Update in Pediatric Regional Anesthesia
Choice of Local Anesthetic Agent for Epidural Infusions in Neonates and Infants: The Case for Chloroprocaine
By Emmanuel Alalade, MD; Joseph D. Tobias, MD; Ralph J. Beltran, MD
Department of Anesthesiology and Pain Medicine
Nationwide Children’s Hospital
The Ohio State University College of Medicine
In the early 1990’s, there was an increased use of postoperative epidural infusions in neonates and infants. Subsequently, several reports documented local anesthetic systemic toxicity (LAST) in infants and children receiving continuous infusions of epidural bupivacaine.1,2 Later investigations determined that infusion rates as high as 0.5 mg/kg/hour had been used in these patients. In response, guidelines were published with the recommendation to limit infusion rates in infants to ≤ 0.2 mg/kg/hr.3 Despite this recommended change in practice, additional concerns were raised with bupivacaine because it was shown that there was the potential for toxicity as serum concentrations continued to increase at 48 hours during a continuous epidural infusion.4 As a result, caution was advised with regard to the use of bupivacaine in epidural infusions lasting more than 48 hours.
Ropivacaine is another amide local anesthetic agent that was introduced as a potential alternative to bupivacaine. It was synthesized in 1957 and released into clinical practice in the United States in 1996. Its development and clinical application were part of an effort to increase safety without limiting the efficacy of local anesthetic (LA) agents. Molecular studies demonstrated a more rapid dissociation of ropivacaine from sodium channels resulting in the potential to decrease cardiotoxicity.5 Additionally, ropivacaine did not accumulate with postoperative epidural infusion rates at 0.2 mg/kg/hour.6 However, clearance remained age-dependent, leading to potentially higher peak plasma concentrations and ongoing concerns for toxicity in neonates and infants.
Although local anesthetic agents of the amide class remain the most frequently chosen medications for continuous epidural analgesia in infants and children, examination of the pharmacokinetics in this population reveals several factors which may predispose these patients to LAST due to gradual accumulation, including decreased hepatic metabolism and altered protein binding with the potential for increased serum and free concentrations as there is a decrease in serum concentrations of albumin and α1-acid glycoprotein, the predominant LA binding proteins.7,8 Delayed clearance of local anesthetic agents also suggests that a longer time would be required for the plasma concentration to return to a non-toxic level once elevated.9 Although LAST is rare in neonates and infants, there is the potential for considerable morbidity and mortality when it occurs.10,11
Given the concerns with LA agents of the amide class, there has remained interest in the identification of alternative LA agents for use in neonates and infants. Chloroprocaine was introduced into clinical practice in 1952.12 Its widespread acceptance and clinical use was initially limited following reports of postoperative back pain and cauda equina syndrome.13 Subsequent work demonstrated that these problems were not related to the primary LA agent itself, but rather the preservatives combined with it. The etiology of cauda equina syndrome was subsequently postulated to be the preservative, sodium bisulfite, while back pain was the result of local paraspinal muscle spasm secondary to chelation of calcium by the preservative, ethylenediaminetetraacetic acid (EDTA).13,14 The more recent clinical use of 2-chloroprocaine has focused on a preservative-free preparation. There have been no reported cases of irreversible cauda equina syndrome with this new formulation, and transient neurological symptoms have been reported to be lower when compared to lidocaine.15,16 Chloroprocaine is rapidly converted to inactive metabolites by plasma cholinesterases with an elimination half-life of minutes even in preterm infants, compared to a half-life of 6-8 hours with bupivacaine.17 This rapid elimination minimizes accumulation, and reduces the risk of toxicity with redosing or continuous infusions with clearance being similar in patients of all ages and unaffected by alterations in hepatic function or developmental aspects of the hepatic microsomal enzyme system.18
