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Development of an optimal lidocaine infusion strategy for neonatal seizures

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Abstract

Introduction

Lidocaine is an effective drug for the treatment of neonatal convulsions not responding to traditional anticonvulsant therapy. However, one of the side-effects is a risk of cardiac arrhythmias. The aim of this study was to develop an optimal dosing strategy with minimal risk of cardiac arrhythmias.

Materials and methods

As a first step, we studied 20 neonates during routine treatment of neonatal seizures with lidocaine. All were given a loading dose of 2 mg/kg in 10 min, followed by the continuous infusion of 6 mg/kg per hour for 12 h, 4 mg/kg per hour for 12 h and finally 2 mg/kg per hour for 12 h. Effectiveness, cardiac toxicity and lidocaine plasma concentrations were then determined.

Results

No cardiac arrhythmias were observed, and lidocaine was effective in 76% of the treatments. In most of the treatments (13 out of 20) maximal lidocaine plasma concentrations were >9 mg/L. Plasma levels >9 mg/L have been related to cardiac toxicity when used as an anti-arrhythmic drug in adults. It was of interest that all preterm infants showed high lidocaine plasma levels. Secondly, we developed the optimal dosing regimen, which was defined as an infusion regimen at which maximal lidocaine plasma concentrations are <9 mg/L. Simulations with the developed pharmacokinetic model indicated a reduction in the infusion duration of lidocaine at 6 mg/kg per hour from 12 to 6 h. Thirdly, the new lidocaine dosing regimen was evaluated. Fifteen neonates (16 treatments) were studied. No cardiac arrhythmias were observed, and lidocaine was effective in 78% of the treatments. In most of the treatments (11 out of 16) maximal lidocaine plasma concentrations were <9 mg/L. Again preterm infants showed relatively high lidocaine plasma levels.

Conclusion

A new lidocaine dosing schedule was developed. This new regimen should have a lower risk of cardiac arrhythmias and appears to be as effective in term infants. For preterm infants the optimal regimen needs to be determined.

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Abbreviations

aEEG:

Amplitude-integrated electroencephalogram

CI:

Confidence interval

CL:

Total plasma clearance

CV:

Coefficient of variation

FPIA:

Fluorescence polarization immunoassay

GX:

Glycinexylidide

HPLC:

High-performance liquid chromatography

MEGX:

Monoethylglycinexylidide

NICU:

Neonatal intensive care unit

OFV:

Objective function value

V:

Volume of distribution

WT:

Weight

References

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

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

    Article  PubMed  CAS  Google Scholar 

  3. Berger I, Steinberg A, Schlesinger Y, Seelenfreund M, Schimmel MS (2002) Neonatal mydriasis: intravenous lidocaine adverse reaction. J Child Neurol 17:400–401

    Article  PubMed  Google Scholar 

  4. Blumer J, Strong JM, Atkinson AJ (1973) The convulsant potency of lidocaine and its N-dealkylated metabolites. J Pharmacol Exp Ther 186:31–36

    PubMed  CAS  Google Scholar 

  5. Burney RG, DiFazio CA, Peach MJ, Petrie KA, Silvester MJ (1974) Anti-arrhythmic effects of lidocaine metabolites. Am Heart J 88:765–769

    Article  PubMed  CAS  Google Scholar 

  6. Campbell TJ, Williams KM (1998) Therapeutic drug monitoring: antiarrhythmic drugs. Br J Clin Pharmacol 46:307–319

    Article  PubMed  CAS  Google Scholar 

  7. DeToledo JC (2000) Lidocaine and seizures. Ther Drug Monit 22:320–322

    Article  PubMed  CAS  Google Scholar 

  8. Ette E, Ludden T (1995) Population pharmacokinetic modeling: the importance of informative graphics. Pharm Res 12: 1845–1855

    Article  PubMed  CAS  Google Scholar 

  9. Ette E (1998) Statistical graphics in pharmacokinetics and pharmacodynamics: a tutorial. Ann Pharmacother 32: 818–828

    Article  PubMed  CAS  Google Scholar 

  10. Gianelly R, von der Groeben JO, Spivack AP, Harrison DC (1967) Effect of lidocaine on ventricular arrhythmias in patients with coronary heart disease. N Engl J Med 277:1215–1219

    Article  PubMed  CAS  Google Scholar 

  11. Hellström-Westas L, Westgren U, Rosén I, Svenningsen NW (1988) Lidocaine for treatment of severe seizures in newborn infants. I. Clinical effects and cerebral electrical activity monitoring. Acta Paediatr Scand 77:79–84

