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.

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.

Neonatal ECMO Study of Temperature (NEST)--a randomised controlled trial.

BACKGROUND: Existing evidence indicates that once mature neonates with severe cardio-respiratory failure become eligible for Extra Corporeal Membrane Oxygenation (ECMO) their chances of intact survival are doubled if they actually receive ECMO. However, significant numbers survive with disability. NEST is a multi-centre randomised controlled trial designed to test whether, in neonates requiring ECMO, cooling to 34 degrees C for the first 48 to 72 hours of their ECMO course leads to improved later health status. Infants allocated to the control group will receive ECMO at 37 degrees C throughout their course, which is currently standard practice around the world. Health status of both groups will be assessed formally at 2 years corrected age. METHODS/DESIGN: All infants recruited to the study will be cared for in one of the four United Kingdom (UK) ECMO centres. Babies who are thought to be eligible will be assessed by the treating clinician who will confirm eligibility, ensure that consent has been obtained and then randomise the baby using a web based system, based at the National Perinatal Epidemiology Unit (NPEU) Clinical Trials Unit. Trial registration.Babies allocated ECMO without cooling will receive ECMO at 37 degrees C +/- 0.2 degrees C. Babies allocated ECMO with cooling will be managed at 34 degrees C +/- 0.2 degrees C for up to 72 hours from the start of their ECMO run. The minimum duration of cooling will be 48 hours. Rewarming (to 37 degrees C) will occur at a rate of no more than 0.5 degrees C per hour. All other aspects of ECMO management will be identical. PRIMARY OUTCOME: Cognitive score from the Bayley Scales of Infant and Toddler Development, 3rd edition (Bayley-III) at age of 2 years (24 - 27 months). DISCUSSION: For the primary analysis, children will be analysed in the groups to which they are assigned, comparing the outcome of all babies allocated to "ECMO with cooling" with all those allocated to "ECMO" alone, regardless of deviation from the protocol or treatment received. For the primary outcome the analysis will compare the mean scores for each group of surviving babies. The rationale for this choice of primary analysis is to give a fair representation of the average ability of assessable children, accepting the limitation that excluding deaths might impose.The consistency of the effect of cooling on the group of babies recruited to the trial will be explored to see whether cooling is of particular help, or not, to specific subgroups of infants, using the statistical test of interaction. Therefore pre-specified subgroup analyses include: (i) whether the ECMO is veno-arterial or veno-venous; (ii) whether the child's oxygenation index at the time of recruitment is <60 or > or = 60; (iii) initial aEEG pattern shown on the cerebral function monitor, and (iv) primary diagnostic group. TRIAL REGISTRATION: Current Controlled Trials ISRCTN72635512.

Mild controlled hypothermia in preterm neonates with advanced necrotizing enterocolitis.

OBJECTIVES: Necrotizing enterocolitis (NEC) with multiple organ dysfunction syndrome (MODS) carries significant morbidity and mortality. There is extensive experimental evidence to support investigation of therapeutic hypothermia in infants with these conditions. We aimed to establish the feasibility and safety of mild hypothermia in preterm neonates with NEC and MODS as a prelude to a randomized trial. METHODS: This was a prospective, nonrandomized pilot study of 15 preterm infants who were referred for surgical intervention of advanced NEC and failure of at least 3 organs. Whole-body cooling was achieved by ambient temperature adjustment with or without cooling mattress. Three groups (n = 5 per group) were cooled to core temperatures of 35.5 degrees C (+/-0.5 degrees C), 34.5 degrees C, and 33.5 degrees C, respectively, for 48 hours before rewarming to 37 degrees C. Infants were carefully assessed to identify adverse effects that potentially were related to cooling and rewarming. A noncooled group (n = 10) with advanced surgical NEC and MODS was used for comparison. Data are medians (interquartile range). RESULTS: Gestational age at birth was 27 weeks (26-30), admission weight was 1.1 kg (1.0-1.7), and admission age was 31 days (12-45). Core temperature was maintained within target range for 90% (88%-97%) of the intended time. Statistically significant relationships were identified between core temperature and heart rate (P < .0001), pH (P < .0001), base excess (P = .003), and blood clot dynamics (longer time to initial clot formation, slower rate of clot formation, and decrease in clot strength; all P < .001) as assessed by thromboelastography. No major clinical problems or adverse events were noted during cooling or rewarming. Comparison with the noncooled group revealed no increase in mortality, bleeding, infection, or need for inotropes in infants who were cooled. CONCLUSIONS: Mild hypothermia for 48 hours in preterm neonates with severe NEC seems both feasible and safe. Additional investigation of the efficacy of this therapeutic intervention in this population is warranted.

Moderate hypothermia to treat perinatal asphyxial encephalopathy.

BACKGROUND: Whether hypothermic therapy improves neurodevelopmental outcomes in newborn infants with asphyxial encephalopathy is uncertain. METHODS: We performed a randomized trial of infants who were less than 6 hours of age and had a gestational age of at least 36 weeks and perinatal asphyxial encephalopathy. We compared intensive care plus cooling of the body to 33.5 degrees C for 72 hours and intensive care alone. The primary outcome was death or severe disability at 18 months of age. Prespecified secondary outcomes included 12 neurologic outcomes and 14 other adverse outcomes. RESULTS: Of 325 infants enrolled, 163 underwent intensive care with cooling, and 162 underwent intensive care alone. In the cooled group, 42 infants died and 32 survived but had severe neurodevelopmental disability, whereas in the noncooled group, 44 infants died and 42 had severe disability (relative risk for either outcome, 0.86; 95% confidence interval [CI], 0.68 to 1.07; P=0.17). Infants in the cooled group had an increased rate of survival without neurologic abnormality (relative risk, 1.57; 95% CI, 1.16 to 2.12; P=0.003). Among survivors, cooling resulted in reduced risks of cerebral palsy (relative risk, 0.67; 95% CI, 0.47 to 0.96; P=0.03) and improved scores on the Mental Developmental Index and Psychomotor Developmental Index of the Bayley Scales of Infant Development II (P=0.03 for each) and the Gross Motor Function Classification System (P=0.01). Improvements in other neurologic outcomes in the cooled group were not significant. Adverse events were mostly minor and not associated with cooling. CONCLUSIONS: Induction of moderate hypothermia for 72 hours in infants who had perinatal asphyxia did not significantly reduce the combined rate of death or severe disability but resulted in improved neurologic outcomes in survivors. (Current Controlled Trials number, ISRCTN89547571.)