Effects of bumetanide on neonatal seizures: A systematic review of animal and human studies.

Abstract

BACKGROUND:

Bumetanide, an inhibitor of the sodium-potassium-chloride cotransporter-1, has been suggested as an adjunct to phenobarbital for treating neonatal seizures.

METHODS:

A systematic review of animal and human studies was conducted to evaluate the efficacy and safety of bumetanide for neonatal seizures. PubMed, Embase, CINAHL and Cochrane databases were searched in March 2023.

RESULTS:

26 animal (rat or mice) studies describing 38 experiments (28 in-vivo and ten in-vitro) and two human studies (one RCT and one open-label dose-finding) were included. The study designs, methods to induce seizures, bumetanide dose, and outcome measures were heterogeneous, with only 4/38 experiments being in animal hypoxia/ischaemia models. Among 38 animal experiments, bumetanide was reported to have antiseizure effects in 21, pro-seizure in six and ineffective in 11. The two human studies (n = 57) did not show the benefits of bumetanide as an add-on agent to phenobarbital in their primary analyses, but one study reported benefit on post-hoc analysis. Overall, hearing impairment was detected in 5/37 surviving infants in the bumetanide group vs. 0/13 in controls. Four of the five infants with hearing impairment had received aminoglycosides concurrently. Other adverse effects reported were diuresis, mild-to-moderate dehydration, hypotension, and electrolyte disturbances. The studies did not report on long-term neurodevelopment. The certainty of the evidence was very low.

CONCLUSION:

Animal data suggest that bumetanide has inconsistent effects as an antiseizure medication in neonates. Data from human studies are scarce and raise some concerns regarding ototoxicity when given with aminoglycosides. Well conducted studies in animal models of hypoxic-ischaemic encephalopathy are urgently needed. Future RCTs, if conducted in human neonates, should have an adequate sample size, assess neurodevelopment, minimize using aminoglycosides, be transparent about the potential ototoxicity in the parent information sheet, conduct early hearing tests and have trial-stopping rules that include hearing impairment as an outcome.

• Authors: Shripada Rao, Asifa Farhat, Abhijeet Rakshasbhuvankar, Sam Athikarisamy, Soumya Ghosh, Lakshmi Nagarajan
• Journal: Seizure (Seizure) Vol. 111 Pg. 206-214 (Oct 2023) ISSN: 1532-2688 [Electronic] England
• PMID: 37690372 (Publication Type: Systematic Review, Journal Article)
• Copyright: Crown Copyright © 2023. Published by Elsevier Ltd. All rights reserved.

Chemical References

• Bumetanide
• Sodium Potassium Chloride Symporter Inhibitors
• Solute Carrier Family 12, Member 2
• Phenobarbital
• Aminoglycosides
• Anticonvulsants

Topics

• Infant, Newborn
• Infant
• Humans
• Rats
• Mice
• Animals
• Bumetanide (adverse effects)
• Ototoxicity (drug therapy)
• Sodium Potassium Chloride Symporter Inhibitors (adverse effects)
• Solute Carrier Family 12, Member 2
• Seizures (drug therapy, chemically induced)
• Epilepsy (drug therapy)
• Phenobarbital (pharmacology, therapeutic use)
• Infant, Newborn, Diseases
• Aminoglycosides (therapeutic use)
• Hearing Loss
• Anticonvulsants (adverse effects)