18 results found
Montaldo P, Lally P, Oliveira V, et al., 2019, Therapeutic hypothermia initiated within 6 hours of birth is associated with reduced brain injury on MR biomarkers in mild hypoxic ischemic encephalopathy: a non-randomised cohort study, Archives of Disease in Childhood. Fetal and Neonatal Edition, Vol: 104, Pages: F515-F520, ISSN: 1359-2998
Objective To examine the effect of therapeutic hypothermia on MR biomarkers and neurodevelopmental outcomes in babies with mild hypoxic-ischaemic encephalopathy (HIE).Design Non-randomised cohort study.Setting Eight tertiary neonatal units in the UK and the USA.Patients 47 babies with mild HIE on NICHD neurological examination performed within 6 hours after birth.Interventions Whole-body cooling for 72 hours (n=32) or usual care (n=15; of these 5 were cooled for <12 hours).Main outcome measures MRI and MR spectroscopy (MRS) within 2 weeks after birth, and a neurodevelopmental outcome assessment at 2 years.Results The baseline characteristics in both groups were similar except for lower 10 min Apgar scores (p=0.02) in the cooled babies. Despite this, the mean (SD) thalamic NAA/Cr (1.4 (0.1) vs 1.6 (0.2); p<0.001) and NAA/Cho (0.67 (0.08) vs 0.89 (0.11); p<0.001) ratios from MRS were significantly higher in the cooled group. Cooled babies had lower white matter injury scores than non-cooled babies (p=0.02). Four (27%) non-cooled babies with mild HIE developed seizures after 6 hours of age, while none of the cooled babies developed seizures (p=0.008). Neurodevelopmental outcomes at 2 years were available in 40 (85%) of the babies. Adverse outcomes were seen in 2 (14.3%) non-cooled babies, and none of the cooled babies (p=0.09).Conclusions Therapeutic hypothermia may have a neuroprotective effect in babies with mild HIE, as demonstrated by improved MRS biomarkers and reduced white matter injury on MRI. This may warrant further evaluation in adequately powered randomised controlled trials.
Montaldo P, Kaforou M, Pollara G, et al., 2019, Whole blood gene expression reveals specific transcriptome changes in neonatal encephalopathy, Neonatology, Vol: 115, Pages: 68-76, ISSN: 1661-7800
BackgroundVariable responses to hypothermic neuroprotection are related to the clinical heterogeneity of encephalopathic babies, hence better disease stratification may facilitate the development of individualized neuroprotective therapies.ObjectivesWe examined if whole blood gene expression analysis can identify specific transcriptome profiles in neonatal encephalopathy. Material and MethodsWe performed next generation sequencing on whole blood RNA from twelve babies with neonatal encephalopathy, and six time-matched healthy term babies. The significantly differentially expressed genes between encephalopathic and control babies were identified. This set of genes was then compared to the host RNA response in septic neonates and subjected to pathway analysis. ResultsWe identified 950 statistically significant genes discriminating perfectly between the healthy controls and neonatal encephalopathy. The major pathways in neonatal encephalopathy were axonal guidance signaling (p =0.0009), granulocyte adhesion and diapedesis (p = 0.003), IL-12 Signaling and Production in Macrophages (p= 0.003) and hypoxia-inducible factor 1α signaling (p = 0.004). There were only 137 genes in common between neonatal encephalopathy and bacterial sepsis sets. ConclusionBabies with neonatal encephalopathy have striking differences in gene expression profiles compared with healthy control and septic babies. Gene expression profile may be useful for disease stratification based and for developing personalized neuroprotective therapies.
