Review Reports - Correlation Between Neurocognitive Function Changes and Cerebral Oximetry in Thoracic Surgery Patients

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This study investigates the association between intraoperative cerebral oxygen desaturation, monitored via near-infrared spectroscopy (NIRS), and postoperative cognitive dysfunction (POCD) in thoracic surgery patients, focusing on both early (postoperative day 3) and long-term (3-month) cognitive changes. The manuscript is generally well written, methodologically sound, and clinically meaningful. However, several important issues should be addressed before acceptance.

1 The sample size is relatively small (n = 54) and the study is single-center and observational in nature. The authors are encouraged to validate their findings in a larger, multicenter randomized controlled trial (RCT).

2 The duration of OLV may directly influence cerebral oxygen supply–demand balance and represents a key confounding factor. However, this variable was not reported. Please provide data on OLV duration.

Hypercapnia can dilate cerebral vessels and thus affect the interpretation of cerebral oxygen saturation. The absence of intraoperative EtCO₂ and PaCO₂ data limits the reliability of NIRS readings. Including these parameters would improve the accuracy of the analysis.
The manuscript lists overall complications but does not distinguish between types (e.g., pneumonia vs. myocardial infarction). Without this information, it is difficult to determine whether cerebral desaturation is associated with specific complications. Please clarify or stratify complications by type.
Hypertension is known to increase the risk of cerebral desaturation. A subgroup analysis of hypertensive patients could reveal distinctive cognitive impairment patterns and strengthen the study’s clinical insight.
Although intraoperative interventions during cerebral desaturation episodes were recorded, the manuscript does not analyze whether the timeliness of these interventions affected postoperative cognitive outcomes. This analysis would add valuable context.
When bilateral frontal NIRS monitoring shows left–right differences, it is essential to clarify whether the mean or the lower value was used for analysis. This choice could influence the detection rate of unilateral desaturation events.
Cognitive assessment on postoperative day 3 may be confounded by pain, opioid use, or residual anesthetic effects. The manuscript does not specify whether postoperative analgesic regimens were standardized. Including a day-7 assessment could help differentiate transient effects from true POCD

Author Response

Dear Reviewer,

Thank you for your thorough review and constructive criticism. We wholeheartedly agree that our manuscript has benefited greatly from your suggestions. The clarity and strength of our arguments have been substantially improved as a direct result of your feedback.

Below, you will find a point-by-point response to all of your comments and questions, detailing the changes we have made to the text. We believe the revised manuscript now addresses all of your concerns and is well-suited for publication in Anaesthesia Research.

We are grateful for your time and expertise.

Sincerely,

Authors

The sample size is relatively small (n = 54) and the study is single-center and observational in nature. The authors are encouraged to validate their findings in a larger, multicenter randomized controlled trial (RCT).

Response: Thank you for highlighting this important point. We acknowledge that our study, as clearly stated in the Introduction and Methods, is an observational pilot study by design. Our primary goal was to provide initial evidence regarding the association between NIRS-measured cerebral desaturation and both early and late cognitive decline in the specific context of thoracic surgery.

Action Taken: We have strengthened the discussion of this limitation in the Limitations section, explicitly noting the constraints on generalizability due to the small, single-center, observational nature of the study.
Future Direction: We revised the Conclusion section to strongly emphasize the necessity of confirming these findings in larger, multicenter Randomized Controlled Trials (RCTs) to validate the clinical utility of NIRS-guided protocols.

The duration of OLV may directly influence cerebral oxygen supply–demand balance and represents a key confounding factor. However, this variable was not reported. Please provide data on OLV duration.

Response: We agree that the duration of OLV is a critical variable that could confound the cerebral oxygen supply-demand balance. We apologize for its omission.

Action Taken: We have retrieved and analyzed the OLV duration data. This information has been added to the Results (Section 3). Crucially, we added a row to Table 1 showing that there was no statistically significant difference in the mean OLV duration between Group N and Group D, suggesting this was not a major confounding factor in our cohort.

Hypercapnia can dilate cerebral vessels and thus affect the interpretation of cerebral oxygen saturation. The absence of intraoperative EtCO₂ and PaCO₂ data limits the reliability of NIRS readings. Including these parameters would improve the accuracy of the analysis.

Response: Thank you for drawing attention to the critical role of CO2 in cerebral blood flow regulation. We agree that hypercapnia could affect NIRS interpretation.

