Neonatal donation: are newborns too young to be recognized?

Neonatal organ and tissue donation is not common practice in the Netherlands. At the same time, there is a transplant waiting list for small size-matched organs and tissues. Multiple factors may contribute to low neonatal donation rates, including a lack of awareness of this option. This study provides insight into potential neonatal organ and tissue donors and reports on how many donors were actually reported to the procurement organization. We performed a retrospective analysis of the mortality database and medical records of two largest neonatal intensive care units (NICUs) in the Netherlands. This study reviewed records of neonates with a gestational age >37 weeks and weight >3000g who died in the period from January 1, 2005 through December 31, 2016. During the study period, 259 term-born neonates died in the two NICUs. In total, 132 neonates with general contra-indications for donation were excluded. The medical records of 127 neonates were examined for donation suitability. We identified five neonates with documented brain death who were not recognized as potential organ and/or tissue donors. Of the remaining neonates, 27 were found suitable for tissue donation. One potential tissue donor had been reported to the procurement organization. In three cases, the possibility of donation was brought up by parents.Conclusion: A low proportion (2%) of neonates who died in the NICUs were found suitable for organ donation, and a higher proportion (12%) were found suitable for tissue donation. We suggest that increased awareness concerning the possibility of neonatal donation would likely increase the identification of potential neonatal donors. What is Known: • There is an urgent need for very small organs and tissues from neonatal donors What is New: • A number of neonates who died in the NICU were suitable organ or/and tissue donors but were not recognized as donors. • Knowledge on neonatal donation possibilities is also important for proper counseling of parents who sometimes inquire for the possibility of organ and tissue donation.

A machine-learning algorithm for neonatal seizure recognition: a multicentre, randomised, controlled trial.

BACKGROUND: Despite the availability of continuous conventional electroencephalography (cEEG), accurate diagnosis of neonatal seizures is challenging in clinical practice. Algorithms for decision support in the recognition of neonatal seizures could improve detection. We aimed to assess the diagnostic accuracy of an automated seizure detection algorithm called Algorithm for Neonatal Seizure Recognition (ANSeR). METHODS: This multicentre, randomised, two-arm, parallel, controlled trial was done in eight neonatal centres across Ireland, the Netherlands, Sweden, and the UK. Neonates with a corrected gestational age between 36 and 44 weeks with, or at significant risk of, seizures requiring EEG monitoring, received cEEG plus ANSeR linked to the EEG monitor displaying a seizure probability trend in real time (algorithm group) or cEEG monitoring alone (non-algorithm group). The primary outcome was diagnostic accuracy (sensitivity, specificity, and false detection rate) of health-care professionals to identify neonates with electrographic seizures and seizure hours with and without the support of the ANSeR algorithm. Neonates with data on the outcome of interest were included in the analysis. This study is registered with ClinicalTrials.gov, NCT02431780. FINDINGS: Between Feb 13, 2015, and Feb 7, 2017, 132 neonates were randomly assigned to the algorithm group and 132 to the non-algorithm group. Six neonates were excluded (four from the algorithm group and two from the non-algorithm group). Electrographic seizures were present in 32 (25·0%) of 128 neonates in the algorithm group and 38 (29·2%) of 130 neonates in the non-algorithm group. For recognition of neonates with electrographic seizures, sensitivity was 81·3% (95% CI 66·7-93·3) in the algorithm group and 89·5% (78·4-97·5) in the non-algorithm group; specificity was 84·4% (95% CI 76·9-91·0) in the algorithm group and 89·1% (82·5-94·7) in the non-algorithm group; and the false detection rate was 36·6% (95% CI 22·7-52·1) in the algorithm group and 22·7% (11·6-35·9) in the non-algorithm group. We identified 659 h in which seizures occurred (seizure hours): 268 h in the algorithm versus 391 h in the non-algorithm group. The percentage of seizure hours correctly identified was higher in the algorithm group than in the non-algorithm group (177 [66·0%; 95% CI 53·8-77·3] of 268 h vs 177 [45·3%; 34·5-58·3] of 391 h; difference 20·8% [3·6-37·1]). No significant differences were seen in the percentage of neonates with seizures given at least one inappropriate antiseizure medication (37·5% [95% CI 25·0 to 56·3] vs 31·6% [21·1 to 47·4]; difference 5·9% [-14·0 to 26·3]). INTERPRETATION: ANSeR, a machine-learning algorithm, is safe and able to accurately detect neonatal seizures. Although the algorithm did not enhance identification of individual neonates with seizures beyond conventional EEG, recognition of seizure hours was improved with use of ANSeR. The benefit might be greater in less experienced centres, but further study is required. FUNDING: Wellcome Trust, Science Foundation Ireland, and Nihon Kohden.

