In this randomized trial involving newborn infants with asphyxial encephalopathy, hypothermic therapy did not significantly reduce the rate of the primary outcome (i.e., death or severe ...neurodevelopmental disability) but did result in improvement in several prespecified secondary neurologic outcomes among survivors.
In newborn infants with asphyxial encephalopathy, hypothermic therapy did not significantly reduce the rate of the primary outcome (i.e., death or severe neurodevelopmental disability) but did result in improvement in several prespecified secondary neurologic outcomes among survivors.
Perinatal asphyxial encephalopathy is associated with high morbidity and mortality rates worldwide and is a major burden for the patient, the family, and society. There is an urgent need to improve outcomes in affected infants.
Experimentally, reducing body temperature to 3 to 5°C below the normal level reduces cerebral injury and improves neurologic function after asphyxia.
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Preliminary clinical studies have found no serious adverse effects of cooling.
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Two randomized, controlled trials, the CoolCap trial
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and the National Institute of Child Health and Human Development (NICHD) trial,
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have reported outcomes among infants at 18 months of age who had . . .
This follow-up study of children who were enrolled in a randomized trial of hypothermia for perinatal asphyxial encephalopathy showed that at the age of 6 to 7 years, the hypothermia group had a ...higher rate of survival with an IQ score of 85 or more than the control group.
Perinatal asphyxial encephalopathy is associated with a high risk of death or early neurodevelopmental impairment. Among survivors, cerebral palsy, functional disability, and cognitive impairment often develop later in childhood. The cost of this condition to patients, their families, and society is high.
In several randomized, controlled trials involving infants with clear evidence of asphyxial encephalopathy, moderate hypothermia (33 to 34°C) for 72 hours, initiated within 6 hours after delivery, has been shown to reduce the risk of death or disability at 18 to 24 months of age and to increase the rate of survival free of disability.
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The observation that . . .
Summary Background Moderate hypothermia in neonates with hypoxic–ischaemic encephalopathy might improve survival and neurological outcomes at up to 18 months of age, although complete neurological ...assessment at this age is difficult. To ascertain more precisely the effect of therapeutic hypothermia on neonatal cerebral injury, we assessed cerebral lesions on MRI scans of infants who participated in the Total Body Hypothermia for Neonatal Encephalopathy (TOBY) trial. Methods In the TOBY trial hypoxic–ischaemic encephalopathy was graded clinically according to the changes seen on amplitude integrated EEG, and infants were randomly assigned to intensive care with or without cooling by central telephone randomisation. The relation between allocation to hypothermia or normothermia and cerebral lesions was assessed by logistic regression with perinatal factors as covariates, and adjusted odds ratios (ORs) were calculated. The TOBY trial is registered, number ISRCTN 89547571. Findings 325 infants were recruited in the TOBY trial between 2002 and 2006. Images were available for analysis from 131 infants. Therapeutic hypothermia was associated with a reduction in lesions in the basal ganglia or thalamus (OR 0·36, 95% CI 0·15–0·84; p=0·02), white matter (0·30, 0·12–0·77; p=0·01), and abnormal posterior limb of the internal capsule (0·38, 0·17–0·85; p=0·02). Compared with non-cooled infants, cooled infants had fewer scans that were predictive of later neuromotor abnormalities (0·41, 0·18–0·91; p=0·03) and were more likely to have normal scans (2·81, 1·13–6·93; p=0·03). The accuracy of prediction by MRI of death or disability to 18 months of age was 0·84 (0·74–0·94) in the cooled group and 0·81 (0·71–0·91) in the non-cooled group. Interpretation Therapeutic hypothermia decreases brain tissue injury in infants with hypoxic–ischaemic encephalopathy. The predictive value of MRI for subsequent neurological impairment is not affected by therapeutic hypothermia. Funding UK Medical Research Council; UK Department of Health.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Summary 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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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.
Significance We investigated the way in which the human thalamus and cortex are functionally connected at the time of normal birth. We found the functional parcellation of the thalamus to be a good facsimile of that found in adult studies. However, although primary cortical regions were almost entirely connected to specific thalamic regions, heteromodal cortex was more widely connected to multiple thalamic regions, giving the potential for an integrative role for these circuits. Development seemed to have been modulated by the experience of premature extrauterine life, with an increase in connectivity to primary sensory cortex, but reduced connectivity between areas of the thalamus and heteromodal cortex known to support higher cognitive functions.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
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.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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Pharmacokinetics of melatonin in preterm infants Merchant, Nazakat M.; Azzopardi, Denis V.; Hawwa, Ahmed F. ...
British journal of clinical pharmacology,
November 2013, Volume:
76, Issue:
5
Journal Article
Peer reviewed
Open access
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.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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.
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).
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.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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