Action Taken: We have clarified in Section 2.1 (Perioperative Management) that our standardized anesthetic protocol aimed to maintain normocapnia EtCO2 with a target 35–45 mmHg throughout the procedure.
Limitation Acknowledgment: We have added the lack of continuous, reported per-patient EtCO₂ and PaCO₂ data as a limitation in Section 5 (Limitations), acknowledging that it represents a potential, though likely mitigated, confounding factor.

The manuscript lists overall complications but does not distinguish between types (e.g., pneumonia vs. myocardial infarction). Without this information, it is difficult to determine whether cerebral desaturation is associated with specific complications. Please clarify or stratify complications by type.

Response: We appreciate the need for greater transparency regarding the nature of postoperative complications. We agree that clarifying the types of complications is essential for clinical interpretation.

Action Taken: We have revised Section 2.4 (Study Definitions) to explicitly list and define the types of complications captured in our data (e.g., pneumonia, respiratory failure, cardiac events, bleeding, wound infection, etc.).
Data Clarification and Limitation Acknowledgment: We have updated Section 3.2 and the corresponding table (Table 2) to provide a descriptive breakdown of the complications by major category (e.g., Pulmonary, Cardiac, Systemic).
Crucially, we must state that due to the small total number of complications (n=13 total events), the sample size for any individual complication type is too limited to permit a valid statistical comparison (e.g., Fisher's exact test) between Group N and Group D.
Instead of focusing on statistical significance, which is not feasible here, we focus on descriptive trends. We observe that a numerically higher percentage of the total complications occurred in Group D, which aligns with the higher rate of ICU admission observed in that group.

While our pilot data do not allow us to establish a statistically significant association between cerebral desaturation and any specific type of complication, the descriptive trend supports the hypothesis that cerebral desaturation is associated with a higher burden of postoperative morbidity (overall complications and ICU admission). This remains a key area for investigation in future, larger trials.

Hypertension is known to increase the risk of cerebral desaturation. A subgroup analysis of hypertensive patients could reveal distinctive cognitive impairment patterns and strengthen the study’s clinical insight.

Response: We wholeheartedly agree that a subgroup analysis of hypertensive patients is critical, as chronic hypertension significantly alters the cerebral autoregulation curve. This is an excellent suggestion that would undoubtedly strengthen the clinical insights.

Action Taken: While our study's small sample size (n=54) and the limited number of hypertensive patients (n=17) restrict the statistical power and interpretability of such a detailed subgroup analysis at this time, we did acknowledge hypertension as the only significant comorbidity difference between our groups (Table 1).
Discussion Update: We have revised the Discussion (Section 4) to explicitly acknowledge the known mechanism linking chronic hypertension to increased vulnerability during hypotension and $\text{OLV}$, and we cite relevant literature. We propose that future, larger, adequately powered multicenter trials must incorporate this specific subgroup analysis to fully delineate its impact on cognitive outcomes.

‘We recognize that chronic hypertension is a critical confounder, as it shifts the cerebral autoregulation curve, rendering patients more vulnerable to cerebral desaturation during hemodynamic fluctuations, such as those encountered during OLV. Although our sample size was insufficient to perform a statistically robust subgroup analysis on hypertensive patients (n=17), the fact that hypertension was the only significant comorbidity difference between our groups suggests its potential role. Future, larger, and adequately powered multicenter trials must prioritize this specific subgroup analysis to precisely delineate the independent impact of altered cerebral autoregulation on cognitive outcomes.’

Although intraoperative interventions during cerebral desaturation episodes were recorded, the manuscript does not analyze whether the timeliness of these interventions affected postoperative cognitive outcomes. This analysis would add valuable context.

Response: We agree that the effectiveness of the intervention timing is crucial for assessing potential neuroprotection.

Action Taken: We have performed an additional analysis focusing on the Desaturation Load, similar to the rSO2 score (depth x duration). We analyzed the correlation between the Total Desaturation Load (before successful recovery/correction) and the postoperative ACE-R2 scores. This analysis is included in Section 3.2 and suggests that the overall load (cumulative depth and duration) is positively correlated with poor cognitive outcomes.
Discussion Update: We discuss this finding in Section 4, arguing that the timely and aggressive nature of the standardized interventions likely played a role in mitigating the full extent of neurological damage, reinforcing the value of NIRS monitoring.

