Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Lidocaine (Lignocaine) Dosing Regimen Based upon a Population Pharmacokinetic Model for Preterm and Term Neonates with Seizures


Background and Objective: The application of lidocaine (lignocaine) as an anticonvulsant in neonates originated more than 40 years ago in Scandinavia. Lidocaine has been shown to be an effective anticonvulsant for the treatment of neonatal seizures that persist in spite of first-line anticonvulsant therapy. However, lidocaine toxicity, mainly in the form of cardiac arrhythmias, can be life threatening. Therapeutic drug monitoring can be useful to prevent toxicity. In a previous study, a dosing regimen was developed for term neonates, but it was not evaluated for preterm neonates. Extrapolation of the previously developed dosing regimen to premature neonates without accounting for differences in pharmacokinetics because of immaturity of phase I metabolism and body fat/water ratio may result in serious toxicity or therapy failure. The objective of this study was to develop an optimized dosing regimen for lidocaine in preterm as well as term neonates, using population pharmacokinetic modelling and simulation.

Methods: The requirements for this dosing regimen were simplicity of implementation, equal initial doses for all weight categories and avoidance of plasma concentrations >9mg/L. After lidocaine administration, blood samples were collected from an arterial line from a total of 46 preterm and term neonates with convulsion, within 10 days after birth. Lidocaine concentrations were measured in plasma using a fluorescence polarization immunoassay. Population pharmacokinetic modelling started with assessment of two important aspects of paediatric pharmacokinetics: relation to body size and the effects of maturation.

Results: In the studied neonatal population (term and preterm neonates with gestational ages up to 10 days), gestational age and bodyweight were closely related. Therefore, the effects of allometry and maturation on lidocaine pharmacokinetics could not be described independently and were described by a combined power estimate of bodyweight on clearance and volume of distribution. Based on this pharmacokinetic model, a dosing strategy for lidocaine for neonatal seizure control was developed, which allows rapid and safe administration of lidocaine in this population. When prospective validation confirms our model, routinely performed therapeutic drug monitoring should no longer be necessary and would only be advised in cases of (suspected) clinical symptoms of over- or underdosing.

Conclusion: A lidocaine dosing regimen for seizure control in preterm and term neonates has been developed using population pharmacokinetic modelling and simulation. Allometry and maturation exponents were combined into one exponent for each pharmacokinetic parameter and could not be described independently. Based on this model, this regimen allows rapid and safe administration of lidocaine in this population.

This is a preview of subscription content, log in to check access.

Table I
Fig. 1
Table II
Fig. 2
Fig. 3
Table III
Fig. 4


  1. 1.

    Pardridge WM, Sakiyama R, Fierer G. Blood-brain barrier transport and brain sequestration of propranolol and lidocaine. Am J Physiol1984; 247(3 Pt 2): R582–8

  2. 2.

    Simon RP, Benowitz NL, Bronstein J, et al. Increased brain uptake of lidocaine during bicuculline-induced status epilepticus in rats. Neurology 1982; 32(2): 196–9

  3. 3.

    Hellstrom-Westas L, Westgren U, Rosen I, et al. Lidocaine for treatment of severe seizures in newborn infants: I. Clinical effects and cerebral electrical activity monitoring. Acta Paediatr Scand 1988; 77(1): 79–84

  4. 4.

    Warnick JE, Kee RD, Yim GK. The effects of lidocaine on inhibition in the cerebral cortex. Anesthesiology 1971; 34(4): 327–32

  5. 5.

    Norell E, Gamstorp I. Neonatal seizures: effect of lidocain. Acta Paediatr Scand Suppl 1970; 206 Suppl 206: 97

  6. 6.

    Hellstrom-Westas L, Svenningsen NW, Westgren U, et al. Lidocaine for treatment of severe seizures in newborn infants: II. Blood concentrations of lidocaine and metabolites during intravenous infusion. Acta Paediatr 1992; 81(1): 35–9

  7. 7.

