Is Erythropoietin Combining with Therapeutic Hypothermia an Efficient and Safe Therapy in Neonatal Hypoxic Ischemic Encephalopathy: A Prospective and Randomized Clinical Trial

Abstract BackgroundTo evaluate the efficacy and safety of erythropoietin (Epo) combined with therapeutic hypothermia (TH) in neonatal hypoxic-ischemic encephalopathy (HIE).MethodsA total of 78 term infants with HIE were assigned randomly to receive Epo (n = 40) or placebo (n = 38). All infants received TH. Blood samples before TH, after TH and after Epo/placebo were collected for measuring TH associated adverse events, Epo associated factors and potential neural biomarkers. Basal ganglia/ watershed (BG/W) scoring system was used to assess brain injury in MRI. Neurodevelopmental evaluations were performed at 18 months by using BayleyScales of Infant Development II (Bayley II).ResultsEpo-treated group tend to have lower serum creatine kinase (CK) concentration (114 vs 202, P = .04) and higher serum K+, Mg2+ concentration (5.0 vs 4.5, P = .03; 1.0 vs 0.9, P = .02) than control group after intervention. Brain MRI was performed in 65 (83%) neonatal. Totally brain injury score was in even distribution between two groups (median, 0 vs 0, P = .61), but injury region in cortex plus basal nuclei comparing with in basal nuclei solely was less common in the Epo than in the control group (21% vs 31%, P = .046). Only forty patients (40/78, 51%) succeeded in achieving 18-month follow up data. The totally adverse outcomes were trend to decline in the Epo group (35% vs 60%, P = .21). No adverse events were ascribed to Epo treatment.ConclusionsThe combination of Epo and TH is proved to be feasible, safe and potential effective.Trial registration: ChiCTR-TRC-14004532, date of registration: April 18th, 2014.

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Wavelet Autoregulation Monitoring Identifies Blood Pressures Associated With Brain Injury in Neonatal Hypoxic-Ischemic Encephalopathy

Frontiers in Neurology ◽

10.3389/fneur.2021.662839 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xiuyun Liu ◽

Aylin Tekes ◽

Jamie Perin ◽

May W. Chen ◽

Bruno P. Soares ◽

...

Keyword(s):

Blood Pressure ◽

Brain Injury ◽

Therapeutic Hypothermia ◽

Near Infrared ◽

Brain Regions ◽

Hypoxic Ischemic Encephalopathy ◽

Volume Index ◽

Arterial Blood ◽

Blood Pressures ◽

Ischemic Encephalopathy

Dysfunctional cerebrovascular autoregulation may contribute to neurologic injury in neonatal hypoxic-ischemic encephalopathy (HIE). Identifying the optimal mean arterial blood pressure (MAPopt) that best supports autoregulation could help identify hemodynamic goals that support neurologic recovery. In neonates who received therapeutic hypothermia for HIE, we hypothesized that the wavelet hemoglobin volume index (wHVx) would identify MAPopt and that blood pressures closer to MAPopt would be associated with less brain injury on MRI. We also tested a correlation-derived hemoglobin volume index (HVx) and single- and multi-window data processing methodology. Autoregulation was monitored in consecutive 3-h periods using near infrared spectroscopy in an observational study. The neonates had a mean MAP of 54 mmHg (standard deviation: 9) during hypothermia. Greater blood pressure above the MAPopt from single-window wHVx was associated with less injury in the paracentral gyri (p = 0.044; n = 63), basal ganglia (p = 0.015), thalamus (p = 0.013), and brainstem (p = 0.041) after adjustments for sex, vasopressor use, seizures, arterial carbon dioxide level, and a perinatal insult score. Blood pressure exceeding MAPopt from the multi-window, correlation HVx was associated with less injury in the brainstem (p = 0.021) but not in other brain regions. We conclude that applying wavelet methodology to short autoregulation monitoring periods may improve the identification of MAPopt values that are associated with brain injury. Having blood pressure above MAPopt with an upper MAP of ~50–60 mmHg may reduce the risk of brain injury during therapeutic hypothermia. Though a cause-and-effect relationship cannot be inferred, the data support the need for randomized studies of autoregulation and brain injury in neonates with HIE.

