A pilot cohort study of cerebral autoregulation and 2-year neurodevelopmental outcomes in neonates with hypoxic-ischemic encephalopathy who received therapeutic hypothermia

Aim: Hypoxic-ischemic encephalopathy is associated with damage to deep gray matter; however, white matter involvement has become recognized. This study explored differences between patients and clinical controls on diffusion tensor imaging, and relationships between diffusion tensor imaging and neurodevelopmental outcomes. Method: Diffusion tensor imaging was obtained for 31 neonates after hypoxic-ischemic encephalopathy treated with therapeutic hypothermia and 10 clinical controls. A subgroup of patients with hypoxic-ischemic encephalopathy (n = 14) had neurodevelopmental outcomes correlated with diffusion tensor imaging scalars. Results: Group differences in diffusion tensor imaging scalars were observed in the putamen, anterior and posterior centrum semiovale, and the splenium of the corpus callosum. Differences in these regions of interest were correlated with neurodevelopmental outcomes between ages 20 and 32 months. Conclusion: Therapeutic hypothermia may not be a complete intervention for hypoxic-ischemic encephalopathy, as neonatal white matter changes may continue to be evident, but further research is warranted. Patterns of white matter change on neonatal diffusion tensor imaging correlated with neurodevelopmental outcomes in this exploratory pilot study.

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Outcomes of Infants with Mild Hypoxic Ischemic Encephalopathy Who Did Not Receive Therapeutic Hypothermia

Biomedicine Hub ◽

10.1159/000502936 ◽

2019 ◽

Vol 4 (3) ◽

pp. 1-9 ◽

Cited By ~ 2

Author(s):

Jonathan Reiss ◽

Mridu Sinha ◽

Jeffrey Gold ◽

Julie Bykowski ◽

Shelley M. Lawrence

Keyword(s):

Therapeutic Hypothermia ◽

Severe Disease ◽

Significant Risk ◽

Brain Magnetic Resonance Imaging ◽

Adverse Outcomes ◽

Hypoxic Ischemic Encephalopathy ◽

Neurodevelopmental Outcomes ◽

Specific Patient ◽

Increased Risk ◽

Ischemic Encephalopathy

Introduction: Accurately diagnosing and treating infants with mild forms of hypoxic ischemic encephalopathy (HIE) is important, as the majority of neonates with signs and symptoms of HIE after birth do not meet clinical criteria for moderate or severe disease. Emerging evidence, however, suggests that infants with mild HIE (mHIE) have an increased risk for neurodevelopmental impairment (NDI). Methods: This retrospective descriptive study examined all inborn infants ≥35 week’s gestational age at a single, level III neonatal intensive care unit (NICU) in California between January 1, 2012, and December 31, 2015. International Classification of Diseases codes were used as a proxy to identify neonates with mHIE but who did not receive therapeutic hypothermia (TH). Short- and long-term neurodevelopmental outcomes were documented, including abnormal (1) brain magnetic resonance imaging within 10 days of birth suggestive of HIE, (2) electroencephalogram with electrographic seizures, (3) neurologic discharge examination, or (4) NDI following NICU discharge. Results: Over the 4-year study period, 25 infants met inclusion criteria. Eight of 25 (32%) infants demonstrated neurologic impairment, defined by an abnormality in at least one of the four categories. The remaining 17 infants were without documented evidence for adverse outcomes. Conclusion: Our results indicate that children with mHIE are at significant risk for neurologic injury and may benefit from more aggressive interventions. Further prospective studies should be completed to determine the efficacy of TH in this specific patient population.

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Serum calcium derangements in neonates with moderate to severe hypoxic ischemic encephalopathy and the impact of therapeutic hypothermia: a cohort study

The Journal of Maternal-Fetal & Neonatal Medicine ◽

10.1080/14767058.2018.1510911 ◽

2018 ◽

Vol 33 (6) ◽

pp. 935-940 ◽

Cited By ~ 1

Author(s):

Sakeer Vayalthrikkovil ◽

Rani Bashir ◽

Maria Espinoza ◽

Leigh Irvine ◽

James N. Scott ◽

...

Keyword(s):

Cohort Study ◽

Therapeutic Hypothermia ◽

Serum Calcium ◽

Hypoxic Ischemic Encephalopathy ◽

The Impact ◽

Ischemic Encephalopathy

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The myocardial function during and after whole-body therapeutic hypothermia for hypoxic–ischemic encephalopathy, a cohort study

Early Human Development ◽

10.1016/j.earlhumdev.2014.01.014 ◽

2014 ◽

Vol 90 (5) ◽

pp. 247-252 ◽

Cited By ~ 22

Author(s):

Eirik Nestaas ◽

Janne Helen Skranes ◽

Asbjørn Støylen ◽

Leif Brunvand ◽

Drude Fugelseth

Keyword(s):

Cohort Study ◽

Therapeutic Hypothermia ◽

Myocardial Function ◽

Hypoxic Ischemic Encephalopathy ◽

Whole Body ◽

Ischemic Encephalopathy

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Treating Seizures after Hypoxic-Ischemic Encephalopathy—Current Controversies and Future Directions

International Journal of Molecular Sciences ◽

10.3390/ijms22137121 ◽

2021 ◽

Vol 22 (13) ◽

pp. 7121

Author(s):

Kelly Q. Zhou ◽

Alice McDouall ◽

Paul P. Drury ◽

Christopher A. Lear ◽

Kenta H. T. Cho ◽

...

