Prospective qualification of early cerebral biomarkers in a randomised trial of treatment with xenon combined with moderate hypothermia after birth asphyxia.

BACKGROUND: The TOBY-Xe proof of concept randomised trial found no effect of xenon combined with hypothermia after birth asphyxia on the lactate to N-acetyl aspartate ratio (Lac/NAA) in the thalamus and fractional anisotropy (FA) in white matter tracts measured within 15 days of birth. To confirm that these biomarkers are qualified to predict long-term outcome after neural rescue therapy we assessed surviving participants at 2-3 years of age. METHODS: Of the 92 infants in TOBY-Xe, one was omitted from the study, 69 survived and we assessed 62 participants, 32 in the hypothermia and xenon and 30 in the hypothermia only groups. We examined the relation between Lac/NAA and FA and the scores of the Bayley Scales of Infant and Toddler Development III and calculated their predictive accuracy for moderate or severe disability or death. RESULTS: Fifteen of 62 participants (24%) developed moderate/severe disability, and 22/92 (24%) died. The Lac/NAA ratio (difference in medians 0.628, 95% CI -0.392 to 4.684) and FA (difference in means -0.055, 95% CI -0.033 to -0.077) differed significantly between participants with or without moderate or severe disability or death and were significantly related with development scores in both groups. Adverse outcomes were correctly identified in 95.65% of cases by Lac/NAA and 78.79% by FA, with adequate mean calibration of the model. INTERPRETATION: The results confirm the qualification of the cerebral magnetic resonance biomarkers employed in the TOBY-Xe study as predictors of outcome after neuroprotective therapy. FUND: The Centre for the Developing Brain, King's College London, UK.

Hypothermia for perinatal asphyxia: trial-based resource use and costs at 6-7 years.

OBJECTIVE: To assess the impact of hypothermic neural rescue for perinatal asphyxia at birth on healthcare costs of survivors aged 6-7 years, and to quantify the relationship between costs and overall disability levels. DESIGN: 6-7 years follow-up of surviving children from the Total Body Hypothermia for Neonatal Encephalopathy (TOBY) trial. SETTING: Community study including a single parental questionnaire to collect information on children's healthcare resource use. PATIENTS: 130 UK children (63 in the control group, 67 in the hypothermia group) whose parents consented and returned the questionnaire. INTERVENTIONS: Intensive care with cooling of the body to 33.5°C for 72 hours or intensive care alone. MAIN OUTCOME MEASURES: Healthcare resource usage and costs over the preceding 6 months. RESULTS: At 6-7 years, mean (SE) healthcare costs per child were £1543 (£361) in the hypothermia group and £2549 (£812) in the control group, giving a saving of -£1005 (95% CI -£2734 to £724). Greater levels of overall disability were associated with progressively higher costs, and more parents in the hypothermia group were employed (64% vs 47%). Results were sensitive to outlying observations. CONCLUSIONS: Cost results although not significant favoured moderate hypothermia and so complement the clinical results of the TOBY Children study. Estimates were however sensitive to the care requirements of two seriously ill children in the control group. A quantification of the relationship between costs and levels of disability experienced will be useful to healthcare professionals, policy makers and health economists contemplating the long-term economic consequences of perinatal asphyxia and hypothermic neural rescue. TRIAL REGISTRATION NUMBER: This study reports on the follow-up of the TOBY clinical trial: ClinicalTrials. gov number NCT01092637.

Hypothermia for perinatal asphyxia: trial-based quality of life at 6-7 years.