Delay in Treatment of Neonatal Seizures: A Retrospective Cohort Study.

INTRODUCTION: Neonatal seizures are common and caused by a variety of underlying disorders. There is increasing evidence that neonatal seizures result in further brain damage. OBJECTIVE: To describe the time interval between diagnosis of amplitude-integrated electroencephalography (aEEG)-confirmed seizures and administration of anti-epileptic drugs (AEDs). METHODS: Single-centre retrospective cohort study, with full-term infants (n = 106) admitted to a level III neonatal intensive care unit between 2012 and 2017 with seizures confirmed on 2-channel aEEG and corresponding raw electroencephalography traces, treated with AEDs. The time interval between the first seizure on the aEEG registration and AED administration was calculated. Factors associated with early treatment were analysed. RESULTS: The median time interval of initiating treatment of aEEG-confirmed seizures was 01:50 h (interquartile range 00:43-4:30 h). Treatment of aEEG-confirmed seizures was initiated <1 h in 34/106 infants (32.1%), between 1 and 2 h in 21/106 infants (19.8%), 2-4 h in 23/106 infants (21.7%), 4-8 h in 14/106 infants (13.2%), and ≥8 h in 14/106 infants (13.2%). Seizures treated <1 h were significantly more often recognized by the seizure detection algorithm (SDA) compared to seizures treated >1 h (67 vs. 42%, p = 0.02) and showed more clinical signs (79.4 vs. 37.5%, p < 0.01). There was no difference for out-of-office hours (23.5 vs. 22.2%, p = 0.88). CONCLUSION: With only 32.1% of the seizures being treated <1 h, there is room for improvement. Timely treatment occurred more often when seizures were clinical or recognised by the SDA. aEEG is a helpful tool for diagnosing seizures 24/7.

Increased Use of Therapeutic Hypothermia in Infants with Milder Neonatal Encephalopathy due to Presumed Perinatal Asphyxia.

INTRODUCTION: Adverse outcomes have been reported in infants with mild neonatal encephalopathy (NE). Increasing clinical experience with the application of therapeutic hypothermia (TH) may have resulted in the treatment of newborns with milder NE during recent years. OBJECTIVE: To determine whether infants treated with TH in the initial years following implementation had a higher degree of NE than infants treated during subsequent years. METHODS: Infants with NE treated with TH from February 2008 until July 2017 were included. Thompson and Sarnat scores, amplitude-integrated electroencephalography (aEEG) background patterns before the start of TH, and neurodevelopmental outcome at 2 years were compared between infants treated from February 2008 until October 2012 (period 1) and infants treated from November 2012 until July 2017 (period 2). RESULTS: 211 newborns with NE were treated with TH (period 1: n = 109, period 2: n = 102). Sarnat scores in period 1 and 2 were mild in 7.3 vs. 28.4%, moderate in 66.1 vs. 44.1%, and severe in 26.6 vs. 22.5%, respectively (p = 0.008). Thompson scores were lower in period 2 (median = 9, IQR 7-12) than in period 1 (median = 10, IQR 8.5-13.5, p = 0.018). The aEEGs and neurodevelopmental outcomes were comparable between the periods. CONCLUSIONS: Based on Thompson and Sarnat scores, but not aEEG background patterns, infants treated during the second period had milder NE than infants treated during the first years following implementation of TH. There was no difference in 2 years neurodevelopmental outcome. Further research is necessary to evaluate the value of TH for infants with clinically mild NE.

