Front. Neurol. Frontiers in Neurology Front. Neurol. 1664-2295 Frontiers Media S.A. 10.3389/fneur.2024.1502762 Neurology Systematic Review Neuromonitoring modalities predicting neurological impairment in pediatric congenital heart disease: a systematic review Van Loo Liselotte 1 2 * † Cools Bjorn 3 4 † Dereymaeker Anneleen 1 5 † Jansen Katrien 1 6 † 1Department of Development and Regeneration, KU Leuven, Leuven, Belgium 2Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium 3Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium 4Department of Pediatrics, Pediatric Cardiology Unit, University Hospitals Leuven, Leuven, Belgium 5Department of Pediatrics, Neonatal Intensive Care Unit, University Hospitals Leuven, Leuven, Belgium 6Department of Pediatrics, Pediatric Neurology Unit, University Hospitals Leuven, Leuven, Belgium

Edited by: Igor Nestrasil, University of Minnesota Health Twin Cities, United States

Reviewed by: Arif Somani, University of Minnesota Twin Cities, United States

Brian Mendel, National Cardiovascular Center Harapan Kita, Indonesia

 *Correspondence: Liselotte Van Loo, liselotte.vanloo@uzleuven.be

†ORCID: Liselotte Van Loo, http://orcid.org/0000-0002-6712-2489

Bjorn Cools, http://orcid.org/0000-0003-3633-4216

Anneleen Dereymaeker, http://orcid.org/0000-0003-3923-1298

Katrien Jansen, http://orcid.org/0000-0002-5503-529X

 18 12 2024 2024 15 1502762 27 09 2024 04 12 2024 Copyright © 2024 Van Loo, Cools, Dereymaeker and Jansen. 2024 Van Loo, Cools, Dereymaeker and Jansen

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The increased risk of neurodevelopmental impairment in children with congenital heart disease (CHD) has been established, but the search for targeted neurological predictors of adverse outcome is ongoing. This systematic review reports on the utility of three functional neuromonitoring modalities, Near-infrared Spectroscopy (NIRS), electroencephalography (EEG) and biochemical biomarkers, in predicting either clinical neurodevelopmental outcome or structural brain abnormalities after pediatric CHD surgery. Medline, Embase, CENTRAL, Web of Science, clinicaltrials.gov and ICTRP were systematically searched for eligible articles. Original research articles, written in English, published before November 2023 and reporting on perioperative NIRS, EEG or biomarkers and their association with clinical neurodevelopmental outcome or neuroimaging in children <17 years undergoing surgery for CHD were included. The search yielded 11,367 citations, of which 40 papers were included in the final review: sixteen articles (n = 908 cases) reported on NIRS, twelve (n = 1,163) on EEG and fifteen (n = 903) on biochemical biomarkers. Three papers reported on a combination of modalities. Median age at time of surgery was 9 (IQR 7–57) days. Postoperative MRI was performed before discharge at varying timepoints. Median age at clinical outcome assessment was 15 (IQR 12–24) months. Limited evidence supports an association of cerebral oxygen extraction, cerebral desaturation and cerebral autoregulation with outcome, but there was significant heterogeneity in results. Perioperative electroencephalographic ictal discharges and abnormal background were associated with impaired neurological outcome and abnormal neuroimaging. Numerous biochemical biomarkers have been reported but showed no consistent relationship with outcome, except for lactate, which could serve as a predictor of poor outcome. There is a need for larger homogeneous cohorts of children with CHD to determine which perioperative modalities might serve as predictors of neurodevelopmental outcome or neuroimaging abnormalities.

Systematic review registration

http://www.crd.york.ac.uk/PROSPERO, CRD42023479344

 neuromonitoring neurodevelopment neuroimaging congenital heart disease near-infrared spectroscopy electroencephalography biomarkers section-at-acceptance Pediatric Neurology Introduction

Congenital heart disease (CHD) is the most common birth defect with a prevalence of about 8 (1–8) per 1,000 live births (9). Around 25–50% of patients with CHD require neonatal cardiac intervention. Medical and surgical advancements have significantly decreased mortality and morbidity, although, survivors of critical CHD remain at risk of neurodevelopmental impairments in several domains, including overall intellectual functioning, speech, language, executive and memory function, gross, fine motor and visual spatial skills (10). Additionally, around a third of children with congenital heart disease have brain abnormalities on preoperative Magnetic Resonance Imaging (MRI), with an additional third acquiring new or increased injury postoperatively (11). The predominant lesions visualized in postoperative patients with CHD are stroke and white matter injury (1, 12, 13). In addition, children without overt lesions have structural abnormalities such as altered brain volumes and cortical folding on fetal and neonatal brain MRI (2–4). Reviews have shown that perioperative cerebral findings can be associated with neurodevelopmental outcome (NDO) although abnormal neuroimaging is not always proportionally associated with clinical outcome and should be interpreted with caution (5–7). The cause of this neurological risk is considered multi-factorial. Inherent disease- (type of cardiopathy, cyanosis) and patient-specific factors such as genetic syndromes or extracardiac anomalies contribute to the neurological risk profile of these infants (8, 14), in addition to the inherent risk of surgical techniques such as atrial septostomy, cardiopulmonary bypass (CPB) or deep hypothermic circulatory arrest (DHCA) (15, 16), postoperative critical illness and low cardiac output syndrome (17).

Because of this inherent risk, the American Heart Association issued recommendations for the follow-up of neurodevelopment in children with CHD (18). As neurodevelopmental follow-up is a resource-intensive practice, it is most important to identify CHD patients at highest risk for impaired neurodevelopment. Current practices focus largely on clinical development, which is only a late predictor, or on brain MRI which can be performed early but is resource-intensive and not easily accessible in an intensive-care setting. In order to allocate these resources to the patients in greatest need, it is necessary to explore different predictive strategies differentiating subsequent neurodevelopmental risk in CHD patients.

Neuromonitoring practices in a pediatric cardiac intensive-care setting vary widely (19). A recent European survey (20) showed similar variety in perioperative neuromonitoring/neuroimaging after pediatric congenital heart disease surgery: near-infrared spectroscopy (NIRS) was most commonly used, with 64% of centers indicating preoperative, 80% intraoperative and 72% postoperative use. Amplitude-integrated electroencephalography (aEEG) was used in 32% of participating centers, and 20% performed postoperative aEEG. Twelve percent of centers performed preoperative continuous EEG (cEEG), none used it in the postoperative period. Twenty percent of centers measured biochemical biomarkers in the postoperative period. Half of the participating centers indicated having a follow-up program in place for children with CHD.

This systematic review provides a comprehensive overview of the available evidence on three perioperative neuromonitoring modalities, NIRS, EEG and biochemical biomarkers, and their association with subsequent clinical neurological outcome or neuroimaging.

 Methods Design

This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines (21). The search strategy was created with help of the biomedical reference librarians of the KU Leuven Libraries – 2Bergen. The protocol was prospectively registered in the international prospective register of systematic reviews (PROSPERO) database (Registration number: CRD42023479344, http://www.crd.york.ac.uk/PROSPERO).

 Eligibility criteria

Studies eligible for inclusion reported on the use of neuromonitoring modalities (EEG, NIRS and/or non-invasive biochemical biomarkers) in pediatric patients with CHD necessitating surgical intervention (excluding catheter interventions), and their association with either clinical neurodevelopmental outcome (NDO) evaluated with a validated scale, instrument or test, or postoperative brain MRI evaluating either brain damage or brain maturation. Studies were excluded if the full text was not available in English. Case reports, case series, conference abstracts and review papers were excluded from the analysis.

 Search strategy and data sources

We comprehensively searched Medline, Embase, CENTRAL, Web of Science, clinicaltrials.gov and the International Clinical Trials Registry Platform (ICTRP) for eligible studies on November 28th, 2023. The full search strategy can be found in the Supplementary materials. Additionally, we hand-searched references of included studies for relevant publications. References for the selected studies were managed in the Rayyan© software.

 Data extraction

After removal of duplicates, all studies were screened based on title and abstract by 2 reviewers (LVL, KJ). Subsequently, the full text of the remaining articles was examined in parallel by 2 reviewers (LVL, KJ) to determine if all inclusion criteria were met. Additionally, the reference list of included articles was manually checked for additional studies. Disagreement was resolved through discussion until consensus was achieved.

One reviewer (LVL) performed data extraction from the manuscripts. The extracted data was summarized in a data extraction sheet. If insufficient data was available from the manuscript, an attempt was made to contact corresponding authors to obtain additional information.

 Data analysis

We summarized data on study design, patient characteristics and type of interventions. Primary outcome was either neurodevelopment assessed with standardized neurodevelopmental testing using a validated test, or postoperative neuroimaging using MRI. Papers who did not report standardized assessments (e.g., chart review for neurodevelopmental impairment) were excluded.

For synthesis of the results, studies were grouped by the different neuromonitoring modalities utilized: EEG, NIRS and biochemical biomarkers. It was not possible to perform a meta-analysis due to the large heterogeneity in interventions, reported outcomes and statistical analyses.

 Assessment of risk of bias and grading of evidence

Individual studies were assessed for risk of bias using the validated Risk Of Bias In Non-randomized Studies – of Exposure (ROBINS-E) tool for observational data (22). The quality of evidence was assessed for each outcome using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach (23), rating the quality of evidence as high, moderate, low or very low in five areas: risk of bias, inconsistency, indirectness, imprecision and publication bias. We aimed to minimize reporting bias by searching clinical trial registries to incorporate unpublished reports.

 Results Study selection

The study selection process is presented in the PRISMA flow diagram (Figure 1). Of the 7,389 records screened, 129 were assessed for eligibility based on full text. We excluded 91 further records: 59 reported on outcomes other than specified in the inclusion criteria (e.g., nonstandardized neurodevelopmental outcome, neuroimaging other than brain MRI), eight articles included different populations (e.g., cardiopathy other than congenital, adults), eight compared interventions than NIRS, EEG or biochemical biomarkers, and 19 articles used non-suitable publication formats (e.g., case reports, case series, review articles). Ultimately, 40 studies met all inclusion criteria and were included in this systematic review (24–63).

