Vicki Livingstone

Bumetanide for the treatment of seizures in newborn babies with hypoxic ischaemic encephalopathy (NEMO): an open-label, dose finding, and feasibility phase 1/2 trial

BACKGROUND Preclinical data suggest that the loop-diuretic bumetanide might be an effective treatment for neonatal seizures. We aimed to assess dose and feasibility of intravenous bumetanide as an add-on to phenobarbital for treatment of neonatal seizures. METHODS In this open-label, dose finding, and feasibility phase 1/2 trial, we recruited full-term infants younger than 48 h who had hypoxic ischaemic encephalopathy and electrographic seizures not responding to a loading-dose of phenobarbital from eight neonatal intensive care units across Europe. Newborn babies were allocated to receive an additional dose of phenobarbital and one of four bumetanide dose levels by use of a bivariate Bayesian sequential dose-escalation design to assess safety and efficacy. We assessed adverse events, pharmacokinetics, and seizure burden during 48 h continuous electroencephalogram (EEG) monitoring. The primary efficacy endpoint was a reduction in electrographic seizure burden of more than 80% without the need for rescue antiepileptic drugs in more than 50% of infants. The trial is registered with ClinicalTrials.gov, number NCT01434225. FINDINGS Between Sept 1, 2011, and Sept 28, 2013, we screened 30 infants who had electrographic seizures due to hypoxic ischaemic encephalopathy. 14 of these infants (10 boys) were included in the study (dose allocation: 0·05 mg/kg, n=4; 0·1 mg/kg, n=3; 0·2 mg/kg, n=6; 0·3 mg/kg, n=1). All babies received at least one dose of bumetanide with the second dose of phenobarbital; three were withdrawn for reasons unrelated to bumetanide, and one because of dehydration. All but one infant also received aminoglycosides. Five infants met EEG criteria for seizure reduction (one on 0·05 mg/kg, one on 0·1 mg/kg and three on 0·2 mg/kg), and only two did not need rescue antiepileptic drugs (ie, met rescue criteria; one on 0·05 mg/kg and one on 0·3 mg/kg). We recorded no short-term dose-limiting toxic effects, but three of 11 surviving infants had hearing impairment confirmed on auditory testing between 17 and 108 days of age. The most common non-serious adverse reactions were moderate dehydration in one, mild hypotension in seven, and mild to moderate electrolyte disturbances in 12 infants. The trial was stopped early because of serious adverse reactions and limited evidence for seizure reduction. INTERPRETATION Our findings suggest that bumetanide as an add-on to phenobarbital does not improve seizure control in newborn infants who have hypoxic ischaemic encephalopathy and might increase the risk of hearing loss, highlighting the risks associated with the off-label use of drugs in newborn infants before safety assessment in controlled trials. FUNDING European Communitys Seventh Framework Programme.

The temporal evolution of electrographic seizure burden in neonatal hypoxic ischemic encephalopathy

Purpose:  Hypoxic ischemic encephalopathy (HIE) accounts for 60% of all neonatal seizures. There is emerging evidence that seizures cause additional injury to the developing brain that has sustained hypoxic ischemic injury. Temporal evolution of clinical seizure burden in HIE has been characterized, with maximum clinical seizure burden (the period of maximum seizure activity) being observed between 12 and 24 h of age. The purpose of our study was to investigate the distribution of electrographic seizure burden (the accumulated duration of seizures over a defined time period), following the initial hypoxic ischemic insult.

Seizure burden and neurodevelopmental outcome in neonates with hypoxic-ischemic encephalopathy.

To examine the relationship between electrographic seizures and long‐term outcome in neonates with hypoxic–ischemic encephalopathy (HIE).

Early postnatal EEG features of perinatal arterial ischaemic stroke with seizures.

Background Stroke is the second most common cause of seizures in term neonates and is associated with abnormal long-term neurodevelopmental outcome in some cases. Objective To aid diagnosis earlier in the postnatal period, our aim was to describe the characteristic EEG patterns in term neonates with perinatal arterial ischaemic stroke (PAIS) seizures. Design Retrospective observational study. Patients Neonates >37 weeks born between 2003 and 2011 in two hospitals. Method Continuous multichannel video-EEG was used to analyze the background patterns and characteristics of seizures. Each EEG was assessed for continuity, symmetry, characteristic features and sleep cycling; morphology of electrographic seizures was also examined. Each seizure was categorized as electrographic-only or electroclinical; the percentage of seizure events for each seizure type was also summarized. Results Nine neonates with PAIS seizures and EEG monitoring were identified. While EEG continuity was present in all cases, the background pattern showed suppression over the infarcted side; this was quite marked (>50% amplitude reduction) when the lesion was large. Characteristic unilateral bursts of theta activity with sharp or spike waves intermixed were seen in all cases. Sleep cycling was generally present but was more disturbed over the infarcted side. Seizures demonstrated a characteristic pattern; focal sharp waves/spike-polyspikes were seen at frequency of 1–2 Hz and phase reversal over the central region was common. Electrographic-only seizure events were more frequent compared to electroclinical seizure events (78 vs 22%). Conclusions Focal electrographic and electroclinical seizures with ipsilateral suppression of the background activity and focal sharp waves are strong indicators of PAIS. Approximately 80% of seizure events were the result of clinically unsuspected seizures in neonates with PAIS. Prolonged and continuous multichannel video-EEG monitoring is advocated for adequate seizure surveillance.

