Bumetanide for treatment of seizures in neonates.

Comment Gustoimages/Science Photo Library Bumetanide for treatment of seizures in neonates Published Online March 10, 2015 http://dx.doi.org/10.1016/ S1474-4422(15)70024-4 See Articles page 469 The medical treatment of seizures in newborn babies has remained unchanged for decades. In the past decade, experts in neurology, neonatology, and epilepsy have met on several occasions to discuss the urgent need to study novel anti-seizure agents in newborns; 1,2 however, since 1999, despite many recommendations, no group has been able to successfully undertake an eﬃ cacy trial to assess treatment of electrographic seizures in neonates. In The Lancet Neur ology, Ronit Pressler and members of the Treatment of NEonatal seizures with Medication Oﬀ - patent (NEMO) consortium 3 report the results of a dose- ﬁ nding and feasibility trial to assess the safety and eﬃ cacy of bumetanide (a loop diuretic with anti-convulsant eﬀ ects in pre-clinical trials) in full-term neonates with hypoxic ischaemic encephalopathy and seizures not responding to a loading dose of phenobarbital. 14 neonates were enrolled (of 24 planned); the trial was terminated early because of a concern for possible increased risk of hearing loss and failure to achieve the a priori outcome for seizure control. Two crucial questions arise from this trial; ﬁ rst, should bumetanide be studied again (perhaps with a diﬀ erent dosing schedule or a diﬀ erent study design)? How does the NEMO experience inform future neonatal seizure drug trials? Whether to study bumetanide again raises issues of safety and eﬃ cacy. Three (27%) of 11 newborn babies had hearing loss. Although there is no obvious comparison group to measure hearing loss in neonates with refractory seizures due to hypoxic ischaemic encephalopathy and receiving aminoglycosides, the rate in neonates receiving bumetanide is higher than the 4–7% reported in trials of hypothermia in neonates with hypoxic ischaemic encephalopathy, 4 and higher than the 3–4% the investigators report from their own previous data. Although the study design does not oﬀ er proof of ototoxicity, the data were suggestive enough to stop the study, and warrant careful thought before new trials are started. As for eﬃ cacy, two (14%) of 14 children had the a priori outcome measure of more than 80% reduction in seizure burden (when compared with baseline, 2 h before administration of study drug), without need for additional rescue seizure drug. However, ﬁ ve children had no seizures during the baseline period, so were de facto treatment failures. Researchers note “ﬂ uctuations [in seizure burden] make the study of electrographic seizures as a primary outcome measure problematic if too short a period is used for comparison.” Nonetheless, this well-done study by experienced investigators has great use to inform future trials for seizure drugs in neonates. The study design was a Bayesian sequential dose escalation design, in which each child received active drug. Although compelling in that it might oﬀ er a quicker answer regarding eﬃ cacy, the design is problematic because it makes it diﬃ cult to adequately measure side-eﬀ ects, and to assess for eﬃ cacy endpoints that fall short of a pre-determined rate of seizure resolution or reduction. Inclusion of a control group would permit more accurate measurement of side-eﬀ ects and better understanding of ﬂ uctuations in seizure burden, and allows for comparisons of seizure burden measured as a continuous variable. The a priori outcome, an 80% reduction in seizures without need for rescue medication in at least 50% of participants is similar to what has been suggested elsewhere. 1,2 However, this stringent outcome measure risks overlooking drugs that have a better safety proﬁ le than standard drugs, such as phenobarbital, with similar or marginally better eﬃ cacy. Additionally, investigators have debated whether neonatal seizure trials should include measurement of developmental outcomes and epilepsy, or whether higher eﬃ cacy for seizure termination is necessary before studying longer- term outcomes. 5 Phenobarbital and phenytoin, common ﬁ rst-line and second-line drugs, harm the developing brain in animal studies, whereas newer agents such as levetiracetam and topiramate do not. 5–7 Future neonatal drug trials need to enroll suﬃ cient participants (preferably randomised with a control group) to account for expected ﬂ uctuations in seizure burden. The choice of outcome measure needs to be carefully weighed, and less stringent measures considered, especially in drugs that are expected to have lower side eﬀ ect proﬁ le than standard care. The investigators appropriately conclude by oﬀ ering caution in the use of oﬀ -label drugs in newborn babies before safety assessment in controlled trials. Use of unstudied agents like levetiracetam is widespread 8 and is probably increasing, despite limited data about their safety and eﬃ cacy. There is an urgent need to study novel agents in neonates with seizures. The NEMO consortium has taken www.thelancet.com/neurology Vol 14 May 2015