PRISMA flow diagram.

Williams et al. (64) performed neonatal high-density, 128-lead, EEG (hdEEG) measurements in children undergoing neonatal cardiac surgery for CHD and measured power (measure of local neural synchrony) and coherence (measure of functional connectivity) as measures of cortical function. While seemingly meeting the inclusion criteria, we excluded this article as the hdEEG is predominantly used in research settings and not deemed feasible in daily clinical practice.

 Characteristics of included studies

All studies were observational. Twenty five studies reported prospectively collected data (24–26, 29, 32–35, 37, 41–43, 45–48, 50, 51, 53–56, 58–60, 63). In 14 studies, data was collected retrospectively (27, 28, 30, 31, 36, 38–40, 44, 49, 52, 57, 61, 62).

Most studies had an upper limit for age at inclusion, varying from 30 days to 17 years, median age at surgery was 9 (IQR 7–57) days. 36/40 studies only included patients with critical CHD whereas 4/40 studies included patients with varying disease severity. 25/40 studies specified the necessity for CPB as an inclusion criterium (24, 26–29, 32, 34, 36–39, 41, 43, 45–47, 50, 54, 56, 57, 59–63). In five studies, measurements were performed surrounding a specific procedure (e.g., stage 1 palliation) and five other studies included only specific cardiac diagnoses [mostly hypoplastic left heart syndrome (HLHS) or dextrotransposition of the great arteries (D-TGA)]. All but one study (28) excluded patients with pre-existing neurologic or genetic comorbidities in order to minimize the influence of other causes of neurodevelopmental impairment.

Sixteen studies reported on NIRS as a predictor, with eight studies reporting clinical neurodevelopmental testing (24–31), four studies using MRI as an outcome marker (32–35), and four studies using a combination of both (36–39). aEEG was utilized in five studies (40–44) and seven studies used cEEG (45–51). Of these, outcome variables were clinical neurodevelopment in nine studies (40–43, 45–49), MRI in two (44, 51) and a combination of both in one study (50). Biochemical biomarkers were compared to clinical NDO in 13 studies (24, 29, 47, 52–61), to brain MRI in one study (63) and to both in one study (62). In total, 2,846 individual cases were assessed, of which 908 with NIRS, 1163 with EEG and 903 with biochemical biomarkers.

As a clinical outcome measure, the Bayley Scales of Infant Development (BSID-II or III) was reported most frequently (n = 25). Other studies reported Pediatric Cerebral Performance Category (PCPC) (n = 2), Pediatric Stroke Outcome Measure (PSOM) (n = 1), age-appropriate IQ testing (Wechsler IQ scales or similar) (n = 5), Denver Developmental Screening test (DDST) (n = 1) or Vineland Adaptive Behavior Scale (VABS) (n = 3). Median age at clinical developmental testing was 15 (IQR 12–24) months.

For MRI-based outcomes, 10 studies used brain injury (stroke, hemorrhage and white matter injury) as outcome measures (32, 34–36, 38, 44, 50, 51, 62, 63), whereas others performed brain volumetry (33, 37, 39). Postoperative MRI was performed before discharge at varying timepoints.

All studies were executed in tertiary or quaternary hospital settings. Sixteen studies took place in the United States (24, 27, 28, 30, 31, 34, 36, 38, 45, 46, 48–50, 57, 59, 62) and 15 in European countries (25, 26, 29, 32, 33, 37, 39, 43, 44, 53, 55, 56, 60, 61, 63). The remaining 9 studies were conducted in Australia, New Zealand, China, Canada and Israel (35, 40–42, 47, 51, 52, 54, 58). No studies were conducted in Low- or Middle-Income Countries.

 Results of included studies

An overview of the study characteristics, inclusion criteria, inclusion period and main results, can be found in Tables 1–3.

Overview of studies reporting on perioperative NIRSa.

Author, Year Type Inclusion criteria Intervention N Outcome and timing Main results
Aly et al. (24) Cohort CPBb, < 1mo cTOIc 54 BSID-IId 6, 15 and 21 mo Average cTOI at 60 min off CPB and 24 h postoperative was lower in patients with poor vs. good NDOe1% decrease in cTOI 24 h postoperative resulted in 7% increased risk in odds of a poor NDO
Carra et al. (25) Cohort <12y2012–2015 cTOI 87 Wechslerf 2y post-operative Increased dose of cerebral desaturation in the 1st 12 h postoperative resulted in lower IQ
Hansen et al. (26) Cohort Stage 1 palliation2006–2010 ScO2g 43 HAWIVA and KET-KIDh 5y Preoperative ScO2 was correlated with NDONo association of NDO with duration of desaturation <40% or any ScO2 postoperative.
Hoffman et al. (27) Cross-sectional Stage 1 palliation2002–2009 ScO2 21 VMIi, varied Average ScO2 in the first 48 postoperative hours was lower in patients who demonstrated VMI scores <85Patients with lower VMI had significantly more hours ScO2 < 45 and < 55%Patients without stroke and with any hourly ScO2 < 45% had lower VMI
Hoffman et al. (28) Cross-sectional CPB, <1y2007–2014 ScO2 178 BSID-IIIj, varied Difference between SaO2k and ScO2 was strongly associated with motor performance but not with cognitive or language performance
Sanchez-De-Toledo et al. (29) Cohort CPB, <17y2009–2010 ScO2 39 PCPCl 2mo postoperative ScO2 values were lower in patients with adverse NDOPatients with adverse NDO had significantly longer periods of ScO2 desaturations and AUC values below 20% of baseline
Simons et al. (30) Cross-sectional <12mo2007 ScO2 26 BSID-III 24mo None of the NIRS variables studied was associated with cognitive or fine motor scores in a multivariable modelPatients with delayed expressive communication were more likely to have lowest ScO2 < 20% as compared with those without delay
Sood et al. (31) Cross-sectional <12mo2007–2010 ScO2 31 BSID-III 24mo Postoperative lowest ScO2 was predictive of cognitive and gross motor delay with thresholds <56 and < 49% respectively
Spaeder et al. (36) Cross-sectional CPB, <6w2006–2012 cTOI 44 BSID-II 6, 15 and 21 moPostoperative MRIm Postoperative cTOI variability was lower in patients with poor NDOThe ability of postoperative cTOI variability to discriminate PDI was fair. Its ability to discriminate MDI was good.A postoperative cTOI variability of less than 1.05 best predicted poor MDIThere was no relationship between postoperative cTOI variability and MRI findings
De Silvestro et al. (37) Cohort CPB, <6w2009–2020 ScO2 31 BSID-III 12moPostoperative MRI NDO did not differ in patients with or without cerebral desaturationPatients with cerebral desaturation <45% had larger relative lateral ventricle volume change per weekPatients with >20% decrease in ScO2 had larger relative lateral ventricle volume change per week than patients without this decrease
Kussman et al. (38) Cross-sectional D-TGA, TOF, TA, VSD or AVSDn, <9mo2001–2004 ScO2 8940 BSID-II 1yPostoperative MRI PDI significantly correlated with average and minimum ScO2 during the 60 min period following cessation of CPBNo correlation was found between any intraoperative NIRS variable and MDI scoreAverage ScO2 from post-induction to 60 min post-CPB was lower in subjects with hemosiderin depositions
Mueller et al. (39) Cross-sectional Stage 2 palliation2012–2016 ScO2 19 BSID-III 25moPostoperative MRI No correlation between intraoperative cerebral NIRS parameters and NDOPositive correlation between the lowest measured intraoperative ScO2 and the lowest measured intracranial, total brain and white matter volumeIntracranial volume was inversely correlated with the AUC of ScO2 < 45%
Claessens et al. (32) Cohort TGA, LVOTO, SVPo, <30d2009–2012, 2016–2017 ScO2, FTOEp 74 Postoperative MRI No relationship between ScO2 or FTOE with brain injury
Kelly et al. (33) Case–control <1y ScO2 30 Preoperative MRI ScO2 showed a modest correlation with whole brain gyrification index and grey matter volume
Lynch et al. (34) Cohort Stage 1 palliation2008–2013 ScO2 37 Pre- and postoperative MRI Patients with new or worsened postoperative periventricular leukomalacia tended to have lower preoperative ScO2
Zou et al. (35) Cohort <5y2020–2021 ScO2, COPIq 65 Postoperative MRI Magnitude of COPI and duration of abnormal COPI correlated with degree of brain injury

Inclusion period is mentioned whenever known. aNear-Infrared Spectroscopy. bCardiopulmonary bypass. cCerebral Tissue Oxygenation Index, formula: TOI (%) = kO2Hb/(kO2Hb + kHHb) where k is the constant scattering contribution, O2Hb is oxygenated hemoglobin and HHb is reduced hemoglobin. dBayley Scales of Infant and Toddler Development, 2nd edition, consisting of Psychomotor Development Index (PDI) and Mental Development Index (MDI), domain scores have population mean 100(SD 15). eNeurodevelopmental outcome. fWechsler preschool and Primary Scale of Intelligence (WPPSI-III-NL) for children 2.5–6 years, Wechsler Intelligence Scale for Children (WISC-III-NL) for children 6–16 years, mean 100(SD 15). gRegional cerebral oxygen saturation. hHannover-Wechsler Intelligence Scale and Cognitive Development Test for Preschool-Age Children and Kognitiver Entwicklungstest für das Kindergartenalter. iBeery-Buktenica Developmental Test of Visual Motor Integration, mean 100(SD 15). jBayley Scales of Infant and Toddler Development, 3rd edition, consisting of Cognitive, Language, Motor (gross and fine motor), Social–Emotional and Adaptive behavior domains, population mean 100(SD 15). kArterial oxygen saturation. lPediatric Cerebral Performance Category, 1 (normal function) – 6 (brain death). mMagnetic Resonance Imaging. nDextrotransposition of the Great Arteries, Tetralogy of Fallot, Truncus Arteriosus and (Atrio)Ventricular Septal Defect. oTransposition of the Great Arteries, Left Ventricle Outflow Tract Obstruction or Single Ventricle Physiology. pFractional Tissue Oxygen Extraction, formula: FTOE = (SaO2 – cTOI)/SaO2. qCerebral oximetry/pressure index, formula: COPI = (nΣxy − (Σx) (Σy))/((nΣx2 − (Σx)2)(nΣy2 − (Σy)2)) where n indicates the number of samples in each dataset, x indicates blood pressure, and y indicates ScO2. COPI > 0.3 indicates disturbed autoregulation.

