Update in Pediatric Regional Anesthesia

LAST But Not the Least - Pediatric Local Anesthetic Systemic Toxicity

By Archana Singaravelu Ramesh, MD
Assistant Professor 
Department of Pediatric Anesthesiology
Yale School of Medicine
New Haven, Connecticut
and Karen R. Boretsky, MD
Boston Children’s Hospital
Harvard Medical School

The use of regional anesthesia (RA) in children has increased dramatically over the past few decades. RA is an important therapeutic modality for pain management in children as it provides superior, opioid–sparing pain relief and has an excellent safety profile. The data provided by several large multicenter databases (PRAN, ADAPEF) are reassuring, with a low incidence of serious complications reported in children.1,2 However, local anesthetic systemic toxicity (LAST), caused by high plasma levels of local anesthetic medications, can occur and manifest as seizures, myocardial depression, and cardiac arrhythmias including bradycardia, ventricular fibrillation and cardiac arrest. Overall, the incidence of LAST in children <18 years of age ranges from .0076% to .01% (PRAN, ADARPEF) which is lower than the incidence reported in large adult series of .087% to 0.1%.1-4  This overview will discuss risk factors, clinical manifestations and current treatment recommendations for LAST in the pediatric population.

Risk Factors

Type of local anesthetic agent
LA medications (LA) belong to one of two basic chemical classifications - aminoamides and aminoesters. The commonly used aminoamides for RA in children are bupivacaine, ropivacaine and levobupivacaine.5,6   These drugs are popular because of their prolonged duration of action, especially since the majority of pediatric RA is used to facilitate postoperative analgesia. Levobupivacaine is not available for use in the USA but is available in most European countries.

Bupivacaine has been historically the most commonly used amide LA in children.  Bupivacaine is a 50:50 mix of R- and S- enantiomers (mirror images or chiral molecules). It is associated with rare and often fatal cardiotoxicity that is enantioselective and attributed to the R-enantiomer.7,8 In response, the past 20 years have seen a gradual replacement of bupivacaine with ropivacaine and levobupivacaine. Levobupivacaine, the pure S-enantiomer of bupivacaine, has significantly less cardiotoxic potential than bupivacaine while possessing similar duration of action and potency.5,9  Ropivacaine has a chemical structure similar to bupivacaine but is a pure s- configuration and shows less cardiac and central nervous system toxic potential. It produces a similar duration of sensory blockade, but less motor blockade than either bupivacaine or levobupivacaine.5,10  Ropivacaine is less potent and equianalgesic dosing is calculated as 1 mg of ropivacaine =0.7 mg of bupivacaine. In dog models, successful resuscitation performed after overdose with bupivacaine, levobupivacaine and ropivacaine  was 50%, 70%, and 90 % respectively, indicating better resuscitation potential with ropivacaine and to a lesser degree, levobupivacaine.11 In addition, free plasma concentrations associated with ropivacaine-induced cardiac collapse were nearly 50% greater than corresponding concentrations of bupivacaine or levobupivacaine.11-13  Infant models are lacking but the reduced toxic potential of ropivacaine and levobupivacaine argue for their preferred use in clinical situations. 

Ester class LA can be used as an alternate to amides in young patients especially when prolonged infusions are desired. Aminoesters are metabolized by pseudocholinesterase in the plasma and are characterized by a relatively short serum half-life. The two most commonly used ester LAs are tetracaine and chloroprocaine. Tetracaine has high protein binding capacity and is longer acting. It is usually restricted to spinal anesthesia due to its low toxic threshold. On the other hand, chloroprocaine has a low protein binding property and is rapidly metabolized by plasmacholinesterase. Due to its short duration of action, it is mostly used as a continuous infusion.  Infants have reduced levels of plasma pseudocholinesterase compared to adults, but with a t1/2 in neonates of 40 seconds compared to 20 seconds in the adult, this increase is not clinically significant.6  Subsequently, when prolonged infusions or higher volumes of LA are needed, chloroprocaine is commonly used in infants without reported serious complications.14,15  Infusion rates of 1.5% 2-chloroprocaine at 0.45-0.7 ml/kg/hr (6-10 mg/kg/hr)  via epidural infusions in former preterm infants show low or negligible plasma 2-chloroprocaine concentrations.16  There have been isolated reports of toxicity associated with 2-chloroprocaine (a seizure and a cardiac arrhythmia) and each event was self-limited (less than 1 minute) with no permanent sequelae.17,18  Most of the literature on 2-chloroprocaine in children includes its use for continuous epidural analgesia.14,15  Small series of continuous paravertebral infusions of 2-chloroprocaine have been reported with efficacy and safety.19 Anecdotally, the author’s institution uses 2-chloroprocaine preferentially for all peripheral nerve block infusions in young infants with good success.

