Hypocarbia is associated with adverse outcomes in hypoxic ischaemic encephalopathy (HIE).

AIM: Hypocarbia in the early postnatal period might exacerbate brain injury in babies with hypoxic ischaemic encephalopathy following birth asphyxia. This mini-review summarised studies on pCO2 values that were monitored periodically in term newborns with moderate/severe hypoxic-ischaemic encephalopathy and correlated with short or long-term outcomes. METHODS: We searched the databases MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), web of science and the Cochrane Library and identified nine studies. RESULTS: Among the nine included studies, therapeutic hypothermia was administered in seven studies. In most studies, blood pCO2 levels were measured from birth till 72 h of life or till the endpoint of therapeutic hypothermia. Eight studies showed that any hypocarbia (moderate or severe, or cumulative) was associated with an increased risk of adverse outcomes in the form of brain injury in MRI, death or neurodevelopmental disability. CONCLUSION: Hypocarbia could lead to adverse short-term and long-term outcomes despite therapeutic hypothermia in neonates with HIE. Hence, it is vital to monitor pCO2 levels closely in these infants and consider strategies to maintain pCO2 levels in the normal range.

Respiratory infections in children born preterm in low and middle-income countries: A systematic review.

CONTEXT: Studies from high-income countries indicates that infants born preterm are at increased risk of respiratory infections; however in the low and middle-income countries (LMICs) data are limited. Our aim was to systematically review the studies evaluating the risk of respiratory infections in preterm children born in LMICs. METHODS: We searched Medline, PubMed, Cumulative Index of Nursing and Allied Health Literature, Embase, and Psych-INFO databases for studies reporting respiratory outcomes in children born preterm in LMICs. Two authors extracted the data and evaluated the risk of bias with appropriate assessment methods independently. RESULTS: Twelve observational studies evaluating 5969 children were included in the review. The risk of lower respiratory tract infection varied from 5% to 73.9%. Similarly, respiratory syncytial virus (RSV) infection risk ranged from 4.4% to 22.7%. The unadjusted relative risk for any respiratory tract infection or lower respiratory tract infection was significantly higher in the children born preterm than in children born at term (1.52 [95% confidence interval 1.25-1.85]). We also noted wide-ranging risk of respiratory infections requiring in-hospital or emergency care (range: 0.5%-27.7%) and hospital stay in children born preterm (range: 6-14.3 days). CONCLUSIONS: Preterm-born children in LMICs are at risk of increased respiratory infections compared to term-born children; however, the baseline risk is variable, although substantial; This highlights the need for preventive strategies, including RSV immunoprophylaxis.

Effect of Enteral Long-Chain Polyunsaturated Fatty Acids on Retinopathy of Prematurity: A Systematic Review and Meta-Analysis.

BACKGROUND: Long-chain polyunsaturated fatty acids (LCPUFA) are critical for the maturation of the brain and retina. Retinopathy of prematurity (ROP) is a preventable cause of blindness in preterm infants. LCPUFA have anti-inflammatory, antioxidant, and antiangiogenesis effects. Supplementation of enteral LCPUFA might mitigate the incidence of ROP in these infants. Available limited randomized studies showed promising results. We aimed to assess the effect of enteral supplementation of LCPUFA on ROP in preterm infants. METHODS: We followed PRISMA guidelines and searched MEDLINE, Cumulative Index of Nursing and Allied Health Literature, Embase, and Cochrane Registry from 1990 to 2021 for the studies that examined the effects of enteral LCPUFA and ROP in preterm infants. We included the studies that satisfied the predefined inclusion criteria. RevMan 5.3 software derived the forest plot of pooled relative risk. We assessed the quality of all the included studies using GRADE recommendations. RESULTS: Nine studies were eligible for the meta-analysis involving 2,482 infants. Of the nine RCTs, six studies provided LCPUFA (DHA/AA) as a separate intervention in different concentrations, and three studies provided formula milk enriched with LCPUFA. In addition, five studies recruited infants below 32 weeks of gestational age. Supplementation of LCPUFA did not reduce the incidence of severe ROP (RR 0.71, 95% CI: 0.50-1.01, 5 studies, 1,822 infants) with very low CoE or any ROP (RR 0.95, 95% CI: 0.73-1.12, 6 studies, 1,177 infants) with very low CoE or ROP requiring treatment (RR 0.92, 95% CI: 0.62-1.38, 4 studies, 1,395 infants) with very low CoE. Regarding safety outcomes, enteral LCPUFA did not increase the risk of necrotizing enterocolitis or mortality. DISCUSSION/CONCLUSION: Supplementation of enteral LCPUFA to preterm infants did not reduce ROP incidence; however, there was a trend toward benefit in mitigating severe form of ROP. More well-designed, large, randomized controlled studies are warranted.

