PONE-D-25-68208Comparing the safety and efficacy of sodium valproate, levetiracetam, and phenytoin in attenuating the severity of agitation in patients with post-traumatic brain injury: an observational studyPLOS One

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Reviewers' comments:

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Comments to the Author

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The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

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3. Have the authors made all data underlying the findings in their manuscript fully available?

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Reviewer #1: Yes

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Reviewer #1: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors of PONE-D-25-68208 conducted a prospective study to compare the safety and efficacy of sodium valproate, levetiracetam, and phenytoin in agitation control in patients managed after traumatic brain injury.

The study concludes that sodium valproate has higher efficacy and rapid beneficial actions in reducing agitation compared to levetiracetam, and the authors suggest that this treatment strategy offers better safety profile than phenytoin and levetiracetam.

I believe that the study was well designed and reported, the reference list is extremely poor and would benefit from inclusion of other relevant works. I do not totally agree with the conclusion that sodium valproate is easier to use than levetiracetam and would also modify the conclusion accordingly. Please see my detailed points below:

The introduction would benefit from additional references on delirium incidence, pathophysiology and management in NeuroIntensive Care Unit and in particularly following admission of silver traumas, given the increased risk in elderly patients. Please consider the followings:

- O'Keeffe F, et al. Serum biomarkers of delirium in critical illness: a systematic review of mechanistic and diagnostic evidence. Intensive Care Med Exp. 2025;13(1):90. doi: 10.1186/s40635-025-00795-z.

- Depreitere B, et al. Unique considerations in the assessment and management of traumatic brain injury in older adults. Lancet Neurol. 2025;24(2):152-165. doi: 10.1016/S1474-4422(24)00454-X.

I would also suggest to provide a better rationale for the use of antiepileptics, the authors provide only one paragraph about that. Ganau et al. provided a clear rationale for such pharmacological class and I would suggest to refer to their section dedicated to antiepileptics:

- Ganau M, et al. Delirium and agitation in traumatic brain injury patients: an update on pathological hypotheses and treatment options. Minerva Anestesiol. 2018;84(5):632-640. doi: 10.23736/S0375-9393.18.12294-2.

The antiepileptic drugs suggested are very effective in TBI patients however at present there is no equipoise on the most appropriate strategy, in fact the randomized trial MAST (see https://clinicaltrials.gov/study/NCT04573803) is still enrolling patients to clarify this matter. At present the only consensus is on the use of sedation plus poly-pharmacological strategy for the management of status epileptics following TBI (see Prisco L, et al. A pragmatic approach to intravenous anaesthetics and electroencephalographic endpoints for the treatment of refractory and super-refractory status epilepticus in critical care. Seizure. 2020;75:153-164. doi: 10.1016/j.seizure.2019.09.011.).

A consideration on those important pieces of scientific research is certainly warranted.

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Reviewer #1: No

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Comparing the safety and efficacy of sodium valproate, levetiracetam, and phenytoin in attenuating the severity of agitation in patients with post-traumatic brain injury: an observational study

PONE-D-25-68208R1

Dear Dr. Gangachannaiah,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Academic Editor

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Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Authors have conducted a robust revision, their rebuttal letter provides a comprehensive outline of the changes made in the manuscript and I'm pleased to say that they have addressed all reviewers' comments

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Reviewer #1: No

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