OBJECTIVE: To assess the impact of hypothermic neural rescue at birth on health-related quality of life (HRQL) in middle childhood. DESIGN: Six-year to 7-year follow-up of surviving children from the Total Body Hypothermia for Neonatal Encephalopathy (TOBY) Trial. SETTING: Community study including a single parental questionnaire to collect information on children's HRQL. PATIENTS: 145 children (70 in the control group, 75 in the hypothermia group) whose parents consented and returned the questionnaire. INTERVENTIONS: Intensive care with cooling of the body to 33.5°C for 72 hours or intensive care alone. MAIN OUTCOME MEASURES: HRQL attributes and utility scores using the Health Utilities Index (HUI). RESULTS: At 6-7 years, speech appeared disproportionately affected when compared with other aspects of HRQL but levels of normal emotional functioning were similar in both groups. The mean (SE) HUI3 HRQL scores were 0.73 (0.05) in the hypothermia group and 0.62 (0.06) in the control group; mean difference (95% CI) 0.11 (-0.04 to 0.26). CONCLUSIONS: Findings of non-significant differences were not unexpected; the study used data from long-term survivors in a neonatal trial and was underpowered. However, results favoured moderate hypothermia and so complement the clinical results of the TOBY Children study. The work provides further insight into the long-term HRQL impact of perinatal asphyxial encephalopathy and provides previously unavailable utility data with which to contemplate the longer term cost-effectiveness of hypothermic neural rescue. TRIAL REGISTRATION NUMBER: This study reports on the follow-up of the TOBY clinical trial: ClinicalTrials.gov number NCT01092637.

Effect of MRI on preterm infants and their families: a randomised trial with nested diagnostic and economic evaluation.

BACKGROUND: We tested the hypothesis that routine MRI would improve the care and well-being of preterm infants and their families. DESIGN: Parallel-group randomised trial (1.1 allocation; intention-to-treat) with nested diagnostic and cost evaluations (EudraCT 2009-011602-42). SETTING: Participants from 14 London hospitals, imaged at a single centre. PATIENTS: 511 infants born before 33 weeks gestation underwent both MRI and ultrasound around term. 255 were randomly allocated (siblings together) to receive only MRI results and 255 only ultrasound from a paediatrician unaware of unallocated results; one withdrew before allocation. MAIN OUTCOME MEASURES: Maternal anxiety, measured by the State-Trait Anxiety inventory (STAI) assessed in 206/214 mothers receiving MRI and 217/220 receiving ultrasound. Secondary outcomes included: prediction of neurodevelopment, health-related costs and quality of life. RESULTS: After MRI, STAI fell from 36.81 (95% CI 35.18 to 38.44) to 32.77 (95% CI 31.54 to 34.01), 31.87 (95% CI 30.63 to 33.12) and 31.82 (95% CI 30.65 to 33.00) at 14 days, 12 and 20 months, respectively. STAI fell less after ultrasound: from 37.59 (95% CI 36.00 to 39.18) to 33.97 (95% CI 32.78 to 35.17), 33.43 (95% CI 32.22 to 34.63) and 33.63 (95% CI 32.49 to 34.77), p=0.02. There were no differences in health-related quality of life. MRI predicted moderate or severe functional motor impairment at 20 months slightly better than ultrasound (area under the receiver operator characteristic curve (CI) 0.74; 0.66 to 0.83 vs 0.64; 0.56 to 0.72, p=0.01) but cost £315 (CI £295-£336) more per infant. CONCLUSIONS: MRI increased costs and provided only modest benefits. TRIAL REGISTRATION: ClinicalTrials.gov NCT01049594 https://clinicaltrials.gov/ct2/show/NCT01049594. EudraCT: EudraCT: 2009-011602-42 (https://www.clinicaltrialsregister.eu/).

Punctate White Matter Lesions Associated With Altered Brain Development And Adverse Motor Outcome In Preterm Infants.

Preterm infants who develop neurodevelopmental impairment do not always have recognized abnormalities on cerebral ultrasound, a modality routinely used to assess prognosis. In a high proportion of infants, MRI detects punctate white matter lesions that are not seen on ultrasonography. To determine the relation of punctate lesions to brain development and early neurodevelopmental outcome we used multimodal brain MRI to study a large cohort of preterm infants. Punctate lesions without other focal cerebral or cerebellar lesions were detected at term equivalent age in 123 (24.3%) (59 male) of the 506 infants, predominantly in the centrum semiovale and corona radiata. Infants with lesions had higher gestational age, birth weight, and less chronic lung disease. Punctate lesions showed a dose dependent relation to abnormalities in white matter microstructure, assessed with tract-based spatial statistics, and reduced thalamic volume (p < 0.0001), and predicted unfavourable motor outcome at a median (range) corrected age of 20.2 (18.4-26.3) months with sensitivity (95% confidence intervals) 71 (43-88) and specificity 72 (69-77). Punctate white matter lesions without associated cerebral lesions are common in preterm infants currently not regarded as at highest risk for cerebral injury, and are associated with widespread neuroanatomical abnormalities and adverse early neurodevelopmental outcome.

