Dominique Acolet

Twenty-Four Hours of Mild Hypothermia in Unsedated Newborn Pigs Starting after a Severe Global Hypoxic-Ischemic Insult Is Not Neuroprotective

Three to 12 h of mild hypothermia (HT) starting after hypoxia-ischemia is neuroprotective in piglets that are anesthetized during HT. Newborn infants suffering from neonatal encephalopathy often ventilate spontaneously and are not necessarily sedated. We aimed to test whether mild posthypoxic HT lasting 24 h was neuroprotective if the animals were not sedated. Thirty-nine piglets (median weight 1.6 kg, range 0.8–2.2 kg; median age 24 h, range 7–48 h) were anesthetized and ventilated and subjected to a 45-min hypoxic (Fio2 ∼ 6%) global insult (n = 36) or sham hypoxia (n = 3). On reoxygenation, 18 were maintained normothermic (NT, 39.0°C) for 72 h, and 21 were cooled from 39 (NT) to 35°C (HT) for the first 24 h before NT was resumed (18 experimental, three sham hypoxia). Cardiovascular parameters and intermittent EEG were documented throughout. The brain was perfusion fixed for neuropathology and five main areas examined using light microscopy. The insult severity (duration in minutes of EEG amplitude < 7μV) was similar in the NT and HT groups, mean ± SD (28 ± 7.2 versus 27 ± 8.6 min), as was the mean Fio2 (5.9 ± 0.7 versus 5.8 ± 0.8%) during the insult. Six NT and seven HT piglets developed posthypoxic seizures that lasted 29 and 30% of the time, respectively. The distribution and degree of injury (0.0–4.0, normal-maximal damage) within the brain (hippocampus, cortex/white matter, cerebellum, basal ganglia, thalamus) were similar in the NT and HT groups (overall score, mean ± SD, 2.3 ± 1.5 versus 2.4 ± 1.3) as was the EEG background amplitude at 3 h (13 ± 3.5 versus 10 ± 3.3 μV). The HT animals shivered and were more active. The sham control group (n = 3) shivered but had normal physiology and neuropathology. Plasma cortisol was significantly higher in the HT group during the HT period, 766 ± 277 versus 244 ± 144 μM at 24 h. Mild postinsult HT for 24 h was not neuroprotective in unsedated piglets and did not reduce the number of animals that developed posthypoxic seizures. Cortisol reached 3 times the NT value at the end of HT. We speculate that the stress of shivering and feeling cold interfered with the previously shown neuroprotective effect of HT. Research on the appropriateness of sedation during clinical HT is urgent.

Therapeutic hypothermia for birth asphyxia in low-resource settings: a pilot randomised controlled trial

This letter describes a study done at Mulago Hospital Kampala Uganda aimed at determining the feasibility of whole-body cooling by use of simple methods in a low-resource setting. The study performed after written informed parental consent randomly assigned standard care plus therapeutic hypothermia or standard care alone on infants within 3 hours of birth. Data suggests that therapeutic hypothermia with whole-body cooling screening informed consent and randomisation are feasible and inexpensive in a special-care baby unit in a low-resource setting. Rigorous randomised trials to determine the safety and efficacy of therapeutic hypothermia in this context are urgently needed so that any benefi ts of this novel therapy can reach areas of the world that might need it most. (excerpt)

Ischaemic and haemorrhagic brain lesions in newborns with seizures and normal Apgar scores.

Serial ultrasound scans and conventional and diffusion weighted magnetic resonance imaging (MRI) were performed on 16 neonates who presented with seizures. The Apgar scores were normal and subsequently no metabolic or infective cause could be found. The aim of the study was to evaluate the extent to which early sequential imaging can elucidate the cause of seizures in apparently neurologically normal infants. Fourteen of the infants had haemorrhagic or ischaemic lesions on MRI and these were detected by ultrasound scanning in 11. Early ultrasound scanning detected the haemorrhagic lesions but the ischaemic lesions were often not seen until the end of the first week of life. Early MRI, however, was able to detect all the ischaemic lesions. The evolution of the insult could be timed by using serial ultrasound scans and a combination of diffusion weighted and conventional MRI during the first week of life, confirming a perinatal insult even in the absence of fetal distress. Although the aetiology of these lesions remains obscure, serial ultrasound scans will detect the presence of cerebral lesions in neonates presenting with isolated seizures but additional MRI sequences will give better definition on type, site, and extent of the pathology.