Overview of studies reporting on perioperative EEGa.

Author, Year Type Inclusion criteria Intervention N Outcome and timing Main results
Gui et al. (40) Cross-sectional <3mo2015–2017 aEEGa 93 BSID-IIb 1y MDI was significantly lower in children with absent postoperative SWCc compared with immature postoperative SWCPDI was significantly lower in children with mild abnormal pre- or postoperative background patternPDI was significantly lower in children with immature preoperative SWC
Gunn et al. (41) Cohort <2mo2005–2008 aEEG 125 BSID-IIId 2y No association between perioperative seizures or preoperative background to NDOeProlonged recovery to continuous background was associated with lower cognitive and motor scoresDelayed recovery of SWC was associated with lower cognitive scores
Gunn et al. (42) Cohort Stage 1 palliation2005–2008 aEEG 25 BSID-III 2y No association between perioperative seizures and NDORecovery to a continuous background within 48 h was associated with a 14-point increase in motor score
Latal et al. (43) Cohort CPBf, <3mo2006–2009 aEEG 50 BSID-II 1yIQ testingg 4y Postoperative seizures were associated with lower MDIPostoperatively persistent discontinuous background was associated with lower MDI and lower IQDelayed recovery of SWC was associated with lower IQ
Claessens et al. (44) Cross-sectional Neonatal surgeryh2009–2019 aEEG 73 Postoperative MRI Abnormal postoperative background pattern was more common in neonates with new postoperative injury than without brain injuryNeonates with postoperative seizures were at higher risk for new brain injury
Gaynor et al. (45) Cohort CPB, <6mo2001–2003 cEEGa 114 BSID-II 1y Frontal onset seizures were predictive of lower MDI scores compared non–frontal-onset seizures
Gaynor et al. (46) Cohort CPB, <6mo, 2001–2003 cEEG 132 Multiplei, 4y No association of seizures with cognition, motor or language outcomes, but increased prevalence of executive dysfunction
Robertson et al. (47) Cohort CPB, <4mo1999–2001 cEEG 35 BSID-II 1y post-operative No difference in NDO between patients with abnormal and normal EEG
Seltzer et al. (48) Cohort <30d cEEG 21 VABSj 5y Infants who developed an isoelectric state had significantly lower communication subscoresIsoelectric state time > 90 min was associated with lower NDOLonger duration of the isoelectric state was associated with lower NDO
Vaughan et al. (49) Cross-sectional <60d cEEG2010–2021 76 BSID-III 9,18,24, 30mo Preoperative diffuse abnormalities were associated with lower cognitive scoresCognitive scores were lower in patients with preoperative waveform discontinuity or postoperative absence of behavioral state changePreoperative continuous waveforms were associated with higher cognitive scores, whereas postoperative continuous waveforms were associated with higher fine motor scoresPreoperative synchrony was associated with higher fine motor scores in the 1st year postoperative
Rappaport et al. (50) Cohort D-TGAk cEEG1988–1992 155 BSID-II 1yPostoperative MRI Children with seizures had lower PDI scores than children without seizuresChildren with EEG seizures were more likely to have MRI abnormalities
Lin et al. (51) Cohort <3y cEEG2019–2021 264 Postoperative MRI EEG abnormalities (except spikes/sharp waves and delta brushes) were associated with degree of brain injuryPatients not recovering to the normal background and SWC by 48 h postoperative had worse degree of injuryLonger duration of isoelectric EEG was associated with more severe postoperative degree of brain injury

Inclusion period is given whenever known. aAmplitude-integrated Electroencephalography (aEEG) and continuous EEG (cEEG). bBayley Scales of Infant and Toddler Development, 2nd edition, consisting of Psychomotor Development Index (PDI) and Mental Development Index (MDI), domain scores have population mean 100(SD 15). cSleep-wake cycling. dBayley Scales of Infant and Toddler Development, 3rd edition, consisting of Cognitive, Language, Motor (gross and fine motor), Social–Emotional and Adaptive behavior domains, population mean 100(SD 15). eNeurodevelopmental outcome. fCardiopulmonary Bypass. gIQ testing either by Wechsler Preschool and Primary Scale of Intelligence-3 (n = 29), Snijders Omen Test of Intelligence (n = 18) or Kaufman-ABC-II (n = 1). hCritical congenital heart disease requiring neonatal surgery, defined as biventricular with or without aortic arch obstruction, or single ventricle physiology.i Comprehensive evaluation with Wechsler Preschool and Primary Scale of Intelligence-3, Preschool Language Test-4, Wide Range assessment of Visual Motor abilities, Developmental test of Visual Motor Integration, NeuroPsychology Attention/Executive functions Domain Score, Child Behavior Checklist, jVineland Adaptive Behavior Scale, z-value mean 0 (SD 1.0). kDextrotransposition of the Great Arteries.

Overview of studies reporting on perioperative biochemical biomarkers.

Author, Year Type Inclusion Intervention N Outcome and timing Main results
Aly et al. (24) Cohort CPBa, < 1mo Lactate 54 BSID-IIb 6, 15, 21mo Patients with mortality or poor NDOc had a higher lactate concentration compared with survivors with good NDO at 60 min off CPB and at 24 h postoperative
Bar-Yosef et al. (52) Case–control <4y2015–2017 S100B 75 PSOMd before discharge S100B z-scores >3SD 6 h post-surgery predicted new neurological deficit (at least 1 point increase in PSOM)S100B z-scores before surgery were significantly associated with new neurological deficit
Cañizo Vázquez et al. (53) Cohort <7 m2017–2019 8-iso-PGF2, S100B 44 BSID-IIIe/ VABSf 24mo Patients with abnormal NDO had higher levels of 8-iso-PGF2 at 24 h postoperative, but without enough power to predict abnormal NDOS100B levels at 72 h postoperative were a strong predictor of abnormal NDO
Cheung et al. (54) Cohort CPB, <6w1996–1999 Lactate 67 BSID-II 18-24mo Lactate >6 mmol/L on day 1 postoperative predicted adverse outcome (death or poor NDO)
Chiperi et al. (55) Cohort <5y2022–2023 GFAP, BDNF, S100B, NSE 42 DDST IIg 4–6mo postoperative GFAP predicted abnormal NDO in cyanotic patients
Gessler et al. (56) Cohort CPB, 3mo-7y IL-6, IL-8 31 BSID-II 6mo post-operative Plasma levels of IL-6 at 3 h post-CPB significantly predicted NDO
Graham et al. (57) Cross-sectional CPB, <1mo2012–2017 GFAP 97 BSID-III 12mo GFAP at cessation of CPB was independently associated with motor composite scoresCognitive and language composite scores were not independently associated with GFAP levels
Gunn et al. (58) Cohort <2mo2005–2008 S100B, lactate 130 BSID-III 2y Higher lactate at 24 h was associated with impaired NDOElevated S100B at 48 h predicted motor outcome
Robertson et al. (47) Cohort CPB, 16d-4mo1999–2001 S100B 35 BSID-II 1y post-operative Elevated levels of S100B immediately postoperative or 24 h after CPB did not predict NDO
Sanchez-De-Toledo et al. (29) Cohort CPB, < 17y2009–2010 NSE, S100B, GFAP, BDNF 39 PCPCh 12mo post-operative No significant differences in serum neuromarkers at baseline, at the end of CPB or 16 h postoperative between groups with different PCPC scores
Trakas et al. (59) Cohort CPB, <30d NSE, S100B 18 PCPC before discharge No significant association of postoperative neuronal biomarker levels and PCPC score at discharge
Vedovelli et al. (60) Cohort CPB, <3y2014–2016 GFAP 45 VABS 18mo Communication IQ was predicted significantly by the highest measured GFAP
Vergine et al. (61) Cross-sectional CPB, <5y2010–2017 GFAP 38 NDIi 1y Maximum GFAP level was significantly associated with NDINo association of GFAP levels with IQ
De Ferranti et al. (62) Cross-sectional D-TGAj1988–1992 Glucose 155 BSID-II 1yPostoperative MRI NDO was not related to perioperative glucose levelsMRI findings were not related to perioperative glucose levels
Jungner et al. (63) Cohort CPB, <30d GFAP, NfL, Tau 33 Postoperative MRI The relative increase in plasma Tau from preoperative concentrations until postoperative day 2 was significantly higher in infants with postoperative white matter injury

aCardiopulmonary Bypass. bBayley Scales of Infant and Toddler Development, 2nd edition, consisting of Psychomotor Development Index (PDI) and Mental Development Index (MDI), domain scores have population mean 100(SD 15). cNeurodevelopmental outcome. dPediatric Stroke Outcome Measure, scores 0 (no deficit) – 10 (maximum deficit). eBayley Scales of Infant and Toddler Development, 3rd edition, consisting of Cognitive, Language, Motor (gross and fine motor), Social–Emotional and Adaptive behavior domains, population mean 100(SD 15). fVineland Adaptive Behavior Scale, z-value mean 0 (SD 1.0). gDenver Developmental Screening test II, consisting of personal-social behavior, fine-motor adaptive function, gross motor function and language domains, adapted to age. hPediatric Cerebral Performance Category, 1 (normal function) – 6 (brain death). iNeurodevelopmental Index. Altered NDI if ≥2 severe impairments at neuropsychological tasks (<2SD) on the NEPSY-II attention, executive function, social skills, theory of mind or emotional recognition testing, an IQ <85 on the Wechsler Preschool and Primary Scale of Intelligence III test or the Wechsler Intelligence Scale for Children IV and/or a clinically relevant score on the Child Behavior Checklist/Conner’s Parent Rating Scales (>65 T scores). jDextrotransposition of the Great Arteries.

