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1.  Early clinical signs in neonates with hypoxic ischemic encephalopathy predict an abnormal amplitude-integrated electroencephalogram at age 6 hours 
BMC Pediatrics  2013;13:52.
An early clinical score predicting an abnormal amplitude-integrated electroencephalogram (aEEG) or moderate-severe hypoxic ischemic encephalopathy (HIE) may allow rapid triage of infants for therapeutic hypothermia. We aimed to determine if early clinical examination could predict either an abnormal aEEG at age 6 hours or moderate-severe HIE presenting within 72 hours of birth.
Sixty infants ≥ 36 weeks gestational age were prospectively enrolled following suspected intrapartum hypoxia and signs of encephalopathy. Infants who were moribund, had congenital conditions that could contribute to the encephalopathy or had severe cardio-respiratory instability were excluded. Predictive values of the Thompson HIE score, modified Sarnat encephalopathy grade (MSEG) and specific individual signs at age 3–5 hours were calculated.
All of the 60 infants recruited had at least one abnormal primitive reflex. Visible seizures and hypotonia at 3–5 hours were strongly associated with an abnormal 6-hour aEEG (specificity 88% and 92%, respectively), but both had a low sensitivity (47% and 33%, respectively). Overall, 52% of the infants without hypotonia at 3–5 hours had an abnormal 6-hour aEEG. Twelve of the 29 infants (41%) without decreased level of consciousness at 3–5 hours had an abnormal 6-hour aEEG (sensitivity 67%; specificity 71%). A Thompson score ≥ 7 and moderate-severe MSEG at 3–5 hours, both predicted an abnormal 6-hour aEEG (sensitivity 100 vs. 97% and specificity 67 vs. 71% respectively). Both assessments predicted moderate-severe encephalopathy within 72 hours after birth (sensitivity 90%, vs. 88%, specificity 92% vs. 100%). The 6-hour aEEG predicted moderate-severe encephalopathy within 72 hours (sensitivity 75%, specificity 100%) but with lower sensitivity (p = 0.0156) than the Thompson score (sensitivity 90%, specificity 92%). However, all infants with a normal 3- and 6-hour aEEG with moderate-severe encephalopathy within 72 hours who were not cooled had a normal 24-hour aEEG.
The encephalopathy assessment described by the Thompson score at age 3–5 hours is a sensitive predictor of either an abnormal 6-hour aEEG or moderate-severe encephalopathy presenting within 72 hours after birth. An early Thompson score may be useful to assist with triage and selection of infants for therapeutic hypothermia.
PMCID: PMC3635928  PMID: 23574923
Asphyxia; Neonate; Hypoxic ischemic encephalopathy; Electroencephalogram; aEEG; Prognostic
2.  Predictive value of the amplitude integrated EEG in infants with hypoxic ischaemic encephalopathy: data from a randomised trial of therapeutic hypothermia 
The amplitude integrated EEG (aEEG) is reputed to be one of the best predictors of neurological outcome following hypoxic ischaemic encephalopathy in term newborns and was used to select infants into trials of neuroprotection with hypothermia, but its predictive value and the effect of moderate hypothermia on the aEEG have not previously been examined in a randomised study. The positive predictive value (PPV) of the aEEG recorded within 6 h of birth for death or disability at 18 months of age was determined in 314 infants born after 35 weeks gestation who were randomised to receive standard care with or without cooling for 72 h. The aEEG was classified according to voltage and by pattern. The PPV of a severely abnormal aEEG assessed by the voltage and pattern methods was 0.63 and 0.59 respectively in non-cooled infants and 0.55 and 0.51 in cooled infants (p>0.05). Although the differences in PPV between cooled and non-cooled groups were not significant, they are consistent with observational studies showing a lower PPV in infants treated with hypothermia, probably due to a neuroprotective effect of cooling.
PMCID: PMC3888630  PMID: 23800393
Neonatology; Neurodisability; Evidence Based Medicine
3.  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.

PMCID: PMC1720950  PMID: 10375357
4.  Predictive value of early continuous amplitude integrated EEG recordings on outcome after severe birth asphyxia in full term infants. 
