Review Reports

Round 1

Reviewer 1 Report

The retrospective analysis analyzed 14 pediatric TBI patients, and evaluated the relationship between the parameters of Co reactivity of brain tissue oxygenation.

Overall, the study and analysis is well written.

Some suggestions as below

1. The abbreviation used in the text need to be checked. The first time you use an abbreviation in the text, present both the spelled-out version and the short form.

For example, Line 34 Carbon dioxide (CO2) , Line 41 BBB (lack of the spelled-out, not in the Line 218.) , Line 59 multimodality neurologic monitoring (MMM), Line 107 DSEM (lack of the spelled-out). Line 141 SAH (lack of the spelled-out)

 

2.Introduction is well written and the background information is adequate. However, BBB breakdown is an important point of view when you interpret the result. I suggest give more instruction to illustrate the BBB breakdown in the introduction.

3.Materials and methods

Regarding the physiological data, the data of this study was collected on the first day after MMM setting. However, since the patient may stay in the ICU for a period, would it possible that the relationship change along with time?

4.Results

Line 133-135. “Eleven patients (79%) were involved in a motor vehicle accident of which were automobile vs. pedestrian, eight automobile vs. bicycle, one automobile vs. motorcycle, and one all-terrain vehicle (ATV) vs. ATV 1.” The sentence need to be clarify in the number.

Line 139. The reference [3-6] seems not adequate to place here?

Line 141-143 I suggest the detail of neuroimage findings to be simplified or refer to Table 1.

Table 1

The abbreviation can be adjusted. Pt to patient, TBI mech, to mechanism. The race could be placed in spell-out.

Some of the abbreviations were lack, for example, FTP, FT

Vasoactive agents, NOR may be substituted by NE, which is more prevalent use

Table 2

The presentation of data as median and IQR need to be explained in the table legend. Usually, the IQR is presented as a range, e.g. 10.0 [8.2-12.2]. (Same issue in Table 5)

Line 198-200

I wonder how do you explain the findings “In comparison to patients with intact CO2 reactivity of PbtO2, those with impaired reactivity were observed to have decreased values of PbtO2, EtCO2 and ABP, as well as increased values of ICP, PRx, and rSO2”.

5.Discussion

The discussion is well written, and give a logic interpretation. In the third paragraph, the importance of BBB integrity is mentioned. However, I wonder if you performed any clinical assessment of BBB disruption in these patients, e.g. DTI or SWI of MRI to evaluate the extent of BBB breakdown in those with impaired CO2 reactivity? If the relationship could be linked to the image, the BBB breakdown would be a more reliable explanation.

6.Conclusion

I suggest the speculation can be mentioned in the discussion, but not in the conclusion.

Author Response

Please see the attachment. 

Author Response File: Author Response.docx

Reviewer 2 Report

The authors present a manuscript describing how changes in partial pressure of brain tissue oxygenation (PbtO₂) relate to the end-tidal carbon dioxide (EtCO₂) after pediatric brain injury. This study examines a small sample of individuals with severe brain injury and reports on biologic findings. Overall, the study informs the medical community about the types of biologic factors that contribute to changes in the brain related to serve brain injury. However, for this journal, further information is needed on how these biological factors relate to recovery and outcomes in children. It is not clear how the information gleaned from this study informs these areas. This study would have a better place in a biologic or medical journal, unless the authors can do major revisions to the introduction and discussion to relate the findings to what the findings indicate for  recovery, behavior or outcomes. 

Author Response

Please see the attachment. 

Author Response File: Author Response.docx

Reviewer 3 Report

Hyperventilation to induce cerebral vasoconstriction and reduce CBF, ICP in line 43, but this study did not perform it.

Is it a child? < 21 years of age in line 58, it was not clear about the children's age definition.

The study showed the association rather than odds ratio that was difficult to understand the risk about the variables.

Is standardized regression coefficients a type of correlation coefficient? in line 113

The different dose sedation will reduce ICP, but the dose of sedation was lacking.

The autonomic function is different lateral with different change, Does the data show lateralization?

Are there differences about the outcome of patients in different groups? CPP=MAP-ICP, more than 70mmHg to keep cerebral auto-regulation. There are some patients with less than 70mmHg, are they related to poor outcome and oxygenation?

This is a small sample size, and in a retrospective study, it needs to add patients to perform multivariate logistic regression to confirm the risk.

Author Response

Please see the attachment. 

Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

The authors have comprehensively addressed reviewer comments. I especially appreciate the association with children's outcomes and behavior as indicated by their inclusion on the GOS findings and the discussion on the relationship of physiologic  findings to outcomes. This helps to clarify that physiologic work is an important component of better understanding recovery and behavior after brain injury. 

Author Response

Dear Editors and Reviewers,

We thank you for the opportunity to revise our manuscript entitled, “Carbon Dioxide Reactivity of Brain Tissue Oxygenation after Pediatric Traumatic Brain Injury”. We have incorporated the feedback of reviewers #2 and #3 into this revised manuscript. Revisions are now included in the revised manuscript in red. We have provided point-by-point responses to the reviewers below:

Reviewer #2

1. “The authors have comprehensively addressed reviewer comments. I especially appreciate the association with children's outcomes and behavior as indicated by their inclusion on the GOS findings and the discussion on the relationship of physiologic findings to outcomes. This helps to clarify that physiologic work is an important component of better understanding recovery and behavior after brain injury.” 