Characterisation of neonatal seizures and their treatment using continuous EEG monitoring: a multicentre experience.

OBJECTIVE: The aim of this multicentre study was to describe detailed characteristics of electrographic seizures in a cohort of neonates monitored with multichannel continuous electroencephalography (cEEG) in 6 European centres. METHODS: Neonates of at least 36 weeks of gestation who required cEEG monitoring for clinical concerns were eligible, and were enrolled prospectively over 2 years from June 2013. Additional retrospective data were available from two centres for January 2011 to February 2014. Clinical data and EEGs were reviewed by expert neurophysiologists through a central server. RESULTS: Of 214 neonates who had recordings suitable for analysis, EEG seizures were confirmed in 75 (35%). The most common cause was hypoxic-ischaemic encephalopathy (44/75, 59%), followed by metabolic/genetic disorders (16/75, 21%) and stroke (10/75, 13%). The median number of seizures was 24 (IQR 9-51), and the median maximum hourly seizure burden in minutes per hour (MSB) was 21 min (IQR 11-32), with 21 (28%) having status epilepticus defined as MSB>30 min/hour. MSB developed later in neonates with a metabolic/genetic disorder. Over half (112/214, 52%) of the neonates were given at least one antiepileptic drug (AED) and both overtreatment and undertreatment was evident. When EEG monitoring was ongoing, 27 neonates (19%) with no electrographic seizures received AEDs. Fourteen neonates (19%) who did have electrographic seizures during cEEG monitoring did not receive an AED. CONCLUSIONS: Our results show that even with access to cEEG monitoring, neonatal seizures are frequent, difficult to recognise and difficult to treat. OBERSERVATION STUDY NUMBER: NCT02160171.

Amplitude-Integrated Electroencephalography for Early Recognition of Brain Injury in Neonates with Critical Congenital Heart Disease.

OBJECTIVE: To study perioperative amplitude-integrated electroencephalography (aEEG) as an early marker for new brain injury in neonates requiring cardiac surgery for critical congenital heart disease (CHD). STUDY DESIGN: This retrospective observational cohort study investigated 76 neonates with critical CHD who underwent neonatal surgery. Perioperative aEEG recordings were evaluated for background pattern (BGP), sleep-wake cycling (SWC), and ictal discharges. Spontaneous activity transient (SAT) rate, inter-SAT interval (ISI), and percentage of time with an amplitude <5 µV were calculated. Routinely obtained preoperative and postoperative magnetic resonance imaging of the brain were reviewed for brain injury (moderate-severe white matter injury, stroke, intraparenchymal hemorrhage, or cerebral sinovenous thrombosis). RESULTS: Preoperatively, none of the neonates showed an abnormal BGP (burst suppression or worse) or ictal discharges. Postoperatively, abnormal BGP was seen in 18 neonates (24%; 95% CI, 14%-33%) and ictal discharges was seen in 13 neonates (17%; 95% CI, 8%-26%). Abnormal BGP and ictal discharges were more frequent in neonates with new postoperative brain injury (P = .08 and .01, respectively). Abnormal brain activity (ie, abnormal BGP or ictal discharges) was the single risk factor associated with new postoperative brain injury in multivariable logistic regression analysis (OR, 4.0; 95% CI, 1.3-12.3; P = .02). Postoperative SAT rate, ISI, or time <5 µV were not associated with new brain injury. CONCLUSION: Abnormal brain activity is an early, bedside marker of new brain injury in neonates undergoing cardiac surgery. Not only ictal discharges, but also abnormal BGP, should be considered a clear sign of underlying brain pathology.

Changes in brain morphology and microstructure in relation to early brain activity in extremely preterm infants.