The background pattern in single channel amplitude integrated EEG recordings (aEEG) was recorded in 47 infants within the first six hours after birth to see if this could predict outcome after birth asphyxia. The aEEG background pattern during the first six hours of life was continuous and of normal voltage in 26 infants. All these infants survived; 25 were healthy, one had delayed psychomotor development. A continuous but extremely low voltage pattern was present in two infants, both of whom survived with severe handicap. Five infants had flat (mainly isoelectric) tracings during the first six hours of life; four died in the neonatal period, and one survived with severe neurological handicap. Burst-suppression pattern was identified in 14 infants, of whom five died, six survived with severe handicap, and three were healthy at follow up. The type of background pattern recorded within the first six postnatal hours in the aEEG tracings predicted outcome correctly in 43 of 47 (91.5%) infants. Use of aEEG monitoring can predict outcome, with a high degree of accuracy, after birth asphyxia, within the first six hours after birth. The predictive value of a suppression-burst pattern was, however, somewhat lower than the other background patterns. The aEEG seems to be a feasible technique for identifying infants at high risk of subsequent brain damage who might benefit from interventionist treatment after asphyxia.
PMCID: PMC2528413  PMID: 7743282
5.  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.
PMCID: PMC1721875  PMID: 15846017
6.  Evolution of Encephalopathy during Whole Body Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy 
The Journal of Pediatrics  2011;160(4):567-572.e3.
To examine the predictive ability of stage of hypoxic-ischemic encephalopathy (HIE) for death or moderate/severe disability at 18 months among neonates undergoing hypothermia.
Study design
Stage of encephalopathy was evaluated at <6 hr of age, during study intervention and at discharge among 204 participants in the NICHD Neonatal Research Network Trial of whole body hypothermia for HIE. HIE was examined as a predictor of outcome by regression models.
Moderate and severe HIE occurred at <6 hrs of age among 68% and 32% of 101 hypothermia group infants and 60% and 40% of 103 control group infants, respectively. At 24 and 48 hrs of study intervention, infants in the hypothermia group had less severe HIE than infants in the control group. Persistence of severe HIE at 72 hrs increased the risk of death or disability after controlling for treatment group. The discharge exam improved the predictive value of stage of HIE at < 6hrs for death/disability.
On serial neurological examinations, improvement in stage of HIE was associated with cooling. Persistence of severe HIE at 72 hours and an abnormal neurological exam at discharge was associated with a greater risk of death or disability.
PMCID: PMC3299861  PMID: 22050871
Neurological examinations; neonates; clinical biomarker; death; disability
7.  Low Voltage aEEG as predictor of Intracranial Hemorrhage in preterm infants 
Pediatric neurology  2011;44(5):364-369.
The objectives of this prospective cohort study were to identify amplitude-integrated electroencephalography (aEEG) background patterns predictive of severe intracranial hemorrhage. Thirty ventilated preterm newborns <1000 grams were assessed using an aEEG cerebral function monitor and ultrasound measurement of cerebral blood flow (CBF) velocity at time of surfactant administration and tracheal suctioning simultaneously during first 48 hours of life. Birth weight was 624 ± 200 g (mean ± SD) and gestational age was 25 ± 2 weeks. Background electrical activity was predominantly discontinuous in 72% of infants. A sharp increase in electrical activity/burst density was observed during surfactant administration and tracheal suctioning in most infants with a 33.5 % increase in mean CBF velocity. Burst suppression with low voltage was identified in 57% infants with grade 3-4 Intracranial hemorrhage, while no infant without hemorrhage exhibited this pattern (P = .014). We conclude that aEEG low voltage burst suppression might have useful clinical applications with 100% positive vale for severe intracranial hemorrhage.
PMCID: PMC3160756  PMID: 21481745
8.  The Prognostic Value of Amplitude-Integrated EEG in Full-Term Neonates with Seizures 
PLoS ONE  2013;8(11):e78960.