Response: Thank you for this feedback.

Reviewer #3

1. “While evidence links low PbtO2 values with poor outcomes, the proposed interventions to optimize levels include raising ABP with vasopressors, optimizing hemoglobin concentration, and increasing PaCO2 to augment CBF [6] from line 507-509. The authors point out the importance of CBF.”

Response: Thank you.

2. “MAP-ICP=CPP, the author omits the importance of the outcome of TBI. There is lack of correlation between PbtO2 and CPP in Table 3.”

Response: We agree with the reviewer that CPP is an important measure as it relates to TBI, and that it is fundamentally a calculation of MAP – ICP. For a multivariate dynamic structural equation model (DSEM) to appropriate investigate the relationship of PbtO2 to the relevant predictive variables regarding CPP, we need to directly measure the actual variables that relate to CPP, which are MAP and ICP. Because CPP is equivalent to MAP – ICP, we cannot include CPP into a multivariate DSEM model that already incorporates MAP and ICP. For the model to be stable, we must only include the inputs that directly relate to the calculation of CPP. 

3. “PbtO2 is an indirect expression of CBF rather than direct effect, the CBF was not shown in this manuscript.”

Response: Thank you for this feedback. We have included in the limitations portion of the discussion section that, “Outside of unique circumstances such as described in Figure 2, direct measures of CBF were not investigated in this study” (Page 12, lines 290-292).

4. “After TBI, CO2 reactivity of PbtO2 can be heterogeneous, with ineffective cerebrovascular pressure reactivity contributing toward impaired reactivity in line 22-23. The author used a small sample and missed CBF data, the conclusion could not fit the study.” 

Response: Thank you for this feedback. We have revised the abstract conclusion to state, “After TBI, CO₂ reactivity can be heterogenous, necessitating further work investigating factors contributing toward impaired reactivity”.

Author Response File: Author Response.docx

Reviewer 3 Report

While evidence links low PbtO2 values with poor outcomes, the proposed interventions to optimize levels include raising ABP with vasopressors, optimizing hemoglobin concentration, and increasing PaCO2 to augment CBF [6] from line 507-509. The authors point out the importance of CBF.

MAP-ICP=CPP, the author omits the importance of the outcome of TBI. There is lack of correlation between PbtO2 and CPP in Table 3.

PbtO2 is an indirect expression of CBF rather than direct effect, the CBF was not shown in this manuscript.

 

After TBI, CO2 reactivity of PbtO2 can be heterogeneous, with ineffective cerebrovascular pressure reactivity contributing toward impaired reactivity in line 22-23. The author used a small sample and missed CBF data, the conclusion could not fit the study. 

Author Response

Dear Editors and Reviewers,

We thank you for the opportunity to revise our manuscript entitled, “Carbon Dioxide Reactivity of Brain Tissue Oxygenation after Pediatric Traumatic Brain Injury”. We have incorporated the feedback of reviewers #2 and #3 into this revised manuscript. Revisions are now included in the revised manuscript in red. We have provided point-by-point responses to the reviewers below:

Reviewer #2

1. “The authors have comprehensively addressed reviewer comments. I especially appreciate the association with children's outcomes and behavior as indicated by their inclusion on the GOS findings and the discussion on the relationship of physiologic findings to outcomes. This helps to clarify that physiologic work is an important component of better understanding recovery and behavior after brain injury.” 

Response: Thank you for this feedback.

Reviewer #3

1. “While evidence links low PbtO2 values with poor outcomes, the proposed interventions to optimize levels include raising ABP with vasopressors, optimizing hemoglobin concentration, and increasing PaCO2 to augment CBF [6] from line 507-509. The authors point out the importance of CBF.”

Response: Thank you.

2. “MAP-ICP=CPP, the author omits the importance of the outcome of TBI. There is lack of correlation between PbtO2 and CPP in Table 3.”

Response: We agree with the reviewer that CPP is an important measure as it relates to TBI, and that it is fundamentally a calculation of MAP – ICP. For a multivariate dynamic structural equation model (DSEM) to appropriate investigate the relationship of PbtO2 to the relevant predictive variables regarding CPP, we need to directly measure the actual variables that relate to CPP, which are MAP and ICP. Because CPP is equivalent to MAP – ICP, we cannot include CPP into a multivariate DSEM model that already incorporates MAP and ICP. For the model to be stable, we must only include the inputs that directly relate to the calculation of CPP. 

3. “PbtO2 is an indirect expression of CBF rather than direct effect, the CBF was not shown in this manuscript.”

Response: Thank you for this feedback. We have included in the limitations portion of the discussion section that, “Outside of unique circumstances such as described in Figure 2, direct measures of CBF were not investigated in this study” (Page 12, lines 290-292).

4. “After TBI, CO2 reactivity of PbtO2 can be heterogeneous, with ineffective cerebrovascular pressure reactivity contributing toward impaired reactivity in line 22-23. The author used a small sample and missed CBF data, the conclusion could not fit the study.” 

Response: Thank you for this feedback. We have revised the abstract conclusion to state, “After TBI, CO₂ reactivity can be heterogenous, necessitating further work investigating factors contributing toward impaired reactivity”.

Author Response File: Author Response.docx