Lally PJ, Montaldo P, Oliveira V, et al., 2019, Magnetic resonance spectroscopy assessment of brain injury after moderate hypothermia in neonatal encephalopathy: a prospective multi-centre study, Lancet Neurology, Vol: 18, Pages: 35-45, ISSN: 1474-4422
BackgroundIn neonatal encephalopathy (NE), the clinical manifestations of injury can only be reliably assessed several years after an intervention, complicating early prognostication and rendering trials of promising neuroprotectants slow and expensive. We aimed to determine the accuracy of thalamic proton magnetic resonance spectroscopy (1H MRS) biomarkers as early predictors of the neurodevelopmental abnormalities observed years after NE.MethodsWe conducted a prospective multi-centre cohort study across eight neonatal intensive care units, recruiting term neonates who received therapeutic hypothermia for NE. We obtained thalamic 1H MRS 4 to 14 days after birth, which were compared to clinical neurodevelopmental tests performed 18 to 24 months later. The primary endpoint was anabnormal outcome, defined as death, or moderate or severe disability. Receiver operating characteristic (ROC) curves were used to examine the strength of the relationship between selected biomarkers and this outcome.FindingsWe recruited 223 infants who all underwent MR imaging and spectroscopy at a median (IQR) age of 7 (5 to 10) days, with 190 (85%) followed up for neurological examination at a median (IQR) age of 23 (20 to 25) months. Of those followed up, 31 (16%) had moderate or severe disability, including one death. The thalamic concentration of Nacetylasparate, [NAA], had an area under the ROC curve (AUC) of 0·99 (95% CI 0·94 to 1·00, n=82), and lactate/NAA peak area ratio had an AUC of 0·94 (95% CI 0·89 to 0·97, n=160). From conventional MRI, abnormal signal in the posterior limb of the internal capsule (PLIC) gave an AUC of 0·82 (95% CI 0·76 to 0·87, n=190). Thalamic [NAA] was independentlyassociated with neurodevelopmental outcome scores on multivariable analysis, and had higher prognostic accuracy than conventional MR imaging (98% versus 87%; p<0·001).InterpretationThalamic 1H MRS measures acquired soon after
Kariholu U, Montaldo P, Markati T, et al., 2018, Therapeutic hypothermia for mild neonatal encephalopathy: A systematic review and meta-analysis, Archives of Disease in Childhood. Fetal and Neonatal Edition, ISSN: 1359-2998
Objectives To examine if therapeutic hypothermia reduces the composite outcome of death, moderate or severe disability at 18 months or more after mild neonatal encephalopathy (NE).Data source MEDLINE, Cochrane database, Scopus and ISI Web of Knowledge databases, using ‘hypoxic ischaemic encephalopathy’, ‘newborn’ and ‘hypothermia’, and ‘clinical trials’ as medical subject headings and terms. Manual search of the reference lists of all eligible articles and major review articles and additional data from the corresponding authors of selected articles.Study selection Randomised and quasirandomised controlled trials comparing therapeutic hypothermia with usual care.Data extraction Safety and efficacy data extracted independently by two reviewers and analysed.Results We included the data on 117 babies with mild NE inadvertently recruited to five cooling trials (two whole-body cooling and three selective head cooling) of moderate and severe NE, in the meta-analysis. Adverse outcomes occurred in 11/56 (19.6%) of the cooled babies and 12/61 (19.7%) of the usual care babies (risk ratio 1.11 (95% CIs 0.55 to 2.25)).Conclusions Current evidence is insufficient to recommend routine therapeutic hypothermia for babies with mild encephalopathy and significant benefits or harm cannot be excluded.
Chalak LF, Nguyen K-A, Prempunpong C, et al., 2018, Prospective research in infants with mild encephalopathy identified in the first six hours of life: neurodevelopmental outcomes at 18-22 months, Pediatric Research, Vol: 84, Pages: 861-868, ISSN: 0031-3998
BACKGROUND: Studies of early childhood outcomes of mild hypoxic-ischemic encephalopathy (HIE) identified in the first 6 h of life are lacking. OBJECTIVE: To evaluate neurodevelopmental outcomes at 18-22 months of PRIME study. STUDY DESIGN: Multicenter, prospective study of mild HIE defined as ≥1 abnormality using the modified Sarnat within 6 h of birth and not meeting cooling criteria. Primary outcome was disability with mild: Bayley III cognitive 70-84 or ≥85 and either Gross Motor Function Classification System (GMFCS) 1 or 2, seizures, or hearing deficit; moderate: cognitive 70-84 and either GMFCS 2, seizures, or hearing deficit; severe: cognitive <70, GMFCS 3-5. RESULTS: Of the 63 infants enrolled, 51 (81%) were evaluated at 19 ± 2 months and 43 (68%) completed Bayley III. Of the 43 infants, 7 (16%) were diagnosed with disability, including 1 cerebral palsy and 2 autism. Bayley scores < 85 in either cognition, motor, or language were detected in 17 (40%): 14 (32%) language, 7 (16%) cognitive, and 6 (14%) motor domain. Infants with disability had more abnormalities on discharge examination and brain MRI, with longer hospital stay (p < 0.001). CONCLUSIONS: In this contemporary untreated cohort of mild HIE, disability occurred in 16% of infants at 18-22 months.
