Liselotte Van Loo
Bjorn Cools
Anneleen Dereymaeker
Katrien Jansen- 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
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
1 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.
2 Methods
2.1 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).
2.2 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.
2.3 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.
2.4 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.
2.5 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.
2.6 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.
3 Results
3.1 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).
Figure 1. 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.
3.2 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.
3.3 Results of included studies
An overview of the study characteristics, inclusion criteria, inclusion period and main results, can be found in Tables 1–3.
Table 1. Overview of studies reporting on perioperative NIRSa.
Table 2. Overview of studies reporting on perioperative EEGa.
Table 3. Overview of studies reporting on perioperative biochemical biomarkers.
3.3.1 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.
3.3.1.1 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).
3.3.1.2 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).
3.3.2 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.
3.3.2.1 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).
3.3.2.2 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).
3.3.3 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).
3.4 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.
Figure 2. 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).
3.5 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.
Figure 3. GRADE assessment of quality of evidence.
4 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.
4.1 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.
4.2 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.
Acknowledgments
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
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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.
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Keywords: neuromonitoring, neurodevelopment, neuroimaging, congenital heart disease, near-infrared spectroscopy, electroencephalography, biomarkers
Citation: Van Loo L, Cools B, Dereymaeker A and Jansen K (2024) Neuromonitoring modalities predicting neurological impairment in pediatric congenital heart disease: a systematic review. Front. Neurol. 15:1502762. doi: 10.3389/fneur.2024.1502762
Edited by:
Igor Nestrasil, University of Minnesota Health Twin Cities, United StatesReviewed by:
Arif Somani, University of Minnesota Twin Cities, United StatesBrian Mendel, National Cardiovascular Center Harapan Kita, Indonesia
Copyright © 2024 Van Loo, Cools, Dereymaeker and Jansen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Liselotte Van Loo, bGlzZWxvdHRlLnZhbmxvb0B1emxldXZlbi5iZQ==
†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