Ss Pauliah

Therapeutic hypothermia for neonatal encephalopathy in low- and middle-income countries: a systematic review and meta-analysis.

Although selective or whole body cooling combined with optimal intensive care improves outcomes following neonatal encephalopathy in high-income countries, the safety and efficacy of cooling in low-and middle-income countries is not known. Objective We performed a systematic review and meta-analysis of all published randomised or quasi-randomised controlled trials of cooling therapy for neonatal encephalopathy in low-and middle-income countries. Results Seven trials, comprising a total of 567 infants were included in the meta-analysis. Most study infants had mild (15%) or moderate encephalopathy (48%) and did not receive invasive ventilation (88%). Cooling devices included water-circulating cooling caps, frozen gel packs, ice, water bottles, and phase-changing material. No statistically significant reduction in neonatal mortality was seen with cooling (risk ratio: 0.74, 95% confidence intervals: 0.44 to 1.25). Data on other neonatal morbidities and long-term neurological outcomes were insufficient. Conclusion Cooling therapy was not associated with a statistically significant reduction in neonatal mortality in low-and middle-income countries although the confidence intervals were wide and not incompatible with results seen in high-income countries. The apparent lack of treatment effect may be due to the heterogeneity and poor quality of the included studies, inefficiency of the low technology cooling devices, lack of optimal neonatal intensive care, sedation and ventilatory support, overuse of oxygen, or may be due to the intrinsic difference in the population, for example higher rates of perinatal infection, obstructed labor, intrauterine growth retardation and maternal malnutrition. Evaluation of the safety and efficacy of cooling in adequately powered randomised controlled trials is required before cooling is offered in routine clinical practice in low-and middle-income countries.

Diagnostic accuracy and limitations of post-mortem MRI for neurological abnormalities in fetuses and children.

AIM To compare the diagnostic accuracy of non-invasive cerebral post-mortem magnetic resonance imaging (PMMRI) specifically for cerebral and neurological abnormalities in a series of fetuses and children, compared to conventional autopsy. MATERIALS AND METHODS Institutional ethics approval and parental consent was obtained. Pre-autopsy cerebral PMMRI was performed in a sequential prospective cohort (n = 400) of fetuses (n = 277; 185 ≤ 24 weeks and 92 > 24 weeks gestation) and children <16 years (n = 123) of age. PMMRI and conventional autopsy findings were reported blinded and independently of each other. RESULTS Cerebral PMMRI had sensitivities and specificities (95% confidence interval) of 88.4% (75.5 to 94.9), and 95.2% (92.1 to 97.1), respectively, for cerebral malformations; 100% (83.9 to 100), and 99.1% (97.2 to 99.7) for major intracranial bleeds; and 87.5% (80.1 to 92.4) and 74.1% (68 to 79.4) for overall brain pathology. Formal neuropathological examination was non-diagnostic due to maceration/autolysis in 43/277 (16%) fetuses; of these, cerebral PMMRI imaging provided clinically important information in 23 (53%). The sensitivity of PMMRI for detecting significant ante-mortem ischaemic injury was only 68% (48.4 to 82.8) overall. CONCLUSIONS PMMRI is an accurate investigational technique for identifying significant neuropathology in fetuses and children, and may provide important information even in cases where autolysis prevents formal neuropathological examination; however, PMMRI is less sensitive at detecting hypoxic-ischaemic brain injury, and may not detect rarer disorders not encountered in this study.

Neonatal encephalopathic cerebral injury in South India assessed by perinatal magnetic resonance biomarkers and early childhood neurodevelopmental outcome.

