Local Anesthetics in Children

Mechanism of Action

Local anesthetics are primarily used to reversibly block action potentials, thereby preventing impulse conduction along neural axons that carry sensory or motor signals. This effect occurs through blockade of voltage-gated sodium channels.[9] Local anesthetics reversibly inhibit voltage-gated sodium channels by preferentially binding to open and inactivated channel states, thereby preventing sodium influx and propagation of action potentials.[3] Isolated local anesthetics can inhibit platelet aggregation and free radical production, thereby exerting anti-inflammatory effects.[4]

A minimum local anesthetic concentration is required to block impulse conduction, and this concentration varies according to the size and degree of myelination of each nerve fiber. Unmyelinated fibers that transmit pain signals require lower concentrations of local anesthetic than myelinated fibers that control muscle contraction. Lower concentrations may provide adequate analgesia because smaller, less myelinated fibers are generally more susceptible to local anesthetic blockade than larger, heavily myelinated motor fibers. Therefore, lower concentrations of local anesthetic can be used for analgesia, especially in children younger than 18 months who have not yet completed myelination of their central nervous systems. Continuous local anesthetic infusions can prolong analgesia by maintaining therapeutic concentrations around the target nerve or neuraxial space.[3] 

The effectiveness of local anesthetics is influenced by tissue pH, extracellular calcium concentration, nerve fiber characteristics, and the frequency of nerve stimulation. Increasing the dose, concentration, or volume of a local anesthetic generally increases the extent and duration of neural blockade.[14]

Pharmacokinetics

For pediatric local anesthetics, the most clinically relevant formulations and pharmacokinetic parameters vary by route of administration. EMLA cream, a eutectic mixture containing 2.5% lidocaine and 2.5% prilocaine, is commonly used for topical analgesia before venipuncture, IV catheter placement, lumbar puncture, and other minor procedures. Following topical application under occlusion, peak plasma concentrations typically occur several hours after application, with reported Tmax values ranging from approximately 2 to 6 hours, depending on application duration and body surface area. The elimination half-life of both lidocaine and prilocaine is approximately 1.5 to 2 hours.[15]

Lidocaine is widely used for local infiltration anesthesia in pediatric patients and is commonly administered as 0.5% to 2% injectable solutions. Following infiltration, systemic absorption is rapid and depends on tissue vascularity and the presence of epinephrine. Peak plasma concentrations are generally observed within 15 to 30 minutes, and lidocaine has an elimination half-life of approximately 1.5 to 2 hours in older children. Neonates may exhibit prolonged elimination because of immature hepatic metabolism.[15]

2-Chloroprocaine, an ester local anesthetic frequently used for caudal and epidural anesthesia in neonates and infants, is available as 1% to 3% solutions. Because chloroprocaine undergoes rapid hydrolysis by plasma cholinesterases, systemic exposure is brief. Peak plasma concentrations occur rapidly after neuraxial administration, typically within 10 to 30 minutes, while the plasma elimination half-life is extremely short, generally less than 1 minute, making it an attractive option in very young children.[16]

Ropivacaine, commonly administered as 0.2% to 0.5% solutions for caudal epidural anesthesia and peripheral nerve blocks, demonstrates pharmacokinetic properties similar to those of bupivacaine but with a more favorable safety profile. Peak plasma concentrations are typically reached within 20 to 60 minutes after administration, and the elimination half-life is approximately 3 to 6 hours. Ropivacaine is frequently favored because of its lower cardiotoxic potential and reduced motor blockade.[17]

Bupivacaine is commonly used for pediatric caudal epidural anesthesia and peripheral nerve blocks and is typically administered as a 0.125% to 0.25% solution. Following caudal administration, peak plasma concentrations are generally achieved within 20 to 45 minutes. The elimination half-life varies with age but is approximately 2.7 to 8 hours, with prolonged elimination reported in neonates and infants because of immature hepatic clearance mechanisms.[18]

Liposomal bupivacaine is a prolonged-release multivesicular liposomal formulation containing 13.3 mg/mL (1.3%) bupivacaine and was approved by the FDA in 2021 for single-dose infiltration in pediatric patients aged 6 years and older. Compared with standard bupivacaine formulations, systemic absorption is delayed, producing a prolonged absorption phase with a Tmax often exceeding 24 hours. The apparent elimination half-life following infiltration is approximately 24 to 34 hours, reflecting sustained drug release from the liposomal carrier system rather than intrinsic bupivacaine metabolism. This extended pharmacokinetic profile contributes to prolonged postoperative analgesia.[19]

Administration

Liposomal bupivacaine is supplied as a 1.3% (13.3 mg/mL) injectable suspension in 10-mL (133 mg) and 20-mL (266 mg) single-dose vials. Liposomal bupivacaine is approved by the FDA for single-dose infiltration in pediatric patients aged 6 years and older for postsurgical local analgesia at a recommended dose of 4 mg/kg, with a maximum dose of 266 mg.