Several investigators have suggested a role for chloroprocaine as an alternative LA agent for regional anesthesia in neonates and infants. Henderson et al. reported preliminary experience with a continuous caudal epidural infusion of 3% 2-chloroprocaine to provide prolonged surgical anesthesia during awake inguinal herniorrhaphy.17 They chose their technique as an alternative to single shot techniques (caudal epidural or spinal anesthesia) which would reliably provide only 60-75 minutes of surgical anesthesia. In a cohort of 10 preterm infants undergoing awake inguinal herniorrhaphy, 3% 2-chloroprocaine was administered as a bolus dose of 1 mL/kg followed by a continuous infusion at 1 mL/kg/hour. Dosing was then escalated as needed. The mean cumulative dose of 2-chloroprocaine was 2.8 ± 1.0 mL/kg/hour (84 ± 30 mg/kg/hour) infused over a mean duration of 95 ± 35 minutes. None of the patients required supplemental analgesia or conversion to general anesthesia and there were no reported complications. At the conclusion of the infusion (mean duration of 95 ± 35 minutes), plasma 2‐chloroprocaine levels were measured in five infants and were 0.0 mg/mL in 4 infants and 0.5 mg/mL in the 5th patient thereby demonstrating the short plasma half-life of chloroprocaine. Ross et al. detailed the postoperative analgesic effects of epidural chloroprocaine in infants following major thoracoabdominal surgeries.19 Eighteen infants (mean age of 1.7 ± 1.8 months; mean weight of 3.8 ± 1.3 kg) received 1% chloroprocaine for epidural analgesia postoperatively for up to 96-hours.19 The epidural infusions included 1% 2‐chloroprocaine ± clonidine (0.5 μg/mL) with an initial average infusion rate of 0.35 mL/kg/hour. The tracheas of 13 of 18 patients were extubated within the first 24 postoperative hours. The mean duration of the epidural infusion was 48.3 hours.
During the first and second 24 postoperative hour periods, the infants received an average of 3.8 ± 2.6 and 1.6 ± 2.4 doses of opioid medications, respectively. Adverse effects were uncommon and transient including hypotension (n = 9), bradycardia (n = 2), and apnea (n = 1). Veneziano et al. reported a similar experience including low pain scores during the first 48 hours of postoperative care in 21 neonates and infants who had major surgical procedures and received an epidural infusion of 2-chloroprocaine.20 Epidural infusions consisted of 1.5% 2‐chloroprocaine ± fentanyl (0.2-1 μg/mL) infusing at 0.25–1.5 mL/kg/hour for a mean duration of 50 hours. Nine of the 21 patients underwent tracheal extubation in the operating room, and all except three had tracheal extubation during the first 24 postoperative hours. Many of these infants required analgesia over a large number of dermatomes due to the surgical procedure involved, and therefore required larger volumes of the epidural infusion to ensure adequate dermatomal spread. Given the restrictions described with amide LA agents, the volumes necessary to obtain complete coverage would have exceeded safe dosing parameters. In addition, several patients had pre-surgical hepatic impairment while others had intra-abdominal surgical procedures, both of which may have further delayed hepatic metabolism of LA agents of the amide class thereby predisposing these patients to LAST, thus making chloroprocaine a prudent choice.
LAST can occur with any of the commonly used LA agents. The safety profile of chloroprocaine over LA agents of the amide class is further demonstrated by the outcomes following its inadvertent systemic injection. Two case reports demonstrated that LAST related to 2-chloroprocaine toxicity following bolus dosing resolved with minimal intervention.21,22 In one case, CNS changes with brief tonic-clonic activity was noted, while a wide complex bradycardia was observed in the other. Both of these events resolved rapidly with minimal to no intervention, further illustrating the potential safety margin of chloroprocaine related to its rapid clearance.
In conclusion, the choice of LA for continuous epidural infusions in very young patients requires the practitioner to consider several factors including the potential for altered pharmacokinetics in neonates and infants. Although LAs of the amide class have been used successfully for decades, there is a potential for toxicity especially with prolonged infusions or repeated bolus dosing. Given the volume and concentration requirements for effective epidural anesthesia, LAs of the ester class such as chloroprocaine may provide effective analgesia while limiting the potential for LAST. The reader is referred to references 23 and 24 for additional information regarding the use of chloroprocaine for regional anesthesia in neonates and infants including preliminary information regarding dosing parameters and use of adjunctive agents including clonidine.23,24 Due to the limited clinical experience with these agents, there remains a need for future prospective trials to fully evaluate dosing regimens, useful adjuncts to improve analgesia such as opioids or clonidine, as well as the efficacy and adverse effect profile of these agents
- McCloskey JJ, Haun SE, Deshpande JK. Bupivacaine toxicity secondary to continuous caudal epidural infusion in children. Anesth Analg. 1992;75:287-290.