Oliveira V, Kumutha JR E N, Somanna J, et al., 2018, Hypothermia for encephalopathy in low-income and middle-income countries: feasibility of whole-body cooling using a low-cost servo-controlled device, BMJ Paediatrics Open, Vol: 2, ISSN: 2399-9772
Although therapeutic hypothermia (TH) is the standard of care for hypoxic ischaemic encephalopathy in high-income countries, the safety and efficacy of this therapy in low-income and middle-income countries (LMICs) is unknown. We aimed to describe the feasibility of TH using a low-cost servo-controlled cooling device and the short-term outcomes of the cooled babies in LMIC. Design: We recruited babies with moderate or severe hypoxic ischaemic encephalopathy (aged <6 hours) admitted to public sector tertiary neonatal units in India over a 28-month period. We administered whole-body cooling (set core temperature 33.5°C) using a servo-controlled device for 72 hours, followed by passive rewarming. We collected the data on short-term neonatal outcomes prior to hospital discharge. Results: Eighty-two babies were included-61 (74%) had moderate and 21 (26%) had severe encephalopathy. Mean (SD) hypothermia cooling induction time was 1.7 hour (1.5) and the effective cooling time 95% (0.08). The mean (SD) hypothermia induction time was 1.7 hour (1.5 hour), core temperature during cooling was 33.4°C (0.2), rewarming rate was 0.34°C (0.16°C) per hour and the effective cooling time was 95% (8%). Twenty-five (51%) babies had gastric bleeds, 6 (12%) had pulmonary bleeds and 21 (27%) had meconium on delivery. Fifteen (18%) babies died before discharge from hospital. Heart rate more than 120 bpm during cooling (P=0.01) and gastric bleeds (P<0.001) were associated with neonatal mortality. Conclusions: The low-cost servo-controlled cooling device maintained the core temperature well within the target range. Adequately powered clinical trials are required to establish the safety and efficacy of TH in LMICs. Clinical trial registration number: NCT01760629.
Prempunpong C, Chalak LF, Garfinkle J, et al., 2017, Prospective research on infants with mild encephalopathy: the PRIME study., Journal of Perinatology, Vol: 38, Pages: 80-85, ISSN: 0743-8346
OBJECTIVE: To determine short-term outcomes of infants with evidence of hypoxia-ischemia at birth and classified as mild neonatal encephalopathy (NE) at <6 h of age. STUDY DESIGN: Prospective multicenter study. Mild NE was defined as ⩾1 abnormal category in modified Sarnat score. Primary outcome was any abnormality on early amplitude integrated electroencephalogram (aEEG) or seizures, abnormal brain magnetic resonance imaging (MRI) or neurological exam at discharge. RESULTS: A total of 54/63 (86%) of enrolled infants had data on components of the primary outcome, which was abnormal in 28/54 (52%): discontinuous aEEG (n=4), MRI (n=9) and discharge exam (n=22). Abnormal tone and/or incomplete Moro were the most common findings. MRI abnormalities were confined to cerebral cortex but two infants had basal ganglia and/or thalamus involvement. The 18 to 24 months follow-up is ongoing. CONCLUSIONS: A larger than expected proportion of mild NE infants with abnormal outcomes was observed. Future research should evaluate safety and efficacy of neuroprotection for mild NE.Journal of Perinatology advance online publication, 2 November 2017; doi:10.1038/jp.2017.164.
