Effect of the Duration of Deep Hypothermic Circulatory Arrest on the Neurodevelopmental Outcomes in Children Undergoing Cardiac Surgery

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Dear Authors,

I was happy to read Your very interesting manuscript, however I found some concerns that I suggest You to correct in order to improve the quality of Your interesting work

Specifically, I think that in Introduction section You could add references in order to better explain some sentences (i.e. line 41 and line 50 "....decrease in the mortality rate of patients undergoing congenital cardiac surgery"; line 54 "....imposes a burden of both the patients and their families"; line 55 "....significant relationship between congenital cardiac surgery and neurodevelopmental complications")

In Introduction section line 53 there is a typing error (..of and..)

 

In Sample and Preoperative data sections The study design and the population recruitment process is poor clear so I suggest You to add a flow-chart-diagram in order to clarify the recruiting process and the study population composition

The inclusion in Your studied population of preterm birth children could represent a significant limitation for the power of Your results, could You better discuss this point in Discussion Section?

Author Response

Dear Reviewer 1: Thank you for your valuable comments. Here is a breakdown of each comment and our response. We thank you and looking forward to work with all the reviewers to publish our study.

Comment 1: I think that in Introduction section You could add references in order to better explain some sentences (i.e. line 41 and line 50 "....decrease in the mortality rate of patients undergoing congenital cardiac surgery"; line 54 "....imposes a burden of both the patients and their families"; line 55 "....significant relationship between congenital cardiac surgery and neurodevelopmental complications")

In Introduction section line 53 there is a typing error (..of and..)

Response 1: Thank you for pointing these out. The manuscript has been edited to include the references for these passages.

 

Comment 2: In Sample and Preoperative data sections The study design and the population recruitment process is poor clear so I suggest You to add a flow-chart-diagram in order to clarify the recruiting process and the study population composition

Response 2: Thank you for your comment. A flowchart (Figure 1) has been added to present the recruitment process.

 

Comment 3: The inclusion in Your studied population of preterm birth children could represent a significant limitation for the power of Your results, could You better discuss this point in Discussion Section?

Response 3: We have included preterm patients, as we tried to match both groups in our analysis. We have also added this as a limitation in our discussion section.

Reviewer 2 Report

Comments and Suggestions for Authors

I find the subject of the research very interesting and original since there are not many studies on pediatric cardiac surgery, which is a difficult field of practice with many possible complications which may arise. While DHCA is a practice which most definitely aids in better outcomes for the patients, it is not without its risks which are clearly presented and investigated here. Since there are very few papers on the matter and on neonates, this manuscript is an important piece of research.
I find the methodology clearly presented and the investigated group well-constituted, since there are limited posibilities to gather more patients to investigate in this age-group.

The conclusions clearly and concisely summarise the findings of the study correlated with other papers on the matter and the references are appropriately chosen to support the findings and discuss them.

 

 

Author Response

Comment 1: I find the subject of the research very interesting and original since there are not many studies on pediatric cardiac surgery, which is a difficult field of practice with many possible complications which may arise. While DHCA is a practice which most definitely aids in better outcomes for the patients, it is not without its risks which are clearly presented and investigated here. Since there are very few papers on the matter and on neonates, this manuscript is an important piece of research.
I find the methodology clearly presented and the investigated group well-constituted, since there are limited posibilities to gather more patients to investigate in this age-group.

The conclusions clearly and concisely summarise the findings of the study correlated with other papers on the matter and the references are appropriately chosen to support the findings and discuss them.

Response 1: Thank you very much for your good feedback, and we look forward to working with you and the reviewers to move this manuscript closer to publication in Pediatric Reports.

Reviewer 3 Report

Comments and Suggestions for Authors

Ghunaim et al. present a study on the neurodevelopmental effects of the application of deep hypothermic circulatory arrest (DHCA). Even if DHCA without any adjunct, such as regional cerebral perfusion, is rarely used in  today, it seems important to investigate which durations can be survived with relatively few complications using DHCA. The impact of the duration of the DHCA is also suggested in the title of the manuscript as the main focus of the study.

