Anthony D Edwards

Assessment of brain tissue injury after moderate hypothermia in neonates with hypoxic-ischaemic encephalopathy : a nested study of a randomised controlled trial

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.

Reduced development of cerebral cortex in extremely preterm infants

Most growth in cortical connections and complexity occurs after 25 weeks. The cerebral cortex of extremely preterm infants when imaged at gestational age 38-42 weeks had less cortical surface area and was less complex than in normal infants born around term (p<0.0148 and p<0.0002, respectively), despite similar term-corrected cerebral tissue volumes. Since deficits acquired during critical periods of brain development may be permanent, these results suggest a neural substrate for the neurocognitive impairment that is frequent among such preterm infants.

Randomized double-blind controlled trial comparing the effects of ibuprofen with indomethacin on cerebral hemodynamics in preterm infants with patent ductus arteriosus

A prospective randomized controlled trial was performed to compare the effects of ibuprofen with indomethacin on cerebral hemodynamics measured using near infrared spectroscopy in preterm infants during treatment for patent ductus arteriosus. Infants were randomly assigned to three intravenous doses of either indomethacin (0.20–0.25 mg/kg, 12 hourly) or ibuprofen (5–10 mg/kg, 24 hourly) and also received a dose of saline. The primary end points of the study were the effects of the first dose on cerebral blood flow (CBF) and cerebral blood volume. Fifteen infants received indomethacin and 18 received ibuprofen. The group mean (SD) values for CBF (mL·100 g−1·min−1) before and after the first dose of indomethacin were 13.6 (4.1) and 8.3 (3.1), respectively, the change being significant (p < 0.001). In contrast, no significant changes in CBF were observed with the first dose of ibuprofen, the respective before and after values being 13.3 (3.2) and 14.9 (4.7) mL·100 g−1·min−1. The median (interquartile range) value for change in cerebral blood volume (mL/100 g) after the first dose in the indomethacin group was −0.4 (−0.3 to −0.6) and in the ibuprofen group was 0.0 (0.1 to −0.1), the difference between the two groups being significant (p < 0.001). Cerebral oxygen delivery changed significantly after the first dose in the indomethacin group but not in the ibuprofen group. Significant reductions in CBF, cerebral blood volume, and cerebral oxygen delivery also occurred after the 24-h dose of indomethacin, but there were no significant changes after the 48-h dose of saline in the indomethacin group or after the 24- and 48-h doses of ibuprofen. The patent ductus arteriosus closure rates after indomethacin and ibuprofen were 93 and 78%, respectively. We conclude that ibuprofen, unlike indomethacin, has no adverse effects on cerebral hemodynamics and appears to mediate patent ductus arteriosus closure.

Intrauterine T-cell activation and increased proinflammatory cytokine concentrations in preterm infants with cerebral lesions

Brain injury is common in very preterm infants, and intrauterine infection is a frequent antecedent of preterm birth. We examined the relation of cerebral damage to intrauterine antigen exposure and inflammation in 50 infants who were born at 23-29 weeks gestation. Higher concentrations of cytokines (tumour necrosis factor alpha [TNF-alpha], and interleukins [IL], 1beta, 6, and 10) and CD45RO(+) T lymphocytes in umbilical blood predicted cerebral lesions detected by magnetic resonance imaging very soon after delivery. Our results suggest that infants who mount an immune response in utero are at higher risk of cerebral lesions.

Numerical Modeling of Temperature Distributions within the Neonatal Head

Introduction of hypothermia therapy as a neuroprotection therapy after hypoxia-ischemia in newborn infants requires appraisal of cooling methods. In this numerical study thermal simulations were performed to test the hypothesis that cooling of the surface of the cranium by the application of a cooling bonnet significantly reduces deep brain temperature and produces a temperature differential between the deep brain and the body core. A realistic three-dimensional (3-D) computer model of infant head anatomy was used, derived from magnetic resonance data from a newborn infant. Temperature distributions were calculated using the Pennes heatsink model. The cooling bonnet was at a constant temperature of 10°C. When modeling head cooling only, a constant body core temperature of 37°C was imposed. The computed result showed no significant cooling of the deep brain regions, only the very superficial regions of the brain are cooled to temperatures of 33–34°C. Poor efficacy of head cooling was still found after a considerable increase in the modeled thermal conductivities of the skin and skull, or after a decrease in perfusion. The results for the heatsink thermal model of the infant head were confirmed by comparison of results computed for a scaled down adult head, using both the heatsink description and a discrete vessel thermal model with both anatomy and vasculature obtained from MR data. The results indicate that significant reduction in brain temperature will only be achieved if the infants core temperature is lowered.