Background and ObjectiveTo investigate the relation of early brain activity with structural (growth of the cortex and cerebellum) and white matter microstructural brain development.MethodsA total of 33 preterm neonates (gestational age 26±1 weeks) without major brain abnormalities were continuously monitored with electroencephalography during the first 48 h of life. Rate of spontaneous activity transients per minute (SAT rate) and inter-SAT interval (ISI) in seconds per minute were calculated. Infants underwent brain magnetic resonance imaging ∼30 (mean 30.5; min: 29.3-max: 32.0) and 40 (41.1; 40.0-41.8) weeks of postmenstrual age. Increase in cerebellar volume, cortical gray matter volume, gyrification index, fractional anisotropy (FA) of posterior limb of the internal capsule, and corpus callosum (CC) were measured.ResultsSAT rate was positively associated with cerebellar growth (P=0.01), volumetric growth of the cortex (P=0.027), increase in gyrification (P=0.043), and increase in FA of the CC (P=0.037). ISI was negatively associated with cerebellar growth (P=0.002).ConclusionsIncreased early brain activity is associated with cerebellar and cortical growth structures with rapid development during preterm life. Higher brain activity is related to FA microstructural changes in the CC, a region responsible for interhemispheric connections. This study underlines the importance of brain activity for microstructural brain development.

Rhythmic EEG patterns in extremely preterm infants: Classification and association with brain injury and outcome.

OBJECTIVE: Classify rhythmic EEG patterns in extremely preterm infants and relate these to brain injury and outcome. METHODS: Retrospective analysis of 77 infants born <28 weeks gestational age (GA) who had a 2-channel EEG during the first 72 h after birth. Patterns detected by the BrainZ seizure detection algorithm were categorized: ictal discharges, periodic epileptiform discharges (PEDs) and other waveforms. Brain injury was assessed with sequential cranial ultrasound (cUS) and MRI at term-equivalent age. Neurodevelopmental outcome was assessed with the BSITD-III (2 years) and WPPSI-III-NL (5 years). RESULTS: Rhythmic patterns were observed in 62.3% (ictal 1.3%, PEDs 44%, other waveforms 86.3%) with multiple patterns in 36.4%. Ictal discharges were only observed in one and excluded from further analyses. The EEG location of the other waveforms (p<0.05), but not PEDs (p=0.238), was significantly associated with head position. No relation was found between the median total duration of each pattern and injury on cUS and MRI or cognition at 2 and 5 years. CONCLUSIONS: Clear ictal discharges are rare in extremely preterm infants. PEDs are common but their significance is unclear. Rhythmic waveforms related to head position are likely artefacts. SIGNIFICANCE: Rhythmic EEG patterns may have a different significance in extremely preterm infants.

A Comparison of the Thompson Encephalopathy Score and Amplitude-Integrated Electroencephalography in Infants with Perinatal Asphyxia and Therapeutic Hypothermia.

BACKGROUND: In previous studies clinical signs or amplitude-integrated electroencephalography (aEEG)-based signs of encephalopathy were used to select infants with perinatal asphyxia for treatment with hypothermia. AIM: The objective of this study was to compare Thompson encephalopathy scores and aEEG, and relate both to outcome. SUBJECTS AND METHODS: Thompson scores, aEEG, and outcome were compared in 122 infants with perinatal asphyxia and therapeutic hypothermia. Of these 122 infants, 41 died and 7 had an adverse neurodevelopmental outcome. A receiver operating characteristics (ROC) analysis was also performed. RESULTS: Thompson scores were higher in infants with more abnormal aEEG background patterns (ANOVA, p < 0.001). The ROC analysis demonstrated that a Thompson score of 11 or higher or an aEEG background pattern of continuous low voltage or worse was associated with an adverse outcome (AUC 0.84 for both). CONCLUSIONS: High Thompson scores and a suppressed aEEG background pattern are associated with an adverse outcome after perinatal asphyxia and therapeutic hypothermia. Further studies are needed to identify the best technique with which to select patients for therapeutic hypothermia.

Severe hypercapnia causes reversible depression of aEEG background activity in neonates: an observational study.