Neonatal seizures pose a high risk for adverse outcome in survived infants. While the prognostic value of amplitude-integrated electroencephalogram (aEEG) is well established in neonates with encephalopathy and asphyxia, neonatal seizure studies focusing on the direct correlation between early aEEG measurement and subsequent neurologic outcome are scarce. In this study, the prognostic value of aEEG features was systematically analyzed in 143 full-term neonates to identify prognostic indicators of neurodevelopmental outcome. Neonatal aEEG features of background pattern, cyclicity, and seizure activity, as well as the etiology of neonatal seizures, were significantly associated with neurodevelopmental outcome at one year of age. aEEG background pattern was highly associated with neurologic outcomes (χ2 = 116.9), followed by aEEG cyclicity (χ2 = 87.2) and seizure etiology (χ2 = 79.3). Multiple linear regression showed that the four predictors explained 71.2% of the variation in neurological outcome, with standardized β coefficients of 0.44, 0.24, 0.22, and 0.14 for the predictors of aEEG background pattern, cyclicity, etiology, and aEEG seizure activity, respectively. This clinically applicable scoring system based on etiology and three aEEG indices would allow pediatricians to assess the risk for neurodevelopmental impairment and facilitate an early intervention in newborns developing seizures.
PMCID: PMC3827298  PMID: 24236076
9.  Video-EEG monitoring in newborns with hypoxic-ischemic encephalopathy treated with hypothermia 
Neurology  2011;76(6):556-562.
Therapeutic hypothermia (TH) is becoming standard of care in newborns with hypoxic-ischemic encephalopathy (HIE). The prognostic value of the EEG and the incidence of seizures during TH are uncertain.
To describe evolution of EEG background and incidence of seizures during TH, and to identify EEG patterns predictive for MRI brain injury.
A total of 41 newborns with HIE underwent TH. Continuous video-EEG was performed during hypothermia and rewarming. EEG background and seizures were reported in a standardized manner. Newborns underwent MRI after rewarming. Sensitivity and specificity of EEG background for moderate to severe MRI brain injury was assessed at 6-hour intervals during TH and rewarming.
EEG background improved in 49%, remained the same in 38%, and worsened in 13%. A normal EEG had a specificity of 100% upon initiation of monitoring and 93% at later time points. Burst suppression and extremely low voltage patterns held the greatest prognostic value only after 24 hours of monitoring, with a specificity of 81% at the beginning of cooling and 100% at later time points. A discontinuous pattern was not associated with adverse outcome in most patients (73%). Electrographic seizures occurred in 34% (14/41), and 10% (4/41) developed status epilepticus. Seizures had a clinical correlate in 57% (8/14) and were subclinical in 43% (6/14).
Continuous video-EEG monitoring in newborns with HIE undergoing TH provides prognostic information about early MRI outcome and accurately identifies electrographic seizures, nearly half of which are subclinical.
PMCID: PMC3053178  PMID: 21300971
10.  Chronological changes of the amplitude-integrated EEG in a neonate with molybdenum cofactor deficiency 
Molybdenum cofactor (Moco) deficiency is a rare neurometabolic disorder, characterized by neurological impairment and refractive seizures, due to toxic accumulation of sulfite in the brain. Earlier it was suggested that in Moco-deficient humans maternal clearance of neurotoxic metabolites prevents prenatal brain damage. However, limited data are available about the time profile in which neurophysiologic deterioration occurs after birth. The amplitude-integrated electroencephalography (aEEG) is a bedside method in neonates to monitor cerebral recovery after hypoxic-ischemic insults, detect epileptic activity, and evaluate antiepileptic drug treatment. We describe a chronological series of changes in aEEG tracings in a neonate with Moco deficiency. He presented with myoclonic spasms and hypertonicity a few hours after birth, however, the aEEG pattern was still normal. Within 2 days, the aEEG rapidly changed into a burst suppression pattern with repetitive seizures. After antiepileptic treatment, the aEEG remained abnormal. In this patient, the normal aEEG pattern at birth may have been due to maternal clearance of sulfite in utero. After birth, accumulation of sulfite causes progressive brain damage, reflected by the progressive depression of the aEEG tracings. This is in agreement with the results from a Moco-deficient mouse model, suggesting that maternal sulfite clearance suppresses prenatal brain damage. To our knowledge, this is the first case report describing the chronological changes in the aEEG pattern in a Moco-deficient patient. Insight into the time profile in which neurologic deterioration in Moco-deficient humans occurs is essential, especially when potential treatment strategies are being evaluated.
PMCID: PMC3757261  PMID: 20865336
11.  Early single-channel aEEG/EEG predicts outcome in very preterm infants 
To characterize early amplitude-integrated electroencephalogram (aEEG) and single-channel EEG (aEEG/EEG) in very preterm (VPT) infants for prediction of long-term outcome.
Forty-nine infants with median (range) gestational age of 25 (22–30) weeks.