Moderate hypothermia within 6 h of birth plus inhaled xenon versus moderate hypothermia alone after birth asphyxia (TOBY-Xe): a proof-of-concept, open-label, randomised controlled trial.

BACKGROUND: Moderate cooling after birth asphyxia is associated with substantial reductions in death and disability, but additional therapies might provide further benefit. We assessed whether the addition of xenon gas, a promising novel therapy, after the initiation of hypothermia for birth asphyxia would result in further improvement. METHODS: Total Body hypothermia plus Xenon (TOBY-Xe) was a proof-of-concept, randomised, open-label, parallel-group trial done at four intensive-care neonatal units in the UK. Eligible infants were 36-43 weeks of gestational age, had signs of moderate to severe encephalopathy and moderately or severely abnormal background activity for at least 30 min or seizures as shown by amplitude-integrated EEG (aEEG), and had one of the following: Apgar score of 5 or less 10 min after birth, continued need for resuscitation 10 min after birth, or acidosis within 1 h of birth. Participants were allocated in a 1:1 ratio by use of a secure web-based computer-generated randomisation sequence within 12 h of birth to cooling to a rectal temperature of 33·5°C for 72 h (standard treatment) or to cooling in combination with 30% inhaled xenon for 24 h started immediately after randomisation. The primary outcomes were reduction in lactate to N-acetyl aspartate ratio in the thalamus and in preserved fractional anisotropy in the posterior limb of the internal capsule, measured with magnetic resonance spectroscopy and MRI, respectively, within 15 days of birth. The investigator assessing these outcomes was masked to allocation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00934700, and with ISRCTN, as ISRCTN08886155. FINDINGS: The study was done from Jan 31, 2012, to Sept 30, 2014. We enrolled 92 infants, 46 of whom were randomly assigned to cooling only and 46 to xenon plus cooling. 37 infants in the cooling only group and 41 in the cooling plus xenon group underwent magnetic resonance assessments and were included in the analysis of the primary outcomes. We noted no significant differences in lactate to N-acetyl aspartate ratio in the thalamus (geometric mean ratio 1·09, 95% CI 0·90 to 1·32) or fractional anisotropy (mean difference -0·01, 95% CI -0·03 to 0·02) in the posterior limb of the internal capsule between the two groups. Nine infants died in the cooling group and 11 in the xenon group. Two adverse events were reported in the xenon group: subcutaneous fat necrosis and transient desaturation during the MRI. No serious adverse events were recorded. INTERPRETATION: Administration of xenon within the delayed timeframe used in this trial is feasible and apparently safe, but is unlikely to enhance the neuroprotective effect of cooling after birth asphyxia. FUNDING: UK Medical Research Council.

Specialization and integration of functional thalamocortical connectivity in the human infant.

Connections between the thalamus and cortex develop rapidly before birth, and aberrant cerebral maturation during this period may underlie a number of neurodevelopmental disorders. To define functional thalamocortical connectivity at the normal time of birth, we used functional MRI (fMRI) to measure blood oxygen level-dependent (BOLD) signals in 66 infants, 47 of whom were at high risk of neurocognitive impairment because of birth before 33 wk of gestation and 19 of whom were term infants. We segmented the thalamus based on correlation with functionally defined cortical components using independent component analysis (ICA) and seed-based correlations. After parcellating the cortex using ICA and segmenting the thalamus based on dominant connections with cortical parcellations, we observed a near-facsimile of the adult functional parcellation. Additional analysis revealed that BOLD signal in heteromodal association cortex typically had more widespread and overlapping thalamic representations than primary sensory cortex. Notably, more extreme prematurity was associated with increased functional connectivity between thalamus and lateral primary sensory cortex but reduced connectivity between thalamus and cortex in the prefrontal, insular and anterior cingulate regions. This work suggests that, in early infancy, functional integration through thalamocortical connections depends on significant functional overlap in the topographic organization of the thalamus and that the experience of premature extrauterine life modulates network development, altering the maturation of networks thought to support salience, executive, integrative, and cognitive functions.