 Association of NIRS with neurological outcome

Cerebral oximetry using NIRS is a non-invasive monitoring technique based on detection of hemoglobin oxygenation using near-infrared light, from which parameters such as Cerebral Oxygen Saturation (ScO2), Cerebral Tissue Oxygenation Index (cTOI) and Fractional Tissue Oxygen Extraction (FTOE) can be derived. Combining NIRS parameters with heart rate or blood pressure measurements allows for the measurement of cerebral autoregulation, for example by calculating Cerebral Oximetry/Pressure Index (COPI), as COPI >0.3 indicates disturbed autoregulation.

Association with clinical NDO

Twelve articles examined the association of NIRS variables with clinical NDO (Table 1).

Pre-operative ScO2 before stage 1 palliation was associated with cognitive scores in the report by Hansen et al. (26). Intraoperatively, a retrospective study of children with biventricular CHD without aortic arch obstruction, found a correlation of intraoperative ScO2 immediately post-CPB surgery with Psychomotor Developmental Index (PDI) but not with Mental Developmental Index (MDI) subscores of the BSID-II (38). In contrast, Mueller et al. did not report any associations between NIRS values during stage 2 palliation and BSID scores (39).

Postoperatively, cTOI after neonatal CPB surgery significantly predicted mortality and poor BSID scores (24), and postoperative cTOI variability was able to discriminate between poor and good BSID (36). Hoffman et al. reported associations of average postoperative ScO2 with NDO after stage 1 palliation (27). Postoperative cerebral desaturation predicted poorer NDO in three mixed CHD populations (25, 28, 31). Conversely, Hansen et al. did not report any association of NDO with NIRS after stage 1 palliation (26).

Some studies reported on findings in the entire perioperative period rather than specific timepoints. Both perioperative ScO2 and cerebral desaturation were associated with NDO in children undergoing CPB surgery in childhood (29). Comparable results on cerebral desaturation were reported in children below 1 year of age, although they only reached significance in the expressive communication BSID subscore (30). Hoffman et al. described an association of cerebral desaturation and the difference between arterial and cerebral oxygenation with NDO in two retrospective cohorts (27, 28). Contrarily, De Silvestro et al. did not find an association between cerebral desaturation around neonatal CPB surgery and BSID scores at 1 year (37).

 Association with brain MRI

The eight studies reporting on the association of NIRS and MRI are summarized in Table 1.

Pre-operative ScO2 values were associated with brain injury after stage 1 palliation in one study (34). Two studies researched intraoperative ScO2: one found an association with both lower brain volumetry in hypoplastic left heart syndrome (HLHS) and the other with brain injury in a mixed cohort (38, 39). Spaeder et al. found no relationship between postoperative cTOI variability and MRI findings (36).

Again, perioperative timepoints were not always specified. An association between perioperative ScO2 and lower brain volumes was found in a mixed cohort by Kelly et al. (33), whereas cerebral desaturation significantly correlated with lower volumetry in the report on HLHS by Mueller et al. and the study on neonatal CPB surgery by De Silvestro et al. (37, 39). Zou et al. found that the magnitude and duration of abnormal COPI correlated with degree of brain injury (35). On the other hand, Claessens et al. did not find an association between ScO2 or FTOE surrounding CPB surgery and brain injury (32).

 Association of EEG with neurological outcome

EEG electrodes are placed on the scalp for detection of the spontaneous electrical activity of the brain. The EEG can be utilized for different indications, such as the detection of subclinical, electrographic seizures and the review of background activity and sleep–wake cycling. cEEG uses the full array of scalp electrodes according to the international 10–20 system (modified for neonates) and provides detailed information on the temporospatial occurrence of electrical potentials. In contrast, aEEG is a simplified method using a more limited number of electrodes (up to 4) and provides a time-compressed signal based on the amplitude of the electrographic signal. It is useful in background detection and detection of sleep–wake cycling, and has its value in seizure detection although with less sensitivity compared to cEEG, and with loss of temporospatial information.

For this review, we included studies reporting on both cEEG and aEEG, as the outcomes of interest should be detectable on both modalities.

Association with clinical NDO

Ten studies examined the association of EEG variables with clinical NDO (Table 2). Four studies used aEEG and six used cEEG.

Using aEEG, Latal et al. showed lower cognitive BSID subscores in patients with electrographic seizures after CPB surgery before 3 months of age (43) whereas Gunn et al. did not report any association between perioperative seizures and BSID scores (41, 42).

Using cEEG, The Boston Circulatory Arrest group showed that electrographic seizures during the arterial switch operation were associated with lower psychomotor BSID subscores at 1 year of age (50). Gaynor et al. found lower cognitive BSID scores with frontal-onset seizures at 1 year of age in children undergoing CPB surgery before 6 months (45) and executive dysfunction at 4 years of age in patients experiencing perioperative electrographic seizures (46). Robertson et al. did not find any association between seizures measured with cEEG and BSID scores (47).

Both Gui et al. and Vaughan et al. described an association of preoperative background pattern with BSID scores (40, 49), whereas two others did not confirm this association (41, 47). All four studies included mixed CHD types. Postoperatively, an abnormal background pattern was consistently associated with poor NDO in 5 studies: in particular, delayed recovery of sleep–wake cycling, duration of the isoelectric state and prolonged discontinuity were associated with poor NDO (40–43, 48).

 Association with brain MRI

Three studies report on the association of postoperative EEG variables with brain injury on MRI (Table 2). Claessens et al. describe both postoperative abnormal background and ictal discharges on aEEG as risk factors for new-onset brain injury (44). The association with electrographic seizures on cEEG is also reported in the Boston Circulatory Arrest cohort (50). In addition, Lin et al. found that electrographic abnormalities seen on cEEG were associated with brain injury, with patients with longer isoelectric traces or not recovering to normal background and sleep–wake cycling by 48 h having worse degree of injury (51).

 Association of biochemical biomarkers with clinical NDO or brain MRI

A large variety of biochemical biomarkers of brain injury are being studied in relation to neurological outcome. The 15 included studies are summarized in Table 3. S100 calcium-binding protein B (S100B) was most studied in association with NDO. Of the seven studies reporting this outcome, four did not find anycorrelation (29, 47, 55, 59). One study found that elevated S100B at 48 h after CHD surgery before 2 months of age predicted BSID motor outcome at 2 years, and another found associations between S100B at 72 h postoperative and BSID at 2 years (53, 58). In addition, In children undergoing CHD surgery before 4 years of age, elevated S100B was associated with new neurological deficit upon discharge (52).

Six studies studied glial fibrillary acidic protein (GFAP) as a predictive biomarker. Chiperi et al. report its predictive ability for DDST scores in cyanotic patients undergoing surgery before 5 years of age (55), while Graham et al. found an association with BSID motor but not with cognitive and language scores in infants undergoing CPB surgery in their first month (57). The highest measured GFAP was able to predict communication intelligence quotient using the VABS at 18 months in the study by Vedovelli et al. (60). In contrast, Vergine et al. did not find an association of GFAP levels during CPB surgery with cognitive abilities, although did relate to the composite neurodevelopmental scoring system used in their study (61). Sanchez-De-Toledo et al. did not did not report significant associations with PCPC scores 12 months after CPB surgery in childhood (29). In addition to GFAP, the report by Jungner et al. examined Neurofilament light polypeptide (NfL) and Tau and described that patients with postoperative white matter injury on brain MRI had a significantly higher increase in plasma Tau levels, but no associations with GFAP or NfL were found (63).

PCPC scores at discharge were not related to levels of neuron-specific enolase (NSE) or brain-derived neurotropic factor (BDNF) in infants undergoing CPB surgery before 30 days, and neither were NSE and PCPC scores at 12 months postoperative in pediatric CPB surgery for CHD (29, 59). Another study reporting DDST scores 4–6 months after surgery, did not find an association with NSE or BDNF levels during CHD surgery (55). Three studies reported that perioperative lactate elevations significantly predicted poor BSID scores (24, 58, 65). Cañizo Vàzquez et al. reported increased levels of 8-iso-prostaglandin F2α (8-iso-PGF2), a urinary biomarker for oxidative stress, in patients with abnormal BSID or VABS scores. In an article by Gessler et al., plasma IL-6 at 3 h post-CPB significantly predicted NDO (56). Lastly, one article explored perioperative glucose levels during the arterial switch operation, but found no association with clinical NDO or MRI (62).

 Risk of bias

Risk of bias across studies was assessed using the ROBINS-E tool. Results are presented in Figure 2. Risk of bias was overall low to moderate, with concerns mostly due to the risk of confounding, inherent to the observational study design. The risk of selection of reported results seemed low overall, given that the reported outcomes were consistent with preregistered protocols and also non-significant data was reported.

ROBINS-E tool for risk of bias assessment.

Four studies were judged to have high risk of bias due to the large proportion of missing data (27, 28, 30, 49). Additionally, the studies by Hoffman et al. (27, 28) selected patients based on referral for neurodevelopmental testing (possibly due to suspicion of developmental impairment). Two studies also included patients with genetic syndromes, likely influencing neurodevelopmental outcome scores (28, 46). Two studies (48, 60) posed some concern for bias because their outcomes were (in part) based on subjective parent-based questionnaires, although this was accounted for by the use of a validated scoring system (VABS).

