Background: Therapeutic hypothermia provides incomplete neuroprotection for neonatal hypoxic-ischemic encephalopathy (HIE). We examined whether hemodynamic goals that support autoregulation are associated with decreased brain injury and whether these relationships are affected by birth asphyxia or vary by anatomic region. Methods: Neonates cooled for HIE received near-infrared spectroscopy autoregulation monitoring to identify the mean arterial blood pressure with optimized autoregulatory function (MAPOPT). Blood pressure deviation from MAPOPT was correlated with brain injury on MRI after adjusting for the effects of arterial carbon dioxide, vasopressors, seizures, and birth asphyxia severity. Results: Blood pressure deviation from MAPOPT related to neurologic injury in several regions independent of birth asphyxia severity. Greater duration and deviation of blood pressure below MAPOPT were associated with greater injury in the paracentral gyri and white matter. Blood pressure within MAPOPT related to lesser injury in the white matter, putamen and globus pallidus, and brain stem. Finally, blood pressures that exceeded MAPOPT were associated with reduced injury in the paracentral gyri. Conclusions: Blood pressure deviation from optimal autoregulatory vasoreactivity was associated with MRI markers of brain injury that, in many regions, were independent of the initial birth asphyxia. Targeting hemodynamic ranges to optimize autoregulation has potential as an adjunctive therapy to hypothermia for HIE.

Journal Section:
Editor's choice
Keywords:
Brain injury, Cerebral blood flow, Hypoxia, Hypoxic-ischemic encephalopathy, Neonates
1.
Shankaran S, Pappas A, McDonald SA, et al: Childhood outcomes after hypothermia for neonatal encephalopathy. N Engl J Med 2012;366:2085-2092.
2.
Azzopardi D, Strohm B, Marlow N, et al: Effects of hypothermia for perinatal asphyxia on childhood outcomes. N Engl J Med 2014;371:140-149.
3.
Howlett JA, Northington FJ, Gilmore MM, et al: Cerebrovascular autoregulation and neurologic injury in neonatal hypoxic-ischemic encephalopathy. Pediatr Res 2013;74:525-535.
4.
Tekes A, Poretti A, Scheurkogel MM, et al: Apparent diffusion coefficient scalars correlate with near-infrared spectroscopy markers of cerebrovascular autoregulation in neonates cooled for perinatal hypoxic-ischemic injury. AJNR Am J Neuroradiol 2015;36:188-193.
5.
Burton VJ, Gerner G, Cristofalo E, et al: A pilot cohort study of cerebral autoregulation and 2-year neurodevelopmental outcomes in neonates with hypoxic-ischemic encephalopathy who received therapeutic hypothermia. BMC Neurol 2015;15:209.
6.
Pollock JM, Deibler AR, Whitlow CT, et al: Hypercapnia-induced cerebral hyperperfusion: an underrecognized clinical entity. AJNR Am J Neuroradiol 2009;30:378-385.
7.
Armstead WM, Riley J, Vavilala MS: Dopamine prevents impairment of autoregulation after traumatic brain injury in the newborn pig through inhibition of up-regulation of endothelin-1 and extracellular signal-regulated kinase mitogen-activated protein kinase. Pediatr Crit Care Med 2013;14:e103-e111.
8.
Armstead WM, Kiessling JW, Riley J, Kofke WA, Vavilala MS: Phenylephrine infusion prevents impairment of ATP- and calcium-sensitive potassium channel-mediated cerebrovasodilation after brain injury in female, but aggravates impairment in male, piglets through modulation of ERK MAPK upregulation. J Neurotrauma 2011;28:105-111.
9.
Massaro AN, Govindan RB, Vezina G, et al: Impaired cerebral autoregulation and brain injury in newborns with hypoxic-ischemic encephalopathy treated with hypothermia. J Neurophysiol 2015;114:818-824.
10.
Tian F, Tarumi T, Liu H, Zhang R, Chalak L: Wavelet coherence analysis of dynamic cerebral autoregulation in neonatal hypoxic-ischemic encephalopathy. Neuroimage Clin 2016;11:124-132.
11.
Lee JK, Kibler KK, Benni PB, et al: Cerebrovascular reactivity measured by near-infrared spectroscopy. Stroke 2009;40:1820-1826.
12.
Shankaran S, Laptook AR, Ehrenkranz RA, et al: Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 2005;353:1574-1584.
13.
Pappas A, Shankaran S, Laptook AR, et al: Hypocarbia and adverse outcome in neonatal hypoxic-ischemic encephalopathy. J Pediatr 2011;158:752.e1-758.e1.
14.
Larson AC, Jamrogowicz JL, Kulikowicz E, et al: Cerebrovascular autoregulation after rewarming from hypothermia in a neonatal swine model of asphyxic brain injury. J Appl Physiol (1985) 2013;115:1433-1442.
15.
