Phenobarbital, midazolam, bumetanide, and neonatal seizures: The devil is in the details

Abstract

Kaila, Löscher, and colleagues report that phenobarbital (PHB) and midazolam (MDZ) attenuate neonatal seizures following birth asphyxia, but the former only when applied before asphyxia and the latter before or after the triggering insult. In contrast, the NKCC1 chloride importer antagonist bumetanide (BUM) had no effect whether applied alone or with PHB. The observations are compelling and in accord with earlier studies. However, there are several general issues that deserve discussion. What is the clinical relevance of these data and the validity of animal models of encephalopathic seizures? Why is it that although they act on similar targets, these agents have different efficacy? Are both PHB and MDZ actions restricted to γ‐aminobutyric acidergic (GABAergic) mechanisms? Why is BUM inefficient in attenuating seizures but capable of reducing the severity of other brain disorders? We suggest that the relative failure of antiepileptic drugs (AEDs) to treat this severe life‐threatening condition is in part explicable by the recurrent seizures that shift the polarity of GABA, thereby counteracting their effects on their target. AEDs might be efficient after a few seizures but not recurrent ones. In addition, PHB and MDZ actions are not limited to GABA signals. BUM efficiently attenuates autism symptomatology notably in patients with tuberous sclerosis but does not reduce the recurrent seizures, illustrating the uniqueness of epilepsies. Therefore, the efficacy of AEDs to treat babies with encephalopathic seizures will depend on the history and severity of the seizures prior to their administration, challenging a universal common underlying mechanism.

Effects of Mutations in TSC Genes on Neurodevelopment and Synaptic Transmission

“…Given the impaired chloride homeostasis in TSC patients, bumetanide, a NKCC1 blocker, was investigated, since it showed promising results in ASD treatment [ 110 , 111 ]. Bumetanide-induced effects were somehow opposite to that of vigabatrine, i.e., useful for treatment of ASD symptoms, but limited for seizure control [ 112 , 113 ].…”

Reply to the commentary by Ben‐Ari and Delpire: Bumetanide and neonatal seizures: Fiction versus reality

“…Among the major differences in the physiology and pathophysiology between pure hypoxia and our asphyxia models is that, in the former, seizures are triggered during the insult, whereas in our “intermittent asphyxia” protocol (for details see Johne et al 2 and Ala‐Kurikka et al 3 ), the seizures commence after the insult, akin to the situation in human neonates. Thus, we were surprised to read in the commentary of Ben‐Ari and Delpire 1 that our work on bumetanide, PB, and midazolam (with asphyxia) was done under “experimental conditions with very minor differences” when compared to the work of Cleary at al., 6 which is based on hypoxia only.…”

“…Y. Ben‐Ari and E. Delpire 1 for their interest in our study 2 on the actions of bumetanide, phenobarbital (PB), and midazolam on neonatal seizures carried out on a novel, physiologically validated model of birth asphyxia 3 ; both papers appear in this issue of Epilepsia . In our reply to their commentary, 1 we wish to rectify the inaccurate descriptions of our model and data. Furthermore, because Ben‐Ari and Delpire 1 suggest that negative data on bumetanide from preclinical and clinical trials of neonatal seizures have few implications for (alleged) bumetanide actions on neurons in other brain disorders (see also Ben‐Ari et al 4 ), we will discuss this topic as well.…”

“…Ben‐Ari and Delpire 1 note that “the main reason for this poor brain availability [of bumetanide] is the fact that ~97% of BUM binds to serum proteins, e.g., albumin.” However, this is not a major factor in the present context. For instance, midazolam is ~95% bound to plasma proteins but, following intravenous administration, it has an almost immediate onset of anticonvulsant action 15 .…”

Don’t Get BUM’d Out: Bumetanide May yet Prove Beneficial for Neonatal Seizures

“…It remains unclear whether BUM can be used as a first-line ASM for neonatal seizures based on the inconclusive (and overall, somewhat underwhelming) human and animal data, but this is unlikely. 14 Seizure responsiveness to BUM (and other agents) may well depend on the seizure etiology, timing of administration, frequency and severity of prior seizures, and many other factors. Nevertheless, there remains theoretical support for BUM as a mechanistically appropriate medication for neonatal seizures.…”