 Quality of evidence

We rated the quality of evidence using the GRADE approach (23), results are presented in Figure 3. The included reports provided mostly low-quality evidence due to their observational nature. Studies were upgraded to moderate-level evidence if they had strong designs, were well conducted, and had few major flaws. Studies were downgraded if there was risk of bias or inconsistency in results.

GRADE assessment of quality of evidence.

 Discussion

This review article summarizes existing data regarding neuromonitoring using perioperative NIRS, EEG, and serum brain biomarkers and their association with neurodevelopmental outcome, brain maturation and brain injury on MRI after surgery for congenital heart disease. This type of data is potentially valuable in risk stratification, in light of recent guidelines supporting neurodevelopmental follow-up for certain subgroups of CHD patients, which is resource-intensive and of variable availability.

First, the majority of studies evaluating NIRS suggest an association between cerebral oxygenation measurements (cTOI, ScO2, cerebral desaturation) and the pre-specified neurological outcomes (either clinical or neuroimaging). It is important to note however, that there was large variability in the thresholds to define cerebral desaturation, as well as the exposure measures (binary outcome versus time below a certain threshold). Interestingly, disturbed cerebral autoregulation seemed to correlate with neurological outcome.

Secondly, electrographic seizures, either measured with cEEG or aEEG, were independently associated with poorer neurological outcome in the majority of reports and patients with prolonged abnormal background patterns or delayed return of sleep–wake cycling, were at risk for adverse outcome.

Thirdly, the predictive ability of biomarkers such as S100B and GFAP is not sufficiently convincing. Postoperatively increased lactate however, was associated with neurodevelopment, in addition to its known associations with short-term adverse outcomes (66, 67). According to the included studies, significant elevation >4–6 mmol/L or persistent elevation beyond 24 h seemed predictive of outcome. This is an important finding as most cardiac centers already routinely measure lactate levels as an indicator of the hemodynamic and metabolic condition of the patient. For the other neuronal markers mentioned in this study, evidence is too sparse to draw a sound conclusion. The ability to draw stronger conclusions and perform meta-analyses was limited by the inconsistency and heterogeneity of the findings. This review provides an update to existing literature by comprehensively and systematically summarizing available data on perioperative neuromonitoring and its association with outcomes. These findings build on recent publications showing that patients with CHD show abnormal electroencephalographic activity even in the preoperative period (68, 69), and impaired perioperative autoregulation which cannot simply be explained by differences in blood pressure (70). In addition, the perioperative period is characterized by significant hemodynamic disturbances and might require even more from the autoregulatory mechanisms of the brain. Moreover, new information on the disrupted autonomic regulation and altered circadian rhythms in CHD is arising.

Knowledge on these neuromonitoring modalities is steadily expanding in different fields of medicine, and it might be possible to extrapolate, without generalizing to the unique group of neonates with CHD. Cerebral NIRS monitoring has been utilized to guide treatment in the preterm population as a predictor of neurodevelopmental impairment in preterm neonates (71, 72), although in a large randomized trial on treatment guided by cerebral oximetry, no difference in serious adverse events was found (73). Secondly, in neonatal and pediatric patients undergoing extracorporeal life support (ECLS), the prognostic value of cerebral oximetry on neurodevelopment was demonstrated (74, 75), and a pilot study highlighted the importance of impaired cerebral autoregulation in patients with acute neurological events (76). aEEG and cEEG are widely used in preterm babies as a biomarker of brain injury, as a modality to monitor brain maturation and as a prognostic tool for subsequent neurodevelopment (77, 78). Fogtmann et al. performed a systematic review on this topic which demonstrated the good predictive value of EEG for NDO after prematurity (79). In hypoxic–ischemic encephalopathy, the prognostic value of NIRS and EEG has repeatedly been demonstrated (80, 81). Specifically, studies showed that that prolonged abnormal background on EEG was associated with impaired neurodevelopment (82–84), and seizure burden was predictive of neurodevelopmental outcome (85–87). EEG seizure burden and asymmetric EEG background correlated with brain injury in two pediatric ECLS populations (88, 89), while background abnormalities predicted poor NDO with good specificity (90). The utility of different neuromonitoring modalities in ECLS is summarized in the review by Felling et al. (91). The information extrapolated from these patient groups could aid in the comprehension of underlying autoregulation mechanisms in patients with CHD. The field of biochemical neurological biomarkers has predominantly been studied in adult settings and evidence from pediatric populations is only recently emerging. For example, a wide array of biomarkers is being assessed for outcome prediction after ischemic stroke in adults (92, 93). In pediatric traumatic brain injury, S100B levels correlated to the extent of brain injury (94). In pediatric ECLS patients, elevation of plasma brain injury biomarkers was associated with unfavorable NDO and brain imaging abnormalities (95). Even though the underlying conditions differ from CHD, they face many similar difficulties concerning hemodynamic disturbances, inflammation, altered cerebral perfusion and reperfusion injury (96), which makes it plausible that neuromonitoring modalities used in these clinical settings could potentially be of use in the setting of CHD. In addition, Chiperi et al. (97) recently published a systematic review on the use of biochemical biomarkers in pediatric CHD surgery: they reported poor predictive value of NSE and BDNF and conflicting results on S100B, but suggested GFAP as a possible biomarker for brain injury.

Limitations

The results of this analysis should be interpreted with necessary caution. Whereas the single studies are overall of good quality, although observational in design, the studies included relatively small and diverse groups of patients, with different cardiac diagnoses, age ranges and treatment strategies. Even though most studies only included patients with normal neurologic exams before surgery, pre-existing comorbidities may be unaccounted for. Studies were conducted in different epochs causing differences in surgical and medical management strategies. Additionally, there was large variability in reported NIRS variables across studies, rendering a quantitative meta-analysis impossible. A possible explanation is that patients with varying CHD types have altered baseline ScO2 from the healthy population, making current definitions of cerebral desaturation (typically ScO2 < 45 or < 65%) less relevant (98). In future analyses, a relative decrease in ScO2 from baseline may be more valuable than absolute values. The duration of EEG monitoring was variable (pre- vs. postoperative, duration of postoperative monitoring) and authors did not control for the effects of sedative medications on EEG traces, possibly introducing bias as the most unstable patients likely received more suppressive medication.

There was large variability in timing of outcome measurements, which were mostly short-term, and instruments for clinical assessment of neurological outcome focused on different neurodevelopmental domains. For example, postoperative PCPC or PSOM may indicate global neurological outcome before discharge, whereas comprehensive neurodevelopmental assessment at preschool age is the preferred method for detailed evaluation of long-term neurological outcomes. No studies were conducted in Low or Middle-Income Countries, limiting generalizability to these countries.

Should we aim to establish guidelines surrounding effective perioperative neuromonitoring, there is a need for larger, more definitive studies with increased consistency in the application of these modalities and definition of clinically useful outcomes. In addition, patient-specific (e.g., socio-economic status, (epi)genetics) and medical factors (e.g., surgical technique, length of stay, ventilation time, sedative use) should be considered as they impact the cerebral compensatory mechanisms and might better explain the variability in neurological outcome in this population. Longer-term data using outcome measures encompassing different neurodevelopmental domains (cognitive, psychomotor, visuospatial, executive functioning) is necessary to more accurately predict the long-term prognosis of these patients.

 Conclusion

To conclude, there is some evidence indicating an association between perioperative non-invasive neuromonitoring modalities and neurological outcome in the CHD population, most convincingly cerebral desaturation and autoregulation measured with NIRS, electrographic seizures, and prolonged background abnormalities on EEG, and elevated lactate in the perioperative period. These results should be interpreted with caution however, and in further research, the standardization of perioperative monitoring application and outcome determination is necessary before clinical implementation of these strategies for neurological prognostication.

 Data availability statement

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.

 Author contributions

LL: Conceptualization, Data curation, Formal analysis, Methodology, Writing – original draft, Writing – review & editing. BC: Conceptualization, Supervision, Writing – original draft, Writing – review & editing. AD: Conceptualization, Supervision, Writing – original draft, Writing – review & editing. KJ: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Supervision, Writing – original draft, Writing – review & editing.

 Funding

The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.

The authors wish to thank Chayenne Van Meel, biomedical reference librarian of the KU Leuven Libraries – 2Bergen – learning Centre Désiré Collen (Leuven, Belgium), for their help in conducting the systematic literature search.

 Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

 Generative AI statement

The author(s) declare that no Generative AI was used in the creation of this manuscript.

 Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

 Supplementary material

The Supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fneur.2024.1502762/full#supplementary-material

 Abbreviations

aEEG, Amplitude-integrated electroencephalography; BSID-II or III, Bayley scales of infant development; BDNF, Brain-derived neurotropic factor; COPI, Cerebral oximetry/pressure index; ScO2, Cerebral oxygen saturation; cTOI, Cerebral tissue oxygenation index; CHD, Congenital heart disease; cEEG, Continuous electroencephalography; CPB, Cardiopulmonary bypass; DHCA, Deep hypothermic circulatory arrest; DDST, Denver developmental screening test; FTOE, Fractional tissue oxygen extraction; GRADE, Grading of recommendations assessment, development and evaluation; GFAP, Glial fibrillary acidic protein; hdEEG, High-density EEG; HLHS, Hypoplastic left heart syndrome; MRI, Magnetic resonance imaging; MDI, Mental developmental index; NIRS, Near-infrared spectroscopy; NDO, Neurodevelopmental outcome; NfL, Neurofilament light polypeptide; NSE, Neuron-specific enolase; PCPC, Pediatric cerebral performance category; PSOM, Pediatric stroke outcome measure; PDI, Psychomotor developmental index; ROBINS-E, Risk of bias in non-randomized studies – of exposure; S100B, S100 calcium-binding protein B; VABS, Vineland adaptive behavior scale.