Sánchez-Illana Á, Thayyil S, Montaldo P, et al., 2017, Novel free-radical mediated lipid peroxidation biomarkers in newborn plasma., Analytica Chimica Acta, Vol: 996, Pages: 88-97, ISSN: 0003-2670
Oxidative stress derived from perinatal asphyxia appears to be closely linked to neonatal brain damage and lipid peroxidation biomarkers have shown to provide predictive power of oxidative stress related pathologies in situations of hypoxia and reoxygenation in the newborn. The objective of this work was to develop and validate of a comprehensive liquid chromatography tandem mass spectrometry approach for the quantitative profiling of 28 isoprostanoids in newborn plasma samples covering a broad range of lipid peroxidation product classes. The method was developed taking into account the specific requirements for its use in neonatology (i.e. limited sample volumes, straightforward sample processing and high analytical throughput). The method was validated following stringent FDA guidelines and was then applied to the analysis of 150 plasma samples collected from newborns. Information obtained from the quantitative analysis of isoprostanoids was critically compared to that provided by a previously developed approach aiming at the semi-quantitative detection of total parameters of fatty acid derived lipid peroxidation biomarkers.
Oliveira V, Singhvi DP, Montaldo P, et al., 2017, Therapeutic hypothermia in mild neonatal encephalopathy: a national survey of practice in the UK, Archives of Disease in Childhood. Fetal and Neonatal Edition, Vol: 103, Pages: F388-F390, ISSN: 1359-2998
Although major cooling trials (and subsequent guidelines) excluded babies with mild encephalopathy, anecdotal evidence suggests that cooling is often offered to these infants. We report a national survey on current cooling practices for babies with mild encephalopathy in the UK. From 74 neonatal units contacted, 68 were cooling centres. We received 54 responses (79%) and included 48 (five excluded due to incomplete data and one found later not to offer cooling). Of these, 36 centres (75%) offered cooling to infants with mild encephalopathy. Although most of the participating units reported targeting 33-34°C core temperature, seven (19%) considered initiating cooling beyond 6 hours of age and 13 (36%) discontinued cooling prior to 72 hours. Babies were ventilated for cooling in two (6%) units and 13 (36%) sedated all cooled babies. Enteral feeding was withheld in 15 (42%) units and reduced below 25% of requirements in eight (22%) units. MRI and neurodevelopmental outcome evaluation were offered to all cooled babies in 29 (80%) and 27 (75%) units, respectively. Further research is necessary to ensure optimal neuroprotection in mild encephalopathy.
Thayyil S, Oliveira V, Lally PJ, et al., 2017, Hypothermia for encephalopathy in low and middle-income countries (HELIX): study protocol for a randomised controlled trial., Trials, Vol: 18, ISSN: 1745-6215
BACKGROUND: Therapeutic hypothermia reduces death and disability after moderate or severe neonatal encephalopathy in high-income countries and is used as standard therapy in these settings. However, the safety and efficacy of cooling therapy in low- and middle-income countries (LMICs), where 99% of the disease burden occurs, remains unclear. We will examine whether whole body cooling reduces death or neurodisability at 18-22 months after neonatal encephalopathy, in LMICs. METHODS: We will randomly allocate 408 term or near-term babies (aged ≤ 6 h) with moderate or severe neonatal encephalopathy admitted to public sector neonatal units in LMIC countries (India, Bangladesh or Sri Lanka), to either usual care alone or whole-body cooling with usual care. Babies allocated to the cooling arm will have core body temperature maintained at 33.5 °C using a servo-controlled cooling device for 72 h, followed by re-warming at 0.5 °C per hour. All babies will have detailed infection screening at the time of recruitment and 3 Telsa cerebral magnetic resonance imaging and spectroscopy at 1-2 weeks after birth. Our primary endpoint is death or moderate or severe disability at the age of 18 months. DISCUSSION: Upon completion, HELIX will be the largest cooling trial in neonatal encephalopathy and will provide a definitive answer regarding the safety and efficacy of cooling therapy for neonatal encephalopathy in LMICs. The trial will also provide important data about the influence of co-existent perinatal infection on the efficacy of hypothermic neuroprotection. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02387385 . Registered on 27 February 2015.
