EBNEO COMMENTARY: Cerebral Saturation and Fractional Tissue Oxygen Extraction Are Associated with Anterior Cerebral Artery Doppler Parameters in Neonates with Congenital Heart Defects

MANUSCRIPT CITATION

Kanaprach P, Michel-Macias C, Mazzarello M, Mir M, Rampakakis E, Wutthigate P, Simoneau J, Villegas D, Moore SS, Shemie SD, Brossard-Racine M, Dancea A, Bertolizio G, Wintermark P, Altit G. Cerebral Saturation and Fractional Tissue Oxygen Extraction Are Associated with Anterior Cerebral Artery Doppler Parameters in Neonates with Congenital Heart Defects. Neonatology 2025; 122(5):519-527. PMID: 40451174.

REVIEWED BY

Ashley L Lynch, MD (corresponding author)
University of Arkansas for Medical Sciences
Arkansas Children’s Hospital
Department of Pediatrics
Division of Neonatology
Allynch@uams.edu

Ethan L Gillett, MD
University of Arkansas for Medical Sciences
Arkansas Children’s Hospital
Department of Pediatrics
Division of Cardiology
ELgillett@uams.edu

TYPE OF INVESTIGATION

Diagnosis

QUESTION

In neonates born at greater than or equal to 35 weeks gestational age with congenital heart defect (CHD), what is the association between bedside measures of cerebral oxygen delivery and utilization and cerebral blood flow as assessed by anterior cerebral artery Doppler during the first week of life?

METHODS

• Design: Single-center prospective observational cohort study
• Allocation: Neonates with CHD born at >35 weeks gestational age and admitted to the study site’s neonatal intensive care unit within their first 7 days of postnatal life
• Blinding: Blinded data extraction for ultrasound Doppler evaluations; unblinded for bedside staff
• Follow-up period: Not applicable
• Setting: Single-center neonatal intensive care unit
• Patients: Neonates with CHD born at >35 weeks gestational age and admitted to a single-center neonatal intensive care unit within their first 7 days of post-natal life from November 2019 to December 2021, excluding those with a significant syndrome with more than one organ anomaly, including cerebral, pulmonary, airway, or intra-abdominal malformations.
• Intervention: Data from continuous cerebral oxygen saturation (CSat) [using near-infrared spectroscopy (NIRS)] and cerebral fractional tissue oxygen extraction (cFTOE) (using simultaneous NIRS and preductal SpO₂) monitoring was collected during the first week of life. Daily anterior cerebral artery (ACA) Doppler was obtained for resistive index (RI) and pulsatility index (PI) from day of life 1-7. When available, blood gas and hemoglobin levels were collected on the same day as the NIRS and ultrasound measurements. For daily transfontanellar cranial ultrasound with Doppler ACA readings, data were anonymized and masked to cardiac defect and NIRS values. The study focused only on the pre-surgical period, data were not collected after surgical intervention for the CHD.
• Outcomes: Relationship between CSat or cFTOE and RI/PI on ACA Doppler during the postnatal period of transitional physiology.
• Analysis and Sample Size: 34 neonates were enrolled, with 142 concomitant data measurements of NIRS and ultrasound Doppler. An average of the CSat values at the exact minute of Doppler ultrasound acquisition of the ACA was extracted, along with pre-ductal saturation for cFTOE calculation. Mixed-effects models evaluated the relationship between CSat/cFTOE and RI/PI-ACA, adjusting for time since birth, partial pressure of carbon dioxide (pCO₂), and hemoglobin levels.
• Patient follow-up: % included in analysis: Not applicable

MAIN RESULTS

The study included 142 concomitant measurements of NIRS and ultrasound parameters during first week of life collected in 34 neonates with various types of CHD. Most (79%) were inborn and had a prenatal diagnosis, and most (74%) received prostaglandins.

• 11 coarctation of aorta / aortic arch hypoplasia
• 7 dextro-transposition of the great arteries (d-TGA)
• 4 tetralogy of Fallot (ToF)
• 3 pulmonary atresia with intact ventricular septum (PAIVS)
• 2 tricuspid atresia
• 2 hypoplastic left heart syndrome (HLHS)
• 1 pulmonary atresia
• 1 congenitally corrected transposition of the great arteries (c-TGA)
• 1 double inlet left ventricle (DILV)
• 1 double outlet right ventricle (DORV)
• 1 with atrioventricular septal defect (AVSD)

Mixed effect models showed significant associations between CSat and cFTOE and the time-corresponding RI-ACA (p = 0.02 and 0.005) and PI-ACA (p = 0.006 and 0.002) values, respectively.

• A 0.1-point increase in RI was associated to a 2.3% decrease in CSat and a 3-point increase in cFTOE
• A 0.1-point increase in PI was associated to a 0.9% decrease in CSat and 1.1-point increase in cFTOE
• Regarding the effect of time, CSat values decreased over the 7-day period; cFTOE increased, mirroring the trends observed in RI and PI of the ACA which also increased over the time period.
• Accounting for confounders including pCO₂ and hemoglobin levels at the time of ultrasound did not alter the strength of the associations.

CONCLUSION

In neonates with CHD during their first week of life, doppler signs indicating increased cerebral blood flow resistance in the ACA correlated with lower CSat and higher cFTOE using NIRS. Given the inherent variations in arterial oxygen content in the CHD population, this provides insight into cerebral oxygen delivery and utilization. More research is needed to assess whether a multimodal bedside approach to assessing cerebrovascular hemodynamics could aid in prevention of brain injury and associated adverse neurodevelopmental outcomes by providing more timely detection of cerebral hypoperfusion.