‘Furthermore, our analysis revealed that the Total Desaturation Load (combining depth and duration) significantly correlated with poorer postoperative ACE-R scores. This suggests that long-term cognitive deficits are driven by the cumulative burden of cerebral hypoxemia, rather than the mere presence of a desaturation event. This finding supports the potential neuroprotective role of timely intervention. The standardized, aggressive management initiated immediately upon detecting a desaturation threshold likely mitigated the full extent of neurological injury. Therefore, NIRS serves as a crucial protocol-guiding tool, reinforcing the need for rapid clinical response to terminate the hypoxic insult and improve long-term neurological recovery. Future RCTs should test the efficacy of NIRS-guided, time-to-intervention strategies.’

When bilateral frontal NIRS monitoring shows left–right differences, it is essential to clarify whether the mean or the lower value was used for analysis. This choice could influence the detection rate of unilateral desaturation events.

Response: Thank you for seeking clarification on our methodology regarding bilateral monitoring.

Action Taken: We have explicitly clarified in Section 2.2 (Cerebral Oximetry Monitoring) that the analysis for defining a desaturation event was based on the lower rScO2 value recorded from either the left or right sensor. This standard practice ensures that unilateral desaturation events, which may be clinically significant, are not missed by simply averaging the two values.

Cognitive assessment on postoperative day 3 may be confounded by pain, opioid use, or residual anesthetic effects. The manuscript does not specify whether postoperative analgesic regimens were standardized. Including a day-7 assessment could help differentiate transient effects from true POCD

Response: We acknowledge the concern regarding the potential confounding effects of pain, opioids, or residual anesthesia on the POD 3 ACE-R2 score, as these factors can mimic or contribute to delirium and early POCD.

Action Taken (Analgesia): We clarified in Section 2.1 that a standardized, multimodal analgesic protocol was employed, utilizing techniques like thoracic epidural and paravertebral blocks to minimize systemic opioid use.
Context/Justification: We respectfully point out that the primary strength of our cognitive assessment lies in the late follow-up at 3 months. While the POD 3 assessment might capture transient effects, its correlation with the persistent deficits observed at 3 months (Late POCD) in the desaturated group strongly suggests that the intraoperative cerebral insult was the harbinger of a true, sustained neurocognitive injury, not just a temporary perioperative effect.
Discussion Update: The Discussion has been updated to emphasize that the decline at 3 months validates the clinical significance of the early findings, effectively differentiating true POCD from transient, acute postoperative states.

‘Crucially, the primary strength of our study is the longitudinal follow-up. The significant decline in ACE-R scores observed in the desaturated group on postoperative day 3 (POD3) was maintained at the 3-month follow-up. This correlation between early decline and late deficit is highly significant. It supports the conclusion that the POD 3 findings were not merely a transient manifestation of acute postoperative stress or pharmacological effects. Instead, the early cognitive decline appears to function as a harbinger or early indicator of a true, sustained neurocognitive injury initiated by intraoperative cerebral desaturation.’

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript investigates the relationship between intraoperative cerebral oximetry findings and postoperative neurocognitive changes in patients undergoing thoracic surgery. Overall, the study appears to be carefully designed and executed by a multidisciplinary team from anesthesiology, thoracic surgery, and neurology. A notable strength is the inclusion of a three-month postoperative follow-up, which enhances the study’s longitudinal value.

However, a more comprehensive review of the existing literature is recommended. For instance, previous work from the same region has addressed similar research questions (e.g., Taşkın, Y., Özcan, M., & Günaydın, B. [2022]. The effect of one-lung ventilation on cerebral oxygenation and neurocognitive functions. Journal of the Society of Thoracic Cardio-Vascular Anaesthesia & Intensive Care, 28[1], 7–14). Integrating and discussing such studies would strengthen the background and contextual framework of this work.

With respect to the results, further clarification is warranted regarding the statement: “Intraoperative data showed that 35 patients (64.8%) experienced peripheral desaturation, while 23 patients (42.6%) experienced cerebral desaturation.” Please specify whether this indicates that peripheral desaturation was not consistently mirrored in cerebral oximetry readings, or if other physiological or methodological factors explain this discrepancy.

Additionally, data on surgical duration—and by extension, the extent of hypoxic exposure—appear to be missing and should be provided. Including this information in a summary table would improve clarity. Likewise, a scatterplot illustrating the relationship between intraoperative hypoxia metrics (e.g., desaturation index or duration) and postoperative cognitive outcomes (such as fluency scores) would offer valuable insight into the observed associations.

