Cerebral Oxygenation and Autoregulation in Preterm Infants: Association With Morbidity and Mortality
Conditions: Intraventricular Hemorrhage of Prematurity, Complications of Prematurity
Sponsor: Stanford University

 
 
 
 
 
 
 
Cerebral oxygenation and autoregulation in preterm infants: 
  Association with morbidity and mortality 
 
 
 
 
 
 
 
 
Principal Investigator:  Valerie Y. Chock, M.D., M.S.Epi1 
Site Investigators: 
Namasivayam Ambalavanan, MBBS, M.D.2; Beau Batton, M.D.3;; 
Lina F. Chalak, M.D., MSCS5; Richard A. Ehrenkranz, M.D.6; Leif 
D. Nelin, M.D.7 
 
 
From the Divisions of Neonatology at:  1Stanford University School of Medicine; 
2University of Alabama at Birmingham; 3Southern Illinois University School of Medicine; 
4University of California San Francisco School of Medicine; 5University of Texas 
Southwestern; 6Yale School of Medicine; 7Nationwide Children’s Hospital, Ohio State 
University 
 
 
February 18, 2016

 
A.  Problem Statement/ Rationale 
Extremely preterm infants are at high risk for early hemodynamic instability. Poor 
modulation of vascular tone, variable responses to agitation, sepsis, development of a 
hemodynamically significant patent ductus arteriosus (hsPDA), and other factors may 
contribute to fluctuations in systemic blood pressure in the first few days of life.  
Moreover, preterm infants are at risk for altered cerebral autoregulation with increased 
periods of cerebral pressure passivity, potentially leading to the development of 
intraventricular hemorrhage (IVH) or white matter injury.  It remains unclear whether 
disturbances in systemic blood pressure also result in compromised end organ 
perfusion.  Near-infrared spectroscopy (NIRS) is a non-invasive technology, well suited 
to bedside monitoring of regional tissue oxygenation in these infants.  This protocol will 
investigate the utility of early NIRS measures in identifying preterm infants at highest risk 
for mortality and significant neonatal CNS morbidities including IVH and periventricular 
leukomalacia (PVL).  The novel approach of measuring regional tissue oxygenation as 
an indicator of end-organ perfusion may contribute substantially to the literature as well 
as to clinical practice.  NIRS monitoring will provide the clinician with evidence of 
abnormal cerebral tissue oxygenation and impaired cerebral autoregulation.  We 
hypothesize that abnormal NIRS measures and increased cerebral pressure passivity in 
extremely preterm infants in the first 96 hours of life will be associated with mortality and 
the development of severe CNS morbidities. 
 
B.  Specific Aims 
1. 
Measure regional cerebral tissue oxygen saturations in the first 96 hours of life in 
extremely preterm infants and identify associations between NIRS measures and 
the following: 
a. Mortality prior to hospital discharge 
b. Severe CNS morbidity including IVH, ventriculomegaly, or PVL as 
diagnosed by cranial ultrasound in the first ten days of life. 
 
2. 
Correlate the degree of cerebral pressure passivity in the first 96 hours of life as 
measured by simultaneous NIRS and arterial blood pressure monitoring with: 
a. Mortality prior to hospital discharge 
b. Development of severe CNS morbidity as defined above 
 
C.  Hypotheses 
1. Lower cerebral tissue oxygenation levels and more frequent fluctuations in 
cerebral oxygenation will be associated with: 
a. Mortality 
b. Severe CNS morbidity 
 
2. Increased periods of cerebral pressure passivity will be associated with: 
a. Mortality 
b. Severe CNS morbidity 
 
D.  Background/ Previous Studies 
Brain Injury in prematurity 
Modern perinatal care has improved survival rates for extremely preterm infants, but 
there has been little to no improvement in their neurodevelopmental outcomes.  Preterm 
infants are at risk for fluctuations in blood pressure and oxygenation. Vulnerability and 
immaturity of the preterm brain may further predispose these infants to developing 