COMMENTARY

The first week of postnatal life is a period of transition for both pulmonary and systemic vascular flow patterns. Owing to associated shunts and altered systemic/pulmonary blood flow, neonates with congenital heart defect (CHD) are at particular risk for disrupted end-organ perfusion and oxygen delivery, including that of the brain. Near-infrared spectroscopy (NIRS) measures venous-weighted cerebral oxygen saturation (CSat) at the frontal cortex, serving as an indirect reflection of cerebral blood flow. CSat is impacted by factors such as tissue perfusion, systemic oxygenation, regional oxygen extraction, and hemoglobin levels, all of which are affected by cardiac function and vascular supply [1, 2]. Cerebral fractional tissue oxygen extraction (cFTOE) reflects the balance between cerebral oxygen utilization and oxygen delivery, and it is operationally defined as (preductal SpO₂ – CSat) / preductal SpO₂. As such, cFTOE can provide insight into cerebral oxygen utilization. Increased cFTOE can be due to decreased oxygen delivery or increased oxygen consumption not met by associated increase in delivery. Likewise, decreased cFTOE can indicate that the brain is using less oxygen or that oxygen delivery has increased relative to utilization [3]. Data on CSat and cFTOE as cerebrovascular metrics in neonates with CHD during the period of postnatal adaptation are limited.

 

Elements of anterior cerebral artery (ACA) doppler such as resistive index (RI) and pulsatility index (PI) assess vascular resistance and flow characteristics in the frontal cortex, and have been shown to correspond to cerebral perfusion pressure [4]. Abnormal RI is a recognized indicator of such newborn pathologies as increased intracranial pressure, brain injury, and diastolic steal [5, 6, 7].

 

This study has made a notable contribution to the literature by applying these established bedside tools to a vulnerable and complex group of patients (neonates with CHD) during a time of critical transitional physiology (postnatal adaptation). The authors recruited 34 neonates with various types of CHD and analyzed 142 concomitant data measurements of NIRS and daily ultrasound doppler over the first 7 days of life. They used mixed-effects models to evaluate the relationship between CSat/cFTOE and RI/PI-ACA, adjusting for time since birth, pCO₂, and hemoglobin levels. Authors found a decline in CSat and rise in cFTOE throughout the first week of life in neonates with CHD, which aligns with findings from prior research [8]. RI and PI both increased over the time period, indicating increased resistance to flow velocities. Authors also reported statistically significant associations between CSat/cFTOE and simultaneous RI/PI values. The findings suggest progressive increase in oxygen extraction, possibly related to diminished blood flow, impaired oxygen delivery, or increased metabolic demand during postnatal transition. Authors theorize that this may be partly owing to altered adaptation due to shunts and abnormal anatomy. Despite the variability of the study population, findings supported consistent directional trends in NIRS and ultrasound. While these results are meaningful, an even greater impact will be gained in translating the findings to earlier detection/management of cerebral hypoperfusion in order to improve neurodevelopmental outcomes.

REFERENCES

1. Vesoulis ZA, Mintzer JP, Chock VY. Neonatal NIRS monitoring: recommendations for data capture and review of analytics. J Perinatol. 2021; 41:675-688.

2. Mulkey SB, Polglase GR. Cerebral oxygen saturation-a useful bedside vital sign for neonatal encephalopathy. J Perinatol. 2021; 41:2577-2579.

3. Schlatzer C, Schwaberger B, Bruckner M, Wolfsberger CH, Pichler G, Urlesberger B, et al. Cerebral fractional tissue oxygen extraction (cFTOE) during immediate fetal-to-neonatal transition: a systematic qualitative review of the literature. Eur J Pediatr. 2024; 183:3635-3645.

4. Robel-Tillig E, Möckel A, Vogtmann C. Normal Doppler ultrasound values of the anterior cerebral artery of premature and newborn infants with reference to cardiac function parameters and intestinal blood flow profile. Z Geburtshilfe Neonatol. 1999; 203:234-40.

5. Gerner GJ, Burton VJ, Poretti A, Bosemani T, Cristofalo E, Tekes A, et al. Transfontanellar duplex brain ultrasonography resistive indices as a prognostic tool in neonatal hypoxic-ischemic encephalopathy before and after treatment with therapeutic hypothermia. J Perinatol. 2016; 36:202-6.

6. Seibert JJ, McCowan TC, Chadduck WM, Adametz JR, Glasier CM, Williamson SL, et al. Duplex pulsed Doppler US versus intracranial pressure in the neonate: clinical and experimental studies. 1989; 171:155-9.

7. Ecury-Goossen GM, Raets MM, Camfferman FA, Vos RH, van Rosmalen J, Reiss IK, et al. Resistive indices of cerebral arteries in very preterm infants: values throughout stay in the neonatal intensive care unit and impact of patent ductus arteriosus. Pediatr Radiol. 2016; 46:1291-300.

8. Lynch JM, Ko T, Busch DR, Newland JJ, Winters ME, Mensah-Brown K, et al. Preoperative cerebral hemodynamics from birth to surgery in neonates with critical congenital heart disease. J Thorac Cardiovasc Surg. 2018; 156:1657-1664.