Although brain injury after neonatal encephalopathy has been characterised well in high-income countries, little is known about such injury in low- and middle-income countries. Such injury accounts for an estimated 1 million neonatal deaths per year. We used magnetic resonance (MR) biomarkers to characterise perinatal brain injury, and examined early childhood outcomes in South India. Methods We recruited consecutive term or near term infants with evidence of perinatal asphyxia and a Thompson encephalopathy score ≥6 within 6 h of birth, over 6 months. We performed conventional MR imaging, diffusion tensor MR imaging and thalamic proton MR spectroscopy within 3 weeks of birth. We computed group-wise differences in white matter fractional anisotropy (FA) using tract based spatial statistics. We allocated Sarnat encephalopathy stage aged 3 days, and evaluated neurodevelopmental outcomes aged 3½ years using Bayley III. Results Of the 54 neonates recruited, Sarnat staging was mild in 30 (56%); moderate in 15 (28%) and severe in 6 (11%), with no encephalopathy in 3 (6%). Six infants died. Of the 48 survivors, 44 had images available for analysis. In these infants, imaging indicated perinatal rather than established antenatal origins to injury. Abnormalities were frequently observed in white matter (n = 40, 91%) and cortex (n = 31, 70%) while only 12 (27%) had abnormal basal ganglia/thalami. Reduced white matter FA was associated with Sarnat stage, deep grey nuclear injury, and MR spectroscopy N-acetylaspartate/choline, but not early Thompson scores. Outcome data were obtained in 44 infants (81%) with 38 (79%) survivors examined aged 3½ years; of these, 16 (42%) had adverse neurodevelopmental outcomes. Conclusions No infants had evidence for established brain lesions, suggesting potentially treatable perinatal origins. White matter injury was more common than deep brain nuclei injury. Our results support the need for rigorous evaluation of the efficacy of rescue hypothermic neuroprotection in low- and middle-income countries.

Cooling in a low-resource environment: Lost in translation

Although cooling therapy has been the standard of care for neonatal encephalopathy (NE) in high-income countries for more than half a decade, it is still not widely used in low- and middle-income countries (LMIC), which bear 99% of the encephalopathy burden; neither is it listed as a priority research area in global health. Here we explore the major roadblocks that prevent the use of cooling in LMIC, including differences in population comorbidities, suboptimal intensive care, and the lack of affordable servo-controlled cooling devices. The emerging data from LMIC suggest that the incidence of coexisting perinatal infections in NE is no different to that in high-income countries, and that cooling can be effectively provided without tertiary intensive care and ventilatory support; however, the data on safety and efficacy of cooling are limited. Without adequately powered clinical trials, the creeping and uncertain introduction of cooling therapy in LMIC will be plagued by residual safety concerns, and any therapeutic benefit will be even more difficult to translate into widespread clinical use.

Magnetic Resonance Biomarkers in Neonatal Encephalopathy (MARBLE): a prospective multicountry study.

Introduction Despite cooling, adverse outcomes are seen in up to half of the surviving infants after neonatal encephalopathy. A number of novel adjunct drug therapies with cooling have been shown to be highly neuroprotective in animal studies, and are currently awaiting clinical translation. Rigorous evaluation of these therapies in phase II trials using surrogate MR biomarkers may speed up their bench to bedside translation. A recent systematic review of single-centre studies has suggested that MR spectroscopy biomarkers offer the best promise; however, the prognostic accuracy of these biomarkers in cooled encephalopathic babies in a multicentre setting using different MR scan makers is not known. Methods and analysis The MR scanners (3 T; Philips, Siemens, GE) in all the participating sites will be harmonised using phantom experiments and healthy adult volunteers before the start of the study. We will then recruit 180 encephalopathic infants treated with whole body cooling from the participating centres. MRI and spectroscopy will be performed within 2 weeks of birth. Neurodevelopmental outcomes will be assessed at 18–24 months of age. Agreement between MR cerebral biomarkers and neurodevelopmental outcome will be reported. The sample size is calculated using the ‘rule of 10’, generally used to calculate the sample size requirements for developing prognostic models. Considering 9 parameters, we require 9×10 adverse events, which suggest that a total sample size of 180 is required. Ethics and dissemination Human Research Ethics Committee approvals have been received from Brent Research Ethics Committee (London), and from Imperial College London (Sponsor). We will submit the results of the study to relevant journals and offer national and international presentations. Trial registration number Clinical Trials.gov Number: NCT01309711.

8.9 Microstructural Changes in Neonatal Encephalopathy Revealed with the Neurite Orientation Dispersion and Density Imaging (NODDI) Model

