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Background and Objectives Therapeutic hypothermia can influence the pharmacokinetics and pharmacodynamics of drugs, the discipline which is called thermopharmacology. We studied the effect of therapeutic hypothermia on the pharmacokinetics of phenobarbital in asphyxiated neonates, and the clinical efficacy and the effect of phenobarbital on the continuous amplitude-integrated electroencephalography (aEEG) in a prospective study. Patients and Methods Data were obtained from the prospective SHIVER study, performed in two of the ten Dutch level III neonatal intensive care units. Phenobarbital data were collected between 2008 and 2010. Newborns were eligible for inclusion if they had a gestational age of at least 36 weeks and presented with perinatal asphyxia and encephalopathy. According to protocol in both hospitals an intravenous (repeated) loading dose of phenobarbital 20 mg/kg divided in 1–2 doses was administered if seizures occurred or were suspected before or during the hypothermic phase. Phenobarbital plasma concentrations were measured in plasma using a fluorescence polarization immunoassay. aEEG was monitored continuously. Results and Conclusion A one-compartmental population pharmacokinetic/pharmacodynamic model was developed using a multi-level Markov transition model. No (clinically relevant) effect of moderate therapeutic hypothermia on phenobarbital pharmacokinetics could be identified. The observed responsiveness was 66 %. While we still advise an initial loading dose of 20 mg/kg, clinicians should not be reluctant to administer an additional dose of 10–20 mg/kg. An additional dose should be given before switching to a second-line anticonvulsant drug. Based on our pharmacokinetic/pharmacodynamic model, administration of phenobarbital under hypothermia seems to reduce the transition rate from a continuous normal voltage (CNV) to discontinuous normal voltage aEEG background level in hypothermic asphyxiated newborns, which may be attributed to the additional neuroprotection of phenobarbital in infants with a CNV pattern.

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.

Background:In preterm infants with respiratory distress syndrome (RDS) nasal continuous positive airway pressure (nCPAP) with the “InSurE” procedure (intubation, surfactant, extubation) is increasingly used. However, its effect on cerebral oxygenation and brain function is not known.Objective:To evaluate the effects of the “InSurE” procedure in infants with RDS on regional cerebral oxygen saturation (rScO2) and relative cerebral fractional tissue oxygen extraction (cFTOE) using near infrared spectroscopy and on electrical brain activity using amplitude-integrated electroencephalography (aEEG).Methods:Sixteen infants with RDS, treated with the “InSurE” procedure, and 16 matched controls with nCPAP, were monitored for mean arterial blood pressure (MABP), arterial oxygen saturation (SaO2), rScO2, cFTOE and aEEG. Ten-minute periods were selected and averaged at 120 and 20 minutes before, during the procedure and at 30 minutes, 1, 2, 6, 12 and 24 h after the start of the “InSurE” procedure. aEEG was analysed by quantitative and qualitative (Burdjalov score) methods.Results:MABP was not different between groups on all time points. rScO2 and cFTOE were comparable between groups, but there was a trend towards lower rScO2 and higher cFTOE 30 minutes after opioid administration in the “InSurE” infants compared with controls (62% (SD 11) vs 68% (SD 10) and 0.30 (SD 0.10 ) vs 0.28 (SD 0.11), respectively). aEEG amplitudes and Burdjalov scores were significantly lower in “InSurE” infants from 30 minutes after opioid administration up to 24 h after the start of the procedure (p<0.05).Conclusion:In the present study, the “InSurE” procedure did not induce perturbation of cerebral oxygen delivery and extraction, whereas electrical brain activity decreased for a prolonged period of time.

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.

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. 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. 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. 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. European Community's Seventh Framework Programme.

We tested the hypothesis that glutamate (Glx) levels as demonstrated by proton magnetic resonance spectroscopy ((1)H-MRS) are elevated in brain tissue of neonates with severe hypoxic-ischemic encephalopathy (HIE). Studies were performed in 26 neonates (median gestational age 40.5 weeks, range 36.7-42.4 weeks; median birth weight 3,360 g, range 2,180-4,200 g). The median postnatal age at the time of testing was 2.5 days (range 1-7 days). HIE was scored according to Sarnat as grade I (n = 4), grade II (n = 15) or grade III (n = 7). Results for neonates with mild to moderate HIE (group 1) were compared to those with severe HIE (group 2). After magnetic resonance imaging, (1)H-MRS was performed in a single volume of interest including the basal ganglia. An echo time of 31 ms was used. After curve-fitting procedures, peak area ratios of different brain metabolites were calculated. The median total Glx/N-acetylaspartate ratio was 1.21 (range 0.64-3.25) in group 1 versus 1.55 (range 1.10-2.75) in group 2 (p = 0.035). The median total Glx/choline ratio was 1.33 (range 0.71-2.52) in group 1 versus 2.14 (range 1.21-3.55) in group 2 (p = 0.019). We concluded that during the first days of life, Glx was elevated in the basal ganglia of neonates with severe HIE.