Age of patient
Infants <12 months of age are a high-risk group for LAST.  Data from the Pediatric Regional Anesthesia Network (PRAN) database (2018) indicates that while infants <12 months comprised 22.8% of total patients, they represented 71.4% of reports of LAST.2 LAST occurred in 5/23,706 infants (0.02%) while the overall reported rate was 7/104,393 (0.007%). Another recent publication reviewed reports of LAST in the literature in both adult and pediatric populations from 2014 to 2016.20 They reported that 20% of documented cases of LAST (n=10) occurred in patients < 12 months of age. Several developmental factors increase the risk of LA accumulation in neonates and young infants. Immature organ systems cause accumulation of LA especially the amide class LA which are dependent on the hepatic and renal system for their metabolism and clearance. Reduced plasma proteins levels, specifically of alpha-1 acid glycoprotein that bind LA, causes an increase in the free fraction of the drug.21 This may also contribute to the increased risk of LAST in infants although the plasma concentration of alpha-1 acid glycoprotein, which is also an acute phase reactant, increases with perioperative stress and inflammation.

Type of regional anesthetic technique
Infants receiving penile nerve block appear to be uniquely susceptible to LAST. There were 7 events of LAST reported following penile nerve blocks from a single institution for an incidence of 0.075% (7/9357).22  Proposed reasons include the following;  1. It is a highly vascular area in a packed space which may cause rapid absorption of LA into the vascular system; 2. Close proximity of the dorsal penile veins to the site of injection increase the risk of direct intravascular injection; 3. The penile block is usually placed by landmark technique and without the use of an intravascular marker for fear of vasoconstriction of the dorsal penile artery and 4. Bupivacaine is the most common LA used for this block given its long duration of action and lack of vasoconstriction compared to ropivacaine

Local anesthetic medication dose
Many of the reported cases of LAST in the pediatric population have occurred following dosing of LA within the proposed maximum LA dose. The recommended maximum doses for LA agents in both adult and pediatric populations are extrapolations from animal experiments, case reports of local anesthetic toxicity, and clinical experiences from the use of various doses and subsequent measurement of blood concentrations and analysis of pharmacokinetic results, rather than from randomized controlled studies. Therefore, for any given LA, it is prudent to use the lowest possible efficacious dose. 

Mode of local anesthetic administration
LAST can be due to direct inadvertent intravascular injection or delayed absorption of LA. Manifestations of LAST occur almost immediately following direct intravascular injections while it takes longer (~20 to 30 mins) if secondary to delayed absorption.  Bolus injection of the LA is the most critical time for occurrence of LAST.2,20  This strongly argues for the use of safety measures such as incremental injection, frequent aspiration, utilization of an intravascular marker and ECG monitoring, and ultrasound-guidance to detect an intravascular injection.  

Safety Measures to Detect Intravascular Injection
Negative aspiration for blood is a valuable technique that has high specificity but unfortunately low sensitivity with a false negative rate as high as 57%.23  A negative initial aspiration of blood does not eliminate the possibility of subsequent positive aspirations necessitating the need for incremental injections with frequent aspiration. The high failure rate of aspiration to detect an intravascular injection requires other safety methods to be concurrently used.

Intravascular markers like epinephrine are commonly used in test doses of LA. The reliability of a test dose to detect an intravascular injection in anesthetized children has seen a gradual increase over time parallel with the introduction of sevoflurane and better definition criteria for positive test dose. The sensitivity to detect an intravascular injection using epinephrine in children anesthetized with sevoflurane is 94%-97%.24-26   

Ultrasound may also help prevent an intravascular injection. Recent adult studies show a reduction in local anesthetic systemic toxicity (LAST) with ultrasound-guidance.3 Large, appropriately powered studies are needed in children to determine similar benefits. 

Clinical Manifestations
Given the concomitant administration of general anesthesia (GA) with RA in pediatric practice, the initial clinical presentation differs from adults. Prodromal symptoms cannot be relied on in young children and in those under general anesthesia. Anesthetized children commonly present with cardiac symptoms because the CNS symptoms are either suppressed or masked by GA. Awake patients are more likely to present with CNS symptoms. CNS manifestations reported in case reports of pediatric LAST include apnea, seizures, and altered level of consciousness.  Reported cardiovascular manifestations include EKG changes (widening of QRS complex, ST-T segment changes and peaked or inverted T-waves), bradycardia, asystole, ventricular tachycardia, hypotension, and cardiac arrest.20

Current Treatment Recommendation
Mounting evidence supports the critical role of intravenous lipid emulsion (ILE) in the management of LAST. ILE as a treatment for LAST was first reported in 2006 in an adult patient.27 Initially, ILE was believed to act solely by a scavenging mechanism.  A multifactorial mechanism is now proposed.28  ILE creates a lipid compartment within the plasma to partition off the LA and carry it away from affected receptors in the heart and nervous system.  Additionally, the ILE acts at the intracellular level to condition the myocardium to protect against the ischemia-reperfusion injury caused by LA agents. Finally, it also provides direct vasoconstrictive and inotropic benefits. 

