Continuing Education Activity

Local anesthetics (LA) consist of amino amide and amino ester medications used for several medical purposes. This activity will cover the indications, mechanism of action, metabolism, adverse effects, and potential toxicity of local anesthetics used in children. It will also discuss the interprofessional team’s role in enhancing care for children who receive local anesthetics.

Objectives:

• Outline indications for the use of local anesthetics.
• Review the mechanism of action of local anesthetics and discuss their metabolism.
• Explain the risks contributing to the adverse effects and toxicity of local anesthetics, and explain local anesthetic systemic toxicity (LAST) and its treatment.
• Identify the interprofessional team strategies for improving the care of and communication about local anesthetic administration and monitoring in children.

Indications

Local anesthetics (LAs) in children are used for procedures from topical application for peripheral IV starts to neuraxial use for regional anesthesia. Recently, intravenous infusions of local anesthetics for systemic neuropathic pain have been used. LAs can also be administered via subcutaneous, intramuscular, and perineural routes.[1] The ester family of LAs consists of 2-chloroprocaine, tetracaine, and procaine, while the amide family of LAs consists of lidocaine, prilocaine, bupivacaine, levobupivacaine, mepivacaine, etidocaine, and ropivacaine.[2][3]  Of the two families of local anesthetics, the amides are more commonly used in pediatric anesthesiology.[3]

Eutectic mixture of LA (EMLA) cream is a mixture of 2.5% lidocaine and 2.5% prilocaine that is often used to numb the skin for peripheral IV starts, subcutaneous port access, port wine birthmark treatments, and lumbar punctures.[4][5][6][2][3] Lidocaine is being used as an intravenous infusion for analgesia in many areas of acute and chronic pain management.  2-chloroprocaine is preferred for use in neonates, while bupivacaine, ropivacaine, and tetracaine are the typical agents of choice for neuraxial and peripheral nerve blocks in children.[7][4][8][2][3][9]

Mechanism of Action

Local anesthetics are primarily used to reversibly block action potentials that create impulse conduction along neural axons carrying sensory or motor signals. This occurs by blocking voltage-gated sodium channels.[8] Acting as weak bases in their ionized form, LAs block nerve conduction at the Na+ channel when it is inactive, thus preventing the opening and flux of ions.[3]  Isolated LAs can inhibit platelet aggregation and the production of free radicals, therefore producing anti-inflammatory properties.[4]

To block impulse conduction, there is a minimum local anesthetic concentration necessary specific to each nerve fiber according to its size and myelination. Unmyelinated fibers that control pain require lower concentrations of LA than myelinated fibers controlling muscle contraction. Therefore, lower concentrations of LA can be used for analgesia, especially in children less than 18 months of age who have not yet completed myelination of their central nervous systems. Local anesthetics given by continuous infusion have a longer duration of action than those given as a single administration.[3] 

The actions of LAs are affected by the pH, the concentration of calcium, and the stimulation of the nerve. Increased dose, concentration, and volume of an LA can prolong block duration by as much as 50%.[10]

Administration

Table 1. Local Anesthetic Recommended Doses (mg/kg)

[1][7] *Dexmedetomidine may be used to prolong the caudal duration of action in the lowest possible dose to achieve benefits.

Table 2.  Local Anesthetic Recommended Doses Continuous Epidural Infusions (mg/kg/hour)

 *Adjuvants can include preservative-free morphine, fentanyl, and sufentanil.[4]

Table 3.  Local Anesthetic Recommended Doses Spinal Anesthesia (mL/kg and mg/kg)

*Adjuvants of preservative-free morphine (10 to 30 mcg/kg) and clonidine (1 to 2 mcg/kg) can be used to prolong the duration of action Corticosteroids, dexmedetomidine, and ketamine are not recommended in children at this time, and clonidine should not be used in infants < 3months old secondary to apnea spells.[4][7]

Table 4.  Local Anesthetic Recommended Doses Single Injection Peripheral Nerve and Fascial Plane Blocks (mg/kg)

*Continuous infusions of 0.1 not 0.3 mg/kg/hour can safely be done with 0.2% ropivacaine or 0.2% bupivacaine.[7]

Adverse Effects

Ester LAs have two main adverse effects in children, the potential for toxicity with pseudocholinesterase (PSE) deficiency or absence and allergic reaction to the metabolite para-aminobenzoic acid (PABA). Amide LAs have multiple avenues through which they can exhibit adverse effects.[1][4][2][3][9] For example, systemic toxicity can lead to derangements in the hemoglobin, brain, heart, and mitochondria.[1][6]  LAST is a rare occurrence in pediatric regional anesthesia as the incidence is 1:10,000.[10]

A LA with an opioid adjunct can result in both urinary retention and pruritis. Naloxone or nalbuphine can be used to treat urinary retention as an intravenous bolus dose (1 mcg/kg or 0.1 mg/kg, respectively). Pruritis can be attenuated with naloxone IV bolus of 1 to 2 mcg/kg with or without a continuous infusion of 1 to 2 mcg/kg/hour.[4]

The risk factors that increase the potential for amide LA adverse effects and toxicity can be categorized into age, comorbidity, and amide LA-related risk factors. Low lean muscle mass and low albumin levels are seen in the extremes of age (neonates, infants, and the elderly). This causes a decrease in the protein binding of amide LA creating higher blood concentrations of free amide LA.[11] Infants and children also have immature hepatic enzyme systems that contribute to the age-related risk of amide LA accumulation.