INTRODUCTION: Elevated carbon dioxide (CO2) blood levels have a depressant effect on the central nervous system and can lead to coma in adults. Less is known about the effect of CO2 on the neurological function of infants. OBJECTIVE: To describe the effect of acute severe hypercapnia (PaCO2 >70 mm Hg) on amplitude-integrated electroencephalography (aEEG) and cerebral oxygenation in newborn infants. STUDY DESIGN: Observational study of full-term and preterm infants with acute severe hypercapnia (identified by arterial blood gas measurements), monitored with aEEG. Visual analysis of the aEEG was performed in all infants. In preterm infants <32 weeks postmenstrual age (PMA), analysis of two-channel EEG was performed. Mean spontaneous activity transients (SAT) rate (SATs/min), interval between SATs (ISI in seconds) and the ISI percentage (ISP) were calculated for 10-min periods before, during and after hypercapnia. Mean regional cerebral oxygen saturation (rScO2) and fractional tissue oxygen extraction (FTOE) measured with near-infrared spectroscopy were also calculated for these periods. RESULTS: Twenty-five infants (21 preterm, 4 full-term) comprising 32 episodes of acute severe hypercapnia were identified. Twenty-seven episodes were accompanied by a transient aEEG depression. Twenty-two episodes in 15 preterm infants <32 weeks PMA were quantitatively analysed. During hypercapnia, SAT rate decreased and ISI and ISP increased significantly. No significant change occurred in rScO2 or FTOE during hypercapnia. CONCLUSION: Profound depression of brain activity due to severe hypercapnia is also seen in infants. It can be recognised by an acute depression of the aEEG, without clinically detectable changes in cerebral oxygenation.

Role of EEG background activity, seizure burden and MRI in predicting neurodevelopmental outcome in full-term infants with hypoxic-ischaemic encephalopathy in the era of therapeutic hypothermia.

OBJECTIVE: To investigate the role of EEG background activity, electrographic seizure burden, and MRI in predicting neurodevelopmental outcome in infants with hypoxic-ischaemic encephalopathy (HIE) in the era of therapeutic hypothermia. METHODS: Twenty-six full-term infants with HIE (September 2011-September 2012), who had video-EEG monitoring during the first 72 h, an MRI performed within the first two weeks and neurodevelopmental assessment at two years were evaluated. EEG background activity at age 24, 36 and 48 h, seizure burden, and severity of brain injury on MRI, were compared and related to neurodevelopmental outcome. RESULTS: EEG background activity was significantly associated with neurodevelopmental outcome at 36 h (p = 0.009) and 48 h after birth (p = 0.029) and with severity of brain injury on MRI at 36 h (p = 0.002) and 48 h (p = 0.018). All infants with a high seizure burden and moderate-severe injury on MRI had an abnormal outcome. The positive predictive value (PPV) of EEG for abnormal outcome was 100% at 36 h and 48 h and the negative predictive value (NPV) was 75% at 36 h and 69% at 48 h. The PPV of MRI was 100% and the NPV 85%. The PPV of seizure burden was 78% and the NPV 71%. CONCLUSION: Severely abnormal EEG background activity at 36 h and 48 h after birth was associated with severe injury on MRI and abnormal neurodevelopmental outcome. High seizure burden was only associated with abnormal outcome in combination with moderate-severe injury on MRI.

Lidocaine response rate in aEEG-confirmed neonatal seizures: Retrospective study of 413 full-term and preterm infants.