Background and aimsEarly prediction of neurodevelopmental outcome following hypoxic-ischaemic encephalopathy remains a challenge. The aim of this retrospective study was to evaluate the aEEG background patterns and Thompson score on admission in asphyxiated neonates receiving hypothermia regarding outcome and neonatal variables.MethodsAfter excluding congenital malformations and muscle paralysis, 89 neonates (January 2008 to June 2012) were included (GA: 39.7 plus or minus 1.8 wks; BW: 3504 plus or minus 640 g). On admission the Thompson score and aEEG were recorded. aEEG was scored as Continuous Normal Voltage (CNV), Discontinuous Normal Voltage (DNV), Burst-Suppression (BS), Continuous Low Voltage (CLV) or Flat Trace (FT). The combination of one or more of the following event (s): death, cerebral palsy, and Griffiths DQ less than 85 at 18 months were considered an adverse outcome. ANOVA, correlation, and binary logistic regression analyses were performed.ResultsThompson scores (in mean plus or minus sd) were associated with aEEG pattern (CNV: 8.3 plus or minus 1.7; DNV: 8.9 plus or minus 1.9; BS: 11.6 plus or minus 3.6; CLV: 12.0 plus or minus 2.1; FT: 13.1 plus or minus 3.2; p < 0.001). Also, both aEEG and Thompson score were statistically correlated with Apgar 1 and 5 min scores (p < 0.05). Using a logistic regression model, both Thompson score (OR = 1.43; 95% CI = [1.15; 1.77]) and aEEG pattern (BS: OR = 4.06; 95% CI = [0.74; 22.16]; CLV: OR = 11.10; 95% CI = [1.38; 89.66]; FT: OR = 13.35; 95% CI = [1.87; 95.31]; reference group: CNV+DNV) were significant predictors of an adverse outcome.ConclusionsBoth Thompson scores and aEEG are associated with outcome in neonates receiving hypothermia for perinatal asphyxia and with 1 min Apgar scores. Further studies are needed to identify which method is preferable for selection of neonates for hypothermia.

Background and aimEarly brain activity is crucial for neuronal growth. It is well known that the cerebral cortex develops rapidly in the last trimester of pregnancy. We investigated whether early brain activity was related to the rate of cortical development over the 10 wks before term equivalent age in preterm infants.Methods35 infants (GA: 27.1 plus or minus 0.7; BW: 937 plus or minus 172) without morphine, were monitored with EEG/aEEG. Three periods were selected at 20-24 h, 32-36 h, 44-48 h. Minimum amplitude,% of timeResultsIncreased SATrate was positively associated with deltaGMv, inner and outer surface (resp beta :7.4, p:0.001; beta :46.6,p:0.002; beta :57.5, p:0.001). Consistent with these findings, ISI was negatively associated with changes in GMv, inner and outer surface ( beta :-3.4, p: 0.007; beta :-17.8, p: 0.034; beta :-27.7, p: 0.006). Min aEEG and% of time <5 mu V were associated with inner and outer surface at 40 wks (respectively: beta :46.2, p:0.043; beta :53.0, p:0.041; and beta :-2.9, p:0.025; beta :-3.5, p:0.019). No effect on thickness and gyrification was found.ConclusionsEarly brain activity seems to be associated with cortical development suggesting that adequate brain activity in the early neuronal networks is necessary to lead to growth and development of neonatal cerebral cortical brain, measured by structural MRI.

Background and aims(a)EEG predicts outcome in full-term infants with HIE. Recently, increased perfusion in the basal ganglia, detected with arterial spin labelling (ASL), was shown to be related to brain injury1. Our aim was to investigate the relationship between (a)EEG and brain tissue perfusion.Methods20 subjects with HIE, eligible for hypothermia, were enrolled. Four 1-hour periods were selected from the (a)EEG: P1 (4-6 h), P2 (20-24 h), P3 (32-36 h) and P4 (44-48 h). Burst-rate (number of burst/min) and IBI (interburst interval) from the rawEEG, minimum (MIN) amplitude ( mu V) and the% of time <5 mu V (% < 5 mu V) of the aEEG, were included in the analysis. Mean perfusion in the basal ganglia and thalami (BGT-CBF) was measured using ASL-MRI.ResultsIn P1 a relation was found for suppressed aEEG signal (% <5 mu V: p = 0.015; R = 0.709; MIN: p = 0.028; R = -0.659) and increased BGT-CBF. Concomitantly, a negative correlation was found between burst-rate and BGT-CBF, MIN in P2-3-4 (p < 0.05), whereas suppressed background pattern expressed by% <5 mu V and IBI correlated positively with higher BGT-CBF (p < 0.05). In the multivariable regression, corrected for sedatives and anti-epileptic medication, the association between EEG parameters and BGT-CBF persisted (p < 0.05), with the exception of burst-rate in P1.ConclusionA depressed cortical activity in the first 48 h after birth, secondary to hypoxic-ischemia, is related to an abnormally increased brain perfusion. Using both techniques together might be of additional value to predict neurodevelopmental outcome.ReferencesWintermark P et al. Am J Neuroradiol 2011; 32:2023-29