Prognostic value of continuous electroencephalographic recording in full term infants with hypoxic ischaemic encephalopathy

The prognostic value of early neonatal continuous electroencephalographic recordings in hypoxic ischaemic encephalopathy was evaluated. Thirty seven full term infants with hypoxic ischaemic encephalopathy were studied. The electroencephalogram (EEG) was recorded using four or eight channel Oxford Medilog recorders and was started as soon as possible after birth. The recordings were initially visually analysed and divided into four categories: three in relation to the grade of discontinuity of the background activity (continuous, discontinuous, and maximum depression) and an additional fourth category to include status epilepticus. The EEGs with discontinuous activity were then analysed by computer to obtain a more objective assessment of discontinuity. The results were related to neurological outcome. Continuous background activity was associated with a normal outcome in all but the three infants who had continuous, but asymmetrical EEGs and who developed contralateral hemiplegia. In the eight infants with discontinuous activity, the outcome appeared to be related to the grade of continuity and the presence of clear convulsions on the EEG. The 10 infants with maximum depression and status epilepticus had severe impairment. These preliminary results suggest that continuous recording of EEGs could be used routinely in term infants with hypoxic ischaemic encephalopathy. Computer analysis can improve the value of this technique, allowing the identification of infants who might benefit from early therapeutic intervention.

Pilot randomized trial of therapeutic hypothermia with serial cranial ultrasound and 18-22 month follow-up for neonatal encephalopathy in a low resource hospital setting in Uganda: study protocol.

AbstractBackgroundThere is now convincing evidence that in industrialized countries therapeutic hypothermia for perinatal asphyxial encephalopathy increases survival with normal neurological function. However, the greatest burden of perinatal asphyxia falls in low and mid-resource settings where it is unclear whether therapeutic hypothermia is safe and effective.AimsUnder the UCL Uganda Womens Health Initiative, a pilot randomized controlled trial in infants with perinatal asphyxia was set up in the special care baby unit in Mulago Hospital, a large public hospital with ~20,000 births in Kampala, Uganda to determine: (i)The feasibility of achieving consent, neurological assessment, randomization and whole body cooling to a core temperature 33-34°C using water bottles(ii)The temperature profile of encephalopathic infants with standard care(iii)The pattern, severity and evolution of brain tissue injury as seen on cranial ultrasound and relation with outcome(iv)The feasibility of neurodevelopmental follow-up at 18-22 months of ageMethods/DesignEthical approval was obtained from Makerere Univer sity and Mulago Hospital. All infants were in-born. Parental consent for entry into the trial was obtained. Thirty-six infants were randomized either to standard care plus cooling (target rectal temperature of 33-34°C for 72 hrs, started within 3 h of birth) or standard care alone. All other aspects of management were the same. Cooling was performed using water bottles filled with tepid tap water (25°C). Rectal, axillary, ambient and surface water bottle temperatures were monitored continuously for the first 80 h. Encephalopathy scoring was performed on days 1-4, a structured, scorable neurological examination and head circumference were performed on days 7 and 17. Cranial ultrasound was performed on days 1, 3 and 7 and scored. Griffiths developmental quotient, head circumference, neurological examination and assessment of gross motor function were obtained at 18-22 months.DiscussionWe will highlight differences in neonatal care and infrastructure that need to be taken into account when considering a large safety and efficacy RCT of therapeutic hypothermia in low and mid resource settings in the future.Trial registrationCurrent controlled trials ISRCTN92213707

Improvement in neonatal intensive care unit care: a cluster randomised controlled trial of active dissemination of information.

Background Research findings are not rapidly or fully implemented into policies and practice in care. Objectives To assess whether an ‘active’ strategy was more likely to lead to changes in policy and practice in preterm baby care than traditional information dissemination. Design Cluster randomised trial. Participants 180 neonatal units (87 active, 93 control) in England; clinicians from active arm units; babies born <27 weeks gestation. Control arm Dissemination of research report; slides; information about newborn care position statement. Active arm As above plus offer to become ‘regional ‘champion’ (attend two workshops, support clinicians to implement research evidence regionally), or attend one workshop, promote implementation of research evidence locally. Main outcome measures timing of surfactant administration; admission temperature; staffing of resuscitation team present at birth. Results 48/87 Lead clinicians in the active arm attended one or both workshops. There was no evidence of difference in post-intervention policies between trial arms. Practice outcomes based on babies in the active (169) and control arms (186), in 45 and 49 neonatal units respectively, showed active arm babies were more likely to have been given surfactant on labour ward (RR=1.30; 95% CI 0.99 to1.70); p=0.06); to have a higher temperature on admission to neonatal intensive care unit (mean difference=0.29oC; 95% CI 0.22 to 0.55; p=0.03); and to have had the babys trunk delivered into a plastic bag (RR=1.27; 95% CI 1.01 to 1.60; p=0.04) than the control group. The effect on having an ‘ideal’ resuscitation team at birth was in the same direction of benefit for the active arm (RR=1.18; 95% CI 0.97 to 1.43; p=0.09). The costs of the intervention were modest. Conclusions This is the first trial to evaluate methods for transferring information from neonatal research into local policies and practice in England. An active approach to research dissemination is both feasible and cost-effective. Trial registration Current controlled trials ISRCTN89683698

Cranial ultrasound findings in well newborn Ugandan infants.

