Pharmacokinetics in children

Bupivacaine is extensively metabolized in the liver, primarily by aromatic hydroxylation to 4-hydroxy-bupivacaine and N-dealkylation to PPX (pipecolylxylidine), both of which are mediated by the cytochrome P450 3A4. About 1% of the bupivacaine is excreted within 24 hours unchanged in the urine and about 5% is excreted as the N-dealkylated metabolite, pipecolylxylidine (PPX) is excreted. Clearance of bupivacaine occurs primarily via metabolism in the liver and it is more sensitive to changes in intrinsic hepatic enzyme function than of the perfusion of the liver. The intrinsic clearance of bupivacaine is only one-third of that in adults at 1 month of age, and two-thirds at 6 months [[SmPC Marcaine; Mazoit 2004].

Bupivacaine is mainly bound to alpha-1-acid glycoprotein (AAG) in plasma, with a plasma binding of 96%. Neonates and infants have a lower AAG concentration in serum as compared with adults; therefore, their free fraction of bupivacaine is increased accordingly. The toxic effects are directly related to unbound drug concentration. During the first 6-9 months of life, AAG concentration progressively increases to reach adults levels by the end of the first year. During continuous epidural anesthesia in young children (ages from 6 days to 5.2 months), a significantly higher plasma concentration of unbound bupivacaine was reported than in older children (ages from 18 months to 9 years). This was associated with a high frequency of early symptoms of systemic toxicity. Plasma concentrations of AAG increase postoperatively (as a result of surgery), resulting in an increase in total concentration but not unbound concentration. Total plasma concentrations can be misleading in this situation. Indeed, it is the unbound concentration and not the unbound fraction that is related to systemic toxicity. A lower intrinsic clearance and a decreased AAG concentration are the two main factors leading to an increased risk of toxic reactions in the younger patients [[SmPC Marcaine; Mazoit 2004].

Table 1. Pharmacokinetics of bupivacaine during initial doses and continuous infusions measured in plasma in epidural anesthesia in children.

dose recommendation of formulary compared to licensed use (on-label versus off-label)

No information is present at this moment.

Available formulations

No information is present at this moment.

Dosages

Renal impaiment in children > 3 months

GFR ≥10 ml/min/1.73m2: Dose adjustment not required.

GFR <10 ml/min/1.73m2: A general recommendation on dose adjustment cannot be provided.

Clinical consequences

 Dose adjustments are not needed when given as a single dose or short treatment duration. Only a small portion of the dose is excreted unchanged by the kidneys [SmPC Marcaine].

The complete list of all undesirable drug reactions can be found in the national Summary of Product Characteristics (SmPC) – click here

Side effects in children

Epidural anesthesia: Bupivacaine in combination with adrenaline: disability, impaired speech, cardio-respiratory depression, seizures.
No major complications that were life-threatening or leading to permanent disability were documented in literature. Some complications described in literature include peri-catheter leaks, catheter dislodgements and kinking of the catheter [Kasanavesi 2015; Thomas 2023].

Spinal anesthesia: Minimal changes in heart rate and blood pressure have been reported in children under 5 years of age, while in older patients (>8 years old), spinal anesthesia can induce bradycardia or hypotension due to the sympathetic block. Complications of spinal anesthesia in children are infrequent and usually minor. There have been no reports of fatal complications or permanent neurological sequelae associated with spinal anesthesia in children. However, some complications described in literature include backache, high or total spinal anesthesia, transient neurological symptoms, hypotension, shivering, and infection [Verma 2014; Gupta 2014; Kabir 2023 ].

The complete list of all warnings and precautions can be found in the national Summary of Product Characteristics (SmPC) – click here

Warnings & precautions in children

Monitoring using a saturation meter, respiration ECG monitor, and blood pressure measurement, as well as a bladder catheter for micturition disorders.

To avoid excessive dosage in obese patients, dose should be calculated on the basis of ideal body-weight .

Interactions

The complete list of all interactions can be found in the national Summary of Product Characteristics (SmPC) – click here

• NERVOUS SYSTEM
• ANESTHETICS

ANESTHETICS, LOCAL

This pages provides a list of drugs from the same ATC class for comparison. This does not necessarily mean that these drugs are interchangeable.

References

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3. López, T., et al., Spinal anesthesia in pediatric patients., Minerva anestesiologica, 2012, 78(1), 78–87
4. Calder, A. et al, Pharmacokinetic profiles of epidural bupivacaine and ropivacaine following single-shot and continuous epidural use in young infants., Paediatric anaesthesia, 2012, 22(5), 430–437
5. Meunier, J. F., et al., Pharmacokinetics of bupivacaine after continuous epidural infusion in infants with and without biliary atresia., Anesthesiology, 2001, 95(1), 87–95
6. Verma, D, et al., Spinal anesthesia in infants and children: A one year prospective audit. , Anesthesia, essays and researches, 2014, 8(3), 324–329
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8. Jang, Y. E., et al., Lumbosacral and thoracolumbosacral cerebrospinal fluid volume changes in neonates, infants, children, and adolescents: A retrospective magnetic resonance imaging study, Paediatric anaesthesia, 2019, 29(1), 92–97
9. Jöhr M. , Regional anaesthesia in neonates, infants and children: an educational review., European journal of anaesthesiology, 2015, 32(5), 289–297
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12. Davandra Patel., Epidural analgesia for children, Continuing Education in Anaesthesia Critical Care & Pain, 2006, 6(2), 63–66.
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16. Luz, G.,et al., Free and total bupivacaine plasma concentrations after continuous epidural anaesthesia in infants and children., Paediatric anaesthesia,, 1998, 8(6), 473–478
17. Shah, R. D., et al, Applications of regional anaesthesia in paediatrics. , British journal of anaesthesia,, 2013, 111, i114–i124
18. Aspen Pharma Trading Limited. 022. , SmPC Marcaine 2.5/5.0 mg/ml oplossing voor injectie.(RVG 08028/08029). 27-10-2022, www.geneesmiddeleninformatiebank.nl
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20. Pacira Ireland Ltd. , SmPC Exparel Liposomal (EU/1/20/1489) Rev 1; 14-11-2022, www.ema.europa.eu
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24. Kabir AKM, et al, Safety Profile and Efficacy of Spinal Anaesthesia in Paediatric Age Group between 3 to 14 Years for Different Surgery., Journal of Medical and Dental Science Research., 2023, 10(2), 38-43

Changes

Therapeutic Drug Monitoring

Overdose