intraventricular hemorrhage or ensuing white matter injury with long term neurological 
impairment.  Hypotension itself may not lead to cerebral ischemia [1] and medications 
used to treat hypotension have different effects on cerebral blood flow [2].  Strategies to 
clarify the timing of insults to the brain and thus potentially intervene before injury occurs 
are essential.  This study will focus on the detection of cerebral oxygenation 
abnormalities and impairment of cerebral autoregulation, which may identify which 
infants are at highest risk for ensuing brain injury. 
NIRS principles 
NIRS permits measurement of regional cerebral oxygenation. Unlike pulse oximetry, 
which is dependent on arterial pulsations, NIRS can effectively detect regional 
oxygenation during low perfusion states.  It has most commonly been used to measure 
cerebral oxygenation, where near-infrared light is transmitted and detected by a sensor 
placed on an infant’s forehead.  Near-infrared light at different wavelengths is measured, 
and as oxy-hemoglobin (HbO2) and deoxy-hemoglobin (HHb) have different absorption 
spectra, regional tissue oxygen saturation (rSO2) can be calculated:  rSO2 = HbO2/ 
(HbO2 + HHb).  This measurement is made at a depth of approximately 2.5-3 cm 
beneath the sensor.  Assuming a weighted average of 20% arterial, 75% venous, and 
5% capillary blood, the rSO2 reflects a regional balance between oxygen supply and 
demand similar to a mixed venous oxygen saturation of the underlying tissue.  While an 
absolute value of rSO2 associated with tissue damage has not been standardized, an 
rSO2 <40% during cardiac surgery may be associated with early post-operative 
neuropsychological dysfunction, a critical reduction in oxygen flux, EEG changes, and 
intracellular anaerobic metabolism and depletion of high-energy phosphates, especially 
when lasting longer than 10 minutes.[3-5] Hypoxia studies performed in piglets 
demonstrated neuronal mitochondrial injury in the hippocampal CA1 zone for cerebral 
rSO2 values 30% to 40% and cellular vacuolization and fragmentation for rSO2 <30%.[6]   
NIRS is non-invasive, requires minimal caregiver attention once properly positioned, 
demonstrates good reproducibility in the neonate [7], and provides a continuous signal, 
which is not affected by changes in blood pressure, pulse, or temperature. However, 
interpretation of NIRS values must be made in the context of other factors that influence 
cerebral blood flow and oxygenation aside from anemia, such as mean arterial blood 
pressure, carbon dioxide tension, glucose levels, metabolic rate, and drug 
administration.  NIRS monitoring has increasingly been utilized in a clinical neonatal 
intensive care setting for preterm infants including for evaluation of patent ductus 
arteriosus treatment, respiratory distress syndrome, therapy for hypotension, NEC, and 
anemia.  
Impairment of cerebral autoregulation 
Preterm infants are at higher risk for impaired cerebral autoregulation, which can also be 
readily detected using NIRS.  NIRS measures of rSO2 provide a good estimate of 
cerebral blood flow. [8-10] This approximation has been validated in animal studies using 
the gold standard radioactive microsphere technique [11, 12] and confirmed by 
transcranial Doppler ultrasound as a reliable method to assess for impaired cerebral 
autoregulation. [10] Specifically, concordance between mean arterial blood pressure and 
rSO2 indicates a pressure passive cerebral circulation and presumed loss of 
autoregulation. [11, 13] The prevalence of pressure passivity has been quantified using a 
PPI defined as the percentage of 10-min epochs with significant coherence between 
mean arterial pressure (MAP) and rSO2 signals in the low frequency range. [11] A NIRS 
study in preterm infants found that cerebral pressure passivity signifying loss of 
autoregulation occurred in a majority of premature infants with a mean PPI of 20%. [11] 

Pressure passivity was associated with low gestational age and birth weight, systemic 
hypotension, and maternal hemodynamic factors.  Loss of autoregulation with 
concordant changes between MAP and cerebral oxygenation in preterm infants was also 
significantly associated with increased severe IVH and PVL [12, 14] and with mortality 
[15] in single center studies. 
 
Neurodevelopmental outcomes in preterm infants 
Abnormal NIRS measures may be associated with poor outcomes in preterm infants.  
For example, decreased cerebral oxygenation and impaired cerebral autoregulation 
have been associated with the subsequent development of severe IVH or PVL [12, 16].  
Clinical predictors currently associated with reductions in the risk of death or profound 
neurodevelopmental impairment include higher gestational age, exposure to antenatal 
steroids, female sex, singleton birth, and higher birth weight [17].  The addition of early 
NIRS measures to these clinical predictors may enhance a clinician’s ability to counsel 
families regarding neurodevelopmental outcomes and the likelihood of intact survival in 
the preterm infant.  
 
E.  Methods: 
1.  Study Design 
This multi-center, prospective observational pilot study will investigate NIRS monitoring 
of end organ oxygenation and cerebral autoregulation at six centers with previous NIRS 
experience with an estimated total enrollment of 100 infants over a one-year period.   
After enrollment, NIRS sensors will be applied to an infant’s forehead to measure 
cerebral oxygenation within the first 96 hours of life.  NIRS data, in addition to blood 
pressure and systemic oxygen saturation, will be continuously acquired until 96 hours of 
age or earlier if arterial access becomes unavailable. Data will be analyzed in 20-minute 
intervals to determine the mean cerebral oxygenation (rSO2) and pressure passivity 
index (PPI as defined below), as well as a low rSO2 index (time with rSO2 <40%).  
Statistical analyses will include logistic regression and longitudinal modeling to 
determine the association between these NIRS measures and the development of in-
hospital mortality or severe neurologic morbidities as previously described.   
 
2. Study Population 
Inclusion Criteria 
Birth weight ≤1250 grams, indwelling arterial catheter, age < 24 hrs old 
Exclusion Criteria 
Lethal chromosomal abnormality, major congenital anomaly, decision not to provide 
full intensive care support, or skin integrity insufficient to allow placement of NIRS 
sensors 
Enrollment of Subjects 
Each participating center will be responsible for obtaining their own IRB approval and 
devising a screening strategy to identify potential subjects.  Informed parental 
consent will be obtained prior to enrollment, either prenatally or postnatally. 
 