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The Effect of the Excretion of Calcium, Magnesium, and Phosphate on the Serum Levels of These Substances in Newborns Who Therapeutic Hypothermia for Hypoxic Ischemic Encephalopathy

10.21203/rs.3.rs-244271/v1 ◽

2021 ◽

Author(s):

Osman Baştuğ ◽

Bahadır İnan ◽

Ahmet Özdemir ◽

Binnaz Çelik ◽

Funda Baştuğ ◽

...

Keyword(s):

Urinary Excretion ◽

Therapeutic Hypothermia ◽

Perinatal Asphyxia ◽

Serum Levels ◽

Hypoxic Ischemic Encephalopathy ◽

Control Group ◽

P Value ◽

Electrolyte Disturbances ◽

Significant Difference ◽

Ischemic Encephalopathy

Abstract Background: Hypocalcemia, hypomagnesemia, and hyperphosphatemia are common electrolyte disturbances in perinatal asphyxia(PA). Different reasons have been proposed for these electrolyte disturbances. This study investigated the effect of the urinary excretion of calcium(Ca), magnesium(Mg), and phosphorus(P) on the serum levels of these substances in babies who were treated using therapeutic hypothermia for hypoxic ischemic encephalopathy(HİE) caused by PA. This study sheds light on the pathophysiology that may cause changes in the serum values of these electrolytes.Method: This study included 21 healthy newborns(control group) and 38 patients(HİE group) who had undergone therapeutic hypothermia due to HİE. Only infants with a gestational age of 36 weeks and above and a birth weight of 2000 g and above were evaluated. The urine and serum Ca, Mg, P, and creatinine levels of all infants were evaluated at 24, 48, and 72 hours.Results: The lower serum Ca value and the higher serum P value of the HİE group were found to be statistically significant compared to the control group. There was no significant difference in serum Mg values between the groups. However, hypomagnesemia was detected in five patients from the HİE group. The urine excretions of these substances, which were checked at different times, were found to be significantly higher in the HİE group compared to the control group.Conclusion: This study determined that the urinary excretion of Ca, Mg, and P has an effect on the serum Ca, Mg, and P levels of infants with HİE.

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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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Use of Therapeutic Hypothermia for Term Infants with Hypoxic-Ischemic Encephalopathy

Pediatric Clinics of North America ◽

10.1016/j.pcl.2009.03.007 ◽

2009 ◽

Vol 56 (3) ◽

pp. 601-616 ◽

Cited By ~ 20

Author(s):

Abbot R. Laptook

Keyword(s):

Therapeutic Hypothermia ◽

Hypoxic Ischemic Encephalopathy ◽

Term Infants ◽

Ischemic Encephalopathy

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Apgar Scores at 10 Minutes and Outcomes in Term and Late Preterm Neonates with Hypoxic-Ischemic Encephalopathy in the Cooling Era

American Journal of Perinatology ◽

10.1055/s-0038-1670637 ◽

2018 ◽

Vol 36 (05) ◽

pp. 545-554 ◽

Cited By ~ 2

Author(s):

Marina Ayrapetyan ◽

Kiran Talekar ◽

Kathleen Schwabenbauer ◽

David Carola ◽

Kolawole Solarin ◽

...

Keyword(s):