Clinical applications of cerebral function monitoring in neonates.

The cerebral function monitor is a device for trend monitoring of changes in the amplitude of the electroencephalogram, typically recorded from one or two pairs of electrodes. Initially developed and introduced to monitor cerebral activity in encephalopathic adult patients or during anaesthesia, it is now most widely used in newborns to assess the severity of encephalopathy and for determining prognosis. The duration and severity of abnormalities of the amplitude-integrated electroencephalogram tracing is highly predictive of subsequent neurologic outcome following neonatal hypoxic-ischemic encephalopathy, including in newborns receiving neuroprotective treatment with prolonged moderate hypothermia. The cerebral function monitor is also used for seizure detection and to monitor response to anticonvulsant therapies. Amplitude-integrated electroencephalography compares well with standard electroencephalography when used to assess the severity of neonatal encephalopathy, but a standard electroencephalogram is still required to provide important information about changes in frequency, and in the synchrony and distribution and other characteristics of cerebral cortical activity. The role of the amplitude-integrated electroencephalogram to identify brain injury in preterm infants remains to be determined.

Early predictors of outcome in infants treated with hypothermia for hypoxic-ischaemic encephalopathy.

Hypoxic-ischaemic encephalopathy (HIE) is a leading cause of acquired neonatal brain injury. Assessment of the severity of cerebral injury and likely neurological outcome in infants with HIE is important for determining management and prognosis, for counselling parents, and for selection for neuroprotective trials. The condition of the infant at birth, the severity of HIE, neurophysiological tests, including amplitude-integrated electroencephalography (aEEG), biochemical markers, and neuroimaging have been used to assess prognosis and predict long-term outcome. The predictive accuracy of these indicators in the early postnatal period is modest. Neurophysiological assessment seems to be most helpful during the first 24 to 48 hours after birth whilst magnetic resonance imaging (MRI) seems most informative later. Several biochemical markers, including serum S100ß and neuron-specific enolase (NSE), are also associated with HIE but their levels depend on the timing of sampling and their prognostic value is uncertain. Comprehensive neurophysiological assessment and neuroimaging may be limited to specialist centres. Therapeutic hypothermia is now standard care in infants with moderate to severe HIE so it is important to examine the influence of hypothermia on the assessment of prognosis in these infants.

Effects of hypothermia for perinatal asphyxia on childhood outcomes.

BACKGROUND: In the Total Body Hypothermia for Neonatal Encephalopathy Trial (TOBY), newborns with asphyxial encephalopathy who received hypothermic therapy had improved neurologic outcomes at 18 months of age, but it is uncertain whether such therapy results in longer-term neurocognitive benefits. METHODS: We randomly assigned 325 newborns with asphyxial encephalopathy who were born at a gestational age of 36 weeks or more to receive standard care alone (control) or standard care with hypothermia to a rectal temperature of 33 to 34°C for 72 hours within 6 hours after birth. We evaluated the neurocognitive function of these children at 6 to 7 years of age. The primary outcome of this analysis was the frequency of survival with an IQ score of 85 or higher. RESULTS: A total of 75 of 145 children (52%) in the hypothermia group versus 52 of 132 (39%) in the control group survived with an IQ score of 85 or more (relative risk, 1.31; P=0.04). The proportions of children who died were similar in the hypothermia group and the control group (29% and 30%, respectively). More children in the hypothermia group than in the control group survived without neurologic abnormalities (65 of 145 [45%] vs. 37 of 132 [28%]; relative risk, 1.60; 95% confidence interval, 1.15 to 2.22). Among survivors, children in the hypothermia group, as compared with those in the control group, had significant reductions in the risk of cerebral palsy (21% vs. 36%, P=0.03) and the risk of moderate or severe disability (22% vs. 37%, P=0.03); they also had significantly better motor-function scores. There was no significant between-group difference in parental assessments of children's health status and in results on 10 of 11 psychometric tests. CONCLUSIONS: Moderate hypothermia after perinatal asphyxia resulted in improved neurocognitive outcomes in middle childhood. (Funded by the United Kingdom Medical Research Council and others; TOBY ClinicalTrials.gov number, NCT01092637.).