Lee JK, Brady KM, Chung SE, et al: A pilot study of cerebrovascular reactivity autoregulation after pediatric cardiac arrest. Resuscitation 2014;85:1387-1393.
16.
Gretchen CB, Rayannavar AS: Cardiology; in Engorn B, Flerlage J (eds): The Harriet Lane Handbook, ed 20. Philadelphia, Saunders, Elsevier, 2015, pp 127-171.
17.
Martinez-Biarge M, Diez-Sebastian J, Wusthoff CJ, et al: Feeding and communication impairments in infants with central grey matter lesions following perinatal hypoxic-ischaemic injury. Eur J Paediatr Neurol 2012;16:688-696.
18.
Rutherford M, Ramenghi LA, Edwards AD, et al: Assessment of brain tissue injury after moderate hypothermia in neonates with hypoxic-ischaemic encephalopathy: a nested substudy of a randomised controlled trial. Lancet Neurol 2010;9:39-45.
19.
van Schie PE, Schijns J, Becher JG, Barkhof F, van Weissenbruch MM, Vermeulen RJ: Long-term motor and behavioral outcome after perinatal hypoxic-ischemic encephalopathy. Eur J Paediatr Neurol 2015;19:354-359.
20.
Cavalleri F, Lugli L, Pugliese M, et al: Prognostic value of diffusion-weighted imaging summation scores or apparent diffusion coefficient maps in newborns with hypoxic-ischemic encephalopathy. Pediatr Radiol 2014;44:1141-1154.
21.
Goergen SK, Ang H, Wong F, et al: Early MRI in term infants with perinatal hypoxic-ischaemic brain injury: interobserver agreement and MRI predictors of outcome at 2 years. Clin Radiol 2014;69:72-81.
22.
Brant R: Assessing proportionality in the proportional odds model for ordinal logistic regression. Biometrics 1990;46:1171-1178.
23.
Monrad P, Sannagowdara K, Bozarth X, et al: Haemodynamic response associated with both ictal and interictal epileptiform activity using simultaneous video electroencephalography/near infrared spectroscopy in a within-subject study. J Near Infrared Spectrosc 2015;23:209-218.
24.
Lingappan K, Kaiser JR, Srinivasan C, Gunn AJ: Relationship between PCO2 and unfavorable outcome in infants with moderate-to-severe hypoxic ischemic encephalopathy. Pediatr Res 2016;80:204-208.
25.
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;35:290-296.
26.
Nanavati T, Seemaladinne N, Regier M, Yossuck P, Pergami P: Can we predict functional outcome in neonates with hypoxic ischemic encephalopathy by the combination of neuroimaging and electroencephalography? Pediatr Neonatol 2015;56:307-316.
27.
Massaro AN: MRI for neurodevelopmental prognostication in the high-risk term infant. Semin Perinatol 2015;39:159-167.
28.
van Laerhoven H, de Haan TR, Offringa M, Post B, van der Lee JH: Prognostic tests in term neonates with hypoxic-ischemic encephalopathy: a systematic review. Pediatrics 2013;131:88-98.
29.
Skranes JH, Cowan FM, Stiris T, Fugelseth D, Thoresen M, Server A: Brain imaging in cooled encephalopathic neonates does not differ between four and 11 days after birth. Acta Paediatr 2015;104:752-758.
30.
Buckley EM, Patel SD, Miller BF, Franceschini MA, Vannucci SJ: In vivo monitoring of cerebral hemodynamics in the immature rat: effects of hypoxia-ischemia and hypothermia. Dev Neurosci 2015;37:407-416.
31.
Lee JK, Brady KM, Mytar JO, et al: Cerebral blood flow and cerebrovascular autoregulation in a swine model of pediatric cardiac arrest and hypothermia. Crit Care Med 2011;39:2337-2345.
32.
Natarajan G, Shankaran S, Laptook AR, et al: Apgar scores at 10 min and outcomes at 6-7 years following hypoxic-ischaemic encephalopathy. Arch Dis Child Fetal Neonatal Ed 2013;98:F473-F479.
33.
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.
34.
Wang B, Armstrong JS, Lee JH, et al: Rewarming from therapeutic hypothermia induces cortical neuron apoptosis in a swine model of neonatal hypoxic-ischemic encephalopathy. J Cereb Blood Flow Metab 2015;35:781-793.
35.
Lee JK, Wang B, Reyes M, et al: Hypothermia and rewarming activate a macroglial unfolded protein response independent of hypoxic-ischemic brain injury in neonatal piglets. Dev Neurosci 2016;38:277-294.
36.
Mueller-Burke D, Koehler RC, Martin LJ: Rapid NMDA receptor phosphorylation and oxidative stress precede striatal neurodegeneration after hypoxic ischemia in newborn piglets and are attenuated with hypothermia. Int J Dev Neurosci 2008;26:67-76.
© 2016 S. Karger AG, Basel
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
2016
You do not currently have access to this content.