    Rademaker CMA, de Vries LS. Pharmacology review: lidocaine for neonatal seizure management. Neo Reviews 2008; 9: e585–9

  8. 8.

    Vento M, de Vries LS, Alberola A, et al. Approach to seizures in the neonatal period: a European perspective. Acta Paediatr 2010; 99(4): 497–501

  9. 9.

    Edgren B, Tilelli J, Gehrz R. Intravenous lidocaine overdosage in a child. J Toxicol Clin Toxicol 1986; 24(1): 51–8

  10. 10.

    Jonville AP, Barbier P, Blond MH, et al. Accidental lidocaine overdosage in an infant. J Toxicol Clin Toxicol 1990; 28(1): 101–6

  11. 11.

    van Rooij LG, Toet MC, Rademaker KM, et al. Cardiac arrhythmias in neonates receiving lidocaine as anticonvulsive treatment. Eur J Pediatr 2004; 163(11): 637–41

  12. 12.

    Lie KI, Wellens HJ, van Capelle FJ, et al. Lidocaine in the prevention of primary ventricular fibrillation: a double-blind, randomized study of 212 consecutive patients. N Engl J Med 1974; 291(25): 1324–6

  13. 13.

    Centini F, Fiore C, Riezzo I, et al. Suicide due to oral ingestion of lidocaine: a case report and review of the literature. Forensic Sci Int 2007; 171(1): 57–62

  14. 14.

    Malingre MM, Van Rooij LG, Rademaker CM, et al. Development of an optimal lidocaine infusion strategy for neonatal seizures. Eur J Pediatr 2006; 165(9): 598–604

  15. 15.

    Kearns GL, Abdel-Rahman SM, Alander SW, et al. Developmental pharmacology: drug disposition, action, and therapy in infants and children. N Engl J Med 2003; 349(12): 1157–67

  16. 16.

    Beal SL, Boeckman AJ, Sheiner LB. NONMEM: user’s guides. San Francisco (CA): University of California at San Francisco, 1988–1992

  17. 17.

    Keizer RJ, van Benten M, Beijnen JH, et al. Pirana and PCluster: a modeling environment and cluster infrastructure for NONMEM. Comput Methods Programs Biomed 2011 Jan; 101(1): 72–9

  18. 18.

    Karlsson MO, Savic RM. Diagnosing model diagnostics. Clin Pharmacol Ther 2007; 82(1): 17–20

  19. 19.

    Ette EI, Ludden TM. Population pharmacokinetic modeling: the importance of informative graphics. Pharm Res 1995; 12(12): 1845–55

  20. 20.

    Ette EI. Statistical graphics in pharmacokinetics and pharmacodynamics: a tutorial. Ann Pharmacother 1998; 32(7-8): 818–28

  21. 21.

    Anderson BJ, Holford NH. Mechanistic basis of using body size and maturation to predict clearance in humans. Drug Metab Pharmacokinet 2009; 24(1): 25–36

  22. 22.

    Ette EI. Stability and performance of a population pharmacokinetic model. J Clin Pharmacol 1997; 37(6): 486–95

  23. 23.

    Comets E, Brendel K, Mentre F. Computing normalised prediction distribution errors to evaluate nonlinear mixed-effect models: the npde add-on package for R. Comput Methods Programs Biomed 2008; 90(2): 154–66

  24. 24.

    Brendel K, Comets E, Laffont C, et al. Evaluation of different tests based on observations for external model evaluation of population analyses. J Pharmacokinet Pharmacodyn 2010; 37(1): 49–65

  25. 25.

    Mentre F, Escolano S. Prediction discrepancies for the evaluation of nonlinear mixed-effects models. J Pharmacokinet Pharmacodyn 2006; 33(3): 345–67

  26. 26.

    van Rooij LG, Toet MC, van Huffelen AC, et al. Effect of treatment of sub-clinical neonatal seizures detected with aEEG: randomized, controlled trial. Pediatrics 2010; 125(2): e358–66

  27. 27.