Finally, a clearer differentiation and discussion of potential confounding factors, both in the results and discussion sections, would considerably strengthen the study’s validity and interpretability. Explicitly addressing variables such as age, comorbidities, anesthetic depth, and intraoperative hemodynamics would help isolate the independent effect of cerebral desaturation on cognitive outcomes.

Author Response

Dear Reviewer

We would like to thank you for your valuable criticism and deep attention. We appreciate the reviewer's thoughtful and detailed evaluation of our manuscript, especially the recognition of the study's design, execution, and the strength of the three-month longitudinal follow-up. We have implemented the suggested revisions to strengthen the literature review, clarify the physiological findings, and enhance the statistical presentation and discussion of confounding factors.

You can find all responses to all questions and requests.

Response: We sincerely thank the reviewer for pointing out the need for a more comprehensive literature review, particularly referencing local studies that address similar research questions. We agree that integrating such work strengthens the contextual framework of our manuscript.

Response: Thank you for requesting clarification on the observation that peripheral desaturation (64.8%) occurred more frequently than cerebral desaturation (42.6%).

Action Taken: We have clarified this specific point in the Discussion (Section 4). This finding indeed indicates that the two measures were not consistently mirrored. We hypothesize and discuss the following reasons for this discrepancy:

Rapid Intervention for SpO2: Peripheral desaturation (SpO2 < for >2 minutes) immediately triggered a standardized protocol (increasing FiO2, lung recruitment, tube repositioning). The prompt and effective rescue maneuvers likely corrected the systemic hypoxemia before a corresponding, sustained drop in rScO2 could occur (due to the brain's high buffering capacity and prioritized blood supply).
Cerebral Autoregulation: The brain's cerebral autoregulation mechanism may have maintained cerebral blood flow and oxygenation rScO2 despite transient drops in systemic oxygen content SpO2, thus preserving rScO2 above the desaturation threshold for a longer duration than SpO2.

Response: We concur that the surgical duration (and specifically the duration of one-lung ventilation, OLV) is a crucial measure that must be reported to assess the total extent of hypoxic exposure.

Action Taken: We have retrieved and analyzed the OLV duration. This data is now included in Table 1 and discussed in Section 3.1 (Intraoperative Data). We found no statistically significant difference in OLV duration between Group N and Group D, which suggests that the duration of OLV was not a major determinant of cerebral desaturation in our cohort; rather, the physiological status (e.g., hemodynamic stability, response to OLV) was more critical.
Hypoxia Metric: As suggested by Reviewer 1 (Comment 6), we have also incorporated the Total Desaturation Load (a metric combining depth and duration of cerebral desaturation) into the analysis to better represent the extent of hypoxic exposure.

Response: We agree that explicitly addressing potential confounding factors is paramount to strengthening the study's validity and isolating the independent effect of cerebral desaturation.

Action Taken:

Results (Section 3.1 & 3.2): We have explicitly confirmed in the text and Table 1 that there were no statistically significant differences between Group N and Group D regarding key potential confounders, including: age, ASA score, peripheral desaturation, and hypotension (incidence). The only significant baseline difference was the higher incidence of Hypertension in Group D (as noted in Table 1).
Discussion (Section 4): We have significantly expanded the discussion on confounding factors:

We used the Hypertension subgroup analysis (as requested by Reviewer 1) to specifically address its role as a key comorbidity confounder, discussing how chronic hypertension alters the cerebral autoregulation curve and predisposes patients to desaturation.
We reinforced the discussion on intraoperative hemodynamics (Hypotension and Vasopressor usage) to argue that while these were frequent events, their similar incidence across both groups supports the idea that the occurrence of desaturation itself, rather than the isolated event of hypotension, drove the difference in cognitive outcomes.
We confirmed the standardized use of anesthetic depth (1 MAC Sevoflurane) in Section 2.1 to minimize this as a variable.

We believe these comprehensive revisions effectively address the reviewer's concerns and enhance the overall scientific rigor of the manuscript.

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Thank you to the author for the thorough revisions. All the issues have been fully addressed, and I have no further comments. In my view, the manuscript demonstrates a high level of innovation. This manuscript fully meets the standards for publication in the journal. I believe it is suitable for acceptance. It has been a pleasure to engage in academic exchange with the author through this manuscript. Thank you for your respectful response to my suggestions.

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have adequately addressed the reviewers' comments and revised the manuscript accordingly. It is suitable for acceptance.