Perinatal Brain Injury: Potential of Innovative NIRS to Optimize Hypothermia

Neonatal encephalopathy (NE) due to hypoxia-ischemia is a major public health concern as it
occurs in 6/1000 live term births and has devastating consequences. Many affected neonates
suffer lifelong motor disabilities and epilepsy, but increasingly the high prevalence of
cognitive and behavioral disabilities is becoming appreciated. In hypoxia-ischemia there is a
decrease in blood and oxygen delivery, followed by reperfusion with transient energy
recovery. What follows is a "window of opportunity" where excitotoxicity and associated
increased cerebral metabolism eventually lead to secondary energy failure and irreversible
cell death. In this window, therapeutic hypothermia (TH) is currently the only treatment
available with proven efficacy. TH acts primarily by decreasing cerebral metabolism, thus
preserving energy stores.

Although the current gold standard for brain injury detection is magnetic resonance imaging
(MRI), MRI is impractical as a screening tool and cannot provide bedside monitoring to
optimize individual responses to therapies. Commercially available continuous wave (CW) near
infrared spectroscopy (NIRS) systems provide bedside measures of cerebral oxygen saturation
(SO2) but SO2 alone cannot assess oxygen metabolism, as oxygen delivery is not taken into
account. What is needed is a bedside tool that can monitor cerebral metabolism to detect
elevations in metabolism that suggest evolving hypoxic-ischemic injury, and decreases in
metabolism that suggest response to therapy. Cerebral oxygen consumption (CMRO2) is a direct
measure of cerebral metabolism and therefore the investigators propose to measure an index of
CMRO2 at the bedside using the innovative combination of Frequency Domain Near-Infrared
Spectroscopy (FDNIRS) and Diffuse Correlation Spectroscopy (DCS). The initial studies from
the investigators show that CMRO2 is elevated in neonates with MRI evidence of perinatal
brain injury, and confirm that neonates on TH have significantly lower CMRO2 than normal
controls. Following these exciting results, they now propose a feasibility study to determine
if FDNIRS-DCS can screen for involvement, assess response to treatment, and predict outcomes
in one of the largest neonatal populations requiring early screening and immediate
intervention: neonatal encephalopathy. To assess early outcomes, the research team proposes
an innovative combination of advanced neurobehavioral testing, regional FDNIRS-DCS measures
and quantitative MRI analysis using MRIs obtained without sedation. If the hypotheses prove
true, it will help in determining if bedside indices of CMRO2 provided by FDNIRS-DCS can
optimize TH for individual neonates, thereby improving neurodevelopmental outcomes. Success
at this stage will also allow exploration of the potential for FDNIRS-DCS to determine the
additional benefits of emerging new treatments for NE and to screen for other treatable
neonatal disorders.

Inclusion criteria:

Neonates must be > 33 weeks gestational age (GA) and meet inclusion criteria for one of the
two groups:

1. Therapeutic Hypothermia (TH) Group:

1. Undergo TH as part of their clinical management

2. Parents consent to multiple measures in the first week of life.

2. No Therapeutic Hypothermia (no-TH) Group:

1. Signs will be defined broadly as any one of the following which can be considered
evidence of NE caused by HIE or other etiologies: i) Seizures alone or ii) any of
the following: abnormal consciousness, difficulty maintaining respiration,
difficulty feeding (presumed central origin), abnormal tone or reflexes.

2. Parents consent to multiple measures in the first week of life.

Exclusion criteria:

Exclusion criteria includes neonates born at GA ≤ 33 weeks or < 2.0 kg, with implanted
devices or other devices that preclude the use of MRI will be excluded from the follow up
MRI session.