Midazolam in the Treatment of Refractory Neonatal Seizures

Sheth, Raj D.; Buckley, David; Gutierrez, Amparo; Gingold, Monique; Bodensteiner, John B.; Penney, Sharon

doi:10.1097/00002826-199619020-00005

Cited by 60 publications

(34 citation statements)

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“…Little information is available on the use of midazolam in neonatal seizures. However, rapid control of status epilepticus with midazolam has been demonstrated with complete clinical and electrographic response in neonates who did not respond to phenobarbital and phenytoin [23, 24, 96]. …”

Section: Resultsmentioning

confidence: 99%

Clinical Pharmacology of Midazolam in Neonates and Children: Effect of Disease—A Review

Pacifici

2014

International Journal of Pediatrics

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Midazolam is a benzodiazepine with rapid onset of action and short duration of effect. In healthy neonates the half-life (t 1/2) and the clearance (Cl) are 3.3-fold longer and 3.7-fold smaller, respectively, than in adults. The volume of distribution (Vd) is 1.1 L/kg both in neonates and adults. Midazolam is hydroxylated by CYP3A4 and CYP3A5; the activities of these enzymes surge in the liver in the first weeks of life and thus the metabolic rate of midazolam is lower in neonates than in adults. Midazolam acts as a sedative, as an antiepileptic, for those infants who are refractory to standard antiepileptic therapy, and as an anaesthetic. Information of midazolam as an anaesthetic in infants are very little. Midazolam is usually administered intravenously; when minimal sedation is required, intranasal administration of midazolam is employed. Disease affects the pharmacokinetics of midazolam in neonates; multiple organ failure reduces the Cl of midazolam and mechanical ventilation prolongs the t 1/2 of this drug. ECMO therapy increases t 1/2, Cl, and Vd of midazolam several times. The adverse effects of midazolam in neonates are scarce: pain, tenderness, and thrombophlebitis may occur. Respiratory depression and hypotension appear in a limited percentage of infants following intravenous infusion of midazolam. In conclusion, midazolam is a safe and effective drug which is employed as a sedative, as antiepileptic agent, for infants who are refractory to standard antiepileptic therapy, and as an anaesthetic.

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Section: Resultsmentioning

confidence: 99%

Clinical Pharmacology of Midazolam in Neonates and Children: Effect of Disease—A Review

Pacifici

2014

International Journal of Pediatrics

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“…Other studies have shown the effectiveness of midazolam and lidocaine as a second-line agent in the treatment of neonatal convulsions [3,8,13,16,18]. Since 1998, lidocaine has been used in our NICU as a second-line drug after phenobarbitone.…”

Section: Discussionmentioning

confidence: 99%

Cardiac arrhythmias in neonates receiving lidocaine as anticonvulsive treatment

et al. 2004

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The present study demonstrates that continuous cardiac monitoring of neonates who receive lidocaine for neonatal seizures is indicated, as there is a risk to develop cardiac arrhythmias. Lidocaine should be discontinued immediately when a cardiac arrhythmia occurs. Lidocaine should not be given to patients with a congenital heart disease and to infants who have already been treated with diphantoine.

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“…Preliminary studies of antiepileptic drugs other than phenobarbital and phenytoin have shown only modest efficacy in smaller cohorts of neonates, although sufficiently powered randomized trials are needed to conclusively demonstrate whether any of these drugs are truly effective. 7,10,32,46,64 The lack of evidence-based treatment recommendations, coupled with the paucity of data regarding the underlying pathophysiology of neonatal seizures, has made their current management far from optimal.…”

Section: Neonatal Seizures Are a Common Problem With Inadequate Treatmentioning

confidence: 99%

The bumetanide-sensitive Na-K-2Cl cotransporter NKCC1 as a potential target of a novel mechanism-based treatment strategy for neonatal seizures

Kahle¹,

Staley

2008

FOC

108

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Seizures that occur during the neonatal period do so with a greater frequency than at any other age, have profound consequences for cognitive and motor development, and are difficult to treat with the existing series of antiepileptic drugs. During development, γ-aminobutyric acid (GABA)ergic neurotransmission undergoes a switch from excitatory to inhibitory due to a reversal of neuronal chloride (Cl–) gradients. The intracellular level of chloride ([Cl–]i) in immature neonatal neurons, compared with mature adult neurons, is about 20–40 mM higher due to robust activity of the chloride-importing Na-K-2Cl cotransporter NKCC1, such that the binding of GABA to ligand-gated GABAA receptor-associated Cl– channels triggers Cl– efflux and depolarizing excitation. In adults, NKCC1 expression decreases and the expression of the genetically related chloride-extruding K-Cl cotransporter KCC2 increases, lowering [Cl–]i to a level such that activation of GABAA receptors triggers Cl– influx and inhibitory hyperpolarization. The excitatory action of GABA in neonates, while playing an important role in neuronal development and synaptogenesis, accounts for the decreased seizure threshold, increased seizure propensity, and poor efficacy of GABAergic anticonvulsants in this age group. Bumetanide, a furosemide-related diuretic already used to treat volume overload in neonates, is a specific inhibitor of NKCC1 at low doses, can switch the GABA equilibrium potential of immature neurons from depolarizing to hyperpolarizing, and has recently been shown to inhibit epileptic activity in vitro and in vivo in animal models of neonatal seizures. The fundamental role of NKCC1 in establishing excitatory GABAergic neurotransmission in the neonate makes it a tempting target of a novel mechanism-based anticonvulsant strategy that could utilize the well-known pharmacology of bumetanide to help treat neonatal seizures.

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Midazolam in the Treatment of Refractory Neonatal Seizures

Cited by 60 publications

References 0 publications

Clinical Pharmacology of Midazolam in Neonates and Children: Effect of Disease—A Review

Clinical Pharmacology of Midazolam in Neonates and Children: Effect of Disease—A Review

Cardiac arrhythmias in neonates receiving lidocaine as anticonvulsive treatment

The bumetanide-sensitive Na-K-2Cl cotransporter NKCC1 as a potential target of a novel mechanism-based treatment strategy for neonatal seizures

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