Nothing Special   »   [go: up one dir, main page]
Skip to main content

Advertisement

Springer Nature Link
Log in

Pharmacotherapy for Neonatal Seizures: Current Knowledge and Future Perspectives

  • Review Article
  • Published:
Drugs Aims and scope Submit manuscript

Abstract

Seizures are the most common neurological emergencies in the neonatal period and are associated with poor neurodevelopmental outcomes. Seizures affect up to five per 1000 term births and population-based studies suggest that they occur even more frequently in premature infants. Seizures are a sign of an underlying cerebral pathology, the most common of which is hypoxic-ischaemic encephalopathy in term infants. Due to a growing body of evidence that seizures exacerbate cerebral injury, effective diagnosis and treatment of neonatal seizures is of paramount importance to reduce long-term adverse outcomes. Electroencephalography is essential for the diagnosis of seizures in neonates due to their subtle clinical expression, non-specific neurological presentation and a high frequency of electro-clinical uncoupling in the neonatal period. Hypoxic-ischaemic encephalopathy may require neuroprotective therapeutic hypothermia, accompanying sedation with opioids, anticonvulsant drugs or a combination of all of these. The efficacy, safety, tolerability and pharmacokinetics of seven anticonvulsant drugs (phenobarbital, phenytoin, levetiracetam, lidocaine, midazolam, topiramate and bumetanide) are reviewed. This review is focused only on studies reporting electrographically confirmed seizures and highlights the knowledge gaps that exist in optimal treatment regimens for neonatal seizures. Randomised controlled trials are needed to establish a safe and effective treatment protocol for neonatal seizures.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Glass HC. Neonatal seizures: advances in mechanisms and management. Clin Perinatol. 2014;41(1):177–90.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Lanska MJ, Lanska DJ. Neonatal seizures in the United States: results of the National Hospital Discharge Survey, 1980–1991. Neuroepidemiology. 1996;15(3):117–25.

    Article  CAS  PubMed  Google Scholar 

  3. World Health Organisation. Guideline on Neonatal Seizures. 2011. http://apps.who.int/mental_health/publications/guidelines_neonatal_seizures/en/. Accessed 17 Apr 2015.

  4. Volpe J. Neonatal Seizures. In: Volpe J, editor. Neurology of the Newborn. 5th ed. Philadelphia: WB Saunders; 2008. p. 203–44.

    Google Scholar 

  5. Lee AC, Kozuki N, Blencowe H, Vos T, Bahalim A, Darmstadt GL, Niermeyer S, Ellis M, Robertson NJ, Cousens S, Lawn JE. Intrapartum-related neonatal encephalopathy incidence and impairment at regional and global levels for 2010 with trends from 1990. Pediatr Res. 2013;74(Suppl 1):50–72.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Lawn JE, Cousens S, Zupan J. 4 million neonatal deaths: when? Where? Why? Lancet. 2005;365(9462):891–900.

    Article  PubMed  Google Scholar 

  7. Mwaniki MK, Atieno M, Lawn JE, Newton CR. Long-term neurodevelopmental outcomes after intrauterine and neonatal insults: a systematic review. Lancet. 2012;379(9814):445–52.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Miller SP, Weiss J, Barnwell A, Ferriero DM, Latal-Hajnal B, Ferrer-Rogers A, Newton N, Partridge JC, Glidden DV, Vigneron DB, Barkovich AJ. Seizure-associated brain injury in term newborns with perinatal asphyxia. Neurology. 2002;58(4):542–8.

    Article  CAS  PubMed  Google Scholar 

  9. Glass HC, Glidden D, Jeremy RJ, Barkovich AJ, Ferriero DM, Miller SP. Clinical neonatal seizures are independently associated with outcome in infants at risk for hypoxic-ischemic brain injury. J Pediatr. 2009;155(3):318–23.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Shah DK, Wusthoff CJ, Clarke P, Wyatt JS, Ramaiah SM, Dias RJ, Becher JC, Kapellou O, Boardman JP. Electrographic seizures are associated with brain injury in newborns undergoing therapeutic hypothermia. Arch Dis Child Fetal Neonatal Ed. 2014;99(3):F219–24.

    Article  PubMed  Google Scholar 

  11. McBride MC, Laroia N, Guillet R. Electrographic seizures in neonates correlate with poor neurodevelopmental outcome. Neurology. 2000;55(4):506–13.

    Article  CAS  PubMed  Google Scholar 

  12. Wu YW, Lynch JK, Nelson KB. Perinatal arterial stroke: understanding mechanisms and outcomes. Semin Neurol. 2005;25(4):424–34.

    Article  PubMed  Google Scholar 

  13. Kirton A, Armstrong-Wells J, Chang T, Deveber G, Rivkin MJ, Hernandez M, Carpenter J, Yager JY, Lynch JK, Ferriero DM. Symptomatic neonatal arterial ischemic stroke: the International Pediatric Stroke Study. Pediatrics. 2011;128(6):e1402–10.

    Article  PubMed  Google Scholar 

  14. Vasudevan C, Levene M. Epidemiology and aetiology of neonatal seizures. Semin Fetal Neonatal Med. 2013;18(4):185–91.

    Article  PubMed  Google Scholar 

  15. Levene MI, Trounce JQ. Cause of neonatal convulsions. Towards more precise diagnosis. Arch Dis Child. 1986;61(1):78–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Beaulieu MJ. Levetiracetam. Neonatal Netw. 2013;32(4):285–8.

    Article  PubMed  Google Scholar 

  17. Dzhala VI, Talos DM, Sdrulla DA, Brumback AC, Mathews GC, Benke TA, Delpire E, Jensen FE, Staley KJ. NKCC1 transporter facilitates seizures in the developing brain. Nat Med. 2005;11(11):1205–13.