Amplitude-integrated electroencephalogram/EEG recorded during the first 72 h and analysed over 0–12, 12–24, 24–48 and 48–72 h, for background pattern, sleep–wake cycling, seizures, interburst intervals (IBI) and interburst percentage (IB%). In total, 2614 h of single-channel EEG examined for seizures. Survivors were assessed at 2 years corrected age with a neurological examination and Bayley Scales of Infant Development-II. Poor outcome was defined as death or survival with neurodevelopmental impairment. Good outcome was defined as survival without impairment.
Thirty infants had good outcome. Poor outcome (n = 19) was associated with depressed aEEG/EEG already during the first 12 h (p = 0.023), and with prolonged IBI and higher IB% at 24 h. Seizures were present in 43% of the infants and associated with intraventricular haemorrhages but not with outcome. Best predictors of poor outcome were burst-suppression pattern [76% correctly predicted; positive predictive value (PPV) 63%, negative predictive value (NPV) 91%], IBI > 6 sec (74% correctly predicted; PPV 67%, NPV 79%) and IB% > 55% at 24 h age (79% correctly predicted; PPV 72%, NPV 80%). In 35 infants with normal cerebral ultrasound during the first 3 days, outcome was correctly predicted in 82% by IB% (PPV 82%, NPV 83%).
Long-term outcome can be predicted by aEEG/EEG with 75–80% accuracy already at 24 postnatal hours in VPT infants, also in infants with no early indication of brain injury.
PMCID: PMC3437495  PMID: 22530996
Burst suppression; Cranial ultrasound; Interburst interval; Neurodevelopmental impairment; Seizure
12.  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.
PMCID: PMC2528491  PMID: 7583610
13.  The Metabolomic Profile of Umbilical Cord Blood in Neonatal Hypoxic Ischaemic Encephalopathy 
PLoS ONE  2012;7(12):e50520.
Hypoxic ischaemic encephalopathy (HIE) in newborns can cause significant long-term neurological disability. The insult is a complex injury characterised by energy failure and disruption of cellular homeostasis, leading to mitochondrial damage. The importance of individual metabolic pathways, and their interaction in the disease process is not fully understood. The aim of this study was to describe and quantify the metabolomic profile of umbilical cord blood samples in a carefully defined population of full-term infants with HIE.
Methods and Findings
The injury severity was defined using both the modified Sarnat score and continuous multichannel electroencephalogram. Using these classification systems, our population was divided into those with confirmed HIE (n = 31), asphyxiated infants without encephalopathy (n = 40) and matched controls (n = 71). All had umbilical cord blood drawn and biobanked at −80°C within 3 hours of delivery. A combined direct injection and LC-MS/MS assay (AbsolutIDQ p180 kit, Biocrates Life Sciences AG, Innsbruck, Austria) was used for the metabolomic analyses of the samples. Targeted metabolomic analysis showed a significant alteration between study groups in 29 metabolites from 3 distinct classes (Amino Acids, Acylcarnitines, and Glycerophospholipids). 9 of these metabolites were only significantly altered between neonates with Hypoxic ischaemic encephalopathy and matched controls, while 14 were significantly altered in both study groups. Multivariate Discriminant Analysis models developed showed clear multifactorial metabolite associations with both asphyxia and HIE. A logistic regression model using 5 metabolites clearly delineates severity of asphyxia and classifies HIE infants with AUC = 0.92. These data describe wide-spread disruption to not only energy pathways, but also nitrogen and lipid metabolism in both asphyxia and HIE.
This study shows that a multi-platform targeted approach to metabolomic analyses using accurately phenotyped and meticulously biobanked samples provides insight into the pathogenesis of perinatal asphyxia. It highlights the potential for metabolomic technology to develop a diagnostic test for HIE.