Whole lung irradiation as a novel treatment for COVID-19: Interim results of an ongoing phase 2 trial in India.

BACKGROUND AND PURPOSE: The main cause of death in COVID-19 pneumonia is acute respiratory distress syndrome which is preceded by massive cytokine release. Low-dose radiation therapy (LDRT) has anti-inflammatory and immunomodulatory effects that can interfere with the inflammatory cascade, reducing the severity of associated cytokine release. MATERIAL & METHODS: 25 patients with RT-PCR proven COVID-19 pneumonia were enrolled between November 2020 and May 2021. All patients had SpO2 < 94 % on room air, respiratory frequency > 24/min and SpO2/FiO2 ratio (SF ratio) of >89 but <357. Patients were treated according to standard COVID-19 management guidelines along with single fraction LDRT of 0.5 Gy to bilateral whole lungs within 10 days of symptom onset and 5 days of hospital admission. RESULTS: LDRT was well tolerated by all patients. There was a statistically significant improvement in oxygenation as given by the SF ratio between pre-RT and day 2 (p < 0.05), day 3 (p < 0.001) and day 7 (p < 0.001) post RT. Demand for supplemental oxygen showed statistically significant reduction between pre-RT and day 2 (p < 0.05), day 3 (p < 0.001), day 7 (p < 0.001) post RT. 88 % patients attained clinical recovery within 10 days post LDRT and median time to hospital discharge from day of LDRT was 6 days. Three patients deteriorated and died. CONCLUSION: As per our initial experience, LDRT appears to be a promising modality of treatment with rapid relief of respiratory distress in selected patients with moderate to severe COVID-19 pneumonia. This translates to early clinical recovery and hospital discharge in the selected patient group.

Transcriptomic profile of adverse neurodevelopmental outcomes after neonatal encephalopathy.

A rapid and early diagnostic test to identify the encephalopathic babies at risk of adverse outcome may accelerate the development of neuroprotectants. We examined if a whole blood transcriptomic signature measured soon after birth, predicts adverse neurodevelopmental outcome eighteen months after neonatal encephalopathy. We performed next generation sequencing on whole blood ribonucleic acid obtained within six hours of birth from the first 47 encephalopathic babies recruited to the Hypothermia for Encephalopathy in Low and middle-income countries (HELIX) trial. Two infants with blood culture positive sepsis were excluded, and the data from remaining 45 were analysed. A total of 855 genes were significantly differentially expressed between the good and adverse outcome groups, of which RGS1 and SMC4 were the most significant. Biological pathway analysis adjusted for gender, trial randomisation allocation (cooling therapy versus usual care) and estimated blood leukocyte proportions revealed over-representation of genes from pathways related to melatonin and polo-like kinase in babies with adverse outcome. These preliminary data suggest that transcriptomic profiling may be a promising tool for rapid risk stratification in neonatal encephalopathy. It may provide insights into biological mechanisms and identify novel therapeutic targets for neuroprotection.

Therapeutic Hypothermia for Neonatal Encephalopathy in Indian Neonatal Units: A Survey of National Practices.

This cross-sectional web-based survey suggests that cooling therapy is offered as standard of care for babies with neonatal encephalopathy in 10/25 (40%) of public and 37/68 (51%) of private level 2 or 3 neonatal units in India. 25 (53%) used locally improvised cooling methods, and the cooling practices differed from established protocols in high-income countries.