OBJECTIVE: To investigate the seizure response rate to lidocaine in a large cohort of infants who received lidocaine as second- or third-line antiepileptic drug (AED) for neonatal seizures. METHODS: Full-term (n = 319) and preterm (n = 94) infants, who received lidocaine for neonatal seizures confirmed on amplitude-integrated EEG (aEEG), were studied retrospectively (January 1992-December 2012). Based on aEEG findings, the response was defined as good (>4 h no seizures, no need for rescue medication); intermediate (0-2 h no seizures, but rescue medication needed after 2-4 h); or no clear response (rescue medication needed <2 h). RESULTS: Lidocaine had a good or intermediate effect in 71.4%. The response rate was significantly lower in preterm (55.3%) than in full-term infants (76.1%, p < 0.001). In full-term infants the response to lidocaine was significantly better than midazolam as second-line AED (21.4% vs. 12.7%, p = 0.049), and there was a trend for a higher response rate as third-line AED (67.6% vs. 57%, p = 0.086). Both lidocaine and midazolam had a higher response rate as third-line AED than as second-line AED (p < 0.001). Factors associated with a good response to lidocaine were the following: higher gestational age, longer time between start of first seizure and administration of lidocaine, lidocaine as third-line AED, use of new lidocaine regimens, diagnosis of stroke, use of digital aEEG, and hypothermia. Multivariable analysis of seizure response to lidocaine included lidocaine as second- or third-line AED and seizure etiology. SIGNIFICANCE: Seizure response to lidocaine was seen in ~70%. The response rate was influenced by gestational age, underlying etiology, and timing of administration. Lidocaine had a significantly higher response rate than midazolam as second-line AED, and there was a trend for a higher response rate as third-line AED. Both lidocaine and midazolam had a higher response rate as third-line compared to second-line AED, which could be due to a pharmacologic synergistic mechanism between the two drugs.

Lidocaine-Associated Cardiac Events in Newborns with Seizures: Incidence, Symptoms and Contributing Factors.

BACKGROUND: Lidocaine is an effective therapy for neonatal seizures; however, it is not widely used, presumably due to the risk of cardiac events. OBJECTIVE: To investigate the incidence of cardiac events in full-term and preterm infants receiving lidocaine for seizures. METHODS: Full-term (n = 368) and preterm (n = 153) infants, admitted to a level 3 neonatal intensive care unit from 1992 to 2012, who received lidocaine for seizures were retrospectively studied. The causal relation between reported cardiac events and lidocaine administration was evaluated based on expected plasma concentrations, symptoms and relevant interactions during cardiac events. RESULTS: Cardiac events were reported in 11/521 infants (2.1%; 9 full-term, 2 preterm). In 7/11 infants the causal relation was considered plausible, in 3/11 questionable and in 1/11 implausible. The incidence was calculated to be 1.3-1.9% (n = 7-10/521), but was only 0.4% (n = 1/246, p = 0.02) when using reduced-dose regimens. Important risk factors for cardiac events were unstable potassium, (congenital) cardiac dysfunction and concurrent phenytoin use. CONCLUSIONS: Lidocaine-associated cardiac events were rare in our cohort, especially since the introduction of new reduced-dose regimens. This indicates that lidocaine is safe to use as an antiepileptic drug in full-term and preterm infants.

Early oxygen-utilization and brain activity in preterm infants.

The combined monitoring of oxygen supply and delivery using Near-InfraRed spectroscopy (NIRS) and cerebral activity using amplitude-integrated EEG (aEEG) could yield new insights into brain metabolism and detect potentially vulnerable conditions soon after birth. The relationship between NIRS and quantitative aEEG/EEG parameters has not yet been investigated. Our aim was to study the association between oxygen utilization during the first 6 h after birth and simultaneously continuously monitored brain activity measured by aEEG/EEG. Forty-four hemodynamically stable babies with a GA < 28 weeks, with good quality NIRS and aEEG/EEG data available and who did not receive morphine were included in the study. aEEG and NIRS monitoring started at NICU admission. The relation between regional cerebral oxygen saturation (rScO2) and cerebral fractional tissue oxygen extraction (cFTOE), and quantitative measurements of brain activity such as number of spontaneous activity transients (SAT) per minute (SAT rate), the interval in seconds (i.e. time) between SATs (ISI) and the minimum amplitude of the EEG in µV (min aEEG) were evaluated. rScO2 was negatively associated with SAT rate (ß=-3.45 [CI=-5.76- -1.15], p=0.004) and positively associated with ISI (ß=1.45 [CI=0.44-2.45], p=0.006). cFTOE was positively associated with SAT rate (ß=0.034 [CI=0.009-0.059], p=0.008) and negatively associated with ISI (ß=-0.015 [CI=-0.026- -0.004], p=0.007). Oxygen delivery and utilization, as indicated by rScO2 and cFTOE, are directly related to functional brain activity, expressed by SAT rate and ISI during the first hours after birth, showing an increase in oxygen extraction in preterm infants with increased early electro-cerebral activity. NIRS monitored oxygenation may be a useful biomarker of brain vulnerability in high-risk infants.