Background Although diffusion tensor imaging (DTI) fractional anisotropy (FA) is commonly used to quantify neural injury, it is non-specific and affected by a number of microstructural changes. Objective To examine alterations in white matter (WM) associated with neonatal encephalopathy (NE), and relate these to tangible biophysical changes using the neurite orientation dispersion and density imaging (NODDI) model. Design/Methods We recruited with parental consent consecutive encephalopathic neonates (Thompson score ≥6) admitted to Calicut Medical College, India over a 6 month period. At age <3 wk diffusion tensor magnetic resonance imaging (DTI, TR/TE = 2800 ms/94 ms, 20 directions, b = 0&1000 s/mm2, 1.8 × 1.8 × 5 mm3) was performed at 1.5T (Siemens Avanto). Sarnat encephalopathy stage (none, mild, moderate or severe) was allocated at day 3. DTI data were fitted to the NODDI model, generating maps of orientation dispersion index (ODI) and neurite density index (NDI). These were compared between infants grouped by encephalopathy severity using tract-based spatial statistics (TBSS). Results Fifty-four infants were recruited; 31 had usable data. The mean FA skeleton is shown in green (Figure 1a). Compared to normal/mild (n = 22) the moderate/severe encephalopathy group (n = 9) had significantly reduced WM FA (Figure 1b: red p < 0.05; yellow p < 0.01) and increased radial diffusivity (RD, Figure 1c). This corresponded to a decrease in NDI (Figure 1d), but not ODI (Figure 1e). Conclusions In this cohort, NODDI fitting indicates that microstructural changes in NE may be due to a reduced neurite density. Further work will establish whether these findings are consistent with those obtained from gold-standard multi-shell diffusion data. Abstract 8.9 Figure 1

PC.110 Hypothermia for Encephalopathy in Low and Middle-Income Countries (HELIX): A Feasibility Study

Background Therapeutic hypothermia improves outcomes after neonatal encephalopathy in high-income countries, however the safety and efficacy of cooling in low- and middle-income countries (LMIC) is not known. Objective To examine the feasibility of whole body cooling using an inexpensive servo-controlled cooling device developed for use in LMIC. Design We recruited 28 newborns (>36 wk and >1.8 kg) aged <6 h, admitted to the neonatal unit at Madras Medical College, India, with moderate or severe neonatal encephalopathy. After informed parental consent, infants were kept naked on a cooling mattress attached to the device (Tecotherm-HELIX), circulating water mixed with alcohol. Following 72 h of cooling, infants were passively rewarmed by switching off the machine and covering the infant with warm clothes. Results 4/16(25%) infants with moderate encephalopathy, and 8/12(67%) with severe encephalopathy died. Thrombocytopenia was seen in 19(68%) infants, gastric bleeds in 10(36%), persistent acidosis in 1(4%) and sclerema in 1(4%). Mean (SD) age and temperature at start of cooling was 4.1(1.1) h, and 35.7(1.5)°C respectively. Mean (SD) induction time was 79(47) minutes, core temperature during cooling was 33.5(0.1) °C, and passive re-warming rate was 0.3(0.1) °C/h (Figure). The ambient temperature of the intensive care unit was 26–33°C. No additional nursing input was required to maintain cooling except refilling the machine with water every 6–8h. The cooling mattress had to be replaced once during the six month study period. Abstract PC.110 Figure Conclusions Effective therapeutic hypothermia can be provided using Tecotherm-HELIX with minimal additional nursing input in LMIC. Future clinical trials should examine the safety and efficacy of cooling in these settings.

PC.26 Feasibility of Magnetic Resonance Spectroscopy in Examining Thalamic Metabolite Concentrations in a Multi-Centre Study of Neonatal Encephalopathy

Background Proton magnetic resonance spectroscopy (MRS) has high prognostic value in hypoxic ischaemic encephalopathy (HIE), however its multi-centre application is limited by inconsistencies between scanners and protocols. N-acetylaspartate (NAA) is predominantly neuronal: cerebral NAA concentration may be a more reliable HIE-severity biomarker than lactate/NAA. Objective To quantify the inter-site and inter-subject variability of NAA concentration measurements. Design/Methods We recruited 5 healthy adult volunteers (aged 24–38, 2 male, 3 female) whom we scanned at 3 UK sites participating in a multi-centre neonatal-brain study (University Hospital, Coventry (UHC); Alder Hey Children’s Hospital, Liverpool (AH); University College Hospital, London (UCLH)). Thalamic NAA concentration was measured using the neonatal brain-water concentration reference protocol (15 × 15 × 15mm3 voxel; PRESS; water-suppressed TR/TE = 2s/288&60ms; TR/TE = 5s/60ms; non-water-suppressed TR = 10s, TE = 60/124/205/316/495/1000 ms). Spectra were post-processed in jMRUI and metabolites fitted with LCModel. Results One volunteer was unavailable for scanning at AH. The mean (SD) NAA concentrations across the remaining four subjects were 15.5(3.4)mmol/kg wet weight, 14.4(0.1) mmol/kg wet weight, and 15.2(0.1) mmol/kg wet weight at UHC, AH and UCLH respectively. This corresponds to a maximum inter-site group mean variation (range/mean) of 8%. The inter-subject variability of mean NAA concentration (SD/mean) was 10%. Conclusions The variation of thalamic NAA concentration between sites was 8% and the standard deviation across subjects was 10%, hence [NAA] may be suitable for multi-centre studies. Abstract PC.26 Figure

