Advances in medical and surgical management have led to increase in survival among infants with severe conditions, including prematurity, birth trauma, and congenital malformations (congenital heart defects and congenital diaphragmatic hernia, among others). Minimizing factors that contribute to neurological morbidity prove to be a significant challenge facing physicians in the routine care of neonates with these conditions. Improving our ability to assess changes in cerebral oxygenation and regulation of cerebral blood flow (CBF) will enhance our understanding of how these changes may contribute toward acquired brain injury in its various forms, including hypoxia-ischemic injury, periventricular leukomalacia (PVL), and perinatal stroke.
PVL is an ideal subject for research because large populations of infants are at risk and outcome studies have demonstrated a detrimental effect of PVL on function and quality of life.1
Animal models of PVL exist and provide a rich background for mechanism of injury.2,3
They also serve as subjects for investigating therapies for PVL protection and prevention. In human beings, premature delivery between 23 and 32 weeks is one of the strongest risk factors for PVL.4–6
During this period, there is an increased vulnerability of the pre-myelinating oligodendrocyte precursors to injury.2
In addition, several studies have shown that infants with complex congenital heart disease (CHD), such as hypoplastic left heart syndrome (HLHS) or d-transposition of the great arteries (d-TGA), are also at risk for PVL.7–12
In both populations of at-risk newborns, hypoxia-ischemia, hypocarbia, and hypotension increase the risk of acquiring PVL.4,5,13–17
In addition, the development of the circulatory system with an immature or absent cerebrovascular autoregulation may also play a significant role.18,19
The ability to regulate CBF begins in utero at an early gestation. Complex regulatory mechanisms maintain adequate blood flow and oxygenation to the fetal brain during growth and development.20
Doppler velocimetry studies using umbilical artery (UA) and middle cerebral artery (MCA) pulsatility or resistance indexes demonstrate the ability of the fetus to autoregulate.21
In a hypoxic environment, the fetus is able to “brain spare” by redistributing UA blood flow to the MCA, providing improved oxygenation to the brain.22,23
Although a compensatory response exists, there is likely a threshold that once reached results in altered brain growth and development. Abnormal CBF dynamics have been observed in intrauterine growth restriction22,24
and in fetuses with complex congenital heart lesions.23,25
MCA pulsatility index, and resistance index are reduced in fetuses with HLHS and d-TGA compared with controls. These differences in cerebrovascular resistance in utero may alter brain development and autoregulatory capacity. Premature and/or very low birth weight (VLBW) infants may have delayed development of this autoregulatory system, increasing the risk of abnormal flow and oxygenation of the brain during periods of hemodynamic instability. Evidence demonstrates lower basal CBF26
along with a compromised ability to regulate blood flow in the face of hemodynamic instability10
in premature infants.
Recent preoperative magnetic resonance imaging (MRI) data from our group provide increasing evidence that brain maturation and growth is influenced by the in utero environment.18
Term-gestation neonates with HLHS and d-TGA had smaller head circumferences and structurally immature brains compared with normal-term controls. These developmental abnormalities may increase the risk of impaired auto-regulatory abilities in infants with complex CHD, and this relationship is under active investigation. The ability to accurately measure CBF and/or changes in CBF in these high-risk neonates during periods of instability will lead to an increased understanding of risk for brain injury.
Very few modalities exist to monitor CBF in high-risk neonates. In the past 2 decades, near infrared spectroscopy (NIRS) has been the primary modality to assess microvascular
cerebral oxygenation, inferring CBF from changes that occur in total hemoglobin concentration (or blood volume).27
Although the use of NIRS has expanded in the clinical setting, most commercially available NIRS devices are limited to quantifying only relative changes in hemodynamic parameters.28
Because they rely on a series of assumptions to derive CBF, they cannot provide direct quantitative measurements of CBF. Transcranial Doppler can be used to measure CBF velocity in the anterior, middle, and posterior cerebral arteries, but its use is limited only to short periods of assessment in neonates secondary to high-energy transmission over longer periods.29
Recent advances in noninvasive imaging modalities, such as arterial spin labeled perfusion magnetic resonance imaging (ASL-pMRI) and diffuse correlation spectroscopy (DCS), provide novel techniques for measurements of CBF in high-risk neonates. These newer modalities provide mechanisms to investigate changes in cerebral oxygen saturations and CBF to further elucidate factors that may contribute to development of brain injury.