, and the dose should be reduced in case it is applied to mucous membranes. Other reported side effects include blanching and rash at the site of application. The duration of action is 1 to 2 hours.
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