PC.45 Quantification of N-Acetylaspartate Concentration in the Neonatal Brain: Initial Results from the Multi-Centre Marble Study

Background Early cerebral proton magnetic resonance spectroscopy (MRS) predicts medium-term outcomes in neonatal encephalopathy (NE). Metabolite peak-area ratios are most commonly used for prognosis, but conflate pathological information from different metabolites. N-acetylaspartate (NAA) is predominantly neuronal and neuronal loss should result in reduced NAA absolute-concentration ([NAA]). Thus, thalamic [NAA] should offer significant prognostic value but is difficult to measure in a clinical setting. We have established a protocol for multi-centre [NAA] measurement with the aim to use it as a surrogate biomarker in phase II clinical trials. Objective To investigate the feasibility and utility of [NAA] quantitation across multiple centres. Design/Methods We recruited cooled, term neonates with NE (by Sarnat grade) with parental consent across participating sites. Using various 3T scanners, thalamic MRS was performed aged 7 ± 4d (PRESS; water-suppressed TR = 2s/TE = 288/60 ms;TR/TE = 5s/60 ms; non-water-suppressed TR = 10s, TE = 60/124/205/316/495/1000 ms, ~30min acquisition). Spectra were post-processed in jMRUI and metabolite contributions determined with LCModel. [NAA] was calculated, correcting for T2 effects and cerebrospinal fluid partial volume. Results Ten cases had sufficient data for [NAA] quantification. Sarnat grading <6h identified infants with highest [NAA] (median (IQR) 10.0(9.7–10.3) mmol/kg wet weight) as mild NE, with a lower [NAA] range for moderate NE (7.0(5.0–7.8) mmol/kg wet weight). Conclusions [NAA] quantification is achievable in a multi-centre setting, and agrees with clinical NE grading during the therapeutic window. Follow-up examinations will allow comparison of neonatal [NAA] with later neurodevelopmental outcomes. Abstract PC.45 Figure

PC.106 Cerebral Injury and Early Childhood Neurodevelopmental Outcome following Neonatal Encephalopathy in a Middle-income Country

Background Although neonatal encephalopathy (NE), accounts for 1 million neonatal deaths annually in low-and middle-income countries (LMIC), underlying brain injury and long term outcomes are not well characterised in LMIC. Objective To examine cerebral injury (using magnetic resonance (MR) biomarkers), and early childhood outcomes after NE in a government hospital in India. Design/Methods We recruited 54 newborns (>36 wk and >1.8 kg) with NE (Thompson score ≥6) at age <6h, admitted to the neonatal unit at Calicut Medical College, India over 6 months. Conventional MRI (1.5T, Siemens Avanto), diffusion tensor MR imaging and thalamic proton MR spectroscopy (MRS) were performed aged <3 wk. Cerebral injury was graded and group-wise differences in white matter (WM) fractional anisotropy (FA) were examined using tract-based spatial statistics (TBSS). In survivors, adverse neurodevelopmental outcome at mean (SD) 3.4(0.2) years was defined as Bayley-III composite cognitive/motor score ≤85, slow head growth or cerebral palsy. Results MR data available from 44 cases showed evidence of acute perinatal injury. WM changes were seen in 40(91%), basal ganglia/thalamic (BGT) injury in 12(27%). Six infants died neonataly, 16(42%) and had adverse neurodevelopmental outcome. TBSS showed a reduction in FA with adverse neurological outcomes, and in those who had moderate/severe BGT or cortical injury. Conclusions Cerebral injury in this cohort appears to be of perinatal origin and may be amenable to treatment. Although NE stage and injury pattern was mild in the majority of infants, adverse outcomes were seen in 42% at 3½ years. Reduced WM FA was associated with adverse neurodevelopmental outcomes.