    Article  CAS  PubMed  Google Scholar 

  18. D’Souza SW, Slater P. Excitatory amino acids in neonatal brain: contributions to pathology and therapeutic strategies. Arch Dis Child Fetal Neonatal Ed. 1995;72(3):F147–50.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Nardou R, Ferrari DC, Ben-Ari Y. Mechanisms and effects of seizures in the immature brain. Semin Fetal Neonatal Med. 2013;18(4):175–84.

    Article  PubMed  Google Scholar 

  20. Kang S, Kadam S. Pre-clinical models of acquired neonatal seizures: differential effects of injury on function of chloride co-transporters. Austin J Cerebrovasc Dis Stroke. 2014;1(6):1026.

    PubMed  PubMed Central  Google Scholar 

  21. Silverstein FS, Jensen FE, Inder T, Hellstrom-Westas L, Hirtz D, Ferriero DM. Improving the treatment of neonatal seizures: National Institute of Neurological Disorders and Stroke workshop report. J Pediatr. 2008;153(1):12–5.

    Article  PubMed  Google Scholar 

  22. McGoldrick MK, Galanopoulou AS. Developmental pharmacology of benzodiazepines under normal and pathological conditions. Epileptic Disord. 2014;16(Suppl 1):59–68.

    Google Scholar 

  23. Fatemi A, Wilson MA, Johnston MV. Hypoxic ischemic encephalopathy in the term infant. Clin Perinatol. 2009;36(4):835–58.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Murray DM, Boylan GB, Ali I, Ryan CA, Murphy BP, Connolly S. Defining the gap between electrographic seizure burden, clinical expression and staff recognition of neonatal seizures. Arch Dis Child Fetal Neonatal Ed. 2008;93(3):F187–91.

    Article  CAS  PubMed  Google Scholar 

  25. Hallberg B, Blennow M. Investigations for neonatal seizures. Semin Fetal Neonatal Med. 2013;18(4):196–201.

    Article  CAS  PubMed  Google Scholar 

  26. Abend NS, Wusthoff CJ, Goldberg EM, Dlugos DJ. Electrographic seizures and status epilepticus in critically ill children and neonates with encephalopathy. Lancet Neurol. 2013;12(12):1170–9.

    Article  PubMed  Google Scholar 

  27. Bye AM, Flanagan D. Spatial and temporal characteristics of neonatal seizures. Epilepsia. 1995;36(10):1009–16.

    Article  CAS  PubMed  Google Scholar 

  28. Srinivasakumar P, Zempel J, Trivedi S, Wallendorf M, Rao R, Smith B, Inder T, Mathur AM. Treating EEG seizures in hypoxic ischemic encephalopathy: a randomized controlled trial. Pediatrics. 2015;136(5):e1302–9.

    Article  PubMed  Google Scholar 

  29. Glykys J, Dzhala VI, Kuchibhotla KV, Feng G, Kuner T, Augustine G, Bacskai BJ, Staley KJ. Differences in cortical versus subcortical GABAergic signaling: a candidate mechanism of electroclinical uncoupling of neonatal seizures. Neuron. 2009;63(5):657–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Scher MS, Alvin J, Gaus L, Minnigh B, Painter MJ. Uncoupling of EEG-clinical neonatal seizures after antiepileptic drug use. Pediatr Neurol. 2003;28(4):277–80.

    Article  PubMed  Google Scholar 

  31. Haynes RL, Borenstein NS, Desilva TM, Folkerth RD, Liu LG, Volpe JJ, Kinney HC. Axonal development in the cerebral white matter of the human fetus and infant. J Comp Neurol. 2005;484(2):156–67.

    Article  PubMed  Google Scholar 

  32. van den Heuvel MP, Kersbergen KJ, de Reus MA, Keunen K, Kahn RS, Groenendaal F, de Vries LS, Benders MJNL. The neonatal connectome during preterm brain development. Cereb Cortex (New York, NY). 2015;25(9):3000–13.

  33. Abend NS, Gutierrez-Colina AM, Monk HM, Dlugos DJ, Clancy RR. Levetiracetam for treatment of neonatal seizures. J Child Neurol. 2011;26(4):465–70.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Shah DK, Boylan GB, Rennie JM. Monitoring of seizures in the newborn. Arch Dis Child Fetal Neonatal Ed. 2012;97(1):F65–9.

    Article  PubMed  Google Scholar 

  35. Shellhaas RA, Soaita AI, Clancy RR. Sensitivity of amplitude-integrated electroencephalography for neonatal seizure detection. Pediatrics. 2007;120(4):770–7.

    Article  PubMed  Google Scholar 

  36. Shah DK, Mackay MT, Lavery S, Watson S, Harvey AS, Zempel J, Mathur A, Inder TE. Accuracy of bedside electroencephalographic monitoring in comparison with simultaneous continuous conventional electroencephalography for seizure detection in term infants. Pediatrics. 2008;121(6):1146–54.

    Article  PubMed  Google Scholar 

  37. Rennie JM, Chorley G, Boylan GB, Pressler R, Nguyen Y, Hooper R. Non-expert use of the cerebral function monitor for neonatal seizure detection. Arch Dis Child Fetal Neonatal Ed. 2004;89(1):F37–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. US National Institutes of Health. ClinicalTrials.gov. 2015. http://clinicaltrials.gov. Accessed 13 July 2015.

  39. Mathieson SR, Stevenson NJ, Low E, Marnane WP, Rennie JM, Temko A, Lightbody G, Boylan GB. Validation of an automated seizure detection algorithm for term neonates. Clin Neurophysiol. 2016;127(1):156–8.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Low E, Mathieson SR, Stevenson NJ, Livingstone V, Ryan CA, Bogue CO, Rennie JM, Boylan GB. Early postnatal EEG features of perinatal arterial ischaemic stroke with seizures. PLoS One. 2014;9(7):e100973.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Pressler R, Binnie CD, Cooper R, Robinson R, editors. Neonatal and paediatric clinical neurophysiology. London: Churchill Livingstone; 2007.