Systemic pro-inflammatory cytokine status following therapeutic hypothermia in a piglet hypoxia-ischemia model.

BACKGROUND: Inflammatory cytokines are implicated in the pathogenesis of perinatal hypoxia-ischemia (HI). The influence of hypothermia (HT) on cytokines after HI is unclear. Our aim was to assess in a piglet asphyxia model, under normothermic (NT) and HT conditions: (i) the evolution of serum cytokines over 48 h and (ii) cerebrospinal fluid (CSF) cytokine levels at 48 h; (iii) serum pro/anti-inflammatory cytokine profile over 48 h and (iv) relation between brain injury measured by magnetic resonance spectroscopy (MRS) and brain TUNEL positive cells with serum cytokines, serum pro/anti-inflammatory cytokines and CSF cytokines. METHODS: Newborn piglets were randomized to NT (n = 5) or HT (n = 6) lasting 2-26 h after HI. Serum samples were obtained 4-6 h before, during and at 6-12 h intervals after HI; CSF was obtained at 48 h. Concentrations of interleukin (IL)-1ß, -4, -6, -8, -10 and TNF-α were measured and pro/anti-inflammatory status compared between groups. White matter and thalamic voxel lactate/N-acetyl aspartate (Lac/NAA) (a measure of both oxidative metabolism and neuronal loss) were acquired at baseline, after HI and at 24 and 36 h. RESULTS: Lac/NAA was reduced at 36 h with HT compared to NT (p = 0.013 basal ganglia and p = 0.033 white matter). HT showed lower serum TNF-α from baseline to 12 h (p < 0.05). Time-matched (acquired within 5 h of each other) serum cytokine and MRS showed correlations between Lac/NAA and serum IL-1ß and IL-10 (all p < 0.01). The pro/anti-inflammatory ratios IL-1ß/IL-10, IL-6/IL-10, IL-4/IL-10 and IL-8/IL-10 were similar in NT and HT groups until 36 h (24 h for IL-6/IL-10); after this, 36 h pro/anti-inflammatory cytokine ratios in the serum were higher in HT compared to NT (p < 0.05), indicating a pro-inflammatory cytokine surge after rewarming in the HT group. In the CSF at 48 h, IL-8 was lower in the HT group (p < 0.05). At 48 h, CSF TNF-α correlated with Lac/NAA (p = 0.02) and CSF IL-8 correlated with white matter TUNEL positive cell death (p = 0.04). CONCLUSIONS: Following cerebral HI, there was a systemic pro-inflammatory surge after rewarming in the HT group, which is counterintuitive to the putative neuroprotective effects of HT. While serum cytokines were variable, elevations in CSF inflammatory cytokines at 48 h were associated with MRS Lac/NAA and white matter cell death.

Brain cell death is reduced with cooling by 3.5°C to 5°C but increased with cooling by 8.5°C in a piglet asphyxia model.

BACKGROUND AND PURPOSE: In infants with moderate to severe neonatal encephalopathy, whole-body cooling at 33°C to 34°C for 72 hours is standard care with a number needed to treat to prevent a adverse outcome of 6 to 7. The precise brain temperature providing optimal neuroprotection is unknown. METHODS: After a quantified global cerebral hypoxic-ischemic insult, 28 piglets aged <24 hours were randomized (each group, n=7) to (1) normothermia (38.5°C throughout) or whole-body cooling 2 to 26 hours after insult to (2) 35°C, (3) 33.5°C, or (4) 30°C. At 48 hours after hypoxia-ischemia, delayed cell death (terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling and cleaved caspase 3) and microglial ramification (ionized calcium-binding adapter molecule 1) were evaluated. RESULTS: At 48 hours after hypoxia-ischemia, substantial cerebral injury was found in the normothermia and 30°C hypothermia groups. However, with 35°C and 33.5°C cooling, a clear reduction in delayed cell death and microglial activation was observed in most brain regions (P<0.05), with no differences between 35°C and 33.5°C cooling groups. A protective pattern was observed, with U-shaped temperature dependence in delayed cell death in periventricular white matter, caudate nucleus, putamen, hippocampus, and thalamus. A microglial activation pattern was also seen, with inverted U-shaped temperature dependence in periventricular white matter, caudate nucleus, internal capsule, and hippocampus (all P<0.05). CONCLUSIONS: Cooling to 35°C (an absolute drop of 3.5°C as in therapeutic hypothermia protocols) or to 33.5°C provided protection in most brain regions after a cerebral hypoxic-ischemic insult in the newborn piglet. Although the relatively wide therapeutic range of a 3.5°C to 5°C drop in temperature reassured, overcooling (an 8.5°C drop) was clearly detrimental in some brain regions.