 

I have some minor comments:

-       If the duration of the DHCA has an impact, which should be the main result of this study, then the reader should also be informed about the actual duration of DHCA. I cannot find such data in the manuscript. For example, it would be useful to show the duration of the DHCA at which the complication rate increases.

-       The DHCA group naturally includes a high proportion of patients with palliative interventions, palliative interventions, in particular Norwood I. The control group consists exclusively of patients who have undergone corrective surgery. In this context, one could expect other problems in the postoperative course, especially in single-ventricle patients, such as oxygen desaturation problems or increased cardio-circulatory complications, even if Sano-shunts has always been used here.

-       The fact that DHCA was used in some patients, as in the arterial switch operation, and not in others, could indicate a more complex procedure, possibly with a more complication-prone postoperative course?

-       I am not sure whether the small number of cases with such different operations actually allows conclusions to be drawn.

-       Line 49 must be reworded: neither DHCA nor LFCPB noticeably reduce the mortality rate. It is probably true that they sometimes make operations possible in the first place, but neither option is healthy.

-       Line 130 "functions" could be replaced by "surgery" or "operation" or “intervention”.

-       The actual correlation between the duration of the DHCA and the complications identified should perhaps also be taken into account.

Comments on the Quality of English Language

Ghunaim et al. present a study on the neurodevelopmental effects of the application of deep hypothermic circulatory arrest (DHCA). Even if DHCA without any adjunct, such as regional cerebral perfusion, is rarely used in  today, it seems important to investigate which durations can be survived with relatively few complications using DHCA. The impact of the duration of the DHCA is also suggested in the title of the manuscript as the main focus of the study.

 

I have some minor comments:

-       If the duration of the DHCA has an impact, which should be the main result of this study, then the reader should also be informed about the actual duration of DHCA. I cannot find such data in the manuscript. For example, it would be useful to show the duration of the DHCA at which the complication rate increases.

-       The DHCA group naturally includes a high proportion of patients with palliative interventions, palliative interventions, in particular Norwood I. The control group consists exclusively of patients who have undergone corrective surgery. In this context, one could expect other problems in the postoperative course, especially in single-ventricle patients, such as oxygen desaturation problems or increased cardio-circulatory complications, even if Sano-shunts has always been used here.

-       The fact that DHCA was used in some patients, as in the arterial switch operation, and not in others, could indicate a more complex procedure, possibly with a more complication-prone postoperative course?

-       I am not sure whether the small number of cases with such different operations actually allows conclusions to be drawn.

-       Line 49 must be reworded: neither DHCA nor LFCPB noticeably reduce the mortality rate. It is probably true that they sometimes make operations possible in the first place, but neither option is healthy.

-       Line 130 "functions" could be replaced by "surgery" or "operation" or “intervention”.

 

-       The actual correlation between the duration of the DHCA and the complications identified should perhaps also be taken into account.

Author Response

Comment 1: If the duration of the DHCA has an impact, which should be the main result of this study, then the reader should also be informed about the actual duration of DHCA. I cannot find such data in the manuscript. For example, it would be useful to show the duration of the DHCA at which the complication rate increases.

Response 1: Thank you for your comment. We presented the mean DHCA duration in Tables 2 and 3 and in lines 131-140. Owing to the non-statistically significant results and the small sample size of our data, we did not go into detailed time sets, as these would not be a true representation of our results.

 

Comment 2: The DHCA group naturally includes a high proportion of patients with palliative interventions, palliative interventions, in particular Norwood I. The control group consists exclusively of patients who have undergone corrective surgery. In this context, one could expect other problems in the postoperative course, especially in single-ventricle patients, such as oxygen desaturation problems or increased cardio-circulatory complications, even if Sano-shunts has always been used here.

-       The fact that DHCA was used in some patients, as in the arterial switch operation, and not in others, could indicate a more complex procedure, possibly with a more complication-prone postoperative course?

-       I am not sure whether the small number of cases with such different operations actually allows conclusions to be drawn.