Comorbidities that can increase the risk of adverse effects and toxicity of amide LA include hepatic dysfunction, cardiac dysfunction, renal dysfunction, neurological dysfunction, and metabolic/mitochondrial dysfunction. Hepatic, cardiac, and renal disease contribute to decreased metabolism and clearance of amide LA. Right to left heart shunt creates increased uptake and concentration of LA. Neurologic and metabolic diseases increase the susceptibility to amide LA accumulation.[1] Acidosis and hypercarbia decrease protein binding of LA, which increases the concentration of free LA and the risk of toxicity.

Amide LA administration itself can lead to the risk of adverse effects and toxicity. Mixing different amide LAs together can result in a cumulative dose that may not be safe. A large volume of amide LA can affect uptake and accumulation, exceeding safe dose levels. Less invasive topical LA may be considered safer, but careful consideration of dosing must be taken to avoid an overdose. Higher lipophilicity of an amide LA can also increase the risk of toxicity by increasing the potency and duration of action. Finally, direct intravascular injection of LAs can cause adverse effects and toxicity. 

The use of epinephrine (1:200,000 or 1:400,000) can indicate intravascular injection by exhibiting a heart rate increase of > 10 beats per minute and systolic blood pressure increase > 15 mmHg.  Preventative techniques include incremental dose injection with aspiration for blood and prolonging the total duration of injection time.  Epinephrine should never be used in blocks that are localized with terminal blood supply (i.e., digital, penile, eye, ear).[4]

Contraindications

Amide LAs are metabolized by the cytochrome P450 (CYP) hepatic enzymes involving carboxylation, hydrolysis, and dealkylation. The immaturity of this hepatic enzyme system in patients less than 6 months old increases the half-life, blood concentration, and potential toxicity of amide LAs.[3][9] Lidocaine and ropivacaine metabolism by CYP1A2 does not reach maturity until near 7 years of age, whereas by 1 year of age children have full capacity to use CYP3A4/7 to metabolize levobupivacaine and bupivacaine.[4] Any disease state that reduces hepatic enzyme function or blood flow will decrease the metabolism of amide LAs.[1]

Ester LAs are metabolized by plasma pseudocholinesterase (PSE) and other nonspecific esterases and include tetracaine and 2-chloroprocaine. Caution should be taken to elicit a history of pseudocholinesterase deficiency in the family or child’s history, as this would create the potential for ester LA accumulation and toxicity. The normal plasma half-life for 2-chloroprocaine in a child with normal PSE concentrations is approximately 60 seconds.[9] This metabolism of ester LAs in the plasma makes 2-chloroprocaine a safer choice in neonates because of their still immature hepatic metabolism.[12] PABA is a metabolite of ester LA drugs and can elicit allergic reactions in certain individuals.[2]

Toxicity

The onset of LA toxicity can be variable ranging from immediate onset to delayed onset hours after the administration of the LA. There may be signs and symptoms that suggest impending LA toxicity, or systemic reactions may occur without forewarning. Peak absorption of LA is most rapid in intercostal block applications, followed by caudal/epidural uptake, then uptake in the brachial plexus, ending with the least rapid uptake from distal peripheral sites (sciatic/femoral) and topical administration.[3]

The direct effect on the mitochondria is to inhibit metabolism and oxidative phosphorylation. Central nervous system (CNS) toxicity can result in seizures, while direct cardiac effects include impaired myocardial contractility and conduction disturbances.  Toxic signs and symptoms may vary from perioral tingling, confusion, dizziness, seizure, hypotension, and cardiac arrest.[1] 

A direct decrease in the rate of depolarization and increased duration of the action potential can result in cardiac arrhythmias and even cardiac arrest. The increased heart rate of neonates and infants makes them more susceptible to the cardiac effects of LA.[4] Hypotension and bradycardia are ominous signs. Low doses of LA are still used to treat epilepsy and convulsions in the pediatric population. However, the therapeutic index is narrow, and at toxic levels, LAs can cause seizures and coma.[4] Other neurologic signs and symptoms include tinnitus, perioral tingling, metallic taste, and agitation.[1][2]