PMCID: PMC3515614  PMID: 23227182
14.  Therapeutic Hypothermia for Neonatal Encephalopathy 
Opinion statement
Neonatal Hypoxic-ischemic encephalopathy in full term infants has been associated with a high risk for morbidity and mortality. The patho-physiology of brain injury following hypoxia-ischemia, noted in preclinical models, is a cascade of events resulting from excitotoxic and oxidative injury culminating in cell death. Hypothermia has been noted to be protective by inhibiting various events in the cascade of injury. Major randomized clinical trials in neonatal HIE have demonstrated reduction in death and disability and continued safety and efficacy of neuroprotection in childhood. There is now clinical and imaging evidence for hypothermia as neuroprotection. Hypothermia should be offered to term infants with either severe acidosis at birth or resuscitation needing continued ventilation and evidence of either moderate or severe encephalopathy within 6 hours of birth. The target temperature should be 33° to 34 °C and duration of cooling should be 72 hours, as per the published trials. Rewarming should be slow, at 0.5 °C per hour. Infants should have serial neurological examinations during and at the end of cooling and at discharge. Multiorgan function should be supported and hypocarbia should be avoided during ventilator therapy. If available, the amplitude integrated EEG should be obtained prior to cooling and following rewarming. All infants should have magnetic resonance brain imaging studies within 1 to 2 weeks of age. Information from the neurological examination, aEEG and MRI studies will be helpful in discussing prognosis with parents. All infants should be followed for a minimum of 18 months to evaluate growth parameters and neurodevelopment al outcome.
PMCID: PMC3519960  PMID: 23007949
Therapeutic hypothermia; Neonatal encephalopathy; Term infants; Neonatal hypoxic-ischemic encephalopathy; Pathophysiology; Neurodevelopmental outcome; Neuroprotection; Head cooling; Whole body cooling; Randomized controlled trials; Knowledge gaps; Adjuvant therapies; Treatment
15.  Seizure identification in the ICU using quantitative EEG displays(e–Pub ahead of print) 
Neurology  2010;75(17):1501-1508.
To evaluate the diagnostic accuracy of 2 quantitative EEG display tools, color density spectral array (CDSA) and amplitude-integrated EEG (aEEG), for seizure identification in the intensive care unit (ICU).
A set of 27 continuous EEG recordings performed in pediatric ICU patients was transformed into 8-channel CDSA and aEEG displays. Three neurophysiologists underwent 2 hours of training to identify seizures using these techniques. They were then individually presented with a series of CDSA and aEEG displays, blinded to the raw EEG, and asked to mark any events suspected to be seizures. Their performance was compared to seizures identified on the underlying conventional EEG.
The 27 EEG recordings contained 553 discrete seizures over 487 hours. The median sensitivity for seizure identification across all recordings was 83.3% using CDSA and 81.5% using aEEG. However, among individual recordings, the sensitivity ranged from 0% to 100%. Factors reducing the sensitivity included low-amplitude, short, and focal seizures. False-positive rates were generally very low, with misidentified seizures occurring once every 17–20 hours.
Both CDSA and aEEG demonstrate acceptable sensitivity and false-positive rates for seizure identification among critically ill children. Accuracy of these tools would likely improve during clinical use, when findings can be correlated in real-time with the underlying raw EEG. In the hands of neurophysiologists, CDSA and aEEG displays represent useful screening tools for seizures during continuous EEG monitoring in the ICU. The suitability of these tools for bedside use by ICU nurses and physicians requires further study.
= amplitude-integrated EEG;
= color density spectral array;
= fast-Fourier transformation;
= intensive care unit.
PMCID: PMC2974462  PMID: 20861452
16.  Predictive value of plasma and cerebrospinal fluid tumour necrosis factor-α and interleukin-1β concentrations on outcome of full term infants with hypoxic-ischaemic encephalopathy 
AIM—To determine the predictive value of plasma and cerebrospinal fluid (CSF) tumour necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) concentrations on the outcome of hypoxic-ischaemic encephalopathy (HIE) in full term infants.
METHODS—Thirty term infants with HIE were included in the study. HIE was classified according to the criteria of Sarnat and Sarnat. Blood and CSF were obtained within the first 24 hours of life and stored until assay. Five infants died soon after hypoxic insult. Neurological examinations and Denver Developmental Screening Test (DDST) were performed at 12 months in the survivors.
RESULTS—At the age of 12 months neurological examination and DDST showed that 11 infants were normal; 14 had abnormal neurological findings and/or an abnormal DDST result. Eleven normal infants were classified as group 1 and 19 infants (14 with abnormal neurological findings and/or an abnormal DDST and five who died) as group 2.CSF IL-1β and TNF-α concentrations in group 2 were significantly higher than those in group 1. Plasma IL-1β and TNF-α concentrations were not significantly different between the two groups. IL-1β, but not TNF-α concentrations, in group 2 were even higher than those in group 1, although non-survivors were excluded from group 2. When the patients were evaluated according to the stages of Sarnat, the difference in the three groups was again significant. Patients whose CSF samples were taken within 6 hours of the hypoxic insult had higher IL-1β and TNF-α concentrations than the patients whose samples were taken after 6hours.