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.

Neonatal ECMO study of temperature (NEST): a randomized controlled trial.

BACKGROUND: Despite evidence to support the use of extracorporeal membrane oxygenation (ECMO) in defined groups of newborn infants, rates of impairment among survivors remain high. Therapeutic hypothermia has been shown to provide neuroprotection in mature infants exposed to perinatal asphyxia. We hypothesized that therapeutic hypothermia during ECMO would reduce the proportion of infants with brain injury, and thus later impairment. METHODS: We conducted a randomized trial in the United Kingdom to compare ECMO with cooling (34°C for the first 48 to 72 hours) with standard ECMO (37°C). The primary outcome was the cognitive composite score of the Bayley Scales of Infant and Toddler Development, 3rd edition, at 2 years. Prespecified secondary outcomes included death, neonatal morbidity, and other neurodevelopmental and behavioral outcomes at 2 years. RESULTS: A total of 111 infants were entered into the study, 14 died before 2 years of age (16% who received ECMO with cooling vs 9% who received ECMO alone). Two infants were lost to follow-up, and 8 were unable to complete the full range of tests. For 45 evaluated infants who received ECMO with cooling, mean cognitive scores at 2 years were 88.0 (SD: 16.2) compared with 90.6 (SD: 13.1) for 48 infants receiving ECMO only (difference in means: -2.6; 95% confidence interval: -8.7 to 3.4). The various secondary outcomes were not significantly different between the groups, but most favored ECMO without cooling. CONCLUSIONS: In newborn infants treated by ECMO, the use of mild hypothermia for the first 48 to 72 hours did not result in improved outcomes up to 2 years of age.

Anticonvulsant effect of xenon on neonatal asphyxial seizures.

Xenon, a monoatomic gas with very high tissue solubility, is a non-competitive inhibitor of N-methyl-D-aspartate (NMDA) glutamate receptor, has antiapoptotic effects and is neuroprotective following hypoxic ischaemic injury in animals. Xenon may be expected to have anticonvulsant effects through glutamate receptor blockade, but this has not previously been demonstrated clinically. We examined seizure activity on the real time and amplitude integrated EEG records of 14 full-term infants with perinatal asphyxial encephalopathy treated within 12 h of birth with 30% inhaled xenon for 24 h combined with 72 h of moderate systemic hypothermia. Seizures were identified on 5 of 14 infants. Seizures stopped during xenon therapy but recurred within a few minutes of withdrawing xenon and stopped again after xenon was restarted. Our data show that subanaesthetic levels of xenon may have an anticonvulsant effect. Inhaled xenon may be a valuable new therapy in this hard-to-treat population.

Pharmacokinetics of melatonin in preterm infants.

AIMS: Preterm infants are deprived of the normal intra-uterine exposure to maternal melatonin and may benefit from replacement therapy. We conducted a pharmacokinetic study to guide potential therapeutic trials. METHODS: Melatonin was administered to 18 preterm infants in doses ranging from 0.04-0.6 µg kg(-1) over 0.5-6 h. Pharmacokinetic profiles were analyzed individually and by population methods. RESULTS: Baseline melatonin was largely undetectable. Infants receiving melatonin at 0.1 µg kg(-1) h(-1) for 2 h showed a median half-life of 15.82 h and median maximum plasma concentration of 203.3 pg ml(-1) . On population pharmacokinetics, clearance was 0.045 l h(-1) , volume of distribution 1.098 l and elimination half-life 16.91 h with gender (P = 0.047) and race (P < 0.0001) as significant covariates. CONCLUSIONS: A 2 h infusion of 0.1 µg kg(-1) h(-1) increased blood melatonin from undetectable to approximately peak adult concentrations. Slow clearance makes replacement of a typical maternal circadian rhythm problematic. The pharmacokinetic profile of melatonin in preterm infants differs from that of adults so dosage of melatonin for preterm infants cannot be extrapolated from adult studies. Data from this study can be used to guide therapeutic clinical trials of melatonin in preterm infants.