    Google Scholar 

  42. Boylan GB, Rennie JM, Chorley G, Pressler RM, Fox GF, Farrer K, Morton M, Binnie CD. Second-line anticonvulsant treatment of neonatal seizures: a video-EEG monitoring study. Neurology. 2004;62(3):486–8.

    Article  CAS  PubMed  Google Scholar 

  43. Weeke LC, Groenendaal F, Toet MC, Benders MJ, Nievelstein RA, van Rooij LG, de Vries LS. The aetiology of neonatal seizures and the diagnostic contribution of neonatal cerebral magnetic resonance imaging. Dev Med Child Neurol. 2015;57(3):248–56.

    Article  PubMed  Google Scholar 

  44. Glass HC, Sullivan JE. Neonatal seizures. Curr Treat Options Neurol. 2009;11(6):405–13.

    Article  PubMed  Google Scholar 

  45. Evans DJ, Levene MI, Tsakmakis M. Anticonvulsants for preventing mortality and morbidity in full term newborns with perinatal asphyxia. Cochrane Database Syst Rev. 2007;(3):CD001240.

  46. van Rooij LG, Toet MC, van Huffelen AC, Groenendaal F, Laan W, Zecic A, de Haan T, van Straaten IL, Vrancken S, van Wezel G, van der Sluijs J, Ter Horst H, Gavilanes D, Laroche S, Naulaers G, de Vries LS. Effect of treatment of subclinical neonatal seizures detected with aEEG: randomized, controlled trial. Pediatrics. 2010;125(2):e358–66.

    Article  PubMed  Google Scholar 

  47. Glass HC, Nash KB, Bonifacio SL, Barkovich AJ, Ferriero DM, Sullivan JE, Cilio MR. Seizures and magnetic resonance imaging-detected brain injury in newborns cooled for hypoxic-ischemic encephalopathy. J Pediatr. 2011;159(5):731–5.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Lynch NE, Stevenson NJ, Livingstone V, Murphy BP, Rennie JM, Boylan GB. The temporal evolution of electrographic seizure burden in neonatal hypoxic ischemic encephalopathy. Epilepsia. 2012;53(3):549–57.

    Article  PubMed  Google Scholar 

  49. Booth D, Evans DJ. Anticonvulsants for neonates with seizures. Cochrane Database Syst Rev. 2004;(4):CD004218.

  50. Borowicz KK, Banach M. Antiarrhythmic drugs and epilepsy. Pharmacol Rep. 2014;66(4):545–51.

    Article  CAS  PubMed  Google Scholar 

  51. Bialer M, White HS. Key factors in the discovery and development of new antiepileptic drugs. Nat Rev Drug Discov. 2010;9(1):68–82.

    Article  CAS  PubMed  Google Scholar 

  52. Irish Medicines Board. Summaries of product characteristics-levetiracetam [Online]. 2013. http://www.medicines.ie. Accessed 5 January 2016.

  53. Nardou R, Yamamoto S, Bhar A, Burnashev N, Ben-Ari Y, Khalilov I. Phenobarbital but not diazepam reduces AMPA/kainate receptor mediated currents and exerts opposite actions on initial seizures in the neonatal rat hippocampus. Front Cell Neurosci. 2011;5:16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. van Rooij LG, Hellstrom-Westas L, de Vries LS. Treatment of neonatal seizures. Semin Fetal Neonatal Med. 2013;18(4):209–15.

    Article  PubMed  Google Scholar 

  55. Slaughter LA, Patel AD, Slaughter JL. Pharmacological treatment of neonatal seizures: a systematic review. J Child Neurol. 2013;28(3):351–64.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Khan O, Chang E, Cipriani C, Wright C, Crisp E, Kirmani B. Use of intravenous levetiracetam for management of acute seizures in neonates. Pediatr Neurol. 2011;44(4):265–9.

    Article  PubMed  Google Scholar 

  57. Glass HC, Poulin C, Shevell MI. Topiramate for the treatment of neonatal seizures. Pediatr Neurol. 2011;44(6):439–42.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Silverstein FS, Ferriero DM. Off-label use of antiepileptic drugs for the treatment of neonatal seizures. Pediatr Neurol. 2008;39(2):77–9.

    Article  PubMed  Google Scholar 

  59. Kim J, Kondratyev A, Gale K. Antiepileptic drug-induced neuronal cell death in the immature brain: effects of carbamazepine, topiramate, and levetiracetam as monotherapy versus polytherapy. J Pharmacol Exp Ther. 2007;323(1):165–73.

    Article  CAS  PubMed  Google Scholar 

  60. Tulloch JK, Carr RR, Ensom MH. A systematic review of the pharmacokinetics of antiepileptic drugs in neonates with refractory seizures. J Pediatr Pharmacol Ther. 2012;17(1):31–44.

    PubMed  PubMed Central  Google Scholar 

  61. Mikati MA, Fayad M, Koleilat M, Mounla N, Hussein R, Kazma A, Yunis K. Efficacy, tolerability, and kinetics of lamotrigine in infants. J Pediatr. 2002;141(1):31–5.

    Article  CAS  PubMed  Google Scholar 

  62. Sampath D, Shmueli D, White AM, Raol YH. Flupirtine effectively prevents development of acute neonatal seizures in an animal model of global hypoxia. Neurosci Lett. 2015;607:46–51.

    Article  CAS  PubMed  Google Scholar 

  63. Lynch NE, Stevenson NJ, Livingstone V, Mathieson S, Murphy BP, Rennie JM, Boylan GB. The temporal characteristics of seizures in neonatal hypoxic ischemic encephalopathy treated with hypothermia. Seizure. 2015;33:60–5.

