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DOI: 10.1055/s-0040-1716341
Utilization of Therapeutic Hypothermia and Neurological Injury in Neonates with Mild Hypoxic-Ischemic Encephalopathy: A Report from Children's Hospital Neonatal Consortium
Funding None.Abstract
Objective This study was aimed to describe utilization of therapeutic hypothermia (TH) in neonates presenting with mild hypoxic-ischemic encephalopathy (HIE) and associated neurological injury on magnetic resonance imaging (MRI) scans in these infants.
Study Design Neonates ≥ 36 weeks' gestation with mild HIE and available MRI scans were identified. Mild HIE status was assigned to hyper alert infants with an exaggerated response to arousal and mild HIE as the highest grade of encephalopathy recorded. MRI scans were dichotomized as “injury” versus “no injury.”
Results A total of 94.5% (257/272) neonates with mild HIE, referred for evaluation, received TH. MRI injury occurred in 38.2% (104/272) neonates and affected predominantly the white matter (49.0%, n = 51). Injury to the deep nuclear gray matter was identified in (10.1%) 20 infants, and to the cortex in 13.4% (n = 14 infants). In regression analyses (odds ratio [OR]; 95% confidence interval [CI]), history of fetal distress (OR = 0.52; 95% CI: 0.28–0.99) and delivery by caesarian section (OR = 0.54; 95% CI: 0.31–0.92) were associated with lower odds, whereas medical comorbidities during and after cooling were associated with higher odds of brain injury (OR = 2.31; 95% CI: 1.37–3.89).
Conclusion Majority of neonates with mild HIE referred for evaluation are being treated with TH. Odds of neurological injury are over two-fold higher in those with comorbidities during and after cooling. Brain injury predominantly involved the white matter.
Key Points
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Increasingly, neonates with mild HIE are being referred for consideration for hypothermia therapy.
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Drift in clinical practice shows growing number of neonates treated with hypothermia as having mild HIE.
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MRI data show that 38% of neonates with mild HIE have brain injury, predominantly in the white matter.
Keywords
therapeutic hypothermia - white matter injury - mild hypoxic-ischemic encephalopathy - MRI - EEGAuthors' Contribution
R.R., U.M., R.D., K.S.L., T.D.Y., M.L.V.D., S.E.H., G.N., E.S.P., J.F., T.W.W., A.M.M., and A.M. made substantial contributions to conception and design of the study and interpretation of data. R.R. prepared the first and final draft of the article and revised it critically for important intellectual content. U.M. and R.D. made substantial contributions in the preparation of the initial draft, and revised it critically for important intellectual content. I.Z. made substantial contributions to the analysis and interpretation of data; revised the article critically for important intellectual content. K.S.L., T.D.Y., M.L.V.D., S.E.H., G.N., E.S.P., J.F., T.W.W., A.M.M., and A.M. revised the article critically for important intellectual content. All authors approved the final manuscript as submitted and accountable for all aspects of the work.
Note
Data in the manuscript were presented in part (abstract) at the Pediatric Academic Societies meeting in Baltimore, MD, on April 29, 2019.
Publication History
Received: 21 April 2020
Accepted: 23 July 2020
Article published online:
06 September 2020
© 2020. Thieme. All rights reserved.
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References
- 1 Murray DM, O'Connor CM, Ryan CA, Korotchikova I, Boylan GB. Early EEG grade and outcome at 5 years after mild neonatal hypoxic ischemic encephalopathy. Pediatrics 2016; 138 (04) e20160659
- 2 Chalak LF, Nguyen KA, Prempunpong C. et al. Prospective research in infants with mild encephalopathy identified in the first six hours of life: neurodevelopmental outcomes at 18-22 months. Pediatr Res 2018; 84 (06) 861-868
- 3 Walsh BH, Neil J, Morey J. et al. The frequency and severity of magnetic resonance imaging abnormalities in infants with mild neonatal encephalopathy. J Pediatr 2017; 187: 26-33.e1
- 4 Gluckman PD, Wyatt JS, Azzopardi D. et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 2005; 365 (9460): 663-670