    Article  PubMed  Google Scholar 

  12. Hellström-Westas L, Svenningsen NW, Westgren U, Rosén I, Lagerstrom PO (1992) Lidocaine for treatment of severe seizures in newborn infants. II. Blood concentrations of lidocaine and metabolites during intravenous infusion. Acta Paediatr 81: 35–39

    Article  PubMed  Google Scholar 

  13. Howard JJ, Mohsenifar Z, Simons SM (1982) Adult respiratory distress syndrome following administration of lidocaine. Chest 81: 644–645

    Article  PubMed  CAS  Google Scholar 

  14. Jonsson EN, Karlsson MO (1999)Xpose, an S-PLUS based model building aid for population analysis with NONMEM. Comp Meth Prog Biomed 58: 51–64

    Article  CAS  Google Scholar 

  15. Lie KI, Wellens HJ, van Capelle FJ, Durrer D (1974) Lidocaine in the prevention of primary ventricular fibrillation. A double-blind randomized study of 212 consecutive patients. N Engl J Med 291: 1324–1326

    Article  PubMed  CAS  Google Scholar 

  16. Orlando R, Piccoli P, De Martin S, Padrini R, Floreani M, Palatini P (2004) Cytochrome P450 1A2 is a major determinant of lidocaine metabolism in vivo: effects of liver function. Clin Pharmacol Ther 75: 80–88

    Article  PubMed  CAS  Google Scholar 

  17. Radvanyi-Bouvet MF, Torricelli A, Rey E, Bavoux F, Walti H (1990) Effects of lidocaine on seizures in the neonatal period: some electro-clinical aspects. In: Wasterlain CG, Vert P (eds) Neonatal seizures. Lippincott, Williams and Wilkins, Philadelphia, pp 277–285

    Google Scholar 

  18. Resar LM, Helfaer MA (1998) Recurrent seizures in a neonate after lidocaine administration. J Perinatol 18:193–195

    PubMed  CAS  Google Scholar 

  19. Rey E, Radvanyi-Bouvet MF, Bodiou C, Richard MO, Torricelli A, Walti H, Olive G (1990) Intravenous lidocaine in the treatment of convulsions in the neonatal period: monitoring plasma levels. Ther Drug Monit 12:316–320

    Article  PubMed  CAS  Google Scholar 

  20. Rothstein P, Dornbusch J, Shaywitz BA (1982) Prolonged seizures associated with the use of viscous lidocaine. J Pediatr 101: 461–463

    Article  PubMed  CAS  Google Scholar 

  21. Van Rooij LG, Toet MC, Rademaker KM, Groenendaal F, de Vries LS (2004) Cardiac arrhythmias in neonates receiving lidocaine as anticonvulsive treatment. Eur J Pediatr 163: 637–641

    PubMed  CAS  Google Scholar 

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Acknowledgements

The authors thank the Department of Clinical Pharmacy and Toxicology of the Leiden University Medical Centre, Leiden, The Netherlands for the analysis of plasma levels of lidocaine, MEGX and GX.

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Authors and Affiliations

  1. Department of Pharmacy, University Medical Centre Utrecht/Wilhelmina Children’s Hospital, Utrecht, The Netherlands

    Mirte M. Malingré, Carin M. A. Rademaker, Tessa F. F. T. Ververs & Charlotte van Kesteren

  2. Department of Neonatology, University Medical Centre Utrecht/Wilhelmina Children’s Hospital, KE 04.123.1, P.O. Box 85090, AB 3508, Utrecht, The Netherlands

    Linda G. M. Van Rooij, Mona C. Toet & Linda S. de Vries

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  1. Mirte M. Malingré
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  2. Linda G. M. Van Rooij
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  3. Carin M. A. Rademaker
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  4. Mona C. Toet
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  5. Tessa F. F. T. Ververs
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  6. Charlotte van Kesteren
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  7. Linda S. de Vries
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Corresponding author

Correspondence to Linda S. de Vries.

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Malingré, M.M., Van Rooij, L.G.M., Rademaker, C.M.A. et al. Development of an optimal lidocaine infusion strategy for neonatal seizures. Eur J Pediatr 165, 598–604 (2006). https://doi.org/10.1007/s00431-006-0136-x

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  • DOI: https://doi.org/10.1007/s00431-006-0136-x

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