Hypothermia For Neonatal Encephalopathy Research Articles

Hypothermia for neonatal encephalopathy: how do we move forward?

Tagin and Gunn suggest that the current criteria from randomised controlled trials of hypothermia for moderate or severe encephalopathy are limiting the application to infants with perinatal hypoxia-ischaemia.1 They propose...

Randomized Controlled Trial Evaluating Hypothermia for Neonatal Encephalopathy in Low- and Middle-Income Countries

Randomized Controlled Trial Evaluating Hypothermia for Neonatal Encephalopathy in Low- and Middle-Income Countries

Development, Reliability, and Testing of a New Rating Scale for Neonatal Encephalopathy

To develop and test the Neonatal Encephalopathy-Rating Scale (NE-RS), a new rating scale to grade the severity of neonatal encephalopathy (NE) within the first 6hours after birth. A 3-phase process was conducted: (1) design of a comprehensive scale that would be specific, sensitive, brief, and unsophisticated; (2) evaluation in a cohort of infants with neonatal encephalopathy and healthy controls; and (3) validation with brain magnetic resonance imaging findings and outcome at 2years of age. We evaluated the NE-RS in 54 infants with NE and 28 healthy infants. The NE-RS had excellent internal consistency (Cronbach alpha coefficient: 0.93 [95% CI 0.86-0.94]) and reliability (intraclass correlation coefficient in the NE cohort 0.996 [95% CI 0.993-0.998; P<.001]). Alertness, posture, motor response, and spontaneous activity were the top discriminators for degrees of NE. The cut-off value for mild vs moderate NE was 8 points (area under the curve [AUC] 0.99, 95% CI 0.85-1.00) and for moderate vs severe NE, 30 points (AUC 0.93, 95% CI 0.81-0.99). The NE-RS was significantly correlated with the magnetic resonance imaging score (Spearman Rho 0.77, P<.001) and discriminated infants who had an adverse outcome (AUC 0.91, 95% CI 0.83-0.99, sensitivity 0.82, specificity 0.81, positive predictive value 0.87, negative predictive value 0.74). The NE-RS is reliable and performs well in reflecting the severity of NE within the first 6hours after birth. This tool could be useful when assessing clinical criteria for therapeutic hypothermia in NE.

Later cooling within 6 h and temperatures outside 33-34 °C are not associated with dysfunctional autoregulation during hypothermia for neonatal encephalopathy.

Background:Cooling delays, temperature outside 33–34°C, and blood pressure below the mean arterial blood pressure with optimal cerebral autoregulation (MAPOPT) might diminish neuroprotection from therapeutic hypothermia in neonates with hypoxic-ischemic encephalopathy (HIE). We hypothesized that longer time to reach temperature <34°C and having temperature outside 33–34°C would be associated with worse autoregulation and greater brain injury.Methods:Neonates with HIE had rectal temperature and near-infrared spectroscopy autoregulation monitoring during hypothermia (n=63) and rewarming (n=58). All underwent brain MRI, and a subset received diffusion tensor imaging MRI before day 10 (n=41).Results:Most neonates reached <34°C at 3–6 h of life. MAPOPT was identified in 54/63 (86%) during hypothermia and in 53/58 (91%) during rewarming. Cooling time was not related to blood pressure deviation from MAPOPT. Later cooling was associated with lower ADC scalar in unilateral posterior centrum semiovale but not in other regions. Temperatures above 34°C were associated with blood pressure above MAPOPT but not with brain injury.Conclusion:In neonates who were predominantly cooled after 3 h, cooling time was not associated with autoregulation or overall brain injury. Blood pressure deviation above MAPOPT was associated with temperature above 34°C. Additional studies are needed in a more heterogeneous population.