Prilocaine alone or as EMLA cream can cause methemoglobinemia, especially in neonates and infants less than 3 months old. The risk of methemoglobinemia is increased by concurrent medication use with medications such as dapsone, acetaminophen, trimethoprim-sulfamethoxazole, phenytoin, phenobarbital, and chloroquine. Treatment of methemoglobinemia is supportive with oxygen and intravenous fluids, and if needed, IV methylene blue 1 to 2 mg/kg infused over 5 minutes or ascorbic acid.[6][13] Methylene blue may be repeated every 30-60 minutes, not to exceed the maximum dose of 7 mg/kg.[13]

Treatment of LA toxicity must prioritize securing the airway, oxygenation, and treatment of cardiac arrest and seizures. It is imperative to prevent acidosis, as this will exacerbate the toxic effects of LAs. A smartphone app developed by the American Society of Regional Anesthesia and Pain Medicine, ASRA LAST, guides and assists in the treatment of suspected or diagnosed LAST. 

In the treatment of LAST first stop the administration of all LAs. Then call for help, maintain ventilation and oxygenation while securing the airway, and consider early use of lipid emulsion therapy and consultation for extracorporeal membrane oxygenation. For CNS and cardiac toxicity, you must control seizures with benzodiazepines (i.e., diazepam 0.05 mg/kg IV bolus, may repeat once) and treat cardiac sequelae with Pediatric Advanced Life Support and Neonatal Resuscitation Program protocols. Care is necessary to know which medications to avoid: vasopressin, calcium channel and beta-adrenergic blockers, and local anesthetics. If epinephrine is used, the dose should be less than 1 microgram/kilogram.[1] Amiodarone is the preferred choice for ventricular arrhythmias caused by LA, but for bupivacaine-induced cardiac toxicity specifically, bretylium 5 mg/kg IV has been found to be effective (maximum dose of 30 mg/kg).[9][2] 

The gold standard for treatment of LAST is 20% lipid emulsion (20 grams in 100 mL or 0.2 g/mL). The recommended dose for pediatric patients begins with an initial bolus dose of 1.5 mL/kg (0.3 g/kg) followed by a continuous infusion of 0.25 mL/kg/min (0.05 g/kg/min), not to exceed 10 mL/kg (2 g/kg) in the first 30 minutes.[1][4] The role of lipid emulsion is to bind LA molecules and immediately increase the volume of distribution of the LA. Lipid emulsion also decreases the elimination of LA, so care is necessary to watch for recurrent toxic effects. Patients that have been stabilized after treatment for LAST need to be observed for at least 2 hours post-seizure and a minimum of 4 to 6 hours after recovery from cardiovascular instability. For those patients that survive cardiac arrest, the observation period needs to be determined on a case-by-case basis.[14]

Enhancing Healthcare Team Outcomes

The care of children receiving LA begins with the professional placing the LA, whether noninvasive, invasive, one-time dose or continuous infusion. Interprofessional communication is key in providing the first level of protection for children receiving LA. That begins with a minimum of two people checking the drug, dose, route, and site of administration, patient allergy profile, and patient weight. (see Tables 1-4) This could be the pharmacist and physician, the anesthesiologist and CRNA, or the nurse on the floor with a nursing colleague. This type of interprofessional teamwork enhances patient-centered care. [Level 5]

Next, one must know the local anesthetic that has been given to appropriately monitor for adequate analgesic effect and maintain vigilance for signs and symptoms of adverse effects and LAST.  Institutions should develop a standard handoff that details the local anesthetic used, the method and timing of the administration of the local anesthetic, and the expected analgesic effect and duration. Signs and symptoms of toxicity should be reviewed. Prompt recognition and treatment of LAST can prevent potentiation of LAST. [Level 1]

Monitoring provides the third level of protection for children receiving LA. Non-invasive blood pressure, pulse oximetry, and electrocardiogram are the minimum required mechanical monitors.[1] Vigilance in observation and communication with the child and family are of equal importance.  As a member of the care team, you must be knowledgeable of the normal use and effect of LA while also being informed of signs and symptoms of adverse effects and toxicity of LA.  If ever in doubt, seek advice and help from other care team members and proceed with emergency protocols as necessary. Early use of lipid emulsion and cardiopulmonary bypass/ECMO consult (both Level 2a) and immediate treatment of seizures (Level 1) improve patient outcomes.

The last level of protection for pediatric patients receiving LA is to implement an institutional, educational program that involves an annual review of local anesthetics, their effects, their potential adverse effects, and ultimately the treatment of LAST.  It would improve team performance to have a system for routine simulations that reviews the treatment and management of LAST in children. For example, vasopressin, beta-adrenergic blockers, and calcium channel blockers should be avoided in the treatment of cardiac arrest (Level 3).[14] These four strategies begin to ensure that the interprofessional team works collaboratively to enhance team performance and the outcomes of children receiving LA.