The following dosing recommendations are derived from published pediatric anesthesia literature, expert consensus statements, and clinical practice guidelines. Unless otherwise specified, these doses do not represent FDA-approved pediatric labeling and should be individualized based on patient age, weight, comorbidities, institutional protocols, and procedural requirements. 

Table 1. Maximum Recommended Doses of Local Anesthetics

Reference for the table.[1][8]

^aDexmedetomidine may be used as an adjuvant to prolong the duration of caudal analgesia. The lowest effective dose is recommended.

Table 2. Recommended Continuous Epidural Infusion Rates of Local Anesthetics in Pediatric Patients

^aEpidural adjuvants may include preservative-free morphine, fentanyl, or sufentanil.[4]

Table 3. Recommended Doses of Local Anesthetics for Pediatric Spinal Anesthesia

Reference for the table.[20]

^aPreservative-free morphine (10-30 mcg/kg) and clonidine (1-2 mcg/kg) may be used as adjuvants to prolong the duration of spinal anesthesia. Corticosteroids, dexmedetomidine, and ketamine are not currently recommended in children. Clonidine should not be used in infants younger than 3 months because of the risk of apnea.[4][8]

Table 4. Recommended Doses of Local Anesthetics for Single-Injection Peripheral Nerve and Fascial Plane Blocks

^aContinuous peripheral nerve or fascial plane infusions may be performed using 0.2% ropivacaine or 0.2% bupivacaine at 0.1-0.3 mg/kg/h, according to institutional pediatric regional anesthesia protocols.[8] When multiple blocks are performed, the cumulative local anesthetic dose should be calculated across all injection sites to reduce the risk of local anesthetic systemic toxicity.[21]

Adverse Effects

Ester local anesthetics may cause adverse effects in children through reduced metabolism in patients with pseudocholinesterase deficiency and, rarely, allergic reactions related to para-aminobenzoic acid metabolites. Amide local anesthetics are more commonly associated with systemic toxicity when excessive plasma concentrations occur.[1][2][3][10] Systemic toxicity may manifest as methemoglobinemia, central nervous system excitation or depression, seizures, cardiovascular instability, arrhythmias, cardiac arrest, and mitochondrial dysfunction.[1][6] Local anesthetic systemic toxicity (LAST) is uncommon in pediatric regional anesthesia. Reported incidence varies by study and technique, with estimates of approximately 8 cases per 100,000 injections in pediatric patients.[14]

Local anesthetics administered with neuraxial opioid adjuncts may be associated with opioid-related adverse effects, including pruritus and urinary retention. These effects may be managed with opioid antagonists or mixed agonist-antagonists, such as naloxone or nalbuphine, according to institutional pediatric anesthesia protocols.[4]

Risk factors for amide local anesthetic toxicity include patient age, comorbidities, total dose, injection site vascularity, and route of administration. Neonates and infants have lower lean muscle mass, lower plasma-binding protein concentrations, particularly alpha-1-acid glycoprotein, and immature hepatic clearance, which may increase the unbound fraction of amide local anesthetics and increase the risk of accumulation.[22] 

Comorbidities that increase the risk of adverse effects include hepatic dysfunction, cardiac dysfunction, renal impairment, neurologic disease, and metabolic or mitochondrial disorders. Hepatic disease may reduce metabolism of amide local anesthetics, while cardiac dysfunction or right-to-left shunting may increase systemic exposure.[1] Acidosis and hypercarbia can increase the unbound fraction of local anesthetics and potentiate cardiovascular and neurologic toxicity.

Local anesthetic administration factors also influence the risk of toxicity. Combining multiple amide local anesthetics may produce additive toxicity, and the cumulative dose should be calculated across all injection sites. Large-volume injections, highly vascular injection sites, topical overuse, continuous infusions, and inadvertent intravascular injection may increase systemic absorption and risk of LAST. More lipophilic agents may have greater potency and longer duration of action, which can contribute to toxicity with excessive doses.