    Article  PubMed  Google Scholar 

  64. Pressler RM, Boylan GB, Marlow N, Blennow M, Chiron C, Cross JH, de Vries LS, Hallberg B, Hellstrom-Westas L, Jullien V, Livingstone V, Mangum B, Murphy B, Murray D, Pons G, Rennie J, Swarte R, Toet MC, Vanhatalo S, Zohar S. Bumetanide for the treatment of seizures in newborn babies with hypoxic ischaemic encephalopathy (NEMO): an open-label, dose finding, and feasibility phase 1/2 trial. Lancet Neurol. 2015;14(5):469–77.

    Article  CAS  PubMed  Google Scholar 

  65. Maartens IA, Wassenberg T, Buijs J, Bok L, de Kleine MJ, Katgert T, Andriessen P. Neurodevelopmental outcome in full-term newborns with refractory neonatal seizures. Acta Paediatr. 2012;101(4):e173–8.

    Article  PubMed  Google Scholar 

  66. Painter MJ, Scher MS, Stein AD, Armatti S, Wang Z, Gardiner JC, Paneth N, Minnigh B, Alvin J. Phenobarbital compared with phenytoin for the treatment of neonatal seizures. N Engl J Med. 1999;341(7):485–9.

    Article  CAS  PubMed  Google Scholar 

  67. Castro Conde JR, Hernandez Borges AA, Domenech Martinez E, Gonzalez Campo C, Perera Soler R. Midazolam in neonatal seizures with no response to phenobarbital. Neurology. 2005;64(5):876–9.

    Article  CAS  PubMed  Google Scholar 

  68. Malingre MM, Van Rooij LG, Rademaker CM, Toet MC, Ververs TF, van Kesteren C, de Vries LS. Development of an optimal lidocaine infusion strategy for neonatal seizures. Eur J Pediatr. 2006;165(9):598–604.

    Article  CAS  PubMed  Google Scholar 

  69. Shany E, Benzaqen O, Watemberg N. Comparison of continuous drip of midazolam or lidocaine in the treatment of intractable neonatal seizures. J Child Neurol. 2007;22(3):255–9.

    Article  PubMed  Google Scholar 

  70. Weeke LC, Toet MC, van Rooij LG, Groenendaal F, Boylan GB, Pressler RM, Hellstrom-Westas L, van den Broek MP, de Vries LS. Lidocaine response rate in aEEG-confirmed neonatal seizures: retrospective study of 413 full-term and preterm infants. Epilepsia. 2015 [Epub ahead of print].

  71. van Rooij LG, Toet MC, Rademaker KM, Groenendaal F, de Vries LS. Cardiac arrhythmias in neonates receiving lidocaine as anticonvulsive treatment. Eur J Pediatr. 2004;163(11):637–41.

    Article  CAS  PubMed  Google Scholar 

  72. van den Broek MP, Huitema AD, van Hasselt JG, Groenendaal F, Toet MC, Egberts TC, de Vries LS, Rademaker CM. Lidocaine (lignocaine) dosing regimen based upon a population pharmacokinetic model for preterm and term neonates with seizures. Clin Pharmacokinet. 2011;50(7):461–9.

    Article  PubMed  Google Scholar 

  73. Lundqvist M, Agren J, Hellstrom-Westas L, Flink R, Wickstrom R. Efficacy and safety of lidocaine for treatment of neonatal seizures. Acta Paediatr. 2013;102(9):863–7.

    Article  CAS  PubMed  Google Scholar 

  74. van Leuven K, Groenendaal F, Toet MC, Schobben AF, Bos SA, de Vries LS, Rademaker CM. Midazolam and amplitude-integrated EEG in asphyxiated full-term neonates. Acta Paediatr. 2004;93(9):1221–7.

    Article  PubMed  Google Scholar 

  75. van den Broek MP, van Straaten HL, Huitema AD, Egberts T, Toet MC, de Vries LS, Rademaker K, Groenendaal F. Anticonvulsant effectiveness and hemodynamic safety of midazolam in full-term infants treated with hypothermia. Neonatology. 2015;107(2):150–6.

    Article  PubMed  CAS  Google Scholar 

  76. Deshmukh A, Wittert W, Schnitzler E, Mangurten HH. Lorazepam in the treatment of refractory neonatal seizures. A pilot study. Am J Dis Child. 1986;140(10):1042–4.

    Article  CAS  PubMed  Google Scholar 

  77. Maytal J, Novak GP, King KC. Lorazepam in the treatment of refractory neonatal seizures. J Child Neurol. 1991;6(4):319–23.

    Article  CAS  PubMed  Google Scholar 

  78. Talos DM, Chang M, Kosaras B, Fitzgerald E, Murphy A, Folkerth RD, Jensen FE. Antiepileptic effects of levetiracetam in a rodent neonatal seizure model. Pediatr Res. 2013;73(1):24–30.

    Article  CAS  PubMed  Google Scholar 

  79. Merhar SL, Schibler KR, Sherwin CM, Meinzen-Derr J, Shi J, Balmakund T, Vinks AA. Pharmacokinetics of levetiracetam in neonates with seizures. J Pediatr. 2011;159(1):152–4.e3.

  80. Briggs DE, French JA. Levetiracetam safety profiles and tolerability in epilepsy patients. Expert Opin Drug Saf. 2004;3(5):415–24.

    Article  CAS  PubMed  Google Scholar 

  81. Filippi L, Fiorini P, Daniotti M, Catarzi S, Savelli S, Fonda C, Bartalena L, Boldrini A, Giampietri M, Scaramuzzo R, Papoff P, Del Balzo F, Spalice A, la Marca G, Malvagia S, Della Bona ML, Donzelli G, Tinelli F, Cioni G, Pisano T, Falchi M, Guerrini R. Safety and efficacy of topiramate in neonates with hypoxic ischemic encephalopathy treated with hypothermia (NeoNATI). BMC Pediatr. 2012;12:144.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Dzhala VI, Brumback AC, Staley KJ. Bumetanide enhances phenobarbital efficacy in a neonatal seizure model. Ann Neurol. 2008;63(2):222–35.