Early clinical predictors of a severely abnormal amplitude-integrated electroencephalogram at 48 hours in cooled neonates.

AIM: There is a need to identify infants with hypoxic ischaemic encephalopathy who have a poor outcome despite therapeutic hypothermia. A severely abnormal amplitude-integrated electroencephalogram at 48 h predicts death or disability. Our aim was to determine whether clinical assessment at age 3-5 h predicts a severely abnormal amplitude-integrated electroencephalogram at 48 h or death in cooled infants. METHODS: Forty-one cooled infants, ≥36 weeks' gestation, with moderate-to-severe hypoxic ischaemic encephalopathy, were prospectively enrolled. Infants who were moribund, had congenital conditions associated with encephalopathy or had severe cardio-respiratory instability were excluded. The predictive abilities of the Thompson encephalopathy score and individual signs at age 3-5 h were assessed. RESULTS: All infants with a Thompson score ≥16 at 3-5 h had a severely abnormal amplitude-integrated electroencephalogram at 6 h and an abnormal short-term outcome. At 48 h, 75% had a severely abnormal aEEG or died vs. 18% with a score <16 (p = 0.004). Multivariate analysis did not find a significant independent association with any of the individual signs. CONCLUSION: The Thompson score could be useful to identify infants who will have a poor outcome despite cooling. A score ≥16 should be validated as a prespecified variable in prospective studies.

Early clinical signs in neonates with hypoxic ischemic encephalopathy predict an abnormal amplitude-integrated electroencephalogram at age 6 hours.

BACKGROUND: An early clinical score predicting an abnormal amplitude-integrated electroencephalogram (aEEG) or moderate-severe hypoxic ischemic encephalopathy (HIE) may allow rapid triage of infants for therapeutic hypothermia. We aimed to determine if early clinical examination could predict either an abnormal aEEG at age 6 hours or moderate-severe HIE presenting within 72 hours of birth. METHODS: Sixty infants ≥ 36 weeks gestational age were prospectively enrolled following suspected intrapartum hypoxia and signs of encephalopathy. Infants who were moribund, had congenital conditions that could contribute to the encephalopathy or had severe cardio-respiratory instability were excluded. Predictive values of the Thompson HIE score, modified Sarnat encephalopathy grade (MSEG) and specific individual signs at age 3-5 hours were calculated. RESULTS: All of the 60 infants recruited had at least one abnormal primitive reflex. Visible seizures and hypotonia at 3-5 hours were strongly associated with an abnormal 6-hour aEEG (specificity 88% and 92%, respectively), but both had a low sensitivity (47% and 33%, respectively). Overall, 52% of the infants without hypotonia at 3-5 hours had an abnormal 6-hour aEEG. Twelve of the 29 infants (41%) without decreased level of consciousness at 3-5 hours had an abnormal 6-hour aEEG (sensitivity 67%; specificity 71%). A Thompson score ≥ 7 and moderate-severe MSEG at 3-5 hours, both predicted an abnormal 6-hour aEEG (sensitivity 100 vs. 97% and specificity 67 vs. 71% respectively). Both assessments predicted moderate-severe encephalopathy within 72 hours after birth (sensitivity 90%, vs. 88%, specificity 92% vs. 100%). The 6-hour aEEG predicted moderate-severe encephalopathy within 72 hours (sensitivity 75%, specificity 100%) but with lower sensitivity (p = 0.0156) than the Thompson score (sensitivity 90%, specificity 92%). However, all infants with a normal 3- and 6-hour aEEG with moderate-severe encephalopathy within 72 hours who were not cooled had a normal 24-hour aEEG. CONCLUSIONS: The encephalopathy assessment described by the Thompson score at age 3-5 hours is a sensitive predictor of either an abnormal 6-hour aEEG or moderate-severe encephalopathy presenting within 72 hours after birth. An early Thompson score may be useful to assist with triage and selection of infants for therapeutic hypothermia.

