Mona C. Toet

Amplitude integrated EEG 3 and 6 hours after birth in full term neonates with hypoxic–ischaemic encephalopathy

AIM To assess the prognostic value of amplitude integrated EEG (aEEG) 3 and 6 hours after birth. METHODS Seventy three term, asphyxiated infants were studied (from two different centres), using the Cerebral Function Monitor (CFM Lectromed). The different aEEG tracings were compared using pattern recognition (flat tracing mainly isoelectric (FT); continuous extremely low voltage (CLV); burst–suppression (BS); discontinuous normal voltage (DNV); continuous normal voltage (CNV)) with subsequent outcome. RESULTS Sixty eight infants were followed up for more than 12 months (range 12 months to 6 years).Twenty one out of 68 infants (31%) showed a change in pattern from 3 to 6 hours, but this was only significant in five cases (24%). In three this changed from BS to CNV with a normal outcome. One infant showed a change in pattern from CNV to FT and had a major handicap at follow up. Another infant showed a change in pattern from DNV to BS, and developed a major handicap at follow up. The other 16 infants did not have any significant changes in pattern: 11 infants had CLV, BS, or FT at 3 and 6 hours and died (n = 9) in the neonatal period or developed a major handicap (n = 2). Five infants had a CNV or DNV pattern at 3 and 6 hours, with a normal outcome. The sensitivity and specificity of BS, together with FT and CLV, for poor outcome at 3 hours was 0.85 and 0.77, respectively; at 6 hours 0.91 and 0.86, respectively. The positive predictive value (PPV) was 78% and the negative predictive value (NPV) 84% 3 hours after birth. At 6 hours the PPV was 86% and the NPV was 91%. CONCLUSION aEEG could be very useful for selecting those infants who might benefit from intervention after birth asphyxia.

Predictive value of early neuroimaging, pulsed Doppler and neurophysiology in full term infants with hypoxic-ischaemic encephalopathy.

To evaluate their prognostic value, five different non-invasive techniques were used on 34 full term infants with hypoxic-ischaemic encephalopathy (HIE) within six hours of delivery. Cranial ultrasonography, the resistance index (RI) of the middle cerebral artery obtained with Doppler ultrasonography, somatosensory evoked potentials (SEPs), visual evoked potentials (VEPs) and the cerebral function monitor (CFM) were used. According to the criteria of Sarnat, 11 infants developed mild, seven moderate, and 16 severe encephalopathy. The CFM had the highest positive (PPV 84.2%) and negative predictive value (NPV 91.7%). All but one of the infants with a continuous pattern had a good outcome. The CFM of 11 cases with a suppression-burst pattern changed to a continuous pattern over 24 to 48 hours in four infants, and was associated with a normal outcome in three. All five cases with an isoelectric CFM died. The SEPs also provided useful information (PPV 81.8%; NPV 91.7%). VEPs were often delayed during the first hours or life and did not carry a poor prognosis in five of 14 cases (PPV 77.3%). Both ultrasonography and Doppler RI were of little value, as they were almost always normal at this early stage. In 34 full term infants with HIE, studied within 6 hours of life, the CFM and SEPs provided the most useful information about the expected course of encephalopathy and subsequent neurodevelopmental outcome.

Impact of patent ductus arteriosus and subsequent therapy with indomethacin on cerebral oxygenation in preterm infants.

OBJECTIVES. A hemodynamically important patent ductus arteriosus is a common problem in the first week of life in the preterm infant. Although patent ductus arteriosus induces alterations in organ perfusion, scarce information is available of the impact of patent ductus arteriosus and its subsequent treatment on the oxygen supply and oxygen extraction of the brain. We investigated the impact of patent ductus arteriosus and its treatment with indomethacin on regional cerebral oxygen saturation and fractional tissue oxygen extraction by using near-infrared spectroscopy. PATIENTS AND METHODS. Twenty infants with patent ductus arteriosus (gestational age: <32 weeks), subsequently treated with indomethacin, were monitored for mean arterial blood pressure, arterial oxygen saturation, near-infrared spectroscopy–determined regional cerebral oxygen saturation, and fractional tissue oxygen extraction ([arterial oxygen saturation − regional cerebral oxygen saturation]/arterial oxygen saturation). Ten-minute periods were selected and averaged during patent ductus arteriosus, at 10, 20, 30, 60, and 120 minutes, and at 6,12, 24, and 36 hours after starting indomethacin treatment (to ductal closure) for mean arterial blood pressure, arterial oxygen saturation, regional cerebral oxygen saturation, and fractional tissue oxygen extraction. The patients with patent ductus arteriosus were matched for gestational age, birth weight, postnatal age, and severity of respiratory distress syndrome with infants without patent ductus arteriosus, who served as control subjects. RESULTS. Mean arterial blood pressure and regional cerebral oxygen saturation were significantly lower and fractional tissue oxygen extraction significantly higher compared with the control infants during patent ductus arteriosus (mean arterial blood pressure: 33 ± 5 vs 38 ± 6 mmHg; regional cerebral oxygen saturation: 62% ± 9% vs 72% ± 10%; fractional tissue oxygen extraction: 0.34 ± 0.1 vs 0.25 ± 0.1, respectively). Regional cerebral oxygen saturation and fractional tissue oxygen extraction were lower and higher, respectively, up to 24 hours after the start of indomethacin but normalized to control values afterward. Indomethacin had no additional negative effect on cerebral oxygenation. CONCLUSIONS. A hemodynamically significant patent ductus arteriosus has a negative effect on cerebral oxygenation in the premature infant. Subsequent and adequate treatment of a patent ductus arteriosus may prevent diminished cerebral perfusion and subsequent decreased oxygen delivery, which reduces the change of damage to the vulnerable immature brain.