Measurement of Cerebral Blood Flow in Newborn Infants Using Near Infrared Spectroscopy with Indocyanine Green

Elevated CK-MB Does Not Reliably Indicate Myocardial Injury During Intravenous Terbutaline Therapy for the Treatment of Status Asthmaticus† 186

Treatment of asphyxiated newborns with moderate hypothermia in routine clinical practice: how cooling is managed in the UK outside a clinical trial

Background: This is a phase 4 study of infants registered with the UK TOBY Cooling Register from December 2006 to February 2008. The registry was established on completion of enrolment to the TOBY randomised trial of treatment with whole body hypothermia following perinatal asphyxia at the end of November 2006. Methods: We collected information about patient characteristics, condition at birth, resuscitation details, severity of encephalopathy, hourly temperature record, clinical complications and outcomes before hospital discharge. Results: 120 infants born at a median of 40 (IQR 38–41) weeks’ gestation and weighing a median of 3287 (IQR 2895–3710) g at birth were studied. Cooling was started at a median of 3 h 54 min (IQR 2 h–5 h 32 min) after birth. All but three infants underwent whole body cooling. The mean (SD) rectal temperature from 6 to 72 h of the cooling period was 33.57°C (0.51°C). The daily encephalopathy score fell: median (IQR) 11 (6–15), 9.7 (5–14), 8 (5–13) and 7 (2–12) on days 1–4 after birth, respectively. 51% of the infants established full oral feeding at a median (range) of 9 (4–24) days. 26% of the study infants died. MRI was consistent with hypoxia-ischaemia in most cases. Clinical complications were not considered to be due to hypothermia. Conclusion: In the UK, therapeutic hypothermia following perinatal asphyxia is increasingly being provided. The target body temperature is successfully achieved and the clinical complications observed were not attributed to hypothermia. Treatment with hypothermia may have prevented the worsening of the encephalopathy that is commonly observed following asphyxia.

Therapeutic hypothermia following perinatal asphyxia

Well constructed and carefully analysed trials of hypothermic neural rescue therapy for infants with neonatal encephalopathy have recently been reported. The data suggest that either selective head cooling or total body cooling reduces the combined chance of death or disability after birth asphyxia. However, as there are still unanswered questions about these treatments, many may still feel that further data are needed before health care policy can be changed to make cooling the standard of care for all babies with suspected birth asphyxia.

Monitoring of deep brain temperature in infants using multi-frequency microwave radiometry and thermal modelling

In this study we present a design for a multi-frequency microwave radiometer aimed at prolonged monitoring of deep brain temperature in newborn infants and suitable for use during hypothermic neural rescue therapy. We identify appropriate hardware to measure brightness temperature and evaluate the accuracy of the measurements. We describe a method to estimate the tissue temperature distribution from measured brightness temperatures which uses the results of numerical simulations of the tissue temperature as well as the propagation of the microwaves in a realistic detailed three-dimensional infant head model. The temperature retrieval method is then used to evaluate how the statistical fluctuations in the measured brightness temperatures limit the confidence interval for the estimated temperature: for an 18 degrees C temperature differential between cooled surface and deep brain we found a standard error in the estimated central brain temperature of 0.75 degrees C. Evaluation of the systematic errors arising from inaccuracies in model parameters showed that realistic deviations in tissue parameters have little impact compared to uncertainty in the thickness of the bolus between the receiving antenna and the infants head or in the skull thickness. This highlights the need to pay particular attention to these latter parameters in future practical implementation of the technique.

Perinatal cortical growth and childhood neurocognitive abilities

Objective: This observational cohort study addressed the hypothesis that after preterm delivery brain growth between 24 and 44 weeks postmenstrual age (PMA) is related to global neurocognitive ability in later childhood. Methods: Growth rates for cerebral volume and cortical surface area were estimated in 82 infants without focal brain lesions born before 30 weeks PMA by using 217 magnetic resonance images obtained between 24 and 44 weeks PMA. Abilities were assessed at 2 years using the Griffiths Mental Development Scale and at 6 years using the Wechsler Preschool and Primary Scale of Intelligence–Revised (WPPSI-R), the Developmental Neuropsychological Assessment (NEPSY), and the Movement Assessment Battery for Children (MABC). Analysis was by generalized least-squares regression. Results: Mean test scores approximated population averages. Cortical growth was directly related to the Griffiths Developmental Quotient (DQ), the WPPSI-R full-scale IQ, and a NEPSY summary score but not the MABC score and in exploration of subtests to attention, planning, memory, language, and numeric and conceptual abilities but not motor skills. The mean (95% confidence interval) estimated reduction in cortical surface area at term corrected age associated with a 1 SD fall in test score was as follows: DQ 7.0 (5.8–8.5); IQ 6.0 (4.9–7.3); and NEPSY 9.1 (7.5–11.0) % · SD−1. Total brain volume growth was not correlated with any test score. Conclusions: The rate of cerebral cortical growth between 24 and 44 weeks PMA predicts global ability in later childhood, particularly complex cognitive functions but not motor functions.