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 Community's Seventh Framework Programme.

Neuroimaging in neonatal seizures.

Seizures are the most common sign of neurological dysfunction in full-term neonates, with an incidence estimated at 0.15-3.5/1,000 live births. Neonatal seizures often reflect severe underlying brain injury and are associated with high rates of mortality and morbidity. Prognosis is primarily determined by the nature, site and extent of the underlying aetiology, making accurate diagnosis and identification of associated brain lesions essential. Data on neuroimaging in newborns presenting with seizures is limited and most studies report on MRI findings in infants with a specific underlying problem, such as hypoxic-ischaemic encephalopathy, stroke or metabolic disorders. The aim of this review is to discuss the spectrum of neuroimaging findings in full-term newborns presenting with seizures, divided into subgroups with different underlying aetiologies. A standard neonatal MRI protocol is presented.

Anticonvulsant effectiveness and hemodynamic safety of midazolam in full-term infants treated with hypothermia.

BACKGROUND: Midazolam is used as an anticonvulsant in neonatology, including newborns with perinatal asphyxia treated with hypothermia. Hypothermia may affect the safety and effectiveness of midazolam in these patients. OBJECTIVES: The objective was to evaluate the anticonvulsant effectiveness and hemodynamic safety of midazolam in hypothermic newborns and to provide dosing guidance. METHODS: Hypothermic newborns with perinatal asphyxia and treated with midazolam were included. Effectiveness was studied using continuous amplitude-integrated electroencephalography. Hemodynamic safety was assessed using pharmacokinetic-pharmacodynamic modeling with plasma samples and blood pressure recordings (mean arterial blood pressure) under hypothermia. RESULTS: No effect of therapeutic hypothermia on pharmacokinetics could be identified. Add-on seizure control with midazolam was limited (23% seizure control). An inverse relationship between the midazolam plasma concentration and mean arterial blood pressure could be identified. At least one hypotensive episode was experienced in 64%. The concomitant use of inotropes decreased midazolam clearance by 33%. CONCLUSIONS: Under therapeutic hypothermia, midazolam has limited add-on clinical anticonvulsant effectiveness after phenobarbital administration. Due to occurrence of hypotension requiring inotropic support, midazolam is less suitable as a second-line anticonvulsant drug under hypothermia.

The aetiology of neonatal seizures and the diagnostic contribution of neonatal cerebral magnetic resonance imaging.

AIM: The aim of this study was to delineate aetiologies and explore the diagnostic value of cerebral magnetic resonance imaging (MRI) in addition to cranial ultrasonography (cUS) in infants presenting with neonatal seizures. METHOD: This retrospective cohort study comprised infants (gestational age 35.0-42.6wks) with seizures, confirmed by either continuous amplitude-integrated electroencephalography (aEEG) or standard EEG and admitted during a 14-year period to a level three neonatal intensive care unit (n=378; 216 males, 162 females; mean [SD] birthweight 3334g [594]). All infants underwent cUS and MRI (MRI on median of 5 days after birth, range 0-58d) within the first admission period. RESULTS: An underlying aetiology was identified in 354 infants (93.7%). The most common aetiologies identified were hypoxic-ischaemic encephalopathy (46%), intracranial haemorrhage (12.2%), and perinatal arterial ischaemic stroke (10.6%). When comparing MRI with cUS in these 354 infants MRI showed new findings which did not become apparent on cUS, contributing to a diagnosis in 42 (11.9%) infants and providing additional information to cUS, contributing to a diagnosis in 141 (39.8%). cUS alone would have allowed a diagnosis in only 37.9% of infants (134/354). INTERPRETATION: Cerebral MRI contributed to making a diagnosis in the majority of infants. In 11.9% of infants the diagnosis would have been missed if only cUS were used and cerebral MRI added significantly to the information obtained in 39.8% of infants. These data suggest that cerebral MRI should be performed in all newborn infants presenting with EEG- or aEEG-confirmed seizures.