Chalak LF, Prempunpong C, Garfinkle J, et al., 2017, PROSPECTIVE STUDY OF INFANTS WITH MILD ENCEPHALOPATHY: PRIME STUDY, XXV Biennial Meeting of the International Perinatal Collegium, Publisher: WILEY, Pages: 9-9, ISSN: 0803-5253
Chandrasekaran M, Chaban B, Montaldo P, et al., 2017, Predictive value of amplitude-integrated EEG (aEEG) after rescue hypothermic neuroprotection for hypoxic ischemic encephalopathy: a meta-analysis, Journal of Perinatology, Vol: 37, Pages: 684-689, ISSN: 0743-8346
Objective:Amplitude-integrated electroencephalography (aEEG) is a useful bedside tool in predicting the neurodevelopmental outcome after neonatal encephalopathy; however, the prognostic accuracy may be altered by rescue hypothermic neuroprotection. The objective of this study is to examine the prognostic accuracy of aEEG for predicting long-term neurodevelopmental outcomes in term newborn infants undergoing therapeutic hypothermia for neonatal encephalopathy.Study Design:We examined all studies (Medline, Cumulative Index to Nursing and Allied Health Literature and the Cochrane Library; 2000 to 2014) comparing aEEG (6, 24, 48 or 72 h) in term encephalopathic babies undergoing therapeutic hypothermia, with neurodevelopmental outcome at 1 year or more. We extracted individual patient data from the eligible studies to calculate prognostic indices with exact confidence intervals (CIs). We considered continuous normal voltage as normal aEEG pattern and discontinuous normal voltage, burst suppression, flat trace and persistently low voltage as abnormal, and defined adverse outcome as death or moderate/severe disability at 1 year.Results:We reviewed a total of 70 articles, 17 of which met the inclusion criteria. Eight studies were excluded and 9 studies (N=520) were included in the meta-analysis. The pooled sensitivity and specificity for an abnormal trace at 6 h of age to predict adverse outcome were 96% (95% CI 91 to 98%) and 39% (95% CI 32 to 46%). The diagnostic odds ratio of an abnormal trace was highest at 48 h (66.9 (95% CI 19.7, 227.2)).Conclusions:A persistantly abnormal aEEG at 48 h or more is associated with an adverse neurodevelopmal outcome. The positive prognostic value of 6 h aEEG is poor and good outcome may occur despite abnormal aEEG. Conversely, a normal 6 h aEEG has a good negative predictive value although do not exclude adverse outcomes.
Montaldo P, Oliveira V, Lally PJ, et al., 2016, Therapeutic hypothermia in neonatal cervical spine injury, Archives of Disease in Childhood: Fetal & Neonatal Edition, Vol: 101, Pages: F468-F468, ISSN: 1468-2052
Montaldo P, Addison S, Oliveira V, et al., 2016, Quantification of Maceration Changes using Post Mortem MRI in Fetuses, BMC MEDICAL IMAGING, Vol: 16, ISSN: 1471-2342
BackgroundPost mortem imaging is playing an increasingly important role in perinatal autopsy, andcorrect interpretation of imaging changes is paramount. This is particularly importantfollowing intra-uterine fetal death, where there may be fetal maceration. The aim of thisstudy was to investigate whether any changes seen on a whole body fetal post mortemmagnetic resonance imaging (PMMR) correspond to maceration at conventionalautopsy.Methods: We performed pre-autopsy PMMR in 75 fetuses using a 1.5 Tesla SiemensAvanto MR scanner (Erlangen, Germany). PMMR images were reported blinded to theclinical history and autopsy data using a numerical severity scale (0 = no macerationchanges to 2 = severe maceration changes) for 6 different visceral organs (total 12).The degree of maceration at autopsy was categorized according to severity on anumerical scale (1 = no maceration to 4 = severe maceration). We also generatedquantitative maps to measure the liver and lung T2.Results: The mean PMMR maceration score correlated well with the autopsymaceration score (R2=0.93). A PMMR score of ≥ 4.5 had a sensitivity of 91%,specificity of 64%, for detecting moderate or severe maceration at autopsy. Liver andlung T2 were increased in fetuses with maceration scores of 3-4 in comparison tothose with 1-2 (liver p=0.03, lung p=0.02).Conclusions: There was a good correlation between PMMR maceration score and theextent of maceration seen at conventional autopsy. This score may be useful ininterpretation of fetal PMMR.