    Article  CAS  PubMed  Google Scholar 

  83. Schwartzkroin PA, Baraban SC, Hochman DW. Osmolarity, ionic flux, and changes in brain excitability. Epilepsy Res. 1998;32(1–2):275–85.

    Article  CAS  PubMed  Google Scholar 

  84. Haas M, Forbush B 3rd. The Na–K–Cl cotransporters. J Bioenerg Biomembr. 1998;30(2):161–72.

    Article  CAS  PubMed  Google Scholar 

  85. Ben-Ari Y. Excitatory actions of gaba during development: the nature of the nurture. Nat Rev Neurosci. 2002;3(9):728–39.

    Article  CAS  PubMed  Google Scholar 

  86. Pressler RM, Boylan GB, Marlow N, de Vries LS, Blennow M, Chiron C, Cross JH, Hallberg B, Hellstrom-Westas L, Jullien V, Mangum B, Murphy B, Murray D, Pons G, Rennie J, Toet MC, Zohar S. Bumetanide for neonatal seizures-back from the cotside. Nat Rev Neurol. 2015;11(24):724.

    Article  PubMed  Google Scholar 

  87. Donovan MD, O’Brien FE, Boylan GB, Cryan JF, Griffin BT. The effect of organic anion transporter 3 inhibitor probenecid on bumetanide levels in the brain: an integrated in vivo microdialysis study in the rat. J Pharm Pharmacol. 2015;67(4):501–10.

    Article  CAS  PubMed  Google Scholar 

  88. Topfer M, Tollner K, Brandt C, Twele F, Broer S, Loscher W. Consequences of inhibition of bumetanide metabolism in rodents on brain penetration and effects of bumetanide in chronic models of epilepsy. Eur J Neurosci. 2014;39(4):673–87.

    Article  PubMed  Google Scholar 

  89. Tollner K, Brandt C, Topfer M, Brunhofer G, Erker T, Gabriel M, Feit PW, Lindfors J, Kaila K, Loscher W. A novel prodrug-based strategy to increase effects of bumetanide in epilepsy. Ann Neurol. 2014;75(4):550–62.

    Article  PubMed  CAS  Google Scholar 

  90. Tollner K, Brandt C, Romermann K, Loscher W. The organic anion transport inhibitor probenecid increases brain concentrations of the NKCC1 inhibitor bumetanide. Eur J Pharmacol. 2014;746c:167–73.

  91. Brodie MJ, Kwan P. Current position of phenobarbital in epilepsy and its future. Epilepsia. 2012;53(Suppl 8):40–6.

    Article  CAS  PubMed  Google Scholar 

  92. Bittigau P, Sifringer M, Ikonomidou C. Antiepileptic drugs and apoptosis in the developing brain. Ann N Y Acad Sci. 2003;993:103–14.

    Article  CAS  PubMed  Google Scholar 

  93. Loiacono G, Masci M, Zaccara G, Verrotti A. The treatment of neonatal seizures: focus on Levetiracetam. J Matern Fetal Neonatal Med. 2016;29(1):69–74.

    Article  CAS  PubMed  Google Scholar 

  94. Khan O, Cipriani C, Wright C, Crisp E, Kirmani B. Role of intravenous levetiracetam for acute seizure management in preterm neonates. Pediatr Neurol. 2013;49(5):340–3.

    Article  PubMed  Google Scholar 

  95. Sharpe CM, Capparelli EV, Mower A, Farrell MJ, Soldin SJ, Haas RH. A seven-day study of the pharmacokinetics of intravenous levetiracetam in neonates: marked changes in pharmacokinetics occur during the first week of life. Pediatr Res. 2012;72(1):43–9.

    Article  CAS  PubMed  Google Scholar 

  96. Filippi L, la Marca G, Fiorini P, Poggi C, Cavallaro G, Malvagia S, Pellegrini-Giampietro DE, Guerrini R. Topiramate concentrations in neonates treated with prolonged whole body hypothermia for hypoxic ischemic encephalopathy. Epilepsia. 2009;50(11):2355–61.

    Article  CAS  PubMed  Google Scholar 

  97. Filippi L, Poggi C, la Marca G, Furlanetto S, Fiorini P, Cavallaro G, Plantulli A, Donzelli G, Guerrini R. Oral topiramate in neonates with hypoxic ischemic encephalopathy treated with hypothermia: a safety study. J Pediatr. 2010;157(3):361–6.

    Article  CAS  PubMed  Google Scholar 

  98. Alcorn J, McNamara PJ. Pharmacokinetics in the newborn. Adv Drug Deliv Rev. 2003;55(5):667–86.

    Article  CAS  PubMed  Google Scholar 

  99. Marsot A, Brevaut-Malaty V, Vialet R, Boulamery A, Bruguerolle B, Simon N. Pharmacokinetics and absolute bioavailability of phenobarbital in neonates and young infants, a population pharmacokinetic modelling approach. Fundam Clin Pharmacol. 2014;28(4):465–71.

    Article  CAS  PubMed  Google Scholar 

  100. Filippi L, la Marca G, Cavallaro G, Fiorini P, Favelli F, Malvagia S, Donzelli G, Guerrini R. Phenobarbital for neonatal seizures in hypoxic ischemic encephalopathy: a pharmacokinetic study during whole body hypothermia. Epilepsia. 2011;52(4):794–801.

