Correspondence Correspondence: A Claim For Caution in the Use of Promising Bumetanide to Treat Neonatal Seizures DOI: 10.1177/0883073811401395 We read with great interest the recent article by Kahle et al. 1 The role played by the NKCC1 cotransporter, a Cl - uptake mechanism, in the hyperexcitability of the immature brain, is well established. 2 Upregulation of NKCC1 during neurogenesis leads to the collapse of Cl - concentration gra- dient across the plasma membrane, which, in turn, switches the polarity of g-aminobutyric acid (GABA) action toward excitation. Resulting brain overexcitation is one of the sug- gested mechanisms for the seizure propensity in neonates 3 and might explain the low efficiency of classical anticonvul- sive drugs in treating neonatal seizures. In this perspective, bumetanide, as NKCC1 inhibitor, constitutes an interesting adjuvant therapy for neonatal seizures and the first human observation of this effect by Khale et al is encouraging. 1 Yet, the use of this drug as an anticonvulsant in neonates is still controversial. 4 Bumetanide is primarily a potent loop diuretic inhibiting NKCC2, a renal-specific isoform of NKCC1. As such, it has been used for years in both term and extremely premature neo- nates. The pharmacokinetics of bumetanide in this population has been characterized in a few studies. 5 However, besides potential diuretic side effects, the use of bumetanide in new- born as an inhibitor of cerebral NKCC1, in combination with phenobarbital, raises several concerns. First, bumetanide poorly crosses the blood-brain barrier 6 and this might limit its therapeutic effect. The presumed increased permeability of the blood-brain barrier in newborns, and notably during seizures, 7 should be specifically investi- gated for this drug. Alternative routes of administration might be interesting to consider, such as intranasal formulations sug- gested to bypass the blood brain barrier. 8 On the other hand, the high expression of NKCC1 during embryogenesis is crucial for the central nervous system maturation. 2 We recently showed that this cotransporter, besides its role in the increase of intracellular Cl - concentra- tions during embryogenesis, was essential in restoring embryonic neuronal Cl - to homeostatic levels on changes. 9 How inhibition of this key pathway would affect neurogenesis is a challenging question. Neuroapoptosis in the developing brain, associated to long-term behavioral changes, has been demonstrated with drugs acting as N-methyl-D-aspartate (NMDA) receptor antagonists but also with GABA receptor agonists or their combination. 10 The US Food and Drug Administration (FDA) is trying to rationalize the design of further studies in rodents and primates, able to assess the risk of administrating these drugs during a brain growth spurt period. We believe that the use of multiple neurotrans- mission modulators in immature brains should be first tested in animal models addressing precise clinical conditions. One of the most challenging ones, hypoxic-ischemic encephalopathy, is aggravated by an excitotoxicity cascade and today the most promising neuroprotection strategies for asphyxiated new- borns rely on combined therapies, such as hypothermia together with glutamatergic inhibition. 11 The use of bumeta- nide with phenobarbital in this clinical situation should therefore be differentiated from their use during seizures because of hemorrhagic or metabolic insults, and probably directly tested in association with NMDA receptor blockers. To conclude, bumetanide is obviously an attractive add-on therapy for neonatal seizures, targeting unique patterns of the developing brain. Yet, we believe that its potential adverse effects and its effective bioavailability in the central nervous system need to be further investigated before bridging the gap between animal models and human subjects. Joelle Nsimire Chabwine, MD, PhD Department of Neurology Erasmus Hospital, Universite ´ Libre de Bruxelles, Belgium Serge Vanden Eijnden, MD, PhD Department of Neonatology, Erasmus Hospital, Universite ´ Libre de Bruxelles, Belgium Acknowledgments Both authors equally contributed to this article. References 1. Kahle KT, Barnett SM, Sassower KC, Staley KJ. Decreased sei- zure activity in a human neonate treated with bumetanide, an inhi- bitor of the Na(þ)-K(þ)-2Cl(-) cotransporter NKCC1. J Child Neurol. 2009;24:572-576. 2. Ben Ari Y, Gaiarsa JL, Tyzio R, Khazipov R. GABA: a pioneer transmitter that excites immature neurons and generates primitive oscillations. Physiol Rev. 2007;87:1215-1284. Journal of Child Neurology 000(00) 1-2 ª The Author(s) 2011 Reprints and permission: sagepub.com/journalsPermissions.nav http://jcn.sagepub.com