Methyl-isobutyl amiloride reduces brain Lac/NAA, cell death and microglial activation in a perinatal asphyxia model.

Na⁺/H⁺ exchanger (NHE) blockade attenuates the detrimental consequences of ischaemia and reperfusion in myocardium and brain in adult and neonatal animal studies. Our aim was to use magnetic resonance spectroscopy (MRS) biomarkers and immunohistochemistry to investigate the cerebral effects of the NHE inhibitor, methyl isobutyl amiloride (MIA) given after severe perinatal asphyxia in the piglet. Eighteen male piglets (aged < 24 h) underwent transient global cerebral hypoxia-ischaemia and were randomized to (i) saline placebo; or (ii) 3 mg/kg intravenous MIA administered 10 min post-insult and 8 hourly thereafter. Serial phosphorus-31 (³¹P) and proton (¹H) MRS data were acquired before, during and up to 48 h after hypoxia-ischaemia and metabolite-ratio time-series Area under the Curve (AUC) calculated. At 48 h, histological and immunohistochemical assessments quantified regional tissue injury. MIA decreased thalamic lactate/N-acetylaspartate and lactate/creatine AUCs (both p < 0.05) compared with placebo. Correlating with improved cerebral energy metabolism, transferase mediated biotinylated d-UTP nick end-labelling (TUNEL) positive cell density was reduced in the MIA group in cerebral cortex, thalamus and white matter (all p < 0.05) and caspase 3 immunoreactive cells were reduced in pyriform cortex and caudate nucleus (both p < 0.05). Microglial activation was reduced in pyriform and midtemporal cortex (both p < 0.05). Treatment with MIA starting 10 min after hypoxia-ischaemia was neuroprotective in this perinatal asphyxia model.

Melatonin augments hypothermic neuroprotection in a perinatal asphyxia model.

Despite treatment with therapeutic hypothermia, almost 50% of infants with neonatal encephalopathy still have adverse outcomes. Additional treatments are required to maximize neuroprotection. Melatonin is a naturally occurring hormone involved in physiological processes that also has neuroprotective actions against hypoxic-ischaemic brain injury in animal models. The objective of this study was to assess neuroprotective effects of combining melatonin with therapeutic hypothermia after transient hypoxia-ischaemia in a piglet model of perinatal asphyxia using clinically relevant magnetic resonance spectroscopy biomarkers supported by immunohistochemistry. After a quantified global hypoxic-ischaemic insult, 17 newborn piglets were randomized to the following: (i) therapeutic hypothermia (33.5°C from 2 to 26 h after resuscitation, n = 8) and (ii) therapeutic hypothermia plus intravenous melatonin (5 mg/kg/h over 6 h started at 10 min after resuscitation and repeated at 24 h, n = 9). Cortical white matter and deep grey matter voxel proton and whole brain (31)P magnetic resonance spectroscopy were acquired before and during hypoxia-ischaemia, at 24 and 48 h after resuscitation. There was no difference in baseline variables, insult severity or any physiological or biochemical measure, including mean arterial blood pressure and inotrope use during the 48 h after hypoxia-ischaemia. Plasma levels of melatonin were 10 000 times higher in the hypothermia plus melatonin than hypothermia alone group. Melatonin-augmented hypothermia significantly reduced the hypoxic-ischaemic-induced increase in the area under the curve for proton magnetic resonance spectroscopy lactate/N-acetyl aspartate and lactate/total creatine ratios in the deep grey matter. Melatonin-augmented hypothermia increased levels of whole brain (31)P magnetic resonance spectroscopy nucleotide triphosphate/exchangeable phosphate pool. Correlating with improved cerebral energy metabolism, TUNEL-positive nuclei were reduced in the hypothermia plus melatonin group compared with hypothermia alone in the thalamus, internal capsule, putamen and caudate, and there was reduced cleaved caspase 3 in the thalamus. Although total numbers of microglia were not decreased in grey or white matter, expression of the prototypical cytotoxic microglial activation marker CD86 was decreased in the cortex at 48 h after hypoxia-ischaemia. The safety and improved neuroprotection with a combination of melatonin with cooling support phase II clinical trials in infants with moderate and severe neonatal encephalopathy.