3. Study Intervention/ Data Collection 
After enrollment, a NIRS neonatal sensor (Covidien) will be placed on the infant’s 
forehead for continuous monitoring of cerebral saturation. Clinicians will be blinded to 
rSO2 measures by obscuring the monitor with a shield.  NIRS sensors will be assessed 
on a daily basis to evaluate surrounding skin integrity and replaced as necessary. NIRS 
data in addition to continuous patient data including blood pressure and systemic oxygen 

saturation will be acquired at a sampling rate of 1/30 Hz until 96 hours of life.  Data will 
be collected using a Vital Sync bedside device allowing for data integration from the 
bedside monitor and INVOS.  Blood pressure readings will be obtained from an 
indwelling arterial catheter.  All data will be downloaded to media for secure electronic 
submission and subsequent processing by a central analyst.  Data will be identified by 
study number only and will be maintained in a secure location. Total time with missing 
data will be ascertained.  Of the remaining useful NIRS data, mean rSO2 and PPI (total 
percentage time with concordance between rSO2 and mean arterial blood pressure as 
determined in the very low frequency range (1/30 Hz)) will be calculated over 20 minute 
intervals.  Concordance will be defined as a Pearson’s correlation coefficient >0.5.  
Percentage of time with cerebral rSO2 <40% will be defined as a low rSO2 index.  Blood 
gas pCO2 levels will be collected for possible confounding effects of hypocarbia or 
hypercarbia on cerebral blood flow.  Perinatal data including birth weight, gestational 
age, sex, time of blood transfusions, use of pressors, and Score for Neonatal Acute 
Physiology Perinatal Extension II (SNAPPE-II) will be utilized. 
 
4.  Statistical Considerations 
Outcomes 
The primary outcome measures will be mortality before hospital discharge and severe 
CNS morbidity.  Severe CNS injury will be documented by evidence of grade 3 or 4 IVH, 
ventriculomegaly, or periventricular leukomalacia as suggested by echodensity on 
cranial ultrasound in the first ten days of life. 
 
Sample Size Estimate 
This study would be done at eight centers with an estimated total enrollment of 100 
infants over a one-year period.  Literature is unavailable regarding expected differences 
in NIRS measures for preterm infants with CNS morbidity or mortality.  One hundred 
infants will yield 80% power at the 0.05 level of significance to detect an association 
between NIRS measures and morbidity-free survival if 8% of the variance in low rSO2 
index can be explained by the subsequent development of CNS-morbidity or mortality.  
Similar effect size can be expected for the predictor variable PPI.  Power may be 
improved by the inclusion of covariates in the full logistic regression model.   
 
Statistical Analysis 
Analyses will include mixed effects regression models for repeated measures to 
examine the relationship between NIRS measures of low rSO2 index, PPI, and the 
outcome of CNS-morbidity or in-hospital mortality.  Analyses will be adjusted for 
gestational age, birth weight, sex, center, and SNAPPE-II.  Secondary analyses may 
look at additional NIRS measures as predictors including fractional tissue oxygen 
extraction (FTOE) and degree of variability in cerebral saturation levels. 
 
F.  Risks/ Benefits 
The risks of participation are minimal as the study uses non-invasive NIRS monitoring.  
The cerebral oximeter sensor is held in place by an adhesive backing.  Skin irritation 
from the adhesive used to secure the sensors in place is a possible risk, but this has not 
been reported in the literature as a problem [8, 14, 15], and we have not seen it in our 
experience in very low birth weight infants [18].  Insufficient skin integrity to tolerate the 
sensors is an exclusion criterion for this study.  Manufacturer recommendations are to 
change the sensor every 24 hours.  However, our previous experiences with the NIRS 
sensors have allowed us to use one sensor for continuous data collection over 4 days 

without difficulty, although frequent monitoring for skin irritation and effective adhesion of 
the sensors is required.  Skin integrity will be monitored during the protocol and 
evaluated for breakdown by both the bedside nursing staff and the research coordinator.  
If the infant becomes clinically unstable due to manipulation of the NIRS device, the 
acquisition of data will cease and the NIRS sensor and monitoring will be discontinued. 
Any adverse events such as skin breakdown or increased sepsis rates among enrolled 
patients will be tracked and reviewed by the principal investigator. 
While enrolled subjects may not directly benefit from participation in this study, the 
information gained may ultimately help to reduce or prevent brain injury in future preterm 
infants by improving understanding of the relationship of brain injury to changes in 
cerebral oxygenation and blood flow.  The proposed study would also help to establish 
the utility of early continuous NIRS monitoring in the extremely preterm population.  
Results may serve as a basis for future strategies to prevent or ameliorate brain injury 
using NIRS as a monitoring device for both cerebral oxygenation and autoregulation. 
 

 
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