Serum Markers of Brain Injury in Pediatric Patients with Congenital Heart Defects Undergoing Cardiac Surgery: Diagnostic and Prognostic Role

Round 1

Reviewer 1 Report

This prospective, observational, single-center study was designed to evaluate the role of neurobiomarkers such as glial fibrillary acidic protein (GFAP), brain-derived neurotrophic factor (BDNF), protein S100 (pS100), and neuron-specific enolase (NSE) as diagnostic indicators for acute brain injury and as prognostic markers for short-term neurodevelopmental impairment in pediatric patients undergoing cardiac surgery for congenital heart disease (CHD). The findings suggest that GFAP may hold promise as a tool for diagnosing and predicting postoperative brain injury and neurofunctional impairment in cyanotic CHD patients.

Limitations of the study include the following:

1. Small Sample Size: The study included only 42 patients, and it would be beneficial to expand the research to multiple centers to reduce regional bias, improve external validity, and ensure greater generalizability of the study results.
2. Lack of Longer-term Follow-up: While preoperative and 4-6 months postoperative neurodevelopmental assessments were conducted, the absence of MRI examinations to better characterize brain lesions is a limitation. Longer-term follow-up could provide a more comprehensive understanding of neurodevelopmental processes and outcomes.

Correlation vs. Causation: Although the study identified certain correlations, it did not establish causal relationships between neurobiomarkers and acute brain injury or neurodevelopmental disorders. Further experimental research may be required to confirm these relationships.

Minor editing of English language required.

Author Response

Dear Reviewer,

I added comments regarding all three suggested limitations of the study in the final part of the Discussion chapter:

1. Small sample size
2. Lack of long-term follow-up
3. Causal relationship

Please see the attachment were the changes are marked with Track changes.

Thank you for the time used to review my manuscript!

Lacramioara-Eliza Chiperi

Author Response File: Author Response.docx

Reviewer 2 Report

- Recommend mentioning how many of the patients with abnormal developmental scores were cyanotic (abstract line 29)

- Consider rewording line 46-50: "Several factors may play a role in the neurologic perturbations in these patients including genetic abnormalities, hypoxic-ischemic insults in utero, altered fetal brain development, effects of intraoperative interventions (cardiopulmonary bypass) and postoperative complications (thromboembolic events, strokes, intracerebral hemorrhage etc.)."

- Consider rewording Line 50 as the goal of the manuscript is not to identify brain "lesions" (that would need advanced imaging such as MRI), consider using "injury" instead of lesions 

- Line 54 - should be treatment "efficacy" 

- Line 71, genetic and chromosomal are the same, consider rewording to "Exclusion criteria included known genetic abnormalities, known neurologic abnormalities, prematurity (define number of weeks, < 37 or < 35?), presence of extracardiac abnormalities and prior surgeries"

- Figure 1 needs to be modified, the cyanotic CHD group does not have the left side number bar with labels

- Since the goal of the study is to assess whether cardiac surgery has a neurodevelopmental impact, the tables 5-6 are not relevant. Clinicans would be interested in knowing in the developmental scores of the cyanotic and non-cyanotic patients changed from pre op to post-op status instead of comparing them to each other. It is already known that cyanotic patients have lower overall scores and higher risks of neurodevelopmental impairment.

- Are the authors comparing the CHANGE in the neuromarker levels to the CHANGE in the develeopmental scores? This is not clear and I am not sure I understand the clinical relevance of this work 

- All serum biomarkers have been shown to increase after cardiac surgery, authors may consider reviewing and citing this study  doi: 10.1111/aas.14033

-  Minor edits in sentences as suggested above 

Author Response

Dear Reviewer,

I added modifications regarding all your suggestions:

1. I have mentioned how many of the patients with abnormal developmental scores were cyanotic and non-cyanotic
2. I have reworded line 46-50 as suggested
3. I have reworded line 50 as suggested
4. I have reworded line 54 as suggested
5. I have reworded line 71 as suggested
6. I have rearranged figure 1
7. Table 5 and 6 have been modified as suggested
8. “Are the authors comparing the CHANGE in the neuromarker levels to the CHANGE in the developmental scores?” This issue has been clarified in subchapter 3.3.2
9. The suggested study (doi: 1111/aas.14033) was reviewed. We compared it’s results with our study results and citied it

Please see the attachment where the changes are marked with Track changes.

Thank you for the time used to review my manuscript!

Lacramioara-Eliza Chiperi

Author Response File: Author Response.docx