Systemic effects of whole-body cooling to 35 °C, 33.5 °C, and 30 °C in a piglet model of perinatal asphyxia: implications for therapeutic hypothermia.

INTRODUCTION: The precise temperature for optimal neuroprotection in infants with neonatal encephalopathy is unclear. Our aim was to assess systemic effects of whole-body cooling to 35 °C, 33.5 °C, and 30 °C in a piglet model of perinatal asphyxia. METHODS: Twenty-eight anesthetized male piglets aged <24 h underwent hypoxia-ischemia (HI) and were randomized to normothermia or cooling to rectal temperature (Trec) 35 °C, 33.5 °C, or 30 °C during 2-26 h after insult (n = 7 in each group). HR, MABP, and Trec were recorded continuously. RESULTS: Five animals cooled to 30 °C had fatal cardiac arrests. During 30 °C cooling, heart rate (HR) was lower vs. normothermia (P < 0.001). Although mean arterial blood pressure (MABP) did not vary between groups, more fluid boluses were needed at 30 °C than at normothermia (P < 0.02); dopamine use was higher at 30 °C than at normothermia or 35 °C (P = 0.005 and P = 0.02, respectively). Base deficit was increased at 30 °C at 12, 24, and 36 h vs. all other groups (P < 0.05), pH was acidotic at 36 h vs. normothermia (P = 0.04), and blood glucose was higher for the 30 °C group at 12 h vs. the normothermia and 35 °C groups (P < 0.05). Potassium was lower at 12 h in the 30 °C group vs. the 33.5 °C and 35 °C groups. There was no difference in cortisol level between groups. DISCUSSION: Cooling to 30 °C led to metabolic derangement and more cardiac arrests and deaths than cooling to 33.5 °C or 35 °C. Inadvertent overcooling should be avoided.

Xenon augmented hypothermia reduces early lactate/N-acetylaspartate and cell death in perinatal asphyxia.

OBJECTIVE: Additional treatments for therapeutic hypothermia are required to maximize neuroprotection for perinatal asphyxial encephalopathy. We assessed neuroprotective effects of combining inhaled xenon with therapeutic hypothermia after transient cerebral hypoxia-ischemia in a piglet model of perinatal asphyxia using magnetic resonance spectroscopy (MRS) biomarkers supported by immunohistochemistry. METHODS: Thirty-six newborn piglets were randomized (all groups n = 9), with intervention from 2 to 26 hours, to: (1) normothermia; (2) normothermia + 24 hours 50% inhaled xenon; (3) 24 hours hypothermia (33.5°C); or (4) 24 hours hypothermia (33.5°C) + 24 hours 50% inhaled xenon. Serial MRS was acquired before, during, and up to 48 hours after hypoxia-ischemia. RESULTS: Mean arterial blood pressure was lower in all treatment groups compared with normothermia (p < 0.01) (although >40mmHg); the combined therapy group required more fluid boluses (p < 0.05) and inotropes (p < 0.001). Compared with no intervention, both hypothermia and xenon-augmented hypothermia reduced the temporal regression slope magnitudes for phosphorus-MRS inorganic phosphate/exchangeable phosphate pool (EPP) and phosphocreatine/EPP (both p < 0.05); for lactate/N-acetylaspartate (NAA), only xenon-augmented hypothermia reduced the slope (p < 0.01). Xenon-augmented hypothermia also reduced transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL)(+) nuclei and caspase 3 immunoreactive cells in parasagittal cortex and putamen and increased microglial ramification in midtemporal cortex compared with the no treatment group (p < 0.05). Compared with hypothermia, however, combination treatment did not reach statistical significance for any measure. Lactate/NAA showed a strong positive correlation with TUNEL; nucleotide triphosphate/EPP showed a strong negative correlation with microglial ramification (both p < 0.01). INTERPRETATION: Compared with no treatment, xenon-augmented hypothermia reduced cerebral MRS abnormalities and cell death markers in some brain regions. Compared with hypothermia, xenon-augmented hypothermia did not reach statistical significance for any measure. The safety and possible improved efficacy support phase II trials.