CONCLUSIONS—Both cytokines probably contribute to the damage sustained by the central nervous system after hypoxic insult. IL-1β seems to be a better predictor of HIE than TNF-α.

PMCID: PMC1720860  PMID: 10194989
17.  Impact of amplitude-integrated EEG on the clinical care for neonates with seizures 
Pediatric neurology  2012;46(1):32-35.
Amplitude-integrated EEG (aEEG) was introduced relatively recently into neonatal intensive care in the U.S.A. We aimed to evaluate whether aEEG has changed clinical care for neonates with seizures. All 202 neonates treated for seizures at our hospital from 2002 to 2007 were included in this study. Neonates monitored with aEEG (n=67) were compared to a contemporary control group of neonates who were not monitored, despite aEEG availability (n=57), and a historical control group of neonates treated for seizures before aEEG was introduced in our NICU (n=78). 82% of those treated with phenobarbital (137/167) continued treatment after discharge, with no difference among the groups. Adjusted for gestational age and length of stay, there was also no difference among groups in the number of neuroimaging studies or number of anticonvulsants per patient. Fewer patients in the aEEG group, compared to contemporary controls (n=16/67 vs. 29/57, p=0.001) or historical controls (n=38/78, p=0.002), were diagnosed clinically with seizures without electrographic confirmation. We conclude that introducing aEEG did not increase neuroimaging tests, nor did it alter anticonvulsant use. However, diagnostic precision for neonatal seizures improved after aEEG introduction, as fewer neonates were treated for seizures based solely on clinical findings, without electrographic confirmation.
PMCID: PMC3246404  PMID: 22196488
neonatal seizures; electroencephalography; amplitude-integrated EEG; aEEG; EEG; hypoxic ischemic encephalopathy; phenobarbital
18.  Neonatal Seizures: Treatment Practices Among Term and Preterm 
Pediatric Neurology  2012;46(2):111-115.
Neonatal seizures are common clinical conditions in both term and preterm neonates, yet there are no clinical management guidelines to direct care. We surveyed 193 international neurologists and neonatologists to assess management practices seizures in preterm and term neonates among neurologists, neonatologists, and specialists in neonatal neurology or neonatal neurocritical care. We found high reported rates of electroencephalogram (EEG) and amplitude-integrated EEG (aEEG) monitoring for detection of neonatal seizures, prevalent use of older anticonvulsant agents, and high rates of neuroimaging. Overall, responses were similar for term and preterm neonates, however term neonates were more likely to be more heavily investigated, with higher use of EEG and aEEG monitoring of at-risk neonates and higher use of MRI. Continuous monitoring and brain imaging in the setting of neonatal seizures are now standard of care in many centers, though management practices vary widely. Early recognition and management of neonatal seizures and possible underlying injury may lead to increased opportunities for stopping seizures, protecting the brain, and improving developmental outcomes in at risk neonates. There is urgent need for collaboration among neonatologists and neurologists to address the gaps in knowledge regarding management of neonatal seizures in term and preterm neonates.
PMCID: PMC3266555  PMID: 22264706
Infant; neonate; Seizures; Electroencephalography; Magnetic resonance imaging
19.  Prediction of Early Childhood Outcome of Term Infants using Apgar Scores at 10 Minutes following Hypoxic-Ischemic Encephalopathy 
Pediatrics  2009;124(6):1619.
Death or severe disability is so common following an Apgar score of 0 at 10 minutes in observational studies that the Neonatal Resuscitation Program suggests considering discontinuation of resuscitation after 10 minutes of effective CPR.
To determine if Apgar scores at 10 minutes are associated with death or disability in early childhood following perinatal hypoxic-ischemic encephalopathy (HIE).
Design, Setting, and Patients
This is a secondary analysis of infants enrolled in the NICHD Neonatal Research Network hypothermia trial. Infants ≥ 36 weeks gestation had clinical and/or biochemical abnormalities at birth, and encephalopathy at < 6 hours. Logistic regression and classification and regression tree (CART) analysis was used to determine associations between Apgar scores at 10 minutes and neurodevelopmental outcome adjusting for covariates. Associations are expressed as odds ratios (OR) and 95% confidence interval (CI).