Therapeutic Hypothermia ◽

Brain Mri ◽

Brain Magnetic Resonance Imaging ◽

Hypoxic Ischemic Encephalopathy ◽

Preterm Neonates ◽

Short Term ◽

Apgar Scores ◽

Significant Difference ◽

The Brain ◽

Ischemic Encephalopathy

Objective To determine the short-term outcomes (abnormal brain magnetic resonance imaging [MRI]/death) in infants born with a 10-minute Apgar score of 0 who received therapeutic hypothermia and compare them with infants with higher scores. Study Design This is a retrospective review of 293 neonates (gestational age ≥ 35 weeks) born between November 2006 and October 2015 admitted with hypoxic-ischemic encephalopathy who received therapeutic hypothermia. Results of brain MRIs were assessed by the basal ganglia/watershed scoring system. Short-term outcomes were compared between infants with Apgar scores of 0, 1 to 4, and ≥5 at 10 minutes. Results Eight of 17 infants (47%) with an Apgar of 0 at 10 minutes survived, having 4 (24%) without abnormalities on the brain MRI and 7 (41%) without severe abnormalities. There was no significant difference in the combined outcomes of “death/abnormal MRI” and “death/severe abnormalities on the MRI” between infants with Apgar scores of 0 and 1 to 4. Follow-up data were available for six of eight surviving infants, and none had moderate or severe neurodevelopmental impairment. Conclusion In the cooling era, 47% of infants with no audible heart rate at 10 minutes and who were admitted to the neonatal intensive care unit survived; 24% without abnormalities on the brain MRI and 41% without severe abnormalities.

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Can Neonatal Brain MRI be Performed during Active Cooling?

American Journal of Perinatology ◽

10.1055/s-0037-1620270 ◽

2018 ◽

Vol 35 (09) ◽

pp. 837-839

Author(s):

Dhanashree Rajderkar ◽

Nicole Copenhaver ◽

Kristine Boykin ◽

Michael Weiss ◽

Marisa Pacella

Keyword(s):

Diagnostic Imaging ◽

Therapeutic Hypothermia ◽

Study Design ◽

Brain Mri ◽

Hypoxic Ischemic Encephalopathy ◽

Target Temperature ◽

Neonatal Brain ◽

Active Cooling ◽

Temperature Probe ◽

Ischemic Encephalopathy

Objective Due to logistical constraints, physicians traditionally delay diagnostic imaging for neonatal hypoxic-ischemic encephalopathy (HIE) until the neonate has completed all 72 hours of therapeutic hypothermia and rewarming. In some cases, neonates may require neuroimaging before 72 hours has passed. Study Design We present a case in which an MRI was acquired during active hypothermia. Results Upon return to the NICU, Baby X's temperature probe read 33.6 degrees, indicating that hypothermia was likely maintained at the target temperature. Conclusion Active hypothermia is possible during MRI.

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Preschool Language Outcomes following Perinatal Hypoxic-Ischemic Encephalopathy in the Age of Therapeutic Hypothermia

Developmental Neuroscience ◽

10.1159/000499562 ◽

2018 ◽

Vol 40 (5-6) ◽

pp. 627-637 ◽

Cited By ~ 2

Author(s):

Eric M. Chin ◽

Srishti Jayakumar ◽

Ezequiel Ramos ◽

Gwendolyn Gerner ◽

Bruno P. Soares ◽

...

Keyword(s):

Socioeconomic Status ◽

Language Development ◽

Therapeutic Hypothermia ◽

Expressive Language ◽

Brain Mri ◽

Receptive Language ◽

Relative Strength ◽

Hypoxic Ischemic Encephalopathy ◽

Language Deficits ◽

Ischemic Encephalopathy

Early studies following perinatal hypoxic-ischemic encephalopathy (HIE) suggested expressive language deficits and academic difficulties, but there is only limited detailed study of language development in this population since the widespread adoption of therapeutic hypothermia (TH). Expressive and receptive language testing was performed as part of a larger battery with 45 children with a mean age of 26 months following perinatal HIE treated with TH. Overall cohort outcomes as well as the effects of gender, estimated household income, initial pH and base excess, and pattern of injury on neonatal brain MRI were assessed. The cohort overall demonstrated expressive language subscore, visual-reception subscore, and early learning composite scores significantly below test norms, with relative sparing of receptive language subscores. Poorer expressive language manifested as decreased vocabulary size and shorter utterances. Expressive language subscores showed a significant gender effect, and estimated socioeconomic status showed a significant effect on both receptive and expressive language subscores. Initial blood gas markers and modified Sarnat scoring did not show a significant effect on language subscores. Binarized MRI abnormality predicted a significant effect on both receptive and expressive language subscores; the presence of specific cortical/subcortical abnormalities predicted receptive language deficits. Overall, the language development profile of children following HIE in the era of hypothermia shows a relative strength in receptive language. Gender and socioeconomic status predominantly predict expressive language deficits; abnormalities detectable on MRI predominantly predict receptive language deficits.