Keyword(s):

Therapeutic Hypothermia ◽

Newborn Infants ◽

Developing Brain ◽

Hypoxic Ischemic Encephalopathy ◽

Neurodevelopmental Outcomes ◽

High Quality ◽

Future Directions ◽

Phenobarbital Administration ◽

The Impact ◽

Ischemic Encephalopathy

Seizures are common in newborn infants with hypoxic-ischemic encephalopathy and are highly associated with adverse neurodevelopmental outcomes. The impact of seizure activity on the developing brain and the most effective way to manage these seizures remain surprisingly poorly understood, particularly in the era of therapeutic hypothermia. Critically, the extent to which seizures exacerbate brain injury or merely reflect the underlying evolution of injury is unclear. Current anticonvulsants, such as phenobarbital and phenytoin have poor efficacy and preclinical studies suggest that most anticonvulsants are associated with adverse effects on the developing brain. Levetiracetam seems to have less potential neurotoxic effects than other anticonvulsants but may not be more effective. Given that therapeutic hypothermia itself has significant anticonvulsant effects, randomized controlled trials of anticonvulsants combined with therapeutic hypothermia, are required to properly determine the safety and efficacy of these drugs. Small clinical studies suggest that prophylactic phenobarbital administration may improve neurodevelopmental outcomes compared to delayed administration; however, larger high-quality studies are required to confirm this. In conclusion, there is a distinct lack of high-quality evidence for whether and to what extent neonatal seizures exacerbate brain damage after hypoxia-ischemia and how best to manage them in the era of therapeutic hypothermia.

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Lactate Predicts Neurological Outcomes after Perinatal Asphyxia in Post-Hypothermia Era: A Prospective Cohort Study

Life ◽

10.3390/life11111193 ◽

2021 ◽

Vol 11 (11) ◽

pp. 1193

Author(s):

Yi-Fang Tu ◽

Po-Ming Wu ◽

Wen-Hao Yu ◽

Chung-I Li ◽

Cheng-Lin Wu ◽

...

Keyword(s):

Cohort Study ◽

Therapeutic Hypothermia ◽

Blood Lactate ◽

Prospective Cohort Study ◽

Prospective Cohort ◽

Perinatal Asphyxia ◽

Adverse Outcomes ◽

Hypoxic Ischemic Encephalopathy ◽

Neurological Outcomes ◽

Ischemic Encephalopathy

Background: Neonatal hypoxic-ischemic encephalopathy (HIE) is the most common cause of mortality and neurological disability in infancy after perinatal asphyxia. Reliable biomarkers to predict neurological outcomes of neonates after perinatal asphyxia are still not accessible in clinical practice. Methods: A prospective cohort study enrolled neonates with perinatal asphyxia. Biochemical blood tests and cerebral Doppler ultrasound were measured within 6 h of age and at the 4th day old. Neurological outcomes were assessed at 1 year old. Results: Sixty-four neonates with perinatal asphyxia were enrolled. Fifty-eight (90%) had hypoxic-ischemic encephalopathy (HIE) including 20 (34%) Stage I, 21 (36%) Stage II, and 17 (29%) Stage III. In the asphyxiated infants without therapeutic hypothermia, HIE stage, PH, and base excess levels within 6 h of age were the predictors of adverse outcomes. In the asphyxiated infants receiving therapeutic hypothermia, HIE stage failed to predict outcomes. Instead, blood lactate levels and pulsatility index (PI) of medial cerebral arteries (MCA) either in 6 h of age or at the 4th day old independently predicted adverse outcomes. Conclusions: Blood lactate, which is a common accessible test at the hospital and MCA PI on cerebral ultrasound could predict adverse outcomes in asphyxiated infants receiving therapeutic hypothermia.

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Neonatal hypoxic-ischemic encephalopathy diagnosis and treatment: a National Survey in China

BMC Pediatrics ◽

10.1186/s12887-021-02737-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Zheng Wang ◽

Peng Zhang ◽

Wenhao Zhou ◽

Shiwen Xia ◽

Wei Zhou ◽

...