    Thibeault-Eybalin MP, Lortie A, Carmant L. Neonatal seizures: do they damage the brain?. Pediatr Neurol 2009; 40(3): 175–80

  28. 28.

    Benowitz NL, Meister W. Clinical pharmacokinetics of lignocaine. Clin Pharmacokinet 1978; 3(3): 177–201

  29. 29.

    Lerman J, Strong HA, LeDez KM, et al. Effects of age on the serum concentration of alpha 1-acid glycoprotein and the binding of lidocaine in pe-diatric patients. Clin Pharmacol Ther 1989; 46(2): 219–25

  30. 30.

    Hines RN. The ontogeny of drug metabolism enzymes and implications for adverse drug events. Pharmacol Ther 2008; 118(2): 250–67

  31. 31.

    de Wildt SN, Kearns GL, Leeder JS, et al. Cytochrome P450 3A: ontogeny and drug disposition. Clin Pharmacokinet 1999; 37(6): 485–505

  32. 32.

    Hines RN, McCarver DG. The ontogeny of human drug-metabolizing enzymes: phase I oxidative enzymes. J Pharmacol Exp Ther 2002; 300(2): 355–60

  33. 33.

    Mazoit JX, Dalens BJ. Pharmacokinetics of local anaesthetics in infants and children. Clin Pharmacokinet 2004; 43(1): 17–32

  34. 34.

    Thomson AH, Elliott HL, Kelman AW, et al. The pharmacokinetics and pharmacodynamics of lignocaine and MEGX in healthy subjects. J Pharmacokinet Biopharm 1987; 15(2): 101–15

  35. 35.

    Strong JM, Mayfield DE, Atkinson Jr AJ, et al. Pharmacological activity, metabolism, and pharmacokinetics of glycinexylidide. Clin Pharmacol Ther 1975; 17(2): 184–94

  36. 36.

    Alderman EL, Kerber RE, Harrison DC. Evaluation of lidocaine resistance in man using intermittent large-dose infusion techniques. Am J Cardiol 1974; 34(3): 342–9

  37. 37.

    Liu PL, Feldman HS, Giasi R, et al. Comparative CNS toxicity of lidocaine, etidocaine, bupivacaine, and tetracaine in awake dogs following rapid intravenous administration. Anesth Analg 1983; 62(4): 375–9

  38. 38.

    De Toledo JC. Lidocaine and seizures. Ther Drug Monit 2000; 22(3): 320–2

  39. 39.

    Satas S, Johannessen SI, Hoem NO, et al. Lidocaine pharmacokinetics and toxicity in newborn pigs. Anesth Analg 1997; 85(2): 306–12

  40. 40.

    Bernhard CG, Bohm E. The action of local anaesthetics on experimental epilepsy in cats and monkeys. Br J Pharmacol Chemother 1955; 10(3): 288–95

  41. 41.

    Rey E, Radvanyi-Bouvet MF, Bodiou C, et al. Intravenous lidocaine in the treatment of convulsions in the neonatal period: monitoring plasma levels. Ther Drug Monit 1990; 12(4): 316–20

  42. 42.

    van den Broek MP, Groenendaal F, Egberts AC, et al. Effects of hypothermia on pharmacokinetics and pharmacodynamics: a systematic review of pre-clinical and clinical studies. Clin Pharmacokinet 2010; 49(5): 277–94

Download references


No sources of funding were used to conduct this study. All authors have no conflicts of interest that are directly relevant to the content of this study.

Author information

Correspondence to Marcel P. H. van den Broek PharmD.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

van den Broek, M.P.H., Huitema, A.D.R., van Hasselt, J.G.C. et al. Lidocaine (Lignocaine) Dosing Regimen Based upon a Population Pharmacokinetic Model for Preterm and Term Neonates with Seizures. Clin Pharmacokinet 50, 461–469 (2011). https://doi.org/10.2165/11589160-000000000-00000

Download citation


  • Lidocaine
  • Neonatal Intensive Care Unit
  • Therapeutic Drug Monitoring
  • Preterm Neonate
  • Term Neonate