The temporal characteristics of seizures in neonatal hypoxic ischemic encephalopathy treated with hypothermia

PURPOSE The characteristics of electrographic seizures in newborns with hypoxic-ischaemic encephalopathy (HIE) treated with therapeutic hypothermia (TH) are poorly described. This retrospective, observational study provides reference data on the characteristics of seizures and their evolution over time in newborns with HIE receiving whole-body TH. METHOD The cohort under analysis included 23 infants with HIE and seizures defined by multi-channel EEG recordings. Clinical presentation, details of TH and antiepileptic drugs used were recorded. Time from first to last-recorded electrographic seizure (seizure period) was calculated. Temporal characteristics of seizures - total burden, duration, number, burden in minutes per hour, distribution of burden over time (temporal evolution), time from seizure onset to maximum seizure burden (Tmsb), T1, and time from Tmsb to seizure offset, T2 - were analysed. RESULTS The median age at electrographic seizure onset was 13.1h (IQR: 11.4 to 22.0). Tmsb was reached at a median age of 19.4 hours (IQR: 12.2 to 29.7). Median seizure period was 16.5h (IQR: 7.0 to 49.7), median number of seizures per hour was 1.9 (IQR: 1.0 to 3.3). The seizure burden was 4.0 min/h (IQR: 2.0 to 7.0). There was no consistent pattern in the temporal evolution of seizures in neonates treated with TH. The skewness was neither positive nor negative (p-value=0.15), there was no difference between the duration of T1 and T2 (p-value=0.09) and no difference in the seizure burden between T1 and T2 (p=0.09). There was an association between Tmsb and Phenobarbital (PB) administration (r=0.76, p-value<0.001). CONCLUSION There is no consistent temporal evolution of seizure burden in neonates treated with TH. Seizures are diffuse, and their characteristics are variable.

Automated analysis of multi-channel EEG in preterm infants.

OBJECTIVE To develop and validate two automatic methods for the detection of burst and interburst periods in preterm eight-channel electroencephalographs (EEG). To perform a detailed analysis of interobserver agreement on burst and interburst periods and use this as a benchmark for the performance of the automatic methods. To examine mathematical features of the EEG signal and their potential correlation with gestational age. METHODS Multi-channel EEG from 36 infants, born at less than 30 weeks gestation was utilised, with a 10 min artifact-free epoch selected for each subject. Three independent expert observers annotated all EEG activity bursts in the dataset. Two automatic algorithms for burst/interburst detection were applied to the EEG data and their performances were analysed and compared with interobserver agreement. A total of 12 mathematical features of the EEG signal were calculated and correlated with gestational age. RESULTS The mean interobserver agreement was found to be 77% while mean algorithm/observer agreement was 81%. Six of the mathematical features calculated (spectral entropy, Higuchi fractal dimension, spectral edge frequency, variance, extrema median and Hilberts transform amplitude) were found to have significant correlation with gestational age. CONCLUSIONS Automatic detection of burst/interburst periods has been performed in multi-channel EEG of 36 preterm infants. The algorithm agreement with expert observers is found to be on a par with interobserver agreement. Mathematical features of EEG have been calculated which show significant correlation with gestational age. SIGNIFICANCE Automatic analysis of preterm multi-channel EEG is possible. The methods described here have the potential to be incorporated into a fully automatic system to quantitatively assess brain maturity from preterm EEG.

Touch-screen technology usage in toddlers

Objective To establish the prevalence and patterns of use of touch-screen technologies in the toddler population. Design Parental questionnaires were completed for children aged 12 months to 3 years examining access to touch-screen devices and ability to perform common forms of interaction with touch-screen technologies. Results The 82 questionnaires completed on typically developing children revealed 71% of toddlers had access to touch-screen devices for a median of 15 min (IQR: 9.375–26.25) per day. By parental report, 24 months was the median age of ability to swipe (IQR: 19.5–30.5), unlock (IQR: 20.5–31.5) and active looking for touch-screen features (IQR: 22–30.5), while 25 months (IQR: 21–31.25) was the median age of ability to identify and use specific touch-screen features. Overall, 32.8% of toddlers could perform all four skills. Conclusions From 2 years of age toddlers have the ability to interact purposefully with touch-screen devices and demonstrate a variety of common skills required to utilise touch-screen technology.