Changes in serum cytokine and cortisol levels in normothermic and hypothermic term neonates after perinatal asphyxia.

OBJECTIVE: Perinatal asphyxia is characterized by an inflammatory response that contributes to cerebral injury. Therapeutic hypothermia improves neurological outcome in asphyxiated term neonates, but its clear effect on the inflammatory response is unknown. SUBJECTS AND METHODS: A range of cytokines and cortisol levels were measured at the 6th, 12th and 24th postnatal hours in neonates with hypoxic-ischemic encephalopathy treated with standard intensive care on hypothermia (n = 10) or normothermia (n = 8). The influence of postnatal age and hypothermia on serum cytokine and cortisol levels was evaluated. RESULTS: Interleukin (IL)-6 levels (at 6 h of age) and IL-4 levels (at all time points) were significantly lower in asphyxiated neonates treated with hypothermia compared to normothermic neonates. Vascular endothelial growth factor levels were higher in the hypothermia than in the normothermia group at the 6th and 12th postnatal hours. IL-10 levels decreased significantly between 6 and 24 h of age in both groups. However, no difference of IL-10 levels was observed between the study groups. The duration of hypothermia before 6 hours of age correlated with lower levels of IL-6, interferon-γ and tumor necrosis factor-α measured at 6 h of age and IL-10 levels at 12 h of age. Cortisol levels did not differ between the study groups, but did gradually decrease in both groups during the study period. At 6 and 24 h of age, a positive correlation was observed between cortisol and IL-10 levels. CONCLUSIONS: Therapeutic hypothermia may rapidly suppress and modify the immediate cytokine response to asphyxia. The correlation between cytokine levels and duration of hypothermia suggests that the earlier hypothermia is introduced, the more pronounced its beneficial immunomodulatory effect.

Amplitude-integrated electroencephalography in newborns with inborn errors of metabolism.

BACKGROUND: The utility of amplitude-integrated electroencephalography (aEEG) monitoring has been established for patients with neonatal hypoxic-ischemic encephalopathy. OBJECTIVE: To evaluate the role of aEEG in the diagnostic process and treatment of patients with encephalopathy due to inborn errors of metabolism. METHODS: Cases collected through an international registry were divided into 5 groups of metabolic disorders. Common aEEG features were sought for each group. RESULTS: In total, 21/30 (70%) cases had abnormal aEEG background patterns, 18/30 (60%) showed seizure activity. Patients with disorders of energy metabolism, hyperammonemia, and organic/amino acidopathies often showed marked aEEG depression with seizure activity. In contrast, aEEGs of patients with peroxisomal disorders did not show major background abnormalities but seizures were present in 5/6 subjects. We report two features of interest: firstly, two tracings displayed an unusual upward shift of the lower aEEG amplitude margin. Secondly, aEEGs of infants with non-ketotic hyperglycinemia showed a pattern we refer to as 'high-frequency burst-suppression pattern'. CONCLUSIONS: aEEG in patients with inborn errors of metabolism frequently reveals abnormalities and assists clinicians in the clinical assessment, management and monitoring of these patients.

Implementation and conduct of therapeutic hypothermia for perinatal asphyxial encephalopathy in the UK--analysis of national data.

