Myoclonus Associated with Lorazepam Therapy in Very-Low-Birth-Weight Infants

Lee, D. S. C.; Wong, HC; Knoppert, David

doi:10.1159/000244123

Cited by 36 publications

(10 citation statements)

References 18 publications

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“…In fact, in 50% of the neocortical organotypic slices the epileptiform activity increased with diazepam. This observation could explain the paradoxical effect of inducing seizures, myoclonus and/or abnormal movements in some human neonates when benzodiazepines are given . As [Cl − ] i decreases during development, diazepam becomes more effective (100% of slices had a decrease in epileptiform activity at DIV15).…”

Section: Discussionmentioning

confidence: 99%

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Diazepam effect during early neonatal development correlates with neuronal Cl⁻

Glykys

Staley

2015

Ann Clin Transl Neurol

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ObjectiveAlthough benzodiazepines and other GABAA receptors allosteric modulators are used to treat neonatal seizures, their efficacy may derive from actions on subcortical structures. Side effects of benzodiazepines in nonseizing human neonates include myoclonus, seizures, and abnormal movements. Excitatory actions of GABA may underlie both side effects and reduced anticonvulsant activity of benzodiazepines. Neocortical organotypic slice cultures were used to study: (1) spontaneous cortical epileptiform activity during early development; (2) developmental changes in [Cl−]i and (3) whether diazepam's anticonvulsant effect correlated with neuronal [Cl−]i.MethodsEpileptiform activity in neocortical organotypic slice cultures was measured by field potential recordings. Cl− changes during development were assessed by multiphoton imaging of neurons transgenically expressing a Cl‐sensitive fluorophore. Clinically relevant concentrations of diazepam were used to test the anticonvulsant effectiveness at ages corresponding to premature neonates through early infancy.Results(1) Neocortical organotypic slices at days in vitro 5 (DIV5) exhibited spontaneous epileptiform activity. (2) Epileptiform event duration decreased with age. (3) There was a progressive decrease in [Cl−]i over the same age range. (4) Diazepam was ineffective in decreasing epileptiform activity at DIV5‐6, but progressively more effective at older ages through DIV15. (5) At DIV5‐6, diazepam worsened epileptiform activity in 50% of the slices.InterpretationThe neocortical organotypic slice is a useful model to study spontaneous epileptiform activity. Decreasing [Cl−]i during development correlates with decreasing duration of spontaneous epileptiform activity and increasing anticonvulsant efficacy of diazepam. We provide a potential explanation for the reports of seizures and myoclonus induction by benzodiazepines in newborn human neonates and the limited electrographic efficacy of benzodiazepines for the treatment of neonatal seizures.

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Section: Discussionmentioning

confidence: 99%

“…However, they also show decreased effectiveness in this age group . Interestingly, in some premature and full term human neonates, benzodiazepines can actually induce seizures, myoclonus, and abnormal movements . These data suggest that neuronal [Cl − ] i may alter the anticonvulsant effectiveness of benzodiazepines in neonates.…”

Section: Introductionmentioning

confidence: 94%

Diazepam effect during early neonatal development correlates with neuronal Cl⁻

Glykys

Staley

2015

Ann Clin Transl Neurol

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“…16 In fact, lorazepam has caused seizures in newborns. [17][18][19][20][21] Abnormal movements after midazolam administration in preterm infants (Table 1) 8,11,12,22 and adults have been reported. 23 Involuntary epileptiform movements lasting 15-30 seconds in premature newborns with gestational ages under 32 weeks appeared after intravenous boluses of midazolam 200 µg/kg.…”

Section: Discussionmentioning

confidence: 99%

Flumazenil's Reversal of Myoclonic‐like Movements Associated with Midazolam in Term Newborns

2001

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Sedation is an important aspect of care for critically ill newborns. Proper sedation reduces stress during procedures such as mechanical ventilation. Midazolam, a short-acting benzodiazepine, is widely administered as a sedative in newborn intensive care units but is not without side effects. Three term newborns developed myoclonic-like abnormal movements after receiving midazolam. In one, flumazenil controlled the abnormal movements. Flumazenil is a potent benzodiazepine antagonist that competitively blocks the central effects of benzodiazepines. It can reverse the sedative effects of benzodiazepines occurring after diagnostic or therapeutic procedures or after benzodiazepine overdose. Flumazenil may be considered in cases of abnormal movements associated with midazolam. However, further studies are needed to provide guidelines for the administration of this drug in newborns.

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“…The most common etiologies are severe intraventricular hemorrhage, hypoxic ischemic injury and glycine encephalopathy (20,21). Myoclonus has also been reported in premature neonates after receiving intravenous benzodiazepines (22,23). Nonepileptic pathological myoclonus most likely represents brainstem release phenomena, in which cortical inhibition of normally suppressed brainstem activity is lost due to diffuse cerebral injury (18,21,24).…”

Section: Myoclonusmentioning

confidence: 99%