Magnetic resonance spectroscopy assessment of brain injury after moderate hypothermia in neonatal encephalopathy: a prospective multicentre cohort study

SummaryBackgroundIn neonatal encephalopathy, 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 (MR) spectroscopy (MRS) biomarkers as early predictors of the neurodevelopmental abnormalities observed years after neonatal encephalopathy.MethodsWe did a prospective multicentre cohort study across eight neonatal intensive care units in the UK and USA, recruiting term and near-term neonates who received therapeutic hypothermia for neonatal encephalopathy. We excluded infants with life-threatening congenital malformations, syndromic disorders, neurometabolic diseases, or any alternative diagnoses for encephalopathy that were apparent within 6 h of birth. We obtained T1-weighted, T2-weighted, and diffusion-weighted MRI and thalamic proton MRS 4–14 days after birth. Clinical neurodevelopmental tests were done 18–24 months later. The primary outcome was the association between MR biomarkers and an adverse neurodevelopmental outcome, defined as death or moderate or severe disability, measured using a multivariable prognostic model. We used receiver operating characteristic (ROC) curves to examine the prognostic accuracy of the individual biomarkers. This trial is registered with ClinicalTrials.gov, number NCT01309711.FindingsBetween Jan 29, 2013, and June 25, 2016, we recruited 223 infants who all underwent MRI and MRS at a median age of 7 days (IQR 5–10), with 190 (85%) followed up for neurological examination at a median age of 23 months (20–25). Of those followed up, 31 (16%) had moderate or severe disability, including one death. Multiple logistic regression analysis could not be done because thalamic N-acetylaspartate (NAA) concentration alone accurately predicted an adverse neurodevelopmental outcome (area under the curve [AUC] of 0·99 [95% CI 0·94–1·00]; sensitivity 100% [74–100]; specificity 97% [90–100]; n=82); the models would not converge when any additional variable was examined. The AUC (95% CI) of clinical examination at 6 h (n=190) and at discharge (n=167) were 0·72 (0·65–0·78) and 0·60 (0·53–0·68), respectively, and the AUC of abnormal amplitude integrated EEG at 6 h (n=169) was 0·73 (0·65–0·79). On conventional MRI (n=190), cortical injury had an AUC of 0·67 (0·60–0·73), basal ganglia or thalamic injury had an AUC of 0·81 (0·75–0·87), and abnormal signal in the posterior limb of internal capsule (PLIC) had an AUC of 0·82 (0·76–0·87). Fractional anisotropy of PLIC (n=65) had an AUC of 0·82 (0·76–0·87). MRS metabolite peak-area ratios (n=160) of NAA–creatine (<1·29) had an AUC of 0·79 (0·72–0·85), of NAA–choline had an AUC of 0·74 (0·66–0·80), and of lactate–NAA (>0·22) had an AUC of 0·94 (0·89–0·97).InterpretationThalamic proton MRS measures acquired soon after birth in neonatal encephalopathy had the highest accuracy to predict neurdevelopment 2 years later. These methods could be applied to increase the power of neuroprotection trials while reducing their duration.FundingNational Institute for Health Research UK.

Added value of interleukin-1 blockade to hypothermia in neonatal encephalopathy due to inflammatory-sensitized hypoxia-ischemia: a preclinical study. (P3.212)

Added value of interleukin-1 blockade to hypothermia in neonatal encephalopathy due to inflammatory-sensitized hypoxia-ischemia: a preclinical study. (P3.212)

Neonatal Magnetic Resonance Imaging Pattern of Brain Injury as a Biomarker of Childhood Outcomes following a Trial of Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy

To examine the ability of magnetic resonance imaging (MRI) patterns of neonatal brain injury defined by the National Institute of Child Health and Human Development Neonatal Research Network to predict death or IQ at 6-7 years of age following hypothermia for neonatal encephalopathy. Out of 208 participants, 124 had MRI and primary outcome (death or IQ <70) data. The relationship between injury pattern and outcome was assessed. Death or IQ <70 occurred in 4 of 50 (8%) of children with pattern 0 (normal MRI), 1 of 6 (17%) with 1A (minimal cerebral lesions), 1 of 4 (25%) with 1B (extensive cerebral lesions), 3 of 8 (38%) with 2A (basal ganglia thalamic, anterior or posterior limb of internal capsule, or watershed infarction), 32 of 49 (65%) with 2B (2A with cerebral lesions), and 7 of 7 (100%) with pattern 3 (hemispheric devastation), P < .001; this association was also seen within hypothermia and control subgroups. IQ was 90 ± 13 among the 46 children with a normal MRI and 69 ± 25 among the 50 children with an abnormal MRI. In childhood, for a normal outcome, a normal neonatal MRI had a sensitivity of 61%, specificity of 92%, a positive predictive value of 92%, and a negative predictive value of 59%; for death or IQ <70, the 2B and 3 pattern combined had a sensitivity of 81%, specificity of 78%, positive predictive value of 70%, and a negative predictive value of 87%. The Neonatal Research Network MRI pattern of neonatal brain injury is a biomarker of neurodevelopmental outcome at 6-7 years of age. ClinicalTrials.gov: NCT00005772.