Cerebral Oxygenation and Electrical Activity After Birth Asphyxia: Their Relation to Outcome

OBJECTIVE. To determine the value of regional cerebral oxygen saturation (rSo2), fractional cerebral tissue oxygen extraction (FTOE) measured by near-infrared spectroscopy (NIRS), and amplitude integrated electroencephalogram (aEEG) after birth asphyxia in relation to neurodevelopmental outcome. METHODS. NIRS measured rSo2, FTOE, and aEEG were monitored simultaneously, together with arterial oxygen saturation (Sao2) and blood pressure during the first 48 hours after severe birth asphyxia in 18 term infants. FTOE was calculated as [Sao2 − rSo2]/Sao2. Neurodevelopmental outcome was assessed at 3, 9, and 18 months and 3 and 5 years of age. At the time points 6, 12, 18, 24, 30, 36, 42, and 48 hours after birth, the mean values of Sao2, rSo2, FTOE, and mean arterial blood pressure were calculated over a 1-hour period. A stepwise-regression model was used to investigate the relative contribution of rSo2, FTOE, or aEEG to developmental outcome. RESULTS. Nine Infants died during the neonatal period as a result of neurologic deterioration, and 8 infants had a normal outcome at 5 years of age. One child developed learning disabilities and a mild diplegia. The rSo2 and FTOE remained stable in infants with a normal outcome. The rSo2 increased and the FTOE decreased after 24 hours in the infants with an adverse outcome. (rSo2: 65% vs 84% at 12 and 48 hours, respectively; FTOE: 0.32 vs 0.12 at 12 and 48 hours, respectively). aEEG showed the closest relationship with outcome, but also rSo2 showed a significant correlation 24 hours after birth. CONCLUSIONS. rSo2 and FTOE seem to reflect secondary energy failure. aEEG showed the closest relationship with outcome after severe birth asphyxia.

Effect of Treatment of Subclinical Neonatal Seizures Detected With aEEG: Randomized, Controlled Trial

OBJECTIVES: The goals were to investigate how many subclinical seizures in full-term neonates with hypoxic-ischemic encephalopathy (HIE) would be missed without continuous amplitude-integrated electroencephalography (aEEG) and whether immediate treatment of both clinical and subclinical seizures would result in a reduction in the total duration of seizures and a decrease in brain injury, as seen on MRI scans. METHODS: In this multicenter, randomized, controlled trial, term infants with moderate to severe HIE and subclinical seizures were assigned randomly to either treatment of both clinical seizures and subclinical seizure patterns (group A) or blinding of the aEEG registration and treatment of clinical seizures only (group B). All recordings were reviewed with respect to the duration of seizure patterns and the use of antiepileptic drugs (AEDs). MRI scans were scored for the severity of brain injury. RESULTS: Nineteen infants in group A and 14 infants in group B were available for comparison. The median duration of seizure patterns in group A was 196 minutes, compared with 503 minutes in group B (not statistically significant). No significant differences in the number of AEDs were seen. Five infants in group B received AEDs when no seizure discharges were seen on aEEG traces. Six of 19 infants in group A and 7 of 14 infants in group B died during the neonatal period. A significant correlation between the duration of seizure patterns and the severity of brain injury in the blinded group, as well as in the whole group, was found. CONCLUSIONS: In this small group of infants with neonatal HIE and seizures, there was a trend for a reduction in seizure duration when clinical and subclinical seizures were treated. The severity of brain injury seen on MRI scans was associated with a longer duration of seizure patterns.

Recovery of amplitude integrated electroencephalographic background patterns within 24 hours of perinatal asphyxia

Objective: To assess the time course of recovery of severely abnormal initial amplitude integrated electroencephalographic (aEEG) patterns (flat trace (FT), continuous low voltage (CLV), or burst suppression (BS)) in full term asphyxiated neonates, in relation to other neurophysiological and neuroimaging findings and neurodevelopmental outcome. Methods: A total of 190 aEEGs of full term infants were reviewed. The neonates were admitted within 6 hours of birth to the neonatal intensive care unit because of perinatal asphyxia, and aEEG recording was started immediately. In all, 160 infants were included; 65 of these had an initial FT or CLV pattern and 25 an initial BS pattern. Neurodevelopmental outcome was assessed using a full neurological examination and the Griffiths’ mental developmental scale. Results: In the FT/CLV group, the background pattern recovered to continuous normal voltage within 24 hours in six of the 65 infants (9%). All six infants survived the neonatal period; one had a severe disability, and five were normal at follow up. In the BS group, the background pattern improved to normal voltage in 12 of the 25 infants (48%) within 24 hours. Of these infants, one died, five survived with moderate to severe disability, two with mild disability, and four were normal. The patients who did not recover within 24 hours either died in the neonatal period or survived with a severe disability. Conclusion: In this study there was a small group of infants who presented with a severely abnormal aEEG background pattern within six hours of birth, but who achieved recovery to a continuous normal background pattern within the first 24 hours. Sixty one percent of these infants survived without, or with a mild, disability.