 References Chen J Zimmerman RA Jarvik GP Nord AS Clancy RR Wernovsky G . Perioperative stroke in infants undergoing open heart operations for congenital heart disease. Ann Thorac Surg. (2009) 88:823–9. doi: 10.1016/j.athoracsur.2009.03.030, PMID: 19699905 Schellen C Ernst S Gruber GM Mlczoch E Weber M Brugger PC . Fetal MRI detects early alterations of brain development in tetralogy of Fallot. Am J Obstet Gynecol. (2015) 213:392. doi: 10.1016/j.ajog.2015.05.046 Sun L Macgowan CK Sled JG Yoo SJ Manlhiot C Porayette P . Reduced fetal cerebral oxygen consumption is associated with smaller brain size in fetuses with congenital heart disease. Circulation. (2015) 131:1313–23. doi: 10.1161/CIRCULATIONAHA.114.013051, PMID: 25762062 Von Rhein M Buchmann A Hagmann C Dave H Bernet V Scheer I . Severe congenital heart defects are associated with global reduction of neonatal brain volumes. J Pediatr. (2015) 167:1259–63.e1. doi: 10.1016/j.jpeds.2015.07.006, PMID: 26233604 Dijkhuizen EI de Munck S de Jonge RCJ Dulfer K van Beynum IM Hunfeld M . Early brain magnetic resonance imaging findings and neurodevelopmental outcome in children with congenital heart disease: a systematic review. Dev Med Child Neurol. (2023) 65:1557–72. doi: 10.1111/dmcn.15588 Mebius MJ Kooi EMW Bilardo CM Bos AF. Brain injury and neurodevelopmental outcome in congenital heart disease: a systematic review. Pediatrics. (2017) 140:55. doi: 10.1542/peds.2016-4055, PMID: 28607205 Phillips K Callaghan B Rajagopalan V Akram F Newburger JW Kasparian NA. Neuroimaging and neurodevelopmental outcomes among individuals with complex congenital heart disease: JACC state-of-the-art review. J Am Coll Cardiol. (2023) 82:2225–45. doi: 10.1016/j.jacc.2023.09.824, PMID: 38030353 Gaynor JW Stopp C Wypij D Andropoulos DB Atallah J Atz AM . Neurodevelopmental outcomes after cardiac surgery in infancy. Pediatrics. (2015) 135:816–25. doi: 10.1542/peds.2014-3825, PMID: 25917996 Hoffman JIE Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol. (2002) 39:1890–900. doi: 10.1016/S0735-1097(02)01886-7 Peyvandi S Latal B Miller SP McQuillen PS. The neonatal brain in critical congenital heart disease: insights and future directions. NeuroImage. (2019) 185:776–82. doi: 10.1016/j.neuroimage.2018.05.045, PMID: 29787864 McQuillen PS Barkovich AJ Hamrick SE Perez M Ward P Glidden DV . Temporal and anatomic risk profile of brain injury with neonatal repair of congenital heart defects. Stroke. (2007) 38:736–41. doi: 10.1161/01.STR.0000247941.41234.90, PMID: 17261728 Galli KK Zimmerman RA Jarvik GP Wernovsky G Kuypers MK Clancy RR . Periventricular leukomalacia is common after neonatal cardiac surgery. J Thorac Cardiovasc Surg. (2004) 127:692–704. doi: 10.1016/j.jtcvs.2003.09.053, PMID: 15001897 Miller SP McQuillen PS Hamrick S Xu D Glidden DV Charlton N . Abnormal brain development in newborns with congenital heart disease. N Engl J Med. (2007) 357:1928–38. doi: 10.1056/NEJMoa067393 Investigators ICCoNI. Impact of operative and postoperative factors on neurodevelopmental outcomes after cardiac operations. Ann Thorac Surg. (2016) 102:843–9. doi: 10.1016/j.athoracsur.2016.05.081 Mahle WT Wernovsky G. Long-term developmental outcome of children with complex congenital heart disease. Clin Perinatol. (2001) 28:235–47. doi: 10.1016/S0095-5108(05)70077-4 McQuillen PS Hamrick SE Perez MJ Barkovich AJ Glidden DV Karl TR . Balloon atrial septostomy is associated with preoperative stroke in neonates with transposition of the great arteries. Circulation. (2006) 113:280–5. doi: 10.1161/CIRCULATIONAHA.105.566752, PMID: 16401771 Claessens NHP Chau V de Vries LS Jansen NJG Au-Young SH Stegeman R . Brain injury in infants with critical congenital heart disease: insights from two clinical cohorts with different practice approaches. J Pediatr. (2019) 215:75–82.e2. doi: 10.1016/j.jpeds.2019.07.017, PMID: 31451185 Marino BS Lipkin PH Newburger JW Peacock G Gerdes M Gaynor JW . Neurodevelopmental outcomes in children with congenital heart disease: evaluation and management: a scientific statement from the American Heart Association. Circulation. (2012) 126:1143–72. doi: 10.1161/CIR.0b013e318265ee8a Kirschen MP LaRovere K Balakrishnan B Erklauer J Francoeur C Ganesan SL . A survey of Neuromonitoring practices in north American pediatric intensive care units. Pediatr Neurol. (2022) 126:125–30. doi: 10.1016/j.pediatrneurol.2021.11.002, PMID: 34864306 Feldmann M Hagmann C de Vries L Disselhoff V Pushparajah K Logeswaran T . Neuromonitoring, neuroimaging, and neurodevelopmental follow-up practices in neonatal congenital heart disease: a European survey. Pediatr Res. (2023) 93:168–75. doi: 10.1038/s41390-022-02063-2, PMID: 35414671 Page MJ McKenzie JE Bossuyt PM Boutron I Hoffmann TC Mulrow CD . The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. (2021) 372:n71. doi: 10.1136/bmj.n71 Rooney A Taylor K Thayer K Silva R Lemeris C Akl A . Risk of Bias in non-randomized studies - of exposure (ROBINS-E). (2023). Schünemann H Brożek J Guyatt G Oxman A. GRADE handbook for grading quality of evidence and strength of recommendations (2013). Aly SA Zurakowski D Glass P Skurow-Todd K Jonas RA Donofrio MT. Cerebral tissue oxygenation index and lactate at 24 hours postoperative predict survival and neurodevelopmental outcome after neonatal cardiac surgery. Congenit Heart Dis. (2017) 12:188–95. doi: 10.1111/chd.12426, PMID: 27862979 Carra G Flechet M Jacobs A Verstraete S Vlasselaers D Desmet L . Postoperative cerebral oxygen saturation in children after congenital cardiac surgery and long-term Total intelligence quotient: a prospective observational study. Crit Care Med. (2021) 49:967–76. doi: 10.1097/CCM.0000000000004852, PMID: 33591016 Hansen JH Rotermann I Logoteta J Jung O Dütschke P Scheewe J . Neurodevelopmental outcome in hypoplastic left heart syndrome: impact of perioperative cerebral tissue oxygenation of the Norwood procedure. J Thorac Cardiovasc Surg. (2016) 151:1358–66. doi: 10.1016/j.jtcvs.2016.02.035, PMID: 27085616 Hoffman GM Brosig CL Mussatto KA Tweddell JS Ghanayem NS. Perioperative cerebral oxygen saturation in neonates with hypoplastic left heart syndrome and childhood neurodevelopmental outcome. J Thorac Cardiovasc Surg. (2013) 146:1153–64. doi: 10.1016/j.jtcvs.2012.12.060, PMID: 23317941 Hoffman GM Brosig CL Bear LM Tweddell JS Mussatto KA. Effect of Intercurrent operation and cerebral oxygenation on developmental trajectory in congenital heart disease. Ann Thorac Surg. (2016) 101:708–16. doi: 10.1016/j.athoracsur.2015.08.059, PMID: 26542436 Sanchez-de-Toledo J Chrysostomou C Munoz R Lichtenstein S Sao-Avilés CA Wearden PD . Cerebral regional oxygen saturation and serum neuromarkers for the prediction of adverse neurologic outcome in pediatric cardiac surgery. Neurocrit Care. (2014) 21:133–9. doi: 10.1007/s12028-013-9934-y, PMID: 24203460 Simons J Sood ED Derby CD Pizarro C. Predictive value of near-infrared spectroscopy on neurodevelopmental outcome after surgery for congenital heart disease in infancy. J Thorac Cardiovasc Surg. (2012) 143:118–25. doi: 10.1016/j.jtcvs.2011.09.007 Sood ED Benzaquen JS Davies RR Woodford E Pizarro C. Predictive value of perioperative near-infrared spectroscopy for neurodevelopmental outcomes after cardiac surgery in infancy. J Thorac Cardiovasc Surg. (2013) 145:438–45. doi: 10.1016/j.jtcvs.2012.10.033, PMID: 23219333 Claessens NHP Jansen NJG Breur J Algra SO Stegeman R Alderliesten T . Postoperative cerebral oxygenation was not associated with new brain injury in infants with congenital heart disease. J Thorac Cardiovasc Surg. (2019) 158:867–77.e1. doi: 10.1016/j.jtcvs.2019.02.106 Kelly CJ Makropoulos A Cordero-Grande L Hutter J Price A Hughes E . Impaired development of the cerebral cortex in infants with congenital heart disease is correlated to reduced cerebral oxygen delivery. Sci Rep. (2017) 7:15088. doi: 10.1038/s41598-017-14939-z, PMID: 29118365 Lynch JM Buckley EM Schwab PJ McCarthy AL Winters ME Busch DR . Time to surgery and preoperative cerebral hemodynamics predict postoperative white matter injury in neonates with hypoplastic left heart syndrome. J Thorac Cardiovasc Surg. (2014) 148:2181–8. doi: 