    Article  CAS  PubMed  Google Scholar 

  101. Shellhaas RA, Ng CM, Dillon CH, Barks JD, Bhatt-Mehta V. Population pharmacokinetics of phenobarbital in infants with neonatal encephalopathy treated with therapeutic hypothermia. Pediatr Crit Care Med. 2013;14(2):194–202.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Patsalos PN, Berry DJ, Bourgeois BF, Cloyd JC, Glauser TA, Johannessen SI, Leppik IE, Tomson T, Perucca E. Antiepileptic drugs—best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia. 2008;49(7):1239–76.

    Article  CAS  PubMed  Google Scholar 

  103. Loughnan PM, Greenwald A, Purton WW, Aranda JV, Watters G, Neims AH. Pharmacokinetic observations of phenytoin disposition in the newborn and young infant. Arch Dis Child. 1977;52(4):302–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Al Za’abi M, Lanner A, Xiaonian X, Donovan T, Charles B. Application of routine monitoring data for determination of the population pharmacokinetics and enteral bioavailability of phenytoin in neonates and infants with seizures. Ther Drug Monit. 2006;28(6):793–9.

  105. Bjorkman S. Prediction of drug disposition in infants and children by means of physiologically based pharmacokinetic (PBPK) modelling: theophylline and midazolam as model drugs. Br J Clin Pharmacol. 2005;59(6):691–704.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Jullien V, Pressler RM, Boylan G, Blennow M, Marlow N, Chiron C, Pons G. Pilot evaluation of the population pharmacokinetics of bumetanide in term newborn infants with seizures. J Clin Pharmacol. 2015 [Epub ahead of print].

  107. Azzopardi DV, Strohm B, Edwards AD, Dyet L, Halliday HL, Juszczak E, Kapellou O, Levene M, Marlow N, Porter E, Thoresen M, Whitelaw A, Brocklehurst P. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med. 2009;361(14):1349–58.

    Article  CAS  PubMed  Google Scholar 

  108. Tagin MA, Woolcott CG, Vincer MJ, Whyte RK, Stinson DA. Hypothermia for neonatal hypoxic ischemic encephalopathy: an updated systematic review and meta-analysis. Arch Pediatr Adolesc Med. 2012;166(6):558–66.

    PubMed  Google Scholar 

  109. Azzopardi D, Strohm B, Marlow N, Brocklehurst P, Deierl A, Eddama O, Goodwin J, Halliday HL, Juszczak E, Kapellou O, Levene M, Linsell L, Omar O, Thoresen M, Tusor N, Whitelaw A, Edwards AD. Effects of hypothermia for perinatal asphyxia on childhood outcomes. N Engl J Med. 2014;371(2):140–9.

    Article  CAS  PubMed  Google Scholar 

  110. Srinivasakumar P, Zempel J, Wallendorf M, Lawrence R, Inder T, Mathur A. Therapeutic hypothermia in neonatal hypoxic ischemic encephalopathy: electrographic seizures and magnetic resonance imaging evidence of injury. J Pediatr. 2013;163(2):465–70.

    Article  PubMed  Google Scholar 

  111. Low E, Boylan GB, Mathieson SR, Murray DM, Korotchikova I, Stevenson NJ, Livingstone V, Rennie JM. Cooling and seizure burden in term neonates: an observational study. Arch Dis Child Fetal Neonatal Ed. 2012;97(4):F267–72.

    Article  PubMed  Google Scholar 

  112. Gancia P, Pomero G. Therapeutic hypothermia in the prevention of hypoxic-ischaemic encephalopathy: new categories to be enrolled. J Matern Fetal Neonatal Med. 2012;25(Suppl 4):94–6.

    PubMed  Google Scholar 

  113. Yang T, Zhuang L, Rei Fidalgo AM, Petrides E, Terrando N, Wu X, Sanders RD, Robertson NJ, Johnson MR, Maze M, Ma D. Xenon and sevoflurane provide analgesia during labor and fetal brain protection in a perinatal rat model of hypoxia-ischemia. PLoS One. 2012;7(5):e37020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Thoresen M, Hobbs CE, Wood T, Chakkarapani E, Dingley J. Cooling combined with immediate or delayed xenon inhalation provides equivalent long-term neuroprotection after neonatal hypoxia-ischemia. J Cereb Blood Flow Metab. 2009;29(4):707–14.

    Article  CAS  PubMed  Google Scholar 

  115. Palmer C, Towfighi J, Roberts RL, Heitjan DF. Allopurinol administered after inducing hypoxia-ischemia reduces brain injury in 7-day-old rats. Pediatr Res. 1993;33(4 Pt 1):405–11.

    CAS  PubMed  Google Scholar 

  116. Kaandorp JJ, Benders MJ, Rademaker CM, Torrance HL, Oudijk MA, de Haan TR, Bloemenkamp KW, Rijken M, van Pampus MG, Bos AF, Porath MM, Oetomo SB, Willekes C, Gavilanes AW, Wouters MG, van Elburg RM, Huisjes AJ, Bakker SC, van Meir CA, von Lindern J, Boon J, de Boer IP, Rijnders RJ, Jacobs CJ, Uiterwaal CS, Mol BW, Visser GH, van Bel F, Derks JB. Antenatal allopurinol for reduction of birth asphyxia induced brain damage (ALLO-Trial); a randomized double blind placebo controlled multicenter study. BMC Pregnancy Childbirth. 2010;10:8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Robertson NJ, Faulkner S, Fleiss B, Bainbridge A, Andorka C, Price D, Powell E, Lecky-Thompson L, Thei L, Chandrasekaran M, Hristova M, Cady EB, Gressens P, Golay X, Raivich G. Melatonin augments hypothermic neuroprotection in a perinatal asphyxia model. Brain. 2013;136(Pt 1):90–105.