Main Outcome Measure
Death or disability (moderate or severe) at 18–22 months of age.
Twenty of 208 infants were excluded (missing data). More than 90% of infants had Apgar scores of 0–2 at 1 minute and Apgars at 5 and 10 minutes shifted to progressively higher values; at 10 minutes 27% of infants had Apgar scores of 0–2. After adjustment each point decrease in Apgar score at 10 minutes was associated with a 45% increase in the odds of death or disability (OR 1.45, CI 1.22–1.72). Death or disability occurred in 76, 82 and 80% of infants with Apgar scores at 10 minutes of 0, 1 and 2, respectively. CART analysis indicated that Apgar scores at 10 minutes were discriminators of outcome.
Apgar scores at 10 minutes provide useful prognostic data before other evaluations are available for infants with HIE. Death or moderate/severe disability is common but not uniform with Apgar scores < 3; caution is needed before adopting a specific time interval to guide duration of resuscitation.
PMCID: PMC2821195  PMID: 19948631
Apgar scores; Hypoxic-Ischemic Encephalopathy; cardiopulmonary resuscitation
20.  Hypothermia for Hypoxic Ischemic Encephalopathy in Infants ≥ 36 weeks 
Early human development  2009;85(10 Suppl):S49.
Hypoxic ischemic encephalopathy is a serious condition affecting infants which can result in death and disability. This is a summary of pathogenesis of HIE, animal studies of cooling for hypoxic and ischemic models, human hypothermia trials, and the American Academy of Pediatrics publication on hypothermia for HIE. Hypothermia for neonatal HIE is continuing to evolve as a therapy. Studies, gaps in knowledge and opportunities for research are presented herein.
PMCID: PMC2813680  PMID: 19762176
21.  Adherence to Hypothermia Guidelines: A French Multicenter Study of Fullterm Neonates 
PLoS ONE  2013;8(12):e83742.
The objective of this study was to describe the French practice of hypothermia treatment (HT) in full-term newborns with hypoxic-ischemic encephalopathy (HIE) and to analyze the deviations from the guidelines of the French Society of Neonatology.
Materials and Methods
From May 2010 to March 2012 we recorded all cases of HIE treated by HT in a French national database. The population was divided into three groups, "optimal HT" (OHT), “late HT” (LHT) and “non-indicated” HT (NIHT), according to the guidelines.
Of the 311 newborns registered in the database and having HT, 65% were classified in the OHT group, 22% and 13% in the LHT and NIHT groups respectively. The severity of asphyxia and HIE were comparable between newborns with OHT and LHT, apart from EEG. HT was initiated at a mean time of 12 hours of life in the LHT group. An acute obstetrical event was more likely to be identified among newborns with LHT (46%), compared to OHT (34%) and NIHT (22%). There was a gradation in the rate of complications from the NIHT group (29%) to the LHT (38%) group and the OHT group (52%). Despite an insignificant difference in the rates of death or abnormal neurological examination at discharge, nearly 60% of newborns in the OHT group had an MRI showing abnormalities, compared to 44% and 49% in the LHT and NIHT groups respectively.
The conduct of the HT for HIE newborns is not consistent with French guidelines for 35% of newborns, 22% being explained by an excessive delay in the start of HT, 13% by the lack of adherence to the clinical indications. This first report illustrates the difficulties in implementing guidelines for HT and should argue for an optimization of perinatal care for HIE.
PMCID: PMC3877096  PMID: 24391817
22.  Hypothermia for newborns with hypoxic ischemic encephalopathy 
Paediatrics & Child Health  2012;17(1):41-43.
Hypoxic ischemic encephalopathy (HIE) remains a significant cause of mortality and long-term disability in late preterm and term infants. Mild therapeutic hypothermia to a rectal temperature of 34±0.5°C initiated as soon as possible within the first 6 h of life decreases mortality and severe long-term neurodevelopmental disabilities in infants with moderate HIE who are ≥36 weeks’ gestational age. There are minimal side effects, and the incidence of disability in survivors is not increased. Infants with severe encephalopathy are less likely to benefit from treatment. Cooling may be achieved by either total body or selective head cooling. As cooling is now considered a standard of care, infants ≥36 weeks’ gestational age who are depressed at birth should be assessed to determine whether they meet the criteria for cooling. There is currently no evidence that therapeutic hypothermia offers any benefit to infants <36 weeks’ gestational age.