Heart rate variability in hypoxic ischemic encephalopathy: correlation with EEG grade and 2-y neurodevelopmental outcome

Background:The study aims to describe heart rate variability (HRV) in neonatal hypoxic ischemic encephalopathy (HIE) and correlate HRV with electroencephalographic (EEG) grade of HIE and neurodevelopmental outcome.Methods:Multichannel EEG and electrocardiography (ECG) were assessed at 12–48 h after birth in healthy and encephalopathic full-term neonates. EEGs were graded (normal, mild, moderate, and severe). Neurodevelopmental outcome was assessed at 2 y of age. Seven HRV features were calculated using normalized-RR (NN) interval. The correlation of these features with EEG grade and outcome were measured using Spearman’s correlation coefficient.Results:HRV was significantly associated with HIE severity (P < 0.05): standard deviation of NN interval (SDNN) (r = −0.62), triangular interpolation of NN interval histogram (TINN) (r = −0.65), mean NN interval (r = −0.48), and the very low frequency (VLF) (r = −0.60), low frequency (LF) (r = −0.67) and high frequency (HF) components of the NN interval (r = −0.60). SDNN at 24 and 48 h were significantly associated (P < 0.05) with neurodevelopmental outcome (r = −0.41 and −0.54, respectively).Conclusion:HRV is associated with EEG grade of HIE and neurodevelopmental outcome. HRV has potential as a prognostic tool to complement EEG.

Sleep–wake cycle of the healthy term newborn infant in the immediate postnatal period

OBJECTIVE To examine sleep-wake cycle (SWC) composition of healthy term infants in the immediate postnatal period using EEG, and investigate factors that might influence it. METHODS Multichannel video-EEG was recorded for a median of 61.9 min (IQR: 60.0-69.3). The absolute and relative scores of sleep states were calculated for each infants recording. Parametric/non-parametric statistical tests and multiple linear regression analysis were used to investigate the influence of perinatal factors on SWC composition. RESULTS Eighty healthy term infants aged 1-36 h were studied. A well-developed SWC was evident as early as within the first 6h after birth. The mean (SD) percentage of active sleep (AS) was 52.1% (12.9) and quiet sleep (QS) was 38.6% (12.5). AS was longer and QS shorter in infants delivered by elective caesarean section (CS) compared to infants delivered by vaginal delivery or emergency CS. CONCLUSIONS This is the first large cohort EEG study that has quantified neonatal sleep. SWC is clearly present immediately after birth, it is dominated by AS, and is influenced by mode of delivery. SIGNIFICANCE This knowledge of the early neonatal EEG/SWC can be used as reference data for EEG studies of neurologically compromised infants.

Peak systolic to end diastolic flow velocity ratio is associated with ductal patency in infants below 32 weeks of gestation

Background Early diagnosis and effective treatment of the patent ductus arteriosus (PDA) in infants less than 32 weeks gestation remains contentious. Objective To determine which clinical and echocardiographic parameters are associated with PDA patency in preterm infants less than 32 weeks gestation. Design/Methods This was a prospective cohort study. An echocardiography (echo) was performed within 12–48 h of birth and a follow-up echo at 1 month of life. Parental consent was obtained. Results 55 babies were enrolled. Median (range) gestation was 28 (24–31) weeks and birth weight 1090 g (470–1800 g). ECHO 1 demonstrated that 50 babies had a PDA present within 48 h of birth, of which 19 were large (≥2 mm) (36%) and 31 were small (59%) on colour Doppler assessment of duct diameter. Three babies died before 1 month. At 1 month 30 babies still had a PDA (58%), 10 of which were large (19%) and 19 were small (36%). Parameters significantly associated with large PDAs versus no PDA at 1 month were gestational age (26 weeks vs 30 weeks, p=0.002), birth weight (860 g vs 1290 g, p=0.007) and ventilator support at 48 h (80% vs 17%, p=0.001). Echo parameters revealed that ductal size on colour Doppler (2.5 mm vs 1.5 mm, p=0.003), end diastolic flow velocity (57 m/s vs 147 m/s, p<0.001) and peak systolic to end diastolic flow velocity ratio (2.29 vs 1.23, p=0.001) at 48 h were associated with large PDAs at 1 month. Conclusions For infants less than 32 weeks gestation a peak systolic to end diastolic flow velocity ratio>2 within 48 h of birth is associated with a persistent large PDA at 1 month of age.