- Agarwal R, Gutlove DP, Lockhart CH. Seizures occurring in pediatric patients receiving continuous infusion of bupivacaine. Anesth Analg. 1992;75:284-286.
- Berde CB. Convulsions associated with pediatric regional anesthesia. Anesth Analg. 1992;75:164-166.
- Larsson BA, Lonnqvist PA, Olsson GL. Plasma concentrations of bupivacaine in neonates after continuous epidural infusion. Anesth Analg. 1997; 84:501-505.
- Graf BM, Abraham I, Eberbach N, Kunst G, Stowe DF, Martin E. Differences in cardiotoxicity of bupivacaine and ropivacaine are the result of physicochemical and stereoselective properties. Anesthesiology. 2002;96:1427-1434.
- Bosenberg A, Cronje L, Thomas J, Lopez T, Crean P, Gustafsson U, Huledal G, Larsson LE . Ropivacaine plasma levels and postoperative analgesia in neonates and infants during 48–72 h continuous epidural infusion following major surgery. Paediatric Anaesth. 2003;13:851-852.
- Peutrell JM, Holder K, Gregory M. Plasma bupivacaine concentrations associated with continuous extradural infusions in babies. Br J Anaesth 1997;78:160-162.
- Philip AG, Hewitt JR. Alpha 1-acid glycoprotein in the neonate with and without infection. Biol Neonate.1983;43:118-124.
- Gunter JB. Benefit and risks of local anesthetics in infants and children. Paediatr Drugs. 2002;4:649-672.
- Alalade, E, Relland LM, Chenault K, Elsey N, Fuchs M, Alpert S, Tobias J. Regional anesthesia facilitates the early recognition of local anesthetic toxicity. J Med Cases. 2019;10:338-342.
- Dickerson DM, Apfelbaum JL. Local anesthetic systemic toxicity. Aesthet Surg J. 2014;34:1111-1119.
- Foldes, FF, McNall PG. 2-Chloroprocaine: a new local anesthetic agent. Anesthesiology. 1952;13:287-296.
- Covino BG. Toxicity of local anesthetic agents. Acta Anaesthesiol Belg. 1988;39:159-164.
- Stevens RA, Urmey WF, Urquhart BL, Kao TC. Back pain after epidural anesthesia with chloroprocaine. Anesthesiology. 1993;78:492-497.
- Hejtmanek MR, Pollock JE. Chloroprocaine for spinal anesthesia: a retrospective analysis. Acta Anaesthesiol Scand. 2011;55:267-272.
- Kouri ME, Kopacz DJ. Spinal 2-chloroprocaine: a comparison with lidocaine in volunteers. Anesth Analg. 2004;98:75-80.
- Henderson K, Sethna NF, Berde CB. Continuous caudal anesthesia for inguinal hernia repair in former preterm infants. J Clin Anesth. 1993;5:129-33.
- Tobias JD, Rasmussen GE, Holcomb GW, Brock JW, Morgan WM. Continuous caudal anaesthesia with chloroprocaine as an adjunct to general anaesthesia in neonates. Can J Anaesth. 1996;43:69-72.
- Ross EL, Reiter PD, Murphy ME, Bielsky AR. Evaluation of prolonged epidural chloroprocaine for postoperative analgesia in infants. J Clin Anesth. 2015;27:463-9.
- Veneziano G, Iliev P, Tripi J, Martin D, Aldrink J, Bhalla T, Tobias J. Continuous chloroprocaine infusion for thoracic and caudal epidurals as a postoperative analgesia modality in neonates, infants, and children. Paediatr Anaesth. 2016;26:84-91.
- Hernandez MA, Boretsky K. Chloroprocaine: local anesthetic systemic toxicity in a 9-month infant with paravertebral catheter. Paediatr Anaesth. 2016;26:665-666.
- Cladis FP, Litman RS. Transient cardiovascular toxicity with unintentional intravascular injection of 3% 2-chloroprocaine in a 2-month-old infant. Anesthesiology. 2004;100:181-183.
- Veneziano G, Tobias JD. Chloroprocaine for epidural anesthesia in infants and children. Paediatr Anaesth. 2017;27:581-590.
- Gibbs A, Kim SS, Heydinger G, Veneziano G, Tobias JD. Postoperative analgesia in neonates and infants using epidural chloroprocaine and clonidine. J Pain Res. 2020;13:2749-2755.