Epinephrine-containing test doses, such as 1:200,000 or 1:400,000, may help detect intravascular injection when heart rate increases or systolic blood pressure rises. Preventive strategies include weight-based dose calculation, use of the lowest effective dose, aspiration before injection, incremental injection, ultrasound guidance when appropriate, prolonged injection time, and postinjection monitoring. Epinephrine-containing local anesthetic solutions should be avoided or used with extreme caution in areas with an end-arterial blood supply unless specifically indicated and supervised by clinicians experienced in pediatric regional anesthesia.[4]

Contraindications

Amide local anesthetics are metabolized primarily in the liver by cytochrome P450 (CYP) enzymes through oxidative N-dealkylation, hydroxylation, and hydrolysis pathways. The immaturity of hepatic enzyme systems in infants younger than 6 months may increase the elimination half-life, systemic exposure, and potential toxicity of amide local anesthetics.[3][10] Lidocaine and ropivacaine are metabolized primarily by CYP1A2 and CYP3A4, and CYP1A2 activity does not reach full maturation until later in childhood. In contrast, CYP3A4/7 activity increases substantially during infancy, contributing to the metabolism of levobupivacaine and bupivacaine.[4] Any disease state that reduces hepatic blood flow or hepatic metabolic capacity may decrease the clearance of amide local anesthetics.[1]

Ester local anesthetics, including tetracaine and 2-chloroprocaine, are metabolized by plasma cholinesterases (pseudocholinesterase) and other nonspecific esterases. A history of pseudocholinesterase deficiency in the patient or family should be elicited, as impaired metabolism may increase the risk of ester local anesthetic accumulation and toxicity. The plasma half-life of 2-chloroprocaine is approximately 20 to 60 seconds, reflecting its rapid hydrolysis by plasma cholinesterases.[10] Because ester local anesthetics are metabolized primarily in plasma rather than in the liver, 2-chloroprocaine is often favored in neonates and young infants when rapid metabolism is desired despite immature hepatic function.[23]

Para-aminobenzoic acid, a metabolite of many ester local anesthetics, may rarely trigger hypersensitivity reactions in susceptible individuals.[2]

Monitoring

Patients receiving local anesthetics should undergo monitoring of cardiovascular status, respiratory function, neurologic status, pain control, and signs of local anesthetic systemic toxicity, with enhanced vigilance in neonates, infants, and patients receiving continuous infusions or neuraxial techniques.[21]

Monitoring for Local Anesthetic Systemic Toxicity

Early manifestations may include:

• Perioral numbness (when verbalized by older children)
• Tinnitus
• Metallic taste
• Agitation
• Tremors
• Altered mental status
• Seizures

Late manifestations may include:

• Hypotension
• Bradycardia
• Conduction abnormalities
• Ventricular arrhythmias
• Cardiovascular collapse

Special monitoring in infants and neonates (because of reduced protein binding and immature hepatic metabolism):

• Monitor closely for excessive sedation
• Monitor for apnea
• Monitor for bradycardia
• Monitor for delayed toxicity after continuous infusions or repeated dosing

Toxicity

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

Local anesthetics can impair mitochondrial energy production by inhibiting oxidative phosphorylation, potentially contributing to cellular toxicity at high systemic concentrations. Central nervous system 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, and hypotension to 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. Neonates and infants may be more susceptible to local anesthetic toxicity because of reduced plasma protein binding, immature hepatic metabolism, and physiologic differences in cardiovascular function. Hypotension and bradycardia are ominous signs. IV lidocaine has been used in selected cases of refractory status epilepticus; however, local anesthetics can cause seizures and coma when toxic plasma concentrations are reached.[4][24][25] 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 younger than 3 months. 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 IV fluids, and if needed, IV methylene blue 1 to 2 mg/kg infused over 5 minutes or ascorbic acid. Methylene blue may be repeated every 30 to 60 minutes, not to exceed a maximum dose of 7 mg/kg.[26] Methylene blue should be used with caution in patients with glucose-6-phosphate dehydrogenase deficiency because hemolysis may occur. The dose of ascorbic acid varies from 25 to 50 mg/kg orally every 8 hours for 7 days in mild cases to 0.5 to 1 g IV every 8 to 12 hours for 8 to 16 doses in severe cases.[27][28]