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Predictors of Long-Term Neurodevelopmental Outcome of Hypoxic-Ischemic Encephalopathy Treated with Therapeutic Hypothermia

Seminars in Neurology ◽

10.1055/s-0040-1702939 ◽

2020 ◽

Vol 40 (03) ◽

pp. 322-334

Author(s):

Ipsita Goswami ◽

Mireille Guillot ◽

Emily W. Y. Tam

Keyword(s):

Brain Injury ◽

Therapeutic Hypothermia ◽

Prognostic Markers ◽

Neurodevelopmental Outcome ◽

Hypoxic Ischemic Encephalopathy ◽

Secondary Brain Injury ◽

Prognostic Utility ◽

Initial Injury ◽

Ischemic Encephalopathy

AbstractHypoxic-ischemic encephalopathy (HIE) is a manifestation of perinatal asphyxial insult that continues to evolve over days to weeks following the initial injury. Therapeutic hypothermia has demonstrated that a proportion of this secondary brain injury may indeed be preventable. However, therapeutic hypothermia has also altered the prognostic utility of many bedside tools that are commonly used as predictors of long-term neurodevelopmental outcome in HIE. Clinicians are often confronted with uncertainty when assessing the prognosis of infants with HIE. Improved understanding of the implications and limitations of individual investigations may inform clinical decisions and allow for timely intervention. This review summarizes the predictive value of currently available prognostic markers in HIE infants in the therapeutic hypothermia era, including clinical, biochemical, neurophysiological, physiological, and neuroimaging predictors.

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The General Movements Assessment in Neonates With Hypoxic Ischemic Encephalopathy

Journal of Child Neurology ◽

10.1177/0883073820981515 ◽

2021 ◽

pp. 088307382098151

Author(s):

Nicole R. Pouppirt ◽

Valerie Martin ◽

Linda Pagnotto-Hammitt ◽

Alicia J. Spittle ◽

John Flibotte ◽

...

Keyword(s):

Cerebral Palsy ◽

Therapeutic Hypothermia ◽

Interrater Reliability ◽

Late Preterm ◽

Hypoxic Ischemic Encephalopathy ◽

Clinical Markers ◽

Term Infants ◽

Neurologic Outcomes ◽

General Movements ◽

Ischemic Encephalopathy

Background: Clinical measures after birth and studies such as electroencephalogram (EEG) and brain imaging do not fully predict neurodevelopmental outcomes of infants with hypoxic-ischemic encephalopathy. Early detection of adverse neurologic outcomes, and cerebral palsy in particular, in high-risk infants is essential for ensuring timely management. The General Movements Assessment is a tool that can be used in the early detection of cerebral palsy in infants with brain injury. The majority of studies on the General Movements Assessment in the late preterm and term population were performed prior to the introduction of therapeutic hypothermia. Aims: To apply the General Movements Assessment in late preterm and term infants with hypoxic-ischemic encephalopathy (including those who received therapeutic hypothermia), to determine if clinical markers of hypoxic-ischemic encephalopathy predict abnormal General Movements Assessment findings, and to evaluate interrater reliability of the General Movements Assessment in this population. Study design: Pilot prospective cohort study Subjects: We assessed 29 late preterm and full-term infants with mild, moderate, and severe hypoxic-ischemic encephalopathy in Philadelphia, PA. Results: Most infants’ general movements normalized by the fidgety age. Only infants with moderate or severe hypoxic-ischemic encephalopathy had abnormal general movements in both the writhing and the fidgety ages (n = 6). Seizure at any point during the initial hospitalization was the clinical sign most predictive of abnormal general movements in the fidgety age (sensitivity 100%, specificity 55%, positive predictive value 40%, negative predictive value 100%). Interrater reliability was greatest during the fidgety age (κ = 0.67). Conclusions: Seizures were the clinical predictor most closely associated with abnormal findings on the General Movements Assessment. However, clinical markers of hypoxic-ischemic encephalopathy are not fully predictive of abnormal General Movements Assessment findings. Larger future studies are needed to evaluate the associations between the General Movements Assessment and childhood neurologic outcomes in patients with hypoxic-ischemic encephalopathy who received therapeutic hypothermia.

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