BACKGROUND: Delay in implementing new treatments into clinical practice results in considerable health and economic opportunity costs. Data from the UK TOBY Cooling Register provides the opportunity to examine how one new effective therapy for newborn infants suspected of suffering asphyxial encephalopathy--therapeutic hypothermia- was implemented in the UK. METHODOLOGY/PRINCIPAL FINDINGS: We analysed returned data forms from inception of the Register in December 2006 to the end of July 2011. Data forms were received for 1384 (67%) of the 2069 infants registered. The monthly rate of notifications increased from median {IQR} 18 {15-31} to 33 {30-39} after the announcement of the results of the recent TOBY trial, and to 50 {36-55} after their publication. This rate further increased to 70 {64-83} following official endorsement of the therapy, and is now close to the expected numbers of eligible infants. Cooling was started at 3.3 {1.5-5.5} hours after birth and the time taken to achieve the target 33-34 °C rectal temperature was 1 {0-3} hours. The rectal temperature was in the target range in 83% of measurements. From 2006 to 2011 there was evidence of extension of treatment to slightly less severely affected infants. 278 of 1362 (20%) infants died at 2.9 {1.4-4.1} days of age. The rates of death fell slightly over the period of the Register and, at two years of age cerebral palsy was diagnosed in 22% of infants; half of these were spastic bilateral. Factors independently associated with adverse outcome were clinical seizures prior to cooling (p<0.001) and severely abnormal amplitude integrated EEG (p<0.001). CONCLUSIONS/SIGNIFICANCE: Therapeutic hypothermia was implemented appropriately within the UK, with significant benefit to patients and the health economy. This may be due in part to participation by neonatal units in clinical trials, the establishment of the national Register, and its endorsement by advisory bodies.

Prediction of neurodevelopmental outcome after hypoxic-ischemic encephalopathy treated with hypothermia by diffusion tensor imaging analyzed using tract-based spatial statistics.

INTRODUCTION: Objective biomarkers are needed to assess neuroprotective therapies after perinatal hypoxic-ischemic encephalopathy (HIE). We tested the hypothesis that, in infants who underwent therapeutic hypothermia after perinatal HIE, neurodevelopmental performance was predicted by fractional anisotropy (FA) values in the white matter (WM) on early diffusion tensor imaging (DTI) as assessed by means of tract-based spatial statistics (TBSS). METHODS: We studied 43 term infants with HIE. Developmental assessments were carried out at a median (range) age of 24 (12-28) mo. RESULTS: As compared with infants with favorable outcomes, those with unfavorable outcomes had significantly lower FA values (P < 0.05) in the centrum semiovale, corpus callosum (CC), anterior and posterior limbs of the internal capsule, external capsules, fornix, cingulum, cerebral peduncles, optic radiations, and inferior longitudinal fasciculus. In a second analysis in 32 assessable infants, the Griffiths Mental Development Scales (Revised) (GMDS-R) showed a significant linear correlation (P < 0.05) between FA values and developmental quotient (DQ) and all its component subscale scores. DISCUSSION: DTI analyzed by TBSS provides a qualified biomarker that can be used to assess the efficacy of additional neuroprotective therapies after HIE.

Serum S100B and neuron-specific enolase levels in normothermic and hypothermic infants after perinatal asphyxia.

AIM: Serum S100B and neuron-specific enolase (NSE) levels are elevated after perinatal asphyxia, but the influence of hypothermia on these proteins has not been previously reported. The aim of this study was to evaluate the effect of systemic hypothermia on these protein levels after perinatal asphyxia, time course, and association with perinatal factors and neurodevelopmental outcome at 2 years of age. METHODS: Serum S100B and NSE levels were measured at fixed time points in asphyxiated infants treated with standard intensive care on hypothermia (HT: n = 13) or normothermia (NT: n = 11). RESULTS: Serum S100B and NSE levels were grossly elevated in both HT and NT groups. Compared with the values at 6 h of age, S100B values decreased over time in both groups (NT: p = 0.002, HT: p = 0.04). Serum S100B values were lower in HT infants compared with those in NT infants (p = 0.047 at 48 h). Serum S100B and NSE values were significantly higher in infants who died or developed severe neurological impairment (S100B, p < 0.05 at all time points; NSE, p = 0.036 at 24 h of age). CONCLUSION: Both NSE and S100B levels are highly elevated following asphyxia. Serum S100B levels were lower in the HT group and strongly correlated with the neurodevelopmental outcome.