    Article  PubMed  Google Scholar 

  118. Mazur M, Miller RH, Robinson S. Postnatal erythropoietin treatment mitigates neural cell loss after systemic prenatal hypoxic-ischemic injury. J Neurosurg Pediatr. 2010;6(3):206–21.

    Article  PubMed  PubMed Central  Google Scholar 

  119. Rangarajan V, Juul SE. Erythropoietin: emerging role of erythropoietin in neonatal neuroprotection. Pediatr Neurol. 2014;51(4):481–8.

    Article  PubMed  PubMed Central  Google Scholar 

  120. Dingley J, Tooley J, Liu X, Scull-Brown E, Elstad M, Chakkarapani E, Sabir H, Thoresen M. Xenon ventilation during therapeutic hypothermia in neonatal encephalopathy: a feasibility study. Pediatrics. 2014;133(5):809–18.

    Article  PubMed  Google Scholar 

  121. Traudt CM, McPherson RJ, Bauer LA, Richards TL, Burbacher TM, McAdams RM, Juul SE. Concurrent erythropoietin and hypothermia treatment improve outcomes in a term nonhuman primate model of perinatal asphyxia. Dev Neurosci. 2013;35(6):491–503.

    CAS  PubMed  Google Scholar 

  122. Traudt CM, Juul SE. Erythropoietin as a neuroprotectant for neonatal brain injury: animal models. Methods Mol Biol. 2013;982:113–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Zhu C, Kang W, Xu F, Cheng X, Zhang Z, Jia L, Ji L, Guo X, Xiong H, Simbruner G, Blomgren K, Wang X. Erythropoietin improved neurologic outcomes in newborns with hypoxic-ischemic encephalopathy. Pediatrics. 2009;124(2):e218–26.

    Article  PubMed  Google Scholar 

  124. Gill H, Thoresen M, Smit E, Davis J, Liu X, Dingley J, Elstad M. Sedation management during therapeutic hypothermia for neonatal encephalopathy: atropine premedication for endotracheal intubation causes a prolonged increase in heart rate. Resuscitation. 2014;85(10):1394–8.

    Article  PubMed  Google Scholar 

  125. Thoresen M, Satas S, Loberg EM, Whitelaw A, Acolet D, Lindgren C, Penrice J, Robertson N, Haug E, Steen PA. Twenty-four hours of mild hypothermia in unsedated newborn pigs starting after a severe global hypoxic-ischemic insult is not neuroprotective. Pediatr Res. 2001;50(3):405–11.

    Article  CAS  PubMed  Google Scholar 

  126. Young GB, da Silva OP. Effects of morphine on the electroencephalograms of neonates: a prospective, observational study. Clin Neurophysiol. 2000;111(11):1955–60.

    Article  CAS  PubMed  Google Scholar 

  127. Bansinath M, Turndorf H, Puig MM. Influence of hypo and hyperthermia on disposition of morphine. J Clin Pharmacol. 1988;28(9):860–4.

    Article  CAS  PubMed  Google Scholar 

  128. Roka A, Melinda KT, Vasarhelyi B, Machay T, Azzopardi D, Szabo M. Elevated morphine concentrations in neonates treated with morphine and prolonged hypothermia for hypoxic ischemic encephalopathy. Pediatrics. 2008;121(4):e844–9.

    Article  PubMed  Google Scholar 

  129. Puig MM, Warner W, Tang CK, Laorden ML, Turndorf H. Effects of temperature on the interaction of morphine with opioid receptors. Br J Anaesth. 1987;59(11):1459–64.

    Article  CAS  PubMed  Google Scholar 

  130. Angeles DM, Ashwal S, Wycliffe ND, Ebner C, Fayard E, Sowers L, Holshouser BA. Relationship between opioid therapy, tissue-damaging procedures, and brain metabolites as measured by proton MRS in asphyxiated term neonates. Pediatr Res. 2007;61(5 Pt 1):614–21.

    Article  CAS  PubMed  Google Scholar 

  131. Stockley’s Drug Interactions. In: Medicines complete database. 2009. http://www.medicinescomplete.com. Accessed: 23 July 2015.

  132. Cilio MR, Ferriero DM. Synergistic neuroprotective therapies with hypothermia. Semin Fetal Neonatal Med. 2010;15(5):293–8.

    Article  PubMed  PubMed Central  Google Scholar 

  133. Tortorici MA, Kochanek PM, Poloyac SM. Effects of hypothermia on drug disposition, metabolism, and response: a focus of hypothermia-mediated alterations on the cytochrome P450 enzyme system. Crit Care Med. 2007;35(9):2196–204.

    Article  CAS  PubMed  Google Scholar 

  134. van den Broek MP, Rademaker CM, van Straaten HL, Huitema AD, Toet MC, de Vries LS, Egberts AC, Groenendaal F. Anticonvulsant treatment of asphyxiated newborns under hypothermia with lidocaine: efficacy, safety and dosing. Arch Dis Child Fetal Neonatal Ed. 2013;98(4):F341–5.

    Article  PubMed  Google Scholar 

  135. Zhou J, Poloyac SM. The effect of therapeutic hypothermia on drug metabolism and response: cellular mechanisms to organ function. Expert Opin Drug Metab Toxicol. 2011;7(7):803–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Shah P, Riphagen S, Beyene J, Perlman M. Multiorgan dysfunction in infants with post-asphyxial hypoxic-ischaemic encephalopathy. Arch Dis Child Fetal Neonatal Ed. 2004;89(2):F152–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Kendall GS, Mathieson S, Meek J, Rennie JM. Recooling for rebound seizures after rewarming in neonatal encephalopathy. Pediatrics. 2012;130(2):e451–5.

    Article  PubMed  Google Scholar 

  138. Barks JD, Liu YQ, Shangguan Y, Silverstein FS. Phenobarbital augments hypothermic neuroprotection. Pediatr Res. 2010;67(5):532–7.