Therapeutic hypothermia for neonatal encephalopathy.

Hypothermia for neonatal encephalopathy is now the standard of care. The purpose of this review is to evaluate recent publications (during the past 18 months) that impact the practice of hypothermia as neuroprotection for neonatal hypoxic-ischemic encephalopathy. The review will examine recent publications that influence clinical care, including committee opinion, meta-analysis, and reports of how this practice has evolved in the clinical arena. Biomarkers of acute injury and outcome will be examined. Research involving the future of hypothermia will be noted. The rate of death or disability following hypothermia therapy has been reduced substantially; the challenge is to evaluate whether mortality or disability can be reduced further following combination therapy.

Hypothermia for neonatal encephalopathy: outcomes at 6–7 years

A USA multicentre study reported in 2005 showed that 72 h of whole-body hypothermia at 33.5° beginning within 6 h of birth improved outcomes at 18–24 months for infants with...

Brain injury following trial of hypothermia for neonatal hypoxic–ischaemic encephalopathy

ObjectiveThe objective of our study was to examine the relationship between brain injury and outcome following neonatal hypoxic–ischaemic encephalopathy treated with hypothermia.Design and patientsNeonatal MRI scans were evaluated in the...

Childhood Outcomes after Hypothermia for Neonatal Encephalopathy

BackgroundWe previously reported early results of a randomized trial of whole-body hypothermia for neonatal hypoxic–ischemic encephalopathy showing a significant reduction in the rate of death or moderate or severe disability at 18 to 22 months of age. Long-term outcomes are now available.MethodsIn the original trial, we assigned infants with moderate or severe encephalopathy to usual care (the control group) or whole-body cooling to an esophageal temperature of 33.5°C for 72 hours, followed by slow rewarming (the hypothermia group). We evaluated cognitive, attention and executive, and visuospatial function; neurologic outcomes; and physical and psychosocial health among participants at 6 to 7 years of age. The primary outcome of the present analyses was death or an IQ score below 70.ResultsOf the 208 trial participants, primary outcome data were available for 190. Of the 97 children in the hypothermia group and the 93 children in the control group, death or an IQ score below 70 occurred in 46 (47%) and 58 (62%), respectively (P=0.06); death occurred in 27 (28%) and 41 (44%) (P=0.04); and death or severe disability occurred in 38 (41%) and 53 (60%) (P=0.03). Other outcome data were available for the 122 surviving children, 70 in the hypothermia group and 52 in the control group. Moderate or severe disability occurred in 24 of 69 children (35%) and 19 of 50 children (38%), respectively (P=0.87). Attention–executive dysfunction occurred in 4% and 13%, respectively, of children receiving hypothermia and those receiving usual care (P=0.19), and visuospatial dysfunction occurred in 4% and 3% (P=0.80).ConclusionsThe rate of the combined end point of death or an IQ score of less than 70 at 6 to 7 years of age was lower among children undergoing whole-body hypothermia than among those undergoing usual care, but the differences were not significant. However, hypothermia resulted in lower death rates and did not increase rates of severe disability among survivors. (Funded by the National Institutes of Health and the Eunice Kennedy Shriver NICHD Neonatal Research Network; ClinicalTrials.gov number, NCT00005772.)