- 5 Shankaran S, Laptook AR, Ehrenkranz RA. et al; National Institute of Child Health and Human Development Neonatal Research Network. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 2005; 353 (15) 1574-1584
- 6 Montaldo P, Lally PJ, Oliveira V. et al. Therapeutic hypothermia initiated within 6 hours of birth is associated with reduced brain injury on MR biomarkers in mild hypoxic-ischaemic encephalopathy: a non-randomised cohort study. Arch Dis Child Fetal Neonatal Ed 2019; 104 (05) F515-F520
- 7 Jacobs SE, Morley CJ, Inder TE. et al; Infant Cooling Evaluation Collaboration. Whole-body hypothermia for term and near-term newborns with hypoxic-ischemic encephalopathy: a randomized controlled trial. Arch Pediatr Adolesc Med 2011; 165 (08) 692-700
- 8 Zhou WH, Cheng GQ, Shao XM. et al; China Study Group. Selective head cooling with mild systemic hypothermia after neonatal hypoxic-ischemic encephalopathy: a multicenter randomized controlled trial in China. J Pediatr 2010; 157 (03) 367-372 , 372.e1–372.e3
- 9 Conway JM, Walsh BH, Boylan GB, Murray DM. Mild hypoxic ischaemic encephalopathy and long term neurodevelopmental outcome - A systematic review. Early Hum Dev 2018; 120: 80-87
- 10 Donda KON, Asare-Afriyie B, Amponsah J, Shingala K, Bhatt P, Dapaah-Siakwan F. National Trends in the Use, Outcomes, and Resource Utilization for THerapeutic Hypothermia for Mild Hypoxic-Ischemic Encephalopathy in the United States, 2012–2016. PAS Meeting 2019; 04/27/2019; Baltimore, MD2019
- 11 Massaro AN, Murthy K, Zaniletti I. et al. Short-term outcomes after perinatal hypoxic ischemic encephalopathy: a report from the Children's Hospitals Neonatal Consortium HIE focus group. J Perinatol 2015; 35 (04) 290-296
- 12 Kracer B, Hintz SR, Van Meurs KP, Lee HC. Hypothermia therapy for neonatal hypoxic ischemic encephalopathy in the state of California. J Pediatr 2014; 165 (02) 267-273
- 13 Saw CL, Rakshasbhuvankar A, Rao S, Bulsara M, Patole S. Current practice of therapeutic hypothermia for mild hypoxic ischemic encephalopathy. J Child Neurol 2019; 34 (07) 402-409
- 14 Murthy K, Dykes FD, Padula MA. et al. The Children's Hospitals Neonatal Database: an overview of patient complexity, outcomes and variation in care. J Perinatol 2014; 34 (08) 582-586
- 15 Papile LA, Baley JE, Benitz W. et al; Committee on Fetus and Newborn. Hypothermia and neonatal encephalopathy. Pediatrics 2014; 133 (06) 1146-1150
- 16 Oliveira V, Singhvi DP, Montaldo P. et al. Therapeutic hypothermia in mild neonatal encephalopathy: a national survey of practice in the UK. Arch Dis Child Fetal Neonatal Ed 2018; 103 (04) F388-F390
- 17 Chevallier M, Ego A, Cans C, Debillon T. French Society of Neonatology. Adherence to hypothermia guidelines: a French multicenter study of fullterm neonates. PLoS One 2013; 8 (12) e83742
- 18 Lally PJ, Montaldo P, Oliveira V. et al. Residual brain injury after early discontinuation of cooling therapy in mild neonatal encephalopathy. Arch Dis Child Fetal Neonatal Ed 2018; 103 (04) F383-F387
- 19 Robertson C, Finer N. Term infants with hypoxic-ischemic encephalopathy: outcome at 3.5 years. Dev Med Child Neurol 1985; 27 (04) 473-484
- 20 Chalak L, Latremouille S, Mir I, Sánchez PJ, Sant'Anna G. A review of the conundrum of mild hypoxic-ischemic encephalopathy: Current challenges and moving forward. Early Hum Dev 2018; 120: 88-94
- 21 DuPont TL, Chalak LF, Morriss MC, Burchfield PJ, Christie L, Sánchez PJ. Short-term outcomes of newborns with perinatal acidemia who are not eligible for systemic hypothermia therapy. J Pediatr 2013; 162 (01) 35-41
- 22 Prempunpong C, Chalak LF, Garfinkle J. et al. Prospective research on infants with mild encephalopathy: the PRIME study. J Perinatol 2017
- 23 van Handel M, Swaab H, de Vries LS, Jongmans MJ. Behavioral outcome in children with a history of neonatal encephalopathy following perinatal asphyxia. J Pediatr Psychol 2010; 35 (03) 286-295
- 24 Chalak LF, Adams-Huet B, Sant'Anna G. A total Sarnat score in mild hypoxic-ischemic encephalopathy can detect infants at higher risk of disability. J Pediatr 2019; 214: 217-221.e1
- 25 Gagne-Loranger M, Sheppard M, Ali N, Saint-Martin C, Wintermark P. Newborns referred for therapeutic hypothermia: association between initial degree of encephalopathy and severity of brain injury (what about the newborns with mild encephalopathy on admission?). Am J Perinatol 2016; 33 (02) 195-202