 

Response 2: Thank you for your detailed comment. The choice of using ASO was made in order to present a complex procedure without the use of DHCA, and this helped us in eliminating confounders in the analysis. We have accounted for these postoperative complications in our analysis, and there were no statistically significant differences in postoperative outcomes (Table 2). We agree that this is likely due to the small number of cases. Although this is a limitation of our study, we believe that the study has added to the literature, and our findings can serve as basis for other studies.

 

Comment 3: Line 49 must be reworded: neither DHCA nor LFCPB noticeably reduce the mortality rate. It is probably true that they sometimes make operations possible in the first place, but neither option is healthy.

Response 3: Thank you for your comment. We have clarified that the improvement in mortality is due to the feasibility of the operations and not because of the unhealthy adjuncts.

 

Comment 4: The actual correlation between the duration of the DHCA and the complications identified should perhaps also be taken into account.

Response 4: Thank you for your comment, we addressed this in response 2. We have taken it into account during the multivariate analysis; however, because of non-statistically significant differences in outcomes, we opted to present the trends of duration instead of using specific cutoffs, as this would have made the data much more confusing for the readers.

Reviewer 4 Report

Comments and Suggestions for Authors

Thank you to the authors for taking the time to report their experience on this sensitive subject.

This is a single-center retrospective study but it has the advantage of bringing together the skills of 2 teams experienced in pediatric cardiology and neurodevelopmental assessment of children.

In the end, there are no definitive statistically significant differences between the DHCA and the control group but only trends. This is well indicated in the conclusion which remains cautious in the interpretation of their results.

 

However, some weaknesses need to be addressed before publication.

The main one concerns the description of genetic factors. You limit the description to Down syndrome, but among the population, a large number of these have conotruncal malformations with a high rate of 22q11 deletion, which is a risk factor for cognitive delay.

Of course, you cannot do these investigations a posteriori, but you must explicitly mention what was done as a genetic assessment. Was this limited to clinical evaluation, karyotyping…

And you must state this limitation in the discussion. Your article deserves to be published provided that it can constitute a solid step for subsequent studies that will combine this genetic evaluation.

 

Another minor weakness lies in the sometimes clunky writing. Please proofread your manuscript from a purely syntactical and logical point of view.

 

After that, this article will be worth publishing and will be a useful and honest article for further investigation into this delicate topic.

Thanks for that

 

Comments on the Quality of English Language

For example: "All 18 patients underwent neurodevelopmental assessment using the Bayley Scales of Infant and Toddler 19 Development (BSTID) by a trained pediatrician. Seventeen of 25 DHCA and six of 10 control patients 20 completed the BSTID assessment." this sentence in the summary is not understandable and is not consistent with the description of the method.

But there are others possible examples

Author Response

Comment 1: The main one concerns the description of genetic factors. You limit the description to Down syndrome, but among the population, a large number of these have conotruncal malformations with a high rate of 22q11 deletion, which is a risk factor for cognitive delay.

Of course, you cannot do these investigations a posteriori, but you must explicitly mention what was done as a genetic assessment. Was this limited to clinical evaluation, karyotyping…

And you must state this limitation in the discussion. Your article deserves to be published provided that it can constitute a solid step for subsequent studies that will combine this genetic evaluation.

Response 1: Thank you for your comment. We only described Down syndrome because it was the only genetic syndrome in our patients. We were limited by the retrospective nature of this study, and we have used a confirmed diagnosis by a pediatrician as our indicator. We have addressed this comment in the limitations section of the discussion.

 

Comment 2: For example: "All 18 patients underwent neurodevelopmental assessment using the Bayley Scales of Infant and Toddler 19 Development (BSTID) by a trained pediatrician. Seventeen of 25 DHCA and six of 10 control patients 20 completed the BSTID assessment." this sentence in the summary is not understandable and is not consistent with the description of the method

Response 2: Thank you for your comment. This has been edited in the abstract (line 21) to clarify that only enrolled patients have been assessed by BSTID, and we specified only the number of patients who had completed the BSTID assessment.

Round 2

Reviewer 4 Report

Comments and Suggestions for Authors

congratulations, you have made the necessary changes. Thank you for your contribution on this delicate subject.