PMCID: PMC3276531  PMID: 23277757
Asphyxia; Cooling; Hypothermia; Hypoxic ischemic encephalopathy; Outcome
23.  Serum cytokines in a clinical trial of hypothermia for neonatal hypoxic-ischemic encephalopathy 
Inflammatory cytokines may mediate hypoxic-ischemic (HI) injury and offer insights into the severity of injury and the timing of recovery. In our randomized, multicenter trial of hypothermia, we analyzed the temporal relationship of serum cytokine levels in neonates with hypoxic-ischemic encephalopathy (HIE) with neurodevelopmental outcome at 12 months. Serum cytokines were measured every 12 hours for 4 days in 28 hypothermic (H) and 22 normothermic (N) neonates with HIE. Monocyte chemotactic protein-1 (MCP-1) and interleukins (IL)-6, IL-8, and IL-10 were significantly higher in the H group. Elevated IL-6 and MCP-1 within 9 hours after birth and low macrophage inflammatory protein 1a (MIP-1a) at 60 to 70 hours of age were associated with death or severely abnormal neurodevelopment at 12 months of age. However, IL-6, IL-8, and MCP-1 showed a biphasic pattern in the H group, with early and delayed peaks. In H neonates with better outcomes, uniform down modulation of IL-6, IL-8, and IL-10 from their peak levels at 24 hours to their nadir at 36 hours was observed. Modulation of serum cytokines after HI injury may be another mechanism of improved outcomes in neonates treated with induced hypothermia.
PMCID: PMC3463879  PMID: 22805873
chemokines; cytokines; hypoxic-ischemic brain injury; induced hypothermia
24.  Treatment advances in neonatal neuroprotection and neurointensive care 
Lancet neurology  2011;10(4):372-382.
Knowledge of the nature, prognosis, and ways to treat brain lesions in neonatal infants has increased remarkably. Neonatal hypoxic-ischaemic encephalopathy (HIE) in term infants, mirrors a progressive cascade of excito-oxidative events that unfold in the brain after an asphyxial insult. In the laboratory, this cascade can be blocked to protect brain tissue through the process of neuroprotection. However, proof of a clinical effect was lacking until the publication of three positive randomised controlled trials of moderate hypothermia for term infants with HIE. These results have greatly improved treatment prospects for babies with asphyxia and altered understanding of the theory of neuroprotection. The studies show that moderate hypothermia within 6 h of asphyxia improves survival without cerebral palsy or other disability by about 40% and reduces death or neurological disability by nearly 30%. The search is on to discover adjuvant treatments that can further enhance the effects of hypothermia.
PMCID: PMC3757153  PMID: 21435600
25.  Therapeutic hypothermia on neonatal transport: 4-year experience in a single NICU 
Journal of Perinatology  2009;30(5):324-329.
Therapeutic hypothermia instituted within 6 h of birth has been shown to improve neurodevelopmental outcomes in term newborns with moderate–to–severe hypoxic–ischemic encephalopathy (HIE). The majority of infants who would benefit from cooling are born at centers that do not offer the therapy, and adding the time for transport will result in delays in therapy, that may lead to suboptimal or no neuroprotection for some patients. Our objective was to evaluate the effect of our center's experience with therapeutic hypothermia on neonatal transport.
Study Design:
Retrospective review of all cases of therapeutic hypothermia at a single neonatal intensive care unit from 2005 to 2009.
Of 50 infants with HIE treated with hypothermia, 40 were outborn and 35 were cooled on transport. The majority of patients were passively cooled by the referring clinicians, then actively cooled by our transport team. Overcooling to <32 °C occurred in 34% of patients, but there were no significant differences in admission vital signs or laboratory values between overcooled and appropriately cooled infants. The average time after birth of initiation of passive cooling was 1.4 h and active cooling was 2.7 h compared with the time of admission to our unit of 5.9 h.
We discuss the important aspects of our program, including the education of referring and receiving clinicians and avoidance of overcooling.
PMCID: PMC2864418  PMID: 19847186
hypothermia; hypoxic-ischemic encephalopathy; neontal transport; neuroprotection; birth asphyxia

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