Cerebral magnetic resonance biomarkers in neonatal encephalopathy: a meta-analysis.

OBJECTIVE: Accurate prediction of neurodevelopmental outcome in neonatal encephalopathy (NE) is important for clinical management and to evaluate neuroprotective therapies. We undertook a meta-analysis of the prognostic accuracy of cerebral magnetic resonance (MR) biomarkers in infants with neonatal encephalopathy. METHODS: We reviewed all studies that compared an MR biomarker performed during the neonatal period with neurodevelopmental outcome at > or =1 year. We followed standard methods recommended by the Cochrane Diagnostic Accuracy Method group and used a random-effects model for meta-analysis. Summary receiver operating characteristic curves and forest plots of each MR biomarker were calculated. chi(2) tests examined heterogeneity. RESULTS: Thirty-two studies (860 infants with NE) were included in the meta-analysis. For predicting adverse outcome, conventional MRI during the neonatal period (days 1-30) had a pooled sensitivity of 91% (95% confidence interval [CI]: 87%-94%) and specificity of 51% (95% CI: 45%-58%). Late MRI (days 8-30) had higher sensitivity but lower specificity than early MRI (days 1-7). Proton MR spectroscopy deep gray matter lactate/N-acetyl aspartate (Lac/NAA) peak-area ratio (days 1-30) had 82% overall pooled sensitivity (95% CI: 74%-89%) and 95% specificity (95% CI: 88%-99%). On common study analysis, Lac/NAA had better diagnostic accuracy than conventional MRI performed at any time during neonatal period. The discriminatory powers of the posterior limb of internal capsule sign and brain-water apparent diffusion coefficient were poor. CONCLUSIONS: Deep gray matter Lac/NAA is the most accurate quantitative MR biomarker within the neonatal period for prediction of neurodevelopmental outcome after NE. Lac/NAA may be useful in early clinical management decisions and counseling parents and as a surrogate end point in clinical trials that evaluate novel neuroprotective therapies.

Diagnostic accuracy of post-mortem magnetic resonance imaging in fetuses, children and adults: a systematic review.

To determine, in a systematic review, the diagnostic accuracy, acceptability and cost-effectiveness of less invasive autopsy by post-mortem MR imaging, in fetuses, children and adults. We searched Medline, Embase, the Cochrane library and reference lists to identify all studies comparing post-mortem MR imaging with conventional autopsy, published between January 1990 and March 2009. 539 abstracts were identified; 15 papers met the inclusion criteria; data from 9 studies were extracted (total: 146 fetuses, 11 children and 24 adults). In accurately identifying the final cause of death or most clinically significant abnormality, post-mortem MR imaging had a sensitivity and specificity of 69% (95% CI-56%, 80%) and 95% (95% CI-88%, 98%) in fetuses, and 28% (95% CI-13%, 47%) and 64% (95% CI-23%, 94%) in children and adults, respectively; however the published data is limited to small, heterogenous and poorly designed studies. Insufficient data is available on acceptability and economic evaluation of post-mortem MR imaging. Well designed, large, prospective studies are required to evaluate the accuracy of post-mortem MR imaging, before it can be offered as a clinical tool.