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.

Treatment of symptomatic congenital cytomegalovirus infection with valganciclovir.

Abstract Cytomegalovirus (CMV) is the most common cause of congenital infection in humans. Some congenitally infected infants will develop sequelae later in life, especially sensorineural hearing loss (SNHL) and mental retardation. There is no generally accepted antiviral therapy for the treatment of symptomatic congenital CMV infections yet. We present a neonate with symptomatic congenital CMV infection, who was treated with intravenous (iv) ganciclovir (GCV) during 18 days and subsequently with oral valganciclovir (VGCV) for 5.5 months, in an attempt to prevent development of SNHL. GCV was given intravenously 10 mg/kg/day in two doses and VGCV doses ranged from 280–850 mg/m2 bidaily (bid). Our experience shows that it is not possible to give a fixed dosing regime for VGCV in neonates and that continuous adaptation of dose is necessary to achieve stable target levels of GCV and to keep the viral load in urine at undetectable level. At 18 months of age no hearing deterioration has occurred. While the current findings are encouraging, the limitations of a single case report with a relatively short follow-up emphasizes the need for further prospective randomized studies to evaluate pharmacokinetics, efficacy and safety of VGCV therapy in neonates with congenital CMV infection.

Midazolam and amplitude-integrated EEG in asphyxiated full-term neonates

Aim: In the present, prospective study, the relation between the levels of midazolam, its two active metabolites—1‐hydroxy‐midazolam (OH‐midazolam) and 1‐hydroxy‐midazolam‐glucuronide (glumidazolam)—and the aEEG were examined. Patients and methods: Fifteen full‐term neonates with seizures due to hypoxic‐ischaemic encephalopathy admitted to our NICU were included. Midazolam (loading dose 0.05 mg/kg in 10min, maintenance dose 0.15mg/kg/h) was used as an add‐on anti‐convulsant after phenobarbital and lidocaine because of continuing seizures. Amplitude‐integrated EEG background pattern was scored at the start of midazolam and at the time of blood sampling as continuous normal voltage (CNV), discontinuous normal voltage (DNV), burst suppression (BS), continuous low voltage (CLV) or flat trace (FT). Serum levels of midazolam, OH‐midazolam and glu‐midazolam were measured at least 8 h after the start with HPLC. Results: In 11/15 patients, seizures were abolished with the addition of midazolam. In the remaining patients, seizure frequency was reduced in one and unchanged in three. Amplitude‐integrated EEG background pattern at the start of midazolam was CNV in two, DNV in six, BS in five and CLV in two. Moderate, temporary suppression of the aEEG background pattern lasting less than 2h was seen in four neonates. Amplitude‐integrated EEG at midazolam sampling was CNV in two, DNV in seven, CLV in two and FT in four. Serum levels of midazolam ranged from 0.10 to 1.76 mg/l, OH‐midazolam from 0.05 to 0.28 mg/l and glu‐midazolam from 0.85 to 4.36 mg/l.

Detection of subclinical electroencephalographic seizure patterns with multichannel amplitude-integrated EEG in full-term neonates

OBJECTIVE To compare the seizure pattern detection rate of single-channel and multichannel amplitude-integrated EEG (aEEG), using conventional EEG (cEEG) as a gold standard, in full-term neonates with hypoxic-ischemic encephalopathy. The optimal electrode derivation for seizure detection with single-channel aEEG was also investigated. METHODS Twelve infants with cEEG seizure patterns (10s) were investigated. cEEG signals were transformed into aEEG signals. Seizure patterns and the number of patients identified with 1 seizure patterns were calculated for single- and multichannel aEEG. RESULTS On cEEG, 121 seizure patterns with a mean duration of 58s were identified, 68% of which occurred over the centrotemporal region. The sensitivity of aEEG for the detection of seizure patterns was 30% (C.I.: 0.22-0.38) for single-channel aEEG and 39% (C.I.: 0.31-0.48) for multichannel aEEG. Multichannel aEEG identified all patients with 1 seizure pattern (C.I.: 0.75-1.00), whereas single-channel aEEG (with C4-C3 as the optimal electrode derivation) identified all but one of the patients (C.I.: 0.66-0.99). CONCLUSIONS Seizure pattern detection rate is slightly better with multichannel aEEG compared with single-channel (C4-C3) aEEG. Multichannel aEEG identified correctly all patients with 1 seizure pattern in this small selection of patients. SIGNIFICANCE Single-channel aEEG may detect most patients (in a selected group) with severe neonatal seizures patterns; patient identification can be improved using multichannel recordings.