10.1016/j.jtcvs.2014.05.081, PMID: 25109755 Zou M Yu L Lin R Feng J Zhang M Ning S . Cerebral autoregulation status in relation to brain injury on electroencephalogram and magnetic resonance imaging in children following cardiac surgery. J Am Heart Assoc. (2023) 12:e028147. doi: 10.1161/JAHA.122.028147, PMID: 37301753 Spaeder MC Klugman D Skurow-Todd K Glass P Jonas RA Donofrio MT. Perioperative near-infrared spectroscopy monitoring in neonates with congenital heart disease: relationship of cerebral tissue oxygenation index variability with neurodevelopmental outcome. Pediatr Crit Care Med. (2017) 18:213–8. doi: 10.1097/PCC.0000000000001056, PMID: 28067688 De Silvestro AA Krüger B Steger C Feldmann M Payette K Krüger J . Cerebral desaturation during neonatal congenital heart surgery is associated with perioperative brain structure alterations but not with neurodevelopmental outcome at 1 year. Eur J Cardiothorac Surg. (2022) 62:138. doi: 10.1093/ejcts/ezac138, PMID: 35373833 Kussman BD Wypij D Laussen PC Soul JS Bellinger DC DiNardo JA . Relationship of intraoperative cerebral oxygen saturation to neurodevelopmental outcome and brain magnetic resonance imaging at 1 year of age in infants undergoing biventricular repair. Circulation. (2010) 122:245–54. doi: 10.1161/CIRCULATIONAHA.109.902338, PMID: 20606124 Mueller M Zajonz T Mann V Koerner C Akintuerk H Yoerueker U . Interrelations of intraoperative changes in cerebral tissue oxygen saturation with brain volumes and neurodevelopment outcome after the comprehensive stage II procedure in infants with Hypoplastic left heart syndrome: a retrospective cohort study. J Cardiothorac Vasc Anesth. (2021) 35:2907–12. doi: 10.1053/j.jvca.2020.12.013 Gui J Liang S Sun Y Liu Y Chen C Wang B . Effect of perioperative amplitude-integrated electroencephalography on neurodevelopmental outcomes following infant heart surgery. Exp Ther Med. (2020) 20:2879–87. doi: 10.3892/etm.2020.9004 Gunn JK Beca J Hunt RW Olischar M Shekerdemian LS. Perioperative amplitude-integrated EEG and neurodevelopment in infants with congenital heart disease. Intensive Care Med. (2012) 38:1539–47. doi: 10.1007/s00134-012-2608-y, PMID: 22653373 Gunn JK Beca J Penny DJ Horton SB d’Udekem YA Brizard CP . Amplitude-integrated electroencephalography and brain injury in infants undergoing Norwood-type operations. Ann Thorac Surg. (2012) 93:170–6. doi: 10.1016/j.athoracsur.2011.08.014, PMID: 22075220 Latal B Wohlrab G Brotschi B Beck I Knirsch W Bernet V. Postoperative amplitude-integrated electroencephalography predicts four-year neurodevelopmental outcome in children with complex congenital heart disease. J Pediatr. (2016) 178:55–60.e1. doi: 10.1016/j.jpeds.2016.06.050, PMID: 27453368 Claessens NHP Noorlag L Weeke LC Toet MC Breur J Algra SO . Amplitude-integrated electroencephalography for early recognition of brain injury in neonates with critical congenital heart disease. J Pediatr. (2018) 202:199–205.e1. doi: 10.1016/j.jpeds.2018.06.048, PMID: 30144931 Gaynor JW Jarvik GP Bernbaum J Gerdes M Wernovsky G Burnham NB . The relationship of postoperative electrographic seizures to neurodevelopmental outcome at 1 year of age after neonatal and infant cardiac surgery. J Thorac Cardiovasc Surg. (2006) 131:181–9. doi: 10.1016/j.jtcvs.2005.08.062, PMID: 16399310 Gaynor JW Jarvik GP Gerdes M Kim DS Rajagopalan R Bernbaum J . Postoperative electroencephalographic seizures are associated with deficits in executive function and social behaviors at 4 years of age following cardiac surgery in infancy. J Thorac Cardiovasc Surg. (2013) 146:132–9. doi: 10.1016/j.jtcvs.2013.04.002, PMID: 23768805 Robertson DR Justo RN Burke CJ Pohlner PG Graham PL Colditz PB. Perioperative predictors of developmental outcome following cardiac surgery in infancy. Cardiol Young. (2004) 14:389–95. doi: 10.1017/S104795110400407X, PMID: 15680045 Seltzer L Swartz MF Kwon J Burchfiel J Cholette JM Wang H . Neurodevelopmental outcomes after neonatal cardiac surgery: role of cortical isoelectric activity. J Thorac Cardiovasc Surg. (2016) 151:1137–44. doi: 10.1016/j.jtcvs.2015.10.065 Vaughan T Hammoud MS Pande A Chu L Cummins K McCloskey O . Can perioperative electroencephalogram and adverse hemodynamic events predict neurodevelopmental outcomes in infants with congenital heart disease? J Thorac Cardiovasc Surg. (2023) 168:342–52. doi: 10.1016/j.jtcvs.2023.10.063 Rappaport LA Wypij D Bellinger DC Helmers SL Holmes GL Barnes PD . Relation of seizures after cardiac surgery in early infancy to neurodevelopmental outcome. Boston Circulatory Arrest Study Group. Circulation. (1998) 97:773–9. doi: 10.1161/01.CIR.97.8.773 Lin R Du N Feng J Li J Li L Cui Y . Perioperative EEG background and discharge abnormalities in children undergoing cardiac surgery: a prospective single-Centre observational study. Br J Anaesth. (2023) 131:360–72. doi: 10.1016/j.bja.2023.04.042, PMID: 37328305 Bar-Yosef O Greidinger D Iskilova M Hemi R Tirosh T Vardi A. Neurological deficit is predicted by S100B in children after cardiac surgery. Clin Chim Acta. (2018) 481:56–60. doi: 10.1016/j.cca.2018.02.032, PMID: 29499197 Cañizo Vázquez D Hadley SM Pérez Ordóñez M Lopez-Abad M Valls A Viñals ML . Oxidative stress and indicators of brain damage following pediatric heart surgery. Antioxidants (Basel). (2022) 11:489. doi: 10.3390/antiox11030489 Cheung PY Chui N Joffe AR Rebeyka IM Robertson CM. Postoperative lactate concentrations predict the outcome of infants aged 6 weeks or less after intracardiac surgery: a cohort follow-up to 18 months. J Thorac Cardiovasc Surg. (2005) 130:837–43. doi: 10.1016/j.jtcvs.2005.04.029, PMID: 16153937 Chiperi LE Huţanu A Tecar C Muntean I. Serum markers of brain injury in pediatric patients with congenital heart defects undergoing cardiac surgery: diagnostic and prognostic role. Clin Pract. (2023) 13:1253–65. doi: 10.3390/clinpract13050113, PMID: 37887089 Gessler P Schmitt B Prètre R Latal B. Inflammatory response and neurodevelopmental outcome after open-heart surgery in children. Pediatr Cardiol. (2009) 30:301–5. doi: 10.1007/s00246-008-9354-5, PMID: 19083140 Graham EM Martin RH Atz AM Hamlin-Smith K Kavarana MN Bradley SM . Association of intraoperative circulating-brain injury biomarker and neurodevelopmental outcomes at 1 year among neonates who have undergone cardiac surgery. J Thorac Cardiovasc Surg. (2019) 157:1996–2002. doi: 10.1016/j.jtcvs.2019.01.040, PMID: 30797587 Gunn JK Beca J Hunt RW Goldsworthy M Brizard CP Finucane K . Perioperative risk factors for impaired neurodevelopment after cardiac surgery in early infancy. Arch Dis Child. (2016) 101:1010–6. doi: 10.1136/archdischild-2015-309449, PMID: 27272973 Trakas E Domnina Y Panigrahy A Baust T Callahan PM Morell VO . Serum neuronal biomarkers in neonates with congenital heart disease undergoing cardiac surgery. Pediatr Neurol. (2017) 72:56–61. doi: 10.1016/j.pediatrneurol.2017.04.011, PMID: 28571730 Vedovelli L Padalino M Suppiej A Sartori S Falasco G Simonato M . Cardiopulmonary-bypass glial fibrillary acidic protein correlates with neurocognitive skills. Ann Thorac Surg. (2018) 106:792–8. doi: 10.1016/j.athoracsur.2018.03.083, PMID: 29733822 Vergine M Vedovelli L Simonato M Tonazzo V Correani A Cainelli E . Perioperative glial fibrillary acidic protein is associated with long-term neurodevelopment outcome of infants with congenital heart disease. Children (Basel). (2021) 8:655. doi: 10.3390/children8080655 de Ferranti S Gauvreau K Hickey PR Jonas RA Wypij D du Plessis A . Intraoperative hyperglycemia during infant cardiac surgery is not associated with adverse neurodevelopmental outcomes at 1, 4, and 8 years. Anesthesiology. (2004) 100:1345–52. doi: 10.1097/00000542-200406000-00005, PMID: 15166552 Jungner Å Lennartsson F Björkman-Burtscher I Blennow K Zetterberg H Ley D. Perioperative brain injury marker concentrations in neonatal open-heart surgery: a prospective observational study. Front Pediatr. (2023) 11:1186061. doi: 10.3389/fped.2023.1186061, PMID: 37622081 Williams IA Tarullo AR Grieve PG Wilpers A Vignola EF Myers MM . Fetal cerebrovascular resistance and neonatal EEG predict 18-month neurodevelopmental outcome