- 26 Skranes JH, Løhaugen G, Schumacher EM. et al. Amplitude-integrated electroencephalography improves the identification of infants with encephalopathy for therapeutic hypothermia and predicts neurodevelopmental outcomes at 2 years of age. J Pediatr 2017; 187: 34-42
- 27 Gunn AJ, Wyatt JS, Whitelaw A. et al; CoolCap Study Group. Therapeutic hypothermia changes the prognostic value of clinical evaluation of neonatal encephalopathy. J Pediatr 2008; 152 (01) 55-58 , 58.e1
- 28 Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study. Arch Neurol 1976; 33 (10) 696-705
- 29 Shankaran S, Laptook AR, Tyson JE. et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Evolution of encephalopathy during whole body hypothermia for neonatal hypoxic-ischemic encephalopathy. J Pediatr 2012; 160 (04) 567-572.e3
- 30 Perretta L, Reed R, Ross G, Perlman J. Is there a role for therapeutic hypothermia administration in term infants with mild neonatal encephalopathy?. J Perinatol 2020; 40 (03) 522-529
- 31 Rao R, Trivedi S, Vesoulis Z, Liao SM, Smyser CD, Mathur AM. Safety and short-term outcomes of therapeutic hypothermia in preterm neonates 34-35 weeks gestational age with hypoxic-ischemic encephalopathy. J Pediatr 2017; 183: 37-42
- 32 de Vries LS, Groenendaal F. Patterns of neonatal hypoxic-ischaemic brain injury. Neuroradiology 2010; 52 (06) 555-566
- 33 Martinez-Biarge M, Bregant T, Wusthoff CJ. et al. White matter and cortical injury in hypoxic-ischemic encephalopathy: antecedent factors and 2-year outcome. J Pediatr 2012; 161 (05) 799-807
- 34 Qiao M, Meng S, Scobie K, Foniok T, Tuor UI. Magnetic resonance imaging of differential gray versus white matter injury following a mild or moderate hypoxic-ischemic insult in neonatal rats. Neurosci Lett 2004; 368 (03) 332-336
- 35 van Kooij BJ, van Handel M, Nievelstein RA, Groenendaal F, Jongmans MJ, de Vries LS. Serial MRI and neurodevelopmental outcome in 9- to 10-year-old children with neonatal encephalopathy. J Pediatr 2010; 157 (02) 221-227.e2
- 36 Cowan F, Rutherford M, Groenendaal F. et al. Origin and timing of brain lesions in term infants with neonatal encephalopathy. Lancet 2003; 361 (9359): 736-742
- 37 Martinez-Biarge M, Cheong JL, Diez-Sebastian J, Mercuri E, Dubowitz LM, Cowan FM. Risk factors for neonatal arterial ischemic stroke: the importance of the intrapartum period. J Pediatr 2016; 173: 62-68.e1
- 38 Martinez-Biarge M, Diez-Sebastian J, Wusthoff CJ, Mercuri E, Cowan FM. Antepartum and intrapartum factors preceding neonatal hypoxic-ischemic encephalopathy. Pediatrics 2013; 132 (04) e952-e959
- 39 Badawi N, Kurinczuk JJ, Keogh JM. et al. Intrapartum risk factors for newborn encephalopathy: the Western Australian case-control study. BMJ 1998; 317 (7172): 1554-1558
- 40 Grass B, El Shahed A, Ly LG. et al. Therapeutic hypothermia for hypoxic-ischemic encephalopathy after perinatal sentinel events: less brain injury on MRI and improved neurodevelopmental outcome at 18-36 months. J Perinatol 2020; 40 (04) 633-639
- 41 Kali GT, Martinez-Biarge M, Van Zyl J, Smith J, Rutherford M. Therapeutic hypothermia for neonatal hypoxic-ischaemic encephalopathy had favourable outcomes at a referral hospital in a middle-income country. Acta Paediatr 2016; 105 (07) 806-815
- 42 Finder M, Boylan GB, Twomey D, Ahearne C, Murray DM, Hallberg B. Two-year neurodevelopmental outcomes after mild hypoxic ischemic encephalopathy in the era of therapeutic hypothermia. JAMA Pediatr 2019
- 43 Goswami IR, Whyte H, Wintermark P. et al. Characteristics and short-term outcomes of neonates with mild hypoxic-ischemic encephalopathy treated with hypothermia. J Perinatol 2020; 40 (02) 275-283
- 44 Wang B, Armstrong JS, Reyes M. et al. White matter apoptosis is increased by delayed hypothermia and rewarming in a neonatal piglet model of hypoxic ischemic encephalopathy. Neuroscience 2016; 316: 296-310
- 45 O'Brien CE, Santos PT, Kulikowicz E. et al. Hypoxia-ischemia and hypothermia independently and interactively affect neuronal pathology in neonatal piglets with short-term recovery. Dev Neurosci 2019; 41 (1,2): 17-33
- 46 Lally PJ, Montaldo P, Oliveira V. et al; MARBLE consortium. Magnetic resonance spectroscopy assessment of brain injury after moderate hypothermia in neonatal encephalopathy: a prospective multicentre cohort study. Lancet Neurol 2019; 18 (01) 35-45
- 47 Annink KV, de Vries LS, Groenendaal F. et al. The long-term effect of perinatal asphyxia on hippocampal volumes. Pediatr Res 2019; 85 (01) 43-49