Keyword(s):

Therapeutic Hypothermia ◽

National Survey ◽

Diagnosis And Treatment ◽

Hypoxic Ischemic Encephalopathy ◽

Current Status ◽

Significant Heterogeneity ◽

National Guidelines ◽

Neurodevelopmental Outcomes ◽

Ischemic Encephalopathy

Abstract Background Neonatal hypoxic-ischemic encephalopathy (HIE) affects as many as 100,000 infants each year in China. Therapeutic hypothermia reduces HIE related mortality and long-term neurodevelopmental disabilities. National guidelines for HIE management were published a decade ago. This study aimed to investigate the current status of HIE diagnosis and treatment in China. Method This prospective cross-sectional national survey used a questionnaire evaluating practices related to HIE management. Descriptive statistics and Chi-square or Fisher’s exact test were used, and a p-value of < 0.05 was considered significant. Results The 273 hospitals that completed the survey were located in 31 of the 34 provincial districts in China. Eighty-eight percent of the hospitals were Level III hospitals, and 74% treated 10 or more HIE cases annually. Awareness rates of the national guidelines for HIE diagnosis, HIE treatment, and therapeutic hypothermia protocol were 85, 63, and 78%, respectively. Neurological manifestations and blood gas were used as HIE diagnostic criteria by 96% (263/273) and 68% (186/273) of the hospitals, respectively. Therapeutic hypothermia was used in 54% (147/273) of hospitals. The percentage of general hospitals that implemented therapeutic hypothermia (43%, 71/165) was significantly lower than that in maternity and infant hospitals (67%, 49/73) (χ2 = 11.752, p = 0.001) and children’s hospitals (77%, 27/35) (χ2 = 13.446, p < 0.001). Reasons for not providing therapeutic hypothermia included reduction of HIE cases in recent years (39%), high cost of cooling devices and treatment (31%), lack of training (26%), and safety concerns (4%). Among the hospitals that provided therapeutic hypothermia, 27% (39/147) were in full compliance with the recommended protocol. Eighty-one percent (222/273) of the hospitals treated HIE infants with putative neuroprotective agents alone or in combination with cooling. Ninety-one percent of the hospitals had long-term neurodevelopmental follow-up programs for infants with HIE. Conclusions There is significant heterogeneity in HIE diagnosis and treatment in China. Therapeutic hypothermia has not become a standard of care for neonatal HIE nationwide. Unproven agents are widely used for HIE treatment. Nationwide standardization of HIE management and dissemination of therapeutic hypothermia represent the opportunities to reduce mortality and improve long-term neurodevelopmental outcomes of children affected by HIE.

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Two-Year Neurodevelopmental Outcomes After Mild Hypoxic Ischemic Encephalopathy in the Era of Therapeutic Hypothermia

JAMA Pediatrics ◽

10.1001/jamapediatrics.2019.4011 ◽

2020 ◽

Vol 174 (1) ◽

pp. 48 ◽

Cited By ~ 13

Author(s):

Mikael Finder ◽

Geraldine B. Boylan ◽

Deirdre Twomey ◽

Caroline Ahearne ◽

Deirdre M. Murray ◽

...

Keyword(s):

Therapeutic Hypothermia ◽

Hypoxic Ischemic Encephalopathy ◽

Neurodevelopmental Outcomes ◽

Ischemic Encephalopathy

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Predictors of Outcomes in Hypoxic-Ischemic Encephalopathy following Hypothermia: A Meta-Analysis

Neonatology ◽

10.1159/000505519 ◽

2020 ◽

Vol 117 (4) ◽

pp. 411-427 ◽

Cited By ~ 2

Author(s):

Sabine Ouwehand ◽

Lisanne C.A. Smidt ◽

Jeroen Dudink ◽

Manon J.N.L. Benders ◽

Linda S. de Vries ◽

...

Keyword(s):

Magnetic Resonance ◽

Therapeutic Hypothermia ◽

Meta Analysis ◽

Neurodevelopmental Outcome ◽

Hypoxic Ischemic Encephalopathy ◽

Resonance Spectroscopy ◽

Test Accuracy ◽

Neurodevelopmental Outcomes ◽

Posterior Limb ◽

Ischemic Encephalopathy

Introduction: Prediction of neurodevelopmental outcome in infants with hypoxic-ischemic encephalopathy remains an important challenge. Various studies have shown that the predictive ability of different modalities changed after the introduction of therapeutic hypothermia. This paper reviews the diagnostic test accuracy of the different modalities that are being used to predict neurodevelopmental outcomes following therapeutic hypothermia. Methods: A systematic literature search was performed using Embase and PubMed. Two reviewers independently included eligible studies and extracted data. The quality of the studies was assessed using the Quality in Prognosis Studies Tool. Meta-analyses were performed where possible. Results: Forty-seven articles and 3 conference abstracts were included, reporting on 3,072infants of whom 39% died or had an adverse neurodevelopmental outcome. A meta-analysis could be performed using 37 articles on (amplitude-integrated) electroencephalography (EEG), conventional magnetic resonance imaging (MRI), diffusion-weighted imaging (DWI), and proton magnetic resonance spectroscopy (1H-MRS). Amplitude-integrated EEG (aEEG) at 24 and 72 h showed similar high diagnostic OR, while aEEG at 6 h and EEG performed less, both due to a low specificity. For MRI, most studies reported scoring systems in which early (<8 days) MRI performed better than late (≥8 days) MRI. Injury to the posterior limb of the internal capsule on MRI or to the thalami on DWI were strong individual predictors, as was an increased lactate/N-acetylaspartate peak on 1H-MRS. Conclusions: In the era of therapeutic hypothermia, the different modalities remain good predictors of neurodevelopmental outcome. However, timing should be taken into account. aEEG may initially be false positive and gets more reliable after 24 h. In contrast, MRI should be used during the first week, as its predictive value decreases afterwards.

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