in infants with congenital heart disease. Ultrasound Obstet Gynecol. (2012) 40:304–9. doi: 10.1002/uog.11144, PMID: 22351034 Cheung EW Chay GW Ma ES Cheung YF. Systemic oxygen saturation and coagulation factor abnormalities before and after the fontan procedure. Am J Cardiol. (2005) 96:1571–5. doi: 10.1016/j.amjcard.2005.07.074, PMID: 16310443 Valencia E Staffa SJ Nathan M Smith-Parrish M Kaza AK DiNardo JA . Hyperlactataemia as a predictor of adverse outcomes post-cardiac surgery in neonates with congenital heart disease. Cardiol Young. (2021) 31:1401–6. doi: 10.1017/S1047951121000263, PMID: 33557993 Reitz JG Zurakowski D Kuhn VA Murnick J Donofrio MT d’Udekem Y . Brain injury and neurodevelopmental outcomes in children undergoing surgery for congenital heart disease. JTCVS Open. (2024) 17:229–47. doi: 10.1016/j.xjon.2023.11.018, PMID: 38420558 Hermans T Thewissen L Gewillig M Cools B Jansen K Pillay K . Functional brain maturation and sleep organisation in neonates with congenital heart disease. Eur J Paediatr Neurol. (2022) 36:115–22. doi: 10.1016/j.ejpn.2021.12.008, PMID: 34954621 ter Horst HJ Mud M Roofthooft MT Bos AF. Amplitude integrated electroencephalographic activity in infants with congenital heart disease before surgery. Early Hum Dev. (2010) 86:759–64. doi: 10.1016/j.earlhumdev.2010.08.028, PMID: 20970264 Votava-Smith JK Statile CJ Taylor MD King EC Pratt JM Nelson DP . Impaired cerebral autoregulation in preoperative newborn infants with congenital heart disease. J Thorac Cardiovasc Surg. (2017) 154:1038–44. doi: 10.1016/j.jtcvs.2017.05.045, PMID: 28634025 Katheria AC Stout J Morales AL Poeltler D Rich WD Steen J . Association between early cerebral oxygenation and neurodevelopmental impairment or death in premature infants. J Perinatol. (2021) 41:743–8. doi: 10.1038/s41372-021-00942-w, PMID: 33589727 Tombolini S De Angelis F Correani A Marchionni P Monachesi C Ferretti E . Is low cerebral near infrared spectroscopy oximetry associated with neurodevelopment of preterm infants without brain injury? J Perinat Med. (2022) 50:625–9. doi: 10.1515/jpm-2021-0498, PMID: 35316597 Hansen ML Pellicer A Hyttel-Sørensen S Ergenekon E Szczapa T Hagmann C . Cerebral oximetry monitoring in extremely preterm infants. N Engl J Med. (2023) 388:1501–11. doi: 10.1056/NEJMoa2207554, PMID: 37075142 Tsou PY Garcia AV Yiu A Vaidya DM Bembea MM. Association of Cerebral Oximetry with outcomes after extracorporeal membrane oxygenation. Neurocrit Care. (2020) 33:429–37. doi: 10.1007/s12028-019-00892-4, PMID: 31925732 Clair MP Rambaud J Flahault A Guedj R Guilbert J Guellec I . Prognostic value of cerebral tissue oxygen saturation during neonatal extracorporeal membrane oxygenation. PLoS One. (2017) 12:e0172991. doi: 10.1371/journal.pone.0172991, PMID: 28278259 Joram N Beqiri E Pezzato S Moscatelli A Robba C Liet J-M . Continuous monitoring of cerebral autoregulation in children supported by extracorporeal membrane oxygenation: a pilot study. Neurocrit Care. (2021) 34:935–45. doi: 10.1007/s12028-020-01111-1 Pavlidis E Lloyd RO Boylan GB. EEG - a valuable biomarker of brain injury in preterm infants. Dev Neurosci. (2017) 39:23–35. doi: 10.1159/000456659 Hayashi-Kurahashi N Kidokoro H Kubota T Maruyama K Kato Y Kato T . EEG for predicting early neurodevelopment in preterm infants: an observational cohort study. Pediatrics. (2012) 130:e891–7. doi: 10.1542/peds.2012-1115, PMID: 22945413 Fogtmann EP Plomgaard AM Greisen G Gluud C. Prognostic accuracy of electroencephalograms in preterm infants: a systematic review. Pediatrics. (2017) 139:1951. doi: 10.1542/peds.2016-1951 Niezen CK Bos AF Sival DA Meiners LC Ter Horst HJ. Amplitude-integrated EEG and cerebral near-infrared spectroscopy in cooled, asphyxiated infants. Am J Perinatol. (2018) 35:904–10. doi: 10.1055/s-0038-1626712, PMID: 29421831 Chock VY Rao A Van Meurs KP. Optimal neuromonitoring techniques in neonates with hypoxic ischemic encephalopathy. Front Pediatr. (2023) 11:1138062. doi: 10.3389/fped.2023.1138062, PMID: 36969281 Glass HC Numis AL Comstock BA Gonzalez FF Mietzsch U Bonifacio SL . Association of EEG background and neurodevelopmental outcome in neonates with hypoxic-ischemic encephalopathy receiving hypothermia. Neurology. (2023) 101:e2223–33. doi: 10.1212/WNL.0000000000207744, PMID: 37816642 Chandrasekaran M Chaban B Montaldo P Thayyil S. Predictive value of amplitude-integrated EEG (aEEG) after rescue hypothermic neuroprotection for hypoxic ischemic encephalopathy: a meta-analysis. J Perinatol. (2017) 37:684–9. doi: 10.1038/jp.2017.14 Bourel-Ponchel E Querne L Flamein F Ghostine-Ramadan G Wallois F Lamblin MD. The prognostic value of neonatal conventional-EEG monitoring in hypoxic-ischemic encephalopathy during therapeutic hypothermia. Dev Med Child Neurol. (2023) 65:58–66. doi: 10.1111/dmcn.15302, PMID: 35711160 Kharoshankaya L Stevenson NJ Livingstone V Murray DM Murphy BP Ahearne CE . Seizure burden and neurodevelopmental outcome in neonates with hypoxic-ischemic encephalopathy. Dev Med Child Neurol. (2016) 58:1242–8. doi: 10.1111/dmcn.13215, PMID: 27595841 Rutherford M Ramenghi LA Edwards AD Brocklehurst P Halliday H Levene M . Assessment of brain tissue injury after moderate hypothermia in neonates with hypoxic–ischaemic encephalopathy: a nested substudy of a randomised controlled trial. Lancet Neurol. (2010) 9:39–45. doi: 10.1016/S1474-4422(09)70295-9, PMID: 19896902 Basti C Maranella E Cimini N Catalucci A Ciccarelli S Del Torto M . Seizure burden and neurodevelopmental outcome in newborns with hypoxic-ischemic encephalopathy treated with therapeutic hypothermia: a single center observational study. Seizure. (2020) 83:154–9. doi: 10.1016/j.seizure.2020.10.021, PMID: 33160202 Lin JJ Banwell BL Berg RA Dlugos DJ Ichord RN Kilbaugh TJ . Electrographic seizures in children and neonates undergoing extracorporeal membrane oxygenation. Pediatr Crit Care Med. (2017) 18:249–57. doi: 10.1097/PCC.0000000000001067, PMID: 28099234 Hanalioglu D Temkit MH Hildebrandt K MackDiaz E Goldstein Z Aggarwal S . Neurophysiologic features reflecting brain injury during pediatric ECMO support. Neurocrit Care. (2023) 40:759–68. doi: 10.1007/s12028-023-01836-9 Chahine A Chenouard A Joram N Berthomieu L Du Pont-Thibodeau G Leclere B . Continuous amplitude-integrated electroencephalography during neonatal and pediatric extracorporeal membrane oxygenation. J Clin Neurophysiol. (2023) 40:317–24. doi: 10.1097/WNP.0000000000000890, PMID: 34387276 Felling RJ Kamerkar A Friedman ML Said AS LaRovere KL Bell MJ . Neuromonitoring during ECMO support in children. Neurocrit Care. (2023) 39:701–13. doi: 10.1007/s12028-023-01675-8, PMID: 36720837 Huang Y Wang Z Huang ZX Liu Z. Biomarkers and the outcomes of ischemic stroke. Front Mol Neurosci. (2023) 16:1171101. doi: 10.3389/fnmol.2023.1171101, PMID: 37342100 Dassan P Keir G Brown MM. Criteria for a clinically informative serum biomarker in acute ischaemic stroke: a review of S100B. Cerebrovasc Dis. (2009) 27:295–302. doi: 10.1159/000199468, PMID: 19202335 Kövesdi E Lückl J Bukovics P Farkas O Pál J Czeiter E . Update on protein biomarkers in traumatic brain injury with emphasis on clinical use in adults and pediatrics. Acta Neurochir. (2010) 152:1–17. doi: 10.1007/s00701-009-0463-6, PMID: 19652904 Bembea MM Rizkalla N Freedy J Barasch N Vaidya D Pronovost PJ . Plasma biomarkers of brain injury as diagnostic tools and outcome predictors after extracorporeal membrane oxygenation. Crit Care Med. (2015) 43:2202–11. doi: 10.1097/CCM.0000000000001145, PMID: 26082978 Sood BG McLaughlin K Cortez J. Near-infrared spectroscopy: applications in neonates. Semin Fetal Neonatal Med. (2015) 20:164–72. doi: 10.1016/j.siny.2015.03.008 Chiperi LE Tecar C Toganel R. Neuromarkers which can predict neurodevelopmental impairment among children with congenital heart defects after cardiac surgery: a systematic literature review. Dev Neurorehabil. (2023) 26:206–15. doi: 10.1080/17518423.2023.2166618, PMID: 36710475 Kim MJ Baek JS Kim JA Cha SG Yu JJ. Cerebral and somatic oxygen saturation in neonates with congenital heart disease before surgery. J Clin Med. (2021) 10:2455. doi: 10.3390/jcm10112455