Background There has been no study assessing cranial ultrasound (cUS) scans in newborn infants born in equatorial Africa. Objective To assess the cUS scans of apparently well newborn term Ugandan infants and to correlate the findings with perinatal data. Methods An observational study of apparently healthy postnatal ward term Ugandan infants at Mulago Hospital, Makerere University Hospital, Kampala, Uganda. Results Data from 112 infants scanned at a median age of 1.4 postnatal days were analysed. Only 57 (51%) infants had scans considered normal, including 30 infants with isolated focal peritrigonal white matter (WM) echogenicity that was very common, occurring in 60 (53%) of infants. More extensive WM echogencities were seen in nine (7.5%) and focal unilateral central grey matter echogenicity in eight (6.5%) infants. Haemorrhage was not common. Subependymal pseudocysts (SEP) and choroid plexus cysts (CPC) occurred in 19.6% of infants each. Four infants only had lenticulostriate vasculopathy. No correlation was found between mode of delivery, birth weight, head circumference or gestational age, maternal HIV status and any cUS abnormality. Conclusions Apparently well term-born Ugandan infants frequently have abnormalities on cUS. These are mainly increased WM echogenicity, SEP and CPC. These may relate to the reported high incidence of congenital infections in this population but this remains to be confirmed. The observations provide baseline data for comparison with scans from sick infants from similar communities and are also important for studies in which cUS will be used to assess progress.

Quality of neonatal care and outcome

High quality of care in neonatology implies providing an appropriate level of care to well newborn babies as well as more specialised care for the few babies who need it. Audit, surveillance and outcome studies may not always capture the complexity of quality of care and its contribution to outcome, and a more focused approach to standards of care evaluation may be required. Future progress in this field in the UK would benefit from a more coordinated approach from different organisations to bring together expertise in large database, management and analysis, audit and a national profile for feedback, evidence-based guidelines and guidelines development skills, expertise in the practice of changes together with the promotion by credible perinatal authorities of clinical practice.

Cerebral measurements made using cranial ultrasound in term Ugandan newborns

BACKGROUND Few cUS studies of cerebral measurements are available for normal term infants. Normative data is important for evaluating cerebral structure size in symptomatic term infants and assessing preterm brain growth by term age. OBJECTIVES To (i) make linear measurements using cranial ultrasound (cUS) for major cerebral structures and intracranial spaces in normal newborn term infants, (ii) correlate these measurements with gestational age (GA), birth weight (BW), head circumference (HC), gender and within one infant (iii) examine inter/intra-observer variation, and (iv) compare these data with those currently available. DESIGN, SETTING AND PATIENTS Linear cUS measurements of major cerebral structures were made in well term-born Ugandan infants at Mulago University Hospital, Kampala. Correlations between the measurements and gender, HC, BW and GA were calculated. Intra- and inter-observer agreements were assessed. RESULTS Data from 106 infants (mean GA 39.20±1.4SD weeks) were analysed. Intra/inter-observer agreement was substantial/excellent. Significant correlations were found between HC and pons anterior-posterior diameter (p<0.01), corpus callosal (CC) length (p=0.02) and transverse cerebellar diameter (TCD, p<0.01) and between BW and CC length (p=0.02), vermis height (<0.01) and thalamo-occipital distance (p=0.03); no significant correlation was found with GA. Within infants CC length and TCD correlated significantly (p=0.019). Males had larger left ventricular indices than females (p=0.04). The data was similar to those from other populations. CONCLUSIONS These data provide reliable reference values for linear measurements of many cerebral structures made using cUS. The data agree well with those from other populations suggesting that cerebral size is similar in different ethnic groups.

The BLISS cluster randomised controlled trial of the effect of 'active dissemination of information' on standards of care for premature babies in England (BEADI) study protocol [ISRCTN89683698]

BackgroundGaps between research knowledge and practice have been consistently reported. Traditional ways of communicating information have limited impact on practice changes. Strategies to disseminate information need to be more interactive and based on techniques reported in systematic reviews of implementation of changes. There is a need for clarification as to which dissemination strategies work best to translate evidence into practice in neonatal units across England. The objective of this trial is to assess whether an innovative active strategy for the dissemination of neonatal research findings, recommendations, and national neonatal guidelines is more likely to lead to changes in policy and practice than the traditional (more passive) forms of dissemination in England.Methods/designCluster randomised controlled trial of all neonatal units in England (randomised by hospital, n = 182 and stratified by neonatal regional networks and neonatal units level of care) to assess the relative effectiveness of active dissemination strategies on changes in local policies and practices. Participants will be mainly consultant lead clinicians in each unit. The intervention will be multifaceted using: audit and feedback; educational meetings for local staff (evidence-based lectures on selected topics, interactive workshop to examine current practice and draw up plans for change); and quality improvement and organisational changes methods. Policies and practice outcomes for the babies involved will be collected before and after the intervention. Outcomes will assess all premature babies born in England during a three month period for timing of surfactant administration at birth, temperature control at birth, and resuscitation team (qualification and numbers) present at birth.Trial registrationCurrent controlled trials ISRCTN89683698