    Article  PubMed  PubMed Central  Google Scholar 

  139. Meyn DF Jr, Ness J, Ambalavanan N, Carlo WA. Prophylactic phenobarbital and whole-body cooling for neonatal hypoxic-ischemic encephalopathy. J Pediatr. 2010;157(2):334–6.

    Article  PubMed  Google Scholar 

  140. van den Broek MP, Groenendaal F, Toet MC, van Straaten HL, van Hasselt JG, Huitema AD, de Vries LS, Egberts AC, Rademaker CM. Pharmacokinetics and clinical efficacy of phenobarbital in asphyxiated newborns treated with hypothermia: a thermopharmacological approach. Clin Pharmacokinet. 2012;51(10):671–9.

    Article  PubMed  CAS  Google Scholar 

  141. Kadar D, Tang BK, Conn AW. The fate of phenobarbitone in children in hypothermia and at normal body temperature. Can Anaesth Soc J. 1982;29(1):16–23.

    Article  CAS  PubMed  Google Scholar 

  142. Liu Y, Barks JD, Xu G, Silverstein FS. Topiramate extends the therapeutic window for hypothermia-mediated neuroprotection after stroke in neonatal rats. Stroke. 2004;35(6):1460–5.

    Article  CAS  PubMed  Google Scholar 

  143. Welzing L, Junghaenel S, Weiss V, Roth B, Mueller C, Wiesen MH. Disposition of midazolam in asphyxiated neonates receiving therapeutic hypothermia–a pilot study. Klin Padiatr. 2013;225(7):398–404.

    Article  CAS  PubMed  Google Scholar 

  144. Fukuoka N, Aibiki M, Tsukamoto T, Seki K, Morita S. Biphasic concentration change during continuous midazolam administration in brain-injured patients undergoing therapeutic moderate hypothermia. Resuscitation. 2004;60(2):225–30.

    Article  CAS  PubMed  Google Scholar 

  145. Lopez-Samblas AM, Adams JA, Goldberg RN, Modi MW. The pharmacokinetics of bumetanide in the newborn infant. Biol Neonate. 1997;72(5):265–72.

    Article  CAS  PubMed  Google Scholar 

  146. Pacifici GM. Clinical pharmacology of the loop diuretics furosemide and bumetanide in neonates and infants. Paediatr Drugs. 2012;14(4):233–46.

    Article  PubMed  Google Scholar 

  147. Empey PE, de Mendizabal NV, Bell MJ, Bies RR, Anderson KB, Kochanek PM, Adelson PD, Poloyac SM. Therapeutic hypothermia decreases phenytoin elimination in children with traumatic brain injury. Crit Care Med. 2013;41(10):2379–87.

    Article  PubMed  PubMed Central  Google Scholar 

  148. Iida Y, Nishi S, Asada A. Effect of mild therapeutic hypothermia on phenytoin pharmacokinetics. Ther Drug Monit. 2001;23(3):192–7.

    Article  CAS  PubMed  Google Scholar 

  149. Bhagat H, Bithal PK, Chouhan RS, Arora R. Is phenytoin administration safe in a hypothermic child? J Clin Neurosci. 2006;13(9):953–5.

    Article  CAS  PubMed  Google Scholar 

  150. Jensen FE. Neonatal seizures: an update on mechanisms and management. Clin Perinatol. 2009;36(4):881–900.

    Article  PubMed  PubMed Central  Google Scholar 

  151. Kanhere S. Recent advances in neonatal seizures. Indian J Pediatr. 2014;81(9):917–25.

    Article  PubMed  Google Scholar 

  152. Donnelly F. EU initiatives for research involving children. Eur J Pediatr. 2008;167(7):837–8.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to extend their gratitude to Dr. Roman Stilling for providing expert help with artwork.

Author information

Authors and Affiliations

  1. Pharmacodelivery group, School of Pharmacy, University College Cork, Cork, Ireland

    Maria D. Donovan & Brendan T. Griffin

  2. Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland

    Maria D. Donovan & John F. Cryan

  3. Irish Centre for Fetal and Neonatal Translational Research, University College Cork and Cork University Maternity Hospital, Cork, Ireland

    Liudmila Kharoshankaya & Geraldine B. Boylan

  4. Department of Paediatrics and Child Health, University College Cork, Cork, Ireland

    Liudmila Kharoshankaya & Geraldine B. Boylan

  5. Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland

    John F. Cryan

Authors
  1. Maria D. Donovan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Brendan T. Griffin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Liudmila Kharoshankaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. John F. Cryan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Geraldine B. Boylan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Geraldine B. Boylan.

Ethics declarations

Funding

MDD is in receipt of an Irish Research Council for Science Engineering and Technology scholarship. GBB was supported under European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no 241479 and by Science Foundation Ireland in the form of a centre grant (INFANT SFI/12/RC/2272). JFC is supported in part by Science Foundation Ireland in the form of a centre grant (Alimentary Pharmabiotic Centre Grant Number SFI/12/RC/2273), by the Health Research Board of Ireland (Grant Numbers HRA_POR/2011/23 and HRA_POR/2012/32) and by the European Community’s Seventh Framework Programme, Grant no. FP7/2007-2013, Grant Agreement number 278948 (TACTICS—Translational Adolescent and Childhood Therapeutic Interventions in Compulsive Syndrome). No funding was specifically received for the publication of this article.

Conflict of interest

Maria Donovan, Brendan Griffin, Liudmila Kharoshankaya, John Cryan and Geraldine Boylan declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Donovan, M.D., Griffin, B.T., Kharoshankaya, L. et al. Pharmacotherapy for Neonatal Seizures: Current Knowledge and Future Perspectives. Drugs 76, 647–661 (2016). https://doi.org/10.1007/s40265-016-0554-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40265-016-0554-7

Keywords

Search

Navigation