Current recommendations advocate for the administration of ILE as a bolus of 1.5ml/kg over 2-3 minutes at the first suggestion of LAST.29 Following attainment of hemodynamic instability, an infusion of 0.25ml/kg/min should be continued for at least 10 minutes. The recommended upper dose limit of ILE has been increased from 10mL/kg to 12 ml/kg, but symptoms usually resolve with smaller doses. Excessive dosing of ILE can result in significant adverse effects. There have been case reports of pancreatitis secondary to lipemia, acute respiratory distress syndrome from pulmonary accumulation of lipid droplets and clogging of the continuous renal replacement therapy filters secondary to the high dose intralipid emulsion used in enteral poisonings in adult patients. In the pediatric population, the details of lipid emulsion medication errors during administration as a component of TPN have been reported in neonates where some received doses 10-18 times the intended dose.31-34  Acute fat overload from ILE can lead to hyperthermia, respiratory distress, pancreatitis and metabolic acidosis. Manifestations have been severe enough to warrant mechanical ventilation and exchange transfusion. No deaths were reported in these infants.

ASRA published a checklist for treatment of LAST.29 Malignant cardiac arrhythmias and cardiovascular collapse are treated differently when LAST is suspected when compared to other etiologies.    

  •  Early aggressive airway management is vital to prevent hypoxia, acidosis and hypercarbia, all of which potentiate LAST and make resuscitation more difficult. 
  • Early use of ILE is advocated.
  • Epinephrine dose should be titrated as needed to support hemodynamic parameters as effective doses are often less generous (1 mcg/kg) than that recommended by PALS guidelines (10 mcg/kg) for other forms of pediatric cardiac arrest.30
  • ECMO should be made available to use for cardiovascular support if needed especially since LAST is a potentially treatable cause of cardiovascular collapse with a good prognosis once treated.
  • Finally, after the patient is stabilized, the event should be reported to lipid rescue.org. They maintain a record of all cases of LAST. Given the low incidence of this complication, pooled data will be essential to further our knowledge of this phenomenon.

In summary, RA is beneficial in children, but practitioners need to be aware of patient factors, individual properties of LA agents and the regional techniques that render the child high risk for LAST.  Children receiving RA must always have standard monitoring in place at the time of block placement and equipment for resuscitation including ILE must always be immediately available.  Use of the lowest possible efficacious dose and a high level of practitioner experience are advocated.

