Original ArticleCerebral Autoregulation and Conventional and Diffusion Tensor Imaging Magnetic Resonance Imaging in Neonatal Hypoxic-Ischemic Encephalopathy
Introduction
Neuroprotective treatment for hypoxic-ischemic encephalopathy (HIE) has focused on therapeutic hypothermia, but this protection is incomplete as nearly half of hypothermia-treated survivors develop moderate to severe disabilities.1, 2 Cerebral autoregulation maintains blood flow across fluctuations in blood pressure. Cerebral vasoreactivity describes the vasodilatory and vasoconstrictive responses to changes in blood pressure that mediate cerebral blood flow autoregulation. Dysfunctional vasoreactivity and autoregulation during resuscitation,3 hypothermia,4 and rewarming5, 6 may contribute to secondary brain injury and poor neurological outcomes in HIE.
The blood pressure range with optimized autoregulatory vasoreactivity—the optimal mean arterial blood pressure (MAP)—can be identified using the hemoglobin volume index (HVx) from near-infrared spectroscopy.7, 8, 9, 10 Conceptually, optimal MAP is located in the center of the blood pressure-cerebral blood flow autoregulation plateau. Vasoreactivity decreases and autoregulation becomes progressively more dysfunctional as blood pressure deviates from optimal MAP. Using optimal MAP as a hemodynamic goal to optimize autoregulatory vasoreactivity in individual neonates reflects a precision medicine approach that contrasts with using generalized blood pressure goals, such as those based on gestational age, that assume similar hemodynamic needs among all neonates. We previously demonstrated a relationship between blood pressure relative to optimal MAP and brain injury on magnetic resonance imaging (MRI)5, 11, 12 and neurodevelopmental outcomes6 in a small cohort of babies with HIE.
Both conventional MRI and diffusion tensor imaging (DTI) can map brain injury. The qualitative National Institute of Child Health and Human Development (NICHD) Neonatology Research Network (NRN) brain injury score analyzes conventional T1- and T2-weighted images to combine subcortical, basal ganglia, thalamus, internal capsule, watershed, and cerebral injuries into one global injury score. A higher NRN score predicts death or disability.13 The NRN score is a standardized, reproducible, qualitative global brain injury scoring system that can be used across institutions in multicenter studies because it uses conventional sequences. Quantitative brain injury can be evaluated with DTI mean diffusivity (MD) scalars. MD identifies compromised microstructural integrity in brain parenchyma after hypoxic-ischemic injury. Region of interest (ROI) analysis can be performed in specific anatomic locations.
In the current study, we extend our prior work5, 6, 11, 12 to validate the relationships between blood pressure, optimal MAP, and brain injury using qualitative and quantitative MRIs with the NRN brain injury score2 and DTI MD scalars in neonates younger than 10 days. We hypothesized that both the NRN score and MD scalars would detect relationships between blood pressure deviation from optimal MAP and brain injury in newborns with HIE. We also hypothesized that absolute values of optimal MAP would be associated with brain injury severity.
Section snippets
Materials and Methods
This observational study was conducted in the Johns Hopkins University neonatal intensive care unit (NICU) with institutional review board approval. We sequentially screened all neonates with HIE admitted to the NICU between September 2010 and July 2015. Written informed consent was obtained from the parents until May 2013, when near-infrared spectroscopy (NIRS) monitoring became the standard of care for HIE treatment at our hospital. The institutional review board then granted a waiver of
Results
We screened 122 neonates with HIE. Forty-seven (39%) did not meet eligibility criteria because of the following: unreliable arterial blood pressure tracing (16), parents did not consent to the study (nine), the patient was transferred out of the NICU for potential extracorporeal membrane oxygenation (six), technical difficulties (five), death before HVx monitoring could be started (five), inadequate resources (three), coagulopathy (one), complex cardiac disease (one), or parents did not speak
Discussion
In an observational pilot study of newborns treated with hypothermia for HIE, we identified relationships between blood pressure regulation relative to optimal MAP and brain injury measured by the global NRN score and regional MD scalars. Greater duration of blood pressure within optimal MAP was related to less injury by NRN score and higher MD in the ACS and the pons. Blood pressure deviation below optimal MAP was associated with lower MD in cerebellar white matter. Higher optimal MAP values
Conclusions
We observed significant relationships between blood pressure deviation from the MAP range with most robust cerebral autoregulatory vasoreactivity and brain injury measured by qualitative and quantitative MRIs. MD scalars from DTI MRI identified detailed relationships between optimal MAP and regional injury that the NRN score did not. Higher optimal MAP and lower MD in multiple brain regions may be related to cytotoxic edema with limited vasodilatory reserve at low blood pressure. Future
Conflicts of interest
JKL, FJN, and RC-V received research support from Medtronic for a separate study. JKL was also a paid advisory board member for Medtronic. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. Medtronic had no role in the current study's design, data collection and analysis, interpretation of the results, writing, or decision to submit our manuscript for publication.
Dedication
We dedicate this manuscript to the Poretti family in loving memory of Dr. Andrea Poretti (AP).
References (29)
- et al.
Cerebral blood flow during reperfusion predicts later brain damage in a mouse and a rat model of neonatal hypoxic-ischemic encephalopathy
Exp Neurol
(2012) - et al.
A pilot study of cerebrovascular reactivity autoregulation after pediatric cardiac arrest
Resuscitation
(2014) - et al.
Periictal activity in cooled asphyxiated neonates with seizures
Seizure
(2017) - et al.
White matter apoptosis is increased by delayed hypothermia and rewarming in a neonatal piglet model of hypoxic ischemic encephalopathy
Neuroscience
(2016) - et al.
Wavelet coherence analysis of dynamic cerebral autoregulation in neonatal hypoxic-ischemic encephalopathy
Neuroimage Clin
(2016) - et al.
Monitoring of cerebrovascular reactivity for determination of optimal blood pressure in preterm infants
J Pediatr
(2015) - et al.
Effects of hypothermia for perinatal asphyxia on childhood outcomes
N Engl J Med
(2014) - et al.
Childhood outcomes after hypothermia for neonatal encephalopathy
N Engl J Med
(2012) - et al.
Impaired cerebral autoregulation and brain injury in newborns with hypoxic-ischemic encephalopathy treated with hypothermia
J Neurophysiol
(2015) - 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)
A pilot cohort study of cerebral autoregulation and 2-year neurodevelopmental outcomes in neonates with hypoxic-ischemic encephalopathy who received therapeutic hypothermia
BMC Neurol
Cerebrovascular autoregulation after rewarming from hypothermia in a neonatal swine model of asphyxic brain injury
J Appl Physiol
Cerebrovascular reactivity measured by near-infrared spectroscopy
Stroke
Cerebrovascular autoregulation in pediatric moyamoya disease
Paediatr Anaesth
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Funding: This work was supported by the National Institutes of Health, Bethesda, MD, USA (grant numbers R01HD070996 [FJN], R01HD074593 [FJN], R01NS060703 [RCK], and K08NS080984 [JKL]), and the Sutland-Pakula Endowment for Neonatal Research (RC-V).