Local Anesthetic Systemic Toxicity

Treatment of local anesthetic toxicity must prioritize securing the airway, oxygenation, and treatment of cardiac arrest and seizures. Preventing acidosis is essential because it exacerbates the toxic effects of local anesthetics. 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, all local anesthetics should be discontinued immediately. Clinicians should call for assistance, maintain ventilation and oxygenation while securing the airway, and consider early use of lipid emulsion therapy and consultation for extracorporeal membrane oxygenation in severe cases. For central nervous system and cardiovascular toxicity, seizures should be treated promptly with benzodiazepines according to institutional pediatric resuscitation protocols, and cardiovascular complications should be managed according to Pediatric Advanced Life Support and Neonatal Resuscitation Program guidelines. Care should be taken to avoid medications that may worsen toxicity, including vasopressin, calcium channel blockers, beta-adrenergic blockers, and additional local anesthetics. If epinephrine is required, small doses (<1 mcg/kg) are recommended. Amiodarone is the preferred antiarrhythmic agent for ventricular arrhythmias associated with LAST. Bretylium is not recommended in contemporary LAST management guidelines.[21]

IV 20% lipid emulsion therapy is a cornerstone of treatment for severe LAST. 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 local anesthetic molecules and immediately increase the volume of distribution of the local anesthetic. Lipid emulsion also decreases the elimination of local anesthetics; therefore, close monitoring is required for recurrent toxicity. Patients stabilized after treatment for LAST should be observed for at least 2 hours after seizures and at least 4 to 6 hours after recovery from cardiovascular instability. For patients who survive cardiac arrest, the observation period needs to be determined on a case-by-case basis.[29]

A local anesthetic with an opioid adjunct can result in both urinary retention and pruritus. Naloxone or nalbuphine can be used to treat urinary retention as an IV bolus dose (1 mcg/kg or 0.1 mg/kg, respectively). Pruritus 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/h.[4]

Enhancing Healthcare Team Outcomes

The safe use of local anesthetics in pediatric patients requires coordinated interprofessional collaboration among physicians, advanced practice providers, certified registered nurse anesthetists, pharmacists, nurses, and other healthcare professionals. Patient safety begins before administration by verifying the correct medication, concentration, dose, route, site of administration, allergy history, and patient weight. Independent double-check systems and standardized medication safety processes help reduce dosing errors and enhance patient-centered care.

Effective communication among team members is essential throughout the continuum of care. Standardized handoff processes should include the local anesthetic administered, route and timing of administration, expected duration of analgesia, and potential adverse effects. Particular attention should be given to risk factors, signs, and symptoms of LAST, as prompt recognition and intervention can significantly improve outcomes.

Ongoing monitoring represents another critical layer of protection. Depending on the route of administration and clinical setting, monitoring may include blood pressure, heart rate, pulse oximetry, electrocardiography, respiratory status, neurologic status, pain control, and signs of toxicity. Nurses and other frontline clinicians play a key role in early detection of adverse effects, while pharmacists contribute by evaluating dosing, drug interactions, cumulative local anesthetic exposure, and the availability of rescue medications. Continuous communication with patients and caregivers further supports timely recognition of complications and reinforces safe care practices. As members of the care team, clinicians must be knowledgeable about the normal use and effects of local anesthetics and be informed about the signs and symptoms of local anesthetics–related adverse effects and toxicity. If in doubt, clinicians should seek advice from other members of the care team and activate emergency protocols as needed. Early use of lipid emulsion therapy and consultation for cardiopulmonary bypass or extracorporeal membrane oxygenation, along with immediate treatment of seizures, improves patient outcomes.

Institutions should maintain evidence-based protocols for the prevention, recognition, and management of LAST. Readily accessible lipid emulsion therapy, emergency response algorithms, and rapid access to critical care resources are essential. Early seizure management, airway stabilization, and consideration of extracorporeal membrane oxygenation in severe cases may improve patient outcomes.

Healthcare organizations should also implement ongoing educational initiatives, including periodic review of local anesthetic pharmacology, adverse effects, and LAST management. Interprofessional simulation training can improve preparedness, communication, and team performance during high-risk events. Regular competency assessments and mock LAST scenarios help ensure that all team members are familiar with current treatment recommendations, including avoidance of vasopressin, calcium channel blockers, and beta-adrenergic blockers during LAST-associated cardiac arrest.[29] Through effective communication, coordinated monitoring, standardized protocols, and continuous education, the interprofessional healthcare team can optimize patient safety, improve outcomes, and enhance the quality of pediatric local anesthetic care.