Hypothermia for neonatal encephalopathy: Nationwide Survey of Clinical Practice in Japan as of August 2010

Therapeutic hypothermia is now recommended as a standard of care for neonatal encephalopathy. Although adherence to standard cooling protocols used in the phase-III trials is essential, empiric approaches have prevailed in Japan. To elucidate the gap between the standard cooling methods and the current practice in Japan. In July 2010, a questionnaire regarding the practice of neonatal encephalopathy was mailed to clinical leads of registered neonatal intensive care units. 56.2% of the units were incapable of offering therapeutic hypothermia because of the reasons such as the shortage of human/medical resources (85.1%) and limited number of cases (21.1%). Eighty-nine centres provided therapeutic hypothermia using either selective-head cooling (88.8%) or whole-body cooling (11.2%). Various target temperatures and cooling durations were used; 20.2% of the units cooled infants without using purpose-built equipments, whereas 14.6% did not continuously monitor the body temperature. Only 43.8% of the units provided therapeutic hypothermia. Even in centres where hypothermia was offered, adherence to the standard protocols was extremely poor. To secure the safety and efficacy, further promotion of the standard cooling protocols is required; an efficient cooling centre network has to be established by optimizing the work forth distribution and transportation system.

Childhood Outcomes after Hypothermia for Neonatal Encephalopathy

Childhood Outcomes after Hypothermia for Neonatal Encephalopathy

Childhood Outcomes after Hypothermia for Neonatal Encephalopathy

Childhood Outcomes after Hypothermia for Neonatal Encephalopathy

Prognostic Accuracy of Thalamic Proton Magnetic Resonance Spectroscopy Following Therapeutic Hypothermia in Neonatal Encephalopathy

Background and aims: Deep grey matter lactate/N-acetylaspartate (Lac/NAA) peak area ratio on proton magnetic resonance spectroscopy (1H MRS) is the best predictor of neurological outcome following neonatal encephalopathy (NE). We evaluated the prognostic accuracy following therapeutic hypothermia (TH).Methods: We performed magnetic resonance imaging (MRI) in consecutive term babies with NE, over a 3 year period before and after introduction of TH. Death or severe neurodisability (BSID 3) at 12 months was considered as an unfavourable outcome.Results: Of 28 babies studied, 11 babies received TH. The median (range) age at MRI was 10 (5,12) days. Thalamic Lac/NAA (>0.29) had 100% sensitivity and specificity for predicting adverse outcome in both normothermic babies and cooled infants (Table 1). The mean (SD) Lac/NAA was high in infants who had unfavorable outcome (Figure 1)Table Full size tableConclusions: The prognostic accuracy of 1H MRS deep gray matter Lac/NAA peak area ratios is unaltered by TH.

Passive cooling for initiation of therapeutic hypothermia in neonatal encephalopathy

Passive cooling for initiation of therapeutic hypothermia in neonatal encephalopathy

Passive cooling for initiation of therapeutic hypothermia in neonatal encephalopathy

ObjectiveTo determine the feasibility of passive cooling to initiate therapeutic hypothermia before and during transport.MethodsConsensus guidelines were developed for passive cooling at the referring hospital and on transport by the...

Therapeutic hypothermia for neonatal encephalopathy: a UK survey of opinion, practice and neuro-investigation at the end of 2007

Therapeutic hypothermia for neonatal encephalopathy: a UK survey of opinion, practice and neuro-investigation at the end of 2007

Outcomes of Head Cooling for Neonatal Encephalopathy

The role of possible clinical factors that might influence the efficacy of treatment with delayed head cooling and mild systemic hypothermia for neonatal encephalopathy was determined in a total of 218 term infants treated at University College, London, UK; University of Auckland, New Zealand; and other centers in the UK, USA, and Canada.

Hypoxic Ischemic Encephalopathy and Hypothermia

Hypoxic ischemic encephalopathy is a rare condition associated with high neonatal mortality and morbidity. Two randomized clinical trials have recently been published showing potentially promising results with hypothermia for neonatal encephalopathy. Additional clinical trials are underway to test cooling as a therapeutic modality for hypoxic ischemic encephalopathy. Outcome information about infants treated with hypothermia is available for children up to approximately 2 years of age. Longer-term outcome (ie, school age information) is currently lacking with respect to benefit and risk. Therapeutic hypothermia offers a potentially promising therapy for hypoxic ischemic encephalopathy. Hypothermia for encephalopathy should be considered an evolving therapy because of lack of long-term safety and efficacy data.