REFERENCES

  1. Ecoffey c, Lacroix F, Giaufré E et al. Epidemiology and morbidity of regional anesthesia in children: a follow-up one-year prospective survey of the French-Language Society of Paediatric Anaesthesiologists (ADARPF). Paediatr Anaesth. 2010; 20(12):1061-9.
  2. Walker BJ, Long JB, Sathyamoorthy M et al. Complications in Pediatric Regional Anesthesia. An Analysis of More than 100,000 Blocks from the Pediatric Regional Anesthesia Network (PRAN). Anesthesiology. 2018; 129(4):721-32.
  3. Barrington MJ, Kluger R. Ultrasound guidance reduces the risk of local anesthetic systemic toxicity following peripheral nerve blockade. Reg Anesth Pain Med. 2013; 38(4):289-99.
  4. Orebaugh SL, Kentor ML, Williams BA.  Adverse outcomes associated with nerve stimulator-guided and ultrasound-guided peripheral nerve blocks by supervised trainees: update of a single-site database. Reg Anesth Pain Med. 2012; 37(6):577-82.
  5. Mazoit JX, Dalens BJ.  Pharmacokinetics of local anaesthetics in infants and children. Clin Pharmacokinet. 2004; 43(1):17-32.
  6. Gunter JB.  Benefit and risks of local anesthetics in infants and children. Paediatr Drugs. 2002; 4(10):649-72.
  7. Di Gregorio G, Neal JM, Rosenquist RW et al. Clinical presentation of local anesthetic systemic toxicity: a review of published cases, 1979 to 2009. Reg Anesth Pain Med. 2010; 35(2):181-7.
  8. Graf BM, Abraham I, Eberbach N et al. Differences in cardiotoxicity of bupivacaine and ropivacaine are the result of physicochemical and stereoselective properties. Anesthesiology. 2002; 96:1427–1434.
  9. G. A. McLeodd, D. Burke. Levobupivacaine.  Anaesthesia 2001; 56(4):331-41.
  10. Mazoit JX, Dalens BJ. Ropivacaine in infants and children. Curr Opin Anaesthesiol. 2003; 16(3):305-7.
  11. Groban L, Deal DD, Vernon JC et al. Cardiac resuscitation after incremental overdosage with lidocaine, bupivacaine, levobupivacaine, and ropivacaine in anesthetized dogs. Anesth Analg. 2001; 92(1):37–43.
  12. Groban L. Central nervous system and cardiac effects from long-acting amide local anesthetic toxicity in the intact animal model. Reg Anesth Pain Med. 2003; 28(1):3–11  Stewart J, Kellett N, Castro D.
  13. The central nervous system and cardiovascular effects of levobupivacaine and ropivacaine in healthy volunteers. Anesth Analg 2003; 97:412–416.
  14. Veneziano G, Tobias JD. Chloroprocaine for epidural anesthesia in infants and children. Paediatr Anaesth. 2017;27(6):581-590.
  15. Muhly WT, Gurnaney HG, Kraemer FW et al. A retrospective comparison of ropivacaine and 2‐chloroprocaine continuous thoracic epidural analgesia for management of post‐thoracotomy pain in infants. Pediatr Anesth. 2015; 25: 1162–1167.
  16. Henderson K, Sethna NF, Berde CB. Continuous caudal anesthesia for inguinal hernia repair in former preterm infants. J Clin Anesth. 1993 ;5(2):129-33.
  17. Cladis FP, Litman RS. Transient cardiovascular toxicity with unintentional intravascular injection of 3% 2-chloroprocaine in a 2-month-old infant. Anesthesiology. 2004; 100(1):181-183. 
  18. Hernandez MA, Boretsky K. Paediatr Anaesth. 2016 ;26(6):665-666.
  19. Bairdain S, Dodson B, Zurakowski D et al. Paravertebral nerve block catheters using chloroprocaine in infants with prolonged mechanical ventilation for treatment of long-gap esophageal atresia. Paediatr Anaesth. 2015; 25(11):1151-7.
  20. Gitman M, Barrington MJ. Local Anesthetic Systemic Toxicity: A Review of Recent Case Reports and Registries. Reg Anesth Pain Med. 2018; 43(2):124-130.
  21. Boretsky KR. A review of regional anesthesia in infants. Pediatric Drugs. 2019; 21:439-49.
  22. Yu RN, Houck CS, Casta A et al.  A A Case Rep. 2016; 7(3):71-5.
  23. Fisher QA, Shaffner DH, Yaster M. Detection of intravascular injection of regional anesthetics in children. 1997; 44:592-98.
  24. Tobias JD. Caudal epidural block: a review of test dosing and recognition of systemic injection in children. Anesth Analg. 2001 Nov;93(5):1156-61. 
  25. Mauch JY, Spielmann N, Hartnack S, Weiss M. Electrocardiographic and haemodynamic alterations caused by three different test solutions of local anaesthetics to detect accidental intravascular injection in children. Br J Anaesth. 2012; 108(2):283-9.
  26. Varghese E, Deepak KM, Chowdary KV. Epinephrine test dose in children: is it interpretable on ECG monitor? Paediatr Anaesth. 2009; 19(11):1090-5.
  27. Rosenblatt MA, Abel M, Fischer GW  et al. Successful use of a 20% lipid emulsion to resuscitate a patient after a presumed bupivacaine‐related cardiac arrest. Anesthesiology. 2006; 105(1):217–8.
  28. Fettiplace MR, Weinberg G. The Mechanisms Underlying Lipid Resuscitation Therapy. Reg Anesth Pain Med. 2018; 43(2):138-149.  
  29. Neal JM, Barrington MJ, Fettiplace MR et al. the Third American Society of Regional Anesthesia and Pain Medicine Practice Advisory on Local Anesthetic Systemic Toxicity. Reg Anesth Pain Med. 2018; 43(2):113-123.
  30. Hiller DB, Gregorio GD, Ripper R et al.  Epinephrine impairs lipid resuscitation from bupivacaine overdose: a threshold effect. Anesthesiology  2009; 111(3): 498–505.
  31. Fairchild KD, Patterson A, Gumpper KF. Overdose of intravenous fat emulsion in a preterm infant: Case report. Nutr Clin Pract. 1999;14:116-9.
  32. Chuo J, Lambert G, Hicks RW. Intralipid medication errors in the neonatal intensive care unit. Jt Comm J Qual Patient Saf. 2007; 33(2):104-11.
  33. Evonne Low, C. Anthony Ryan. Overdose of Intravenous Intralipid in a Premature Neonate.  Jt Comm J Qual Patient Saf. 2007; 33(10):588-9.
  34. Khasawneh W, Bani Hani S. Intravenous Lipid Emulsion Overdose in Infancy: A Case Report and Overview of Opportunities, Challenges and Prevention. Drug Saf Case Rep. 2018;5(1):13.

Back to top