Lally P, PAULIAH S, MONTALDO P, et al., 2015, Magnetic Resonance Biomarkers in Neonatal Encephalopathy (MARBLE): A Prospective Multi-Country Study, BMJ Open, Vol: 5, ISSN: 2044-6055
Despite cooling adverse outcomes are seen in upto 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. Riggorous evaluation of these therapies in phase II trials using surrogate magnetic resonance biomarkers may speed up thier bench to bedside translation. A recent systematic review of single centres studies have suggested that Magnetic resonance spectroscopy biomarkers offers the best promise, however the prognostic accuracy of these biomarkers in cooled encephalopathic babies in a multicentre setting using different MR scan makes is not known.
Montaldo P, Chaban B, Lally PJ, et al., 2015, Quantification of ante-mortem hypoxic ischemic brain injury by post-mortem cerebral magnetic resonance imaging in neonatal encephalopathy, European Journal of Paediatric Neurology, Vol: 19, Pages: 665-671, ISSN: 1090-3798
Post-mortem (PM) magnetic resonance imaging (MRI) is increasingly used as an alternative to conventional autopsy in babies dying from neonatal encephalopathy. However, the confounding effect of post-mortem changes on the detection of ante-mortem ischemic injury is unclear. We examined whether quantitative MR measurements can accurately distinguish ante-mortem ischemic brain injury from artifacts using post-mortem MRI.Methods:We compared PM brain MRI (1.5 T Siemens, Avanto) in 7 infants who died with neonatal encephalopathy (NE) of presumed hypoxic-ischemic origin with 7 newborn infants who had sudden unexplained neonatal death (SUND controls) without evidence of hypoxic-ischemic brain injury at autopsy. We measured apparent diffusion coefficients (ADCs), T1-weighted signal intensity ratios (SIRs) compared to vitreous humor and T2 relaxation times from 19 predefined brain areas typically involved in neonatal encephalopathy.Results:There were no differences in mean ADC values, SIRs on T1-weighted images or T2 relaxation times in any of the 19 predefined brain areas between NE and SUND infants. All MRI images showed loss of cortical gray/white matter differentiation, loss of the normal high signal intensity (SI) in the posterior limb of the internal capsule on T1-weighted images, and high white matter SI on T2-weighted images.Conclusion:Normal post-mortem changes may be easily mistaken for ante-mortem ischemic injury, and current PM MRI quantitative assessment cannot reliably distinguish these. These findings may have important implications for appropriate interpretation of PM imaging findings, especially in medico-legal practice.
Montaldo P, Pauliah SS, Lally PJ, et al., 2015, Cooling in a low-resource environment: Lost in translation, SEMINARS IN FETAL & NEONATAL MEDICINE, Vol: 20, Pages: 72-79, ISSN: 1744-165X
Montaldo P, Montaldo L, Chaban B, et al., 2015, Perinatal infection as risk factor of neonatal encephalopathy, Asphyxia: Risk Factors, Prevalence and Neurological Impacts, Pages: 55-72, ISBN: 9781634822251
© 2015 by Nova Science Publishers, Inc. All rights reserved. Fetal exposure to inflammation and infection has been shown to increase brain vulnerability to hypoxia-ischemia via stimulation of immune and inflammatory responses, chemotaxis, toll-like receptors and cell death. Perinatal infection is a potentially modifiable, risk factor for encephalopathy that has been linked to adverse outcomes. Nevertheless, the exact role of perinatal infection among neonates with a history of encephalopathy, is not yet completely understood. Emerging experimental data suggest that hypothermia may not be neuroprotective after a bacterial lipopolysaccharide-sensitized encephalopathy brain injury whereas it can be neuroprotective if a bacterial lipopolysaccharide-sensitized encephalopathy is not present. Hence, therapeutic hypothermia in the presence of infection might even be deleterious as hypothermia may impair innate immune function, including neutrophil migration and function. This chapter aims to discuss how an infective insult can affect the vulnerability of the neonatal brain to the hypoxic damage. We review whether newborns with encephalopathy and signs of neonatal sepsis are associated with a higher risk of neonatal brain injury and worse long-term neurodevelopmental outcome. Finally, we highlight new therapeutic strategies in this scenario.
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