Early Vasoplegia and Endothelial Protection in Sepsis: A Physiology-Guided Framework for Timely Albumin and Norepinephrine Therapy

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript addresses an interesting and wide overview of delta-sepsi phenotype and the right timing of norepinephrine and albumine therapy strategies. However, the paper would strongly benefit from restructuring, deeper critical synthesis, and clearer linkage among sections.

- The abstract is too general. Please clarify the scope and the results of this study;

- The introduction lacks a clear problem statement and does not articulate the rationale for this review. Explicitly define the clinical/scientific gap and the review’s objectives;

- The manuscript lacks a clear structure. Sections appear disconnected and transitions are abrupt. Please reorganize content into coherent thematic sections with connection and gradual transition among the arguments.

- The review is mostly descriptive. Critical synthesis is limited. Please compare findings across studies, highlight consistencies/discrepancies, and discuss implications and gaps.

- Some references are incomplete or outdated. Ensure consistency with journal formatting standards.

The manuscript has potential but requires substantial restructuring and methodological clarification.

Comments on the Quality of English Language

Several sentences require refinement for clarity and academic tone. Thorough English editing is recommended. Rephrase long or ambiguous sentences.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript is designed as a review of the problem, an explanation of possible solutions, and recommendations for specific situations. The structure is consistent with the style of scientific publications, descriptions, and illustrations complement the text well. The illustrations are precise, algorithmic, and adequately explained. An excellent discussion section, in which the analysed situations are successfully examined from the currently available evidence base and also has a perspective. The material is valuable, informative, and helpful for those working in practical medicine and also in theoretical science, and will undoubtedly be cited in internationally peer-reviewed scientific publications. Reviewer's assessment - publish in the current format.

Author Response

We thank the reviewer for the positive and encouraging assessment of the manuscript. We appreciate the recognition of the structure, clarity, and relevance of the work and are pleased that the review is considered suitable for publication in its current format.

Reviewer 3 Report

Comments and Suggestions for Authors

This narrative review presents a compelling and timely hypothesis that reframes albumin therapy in sepsis from a late corrective measure to an early endothelial-protective strategy. The authors synthesize contemporary evidence on sepsis phenotypes (particularly the δ phenotype), intravascular albumin mass (IVAM), and early vasoplegia detected by non-invasive monitoring to propose a physiology-guided framework for the combined use of early norepinephrine and judicious albumin. The central thesis—targeting a "pre-δ" window of reversible endothelial dysfunction—is innovative and addresses significant limitations of current albumin use based on static serum concentrations. The manuscript is generally well-written, logically structured, and supported by a substantial body of referenced literature, including the authors' own recent prospective work. Key Points for Consideration and Clarification While the proposed framework is promising, several aspects require further elaboration or acknowledgment of limitations to strengthen the manuscript's impact and guide future research. 1 The framework's success hinges on reliably identifying the proposed "pre-δ" or early reversible vasoplegic state. The manuscript would benefit from a more precise, operational definition of this state using the proposed parameters (e.g., thresholds or trends in SVR, IVAM, lactate/albumin ratio, SOFA-CV) to guide inclusion criteria for future trials. How does this state differ definitively from early δ or other phenotypes in real-time? 2 The observational data showing an inverse correlation between fluid balance and IVAM decline is compelling. However, the discussion should more explicitly address the challenge of distinguishing cause and effect. Does positive fluid balance drive IVAM decline via hemodilution and exacerbated leak, or is a falling IVAM (indicating active leak) a cause of fluid maldistribution and positive balance? The proposed therapeutic model (early NE to reduce fluid need, plus albumin) seems to target both possibilities, but this nuance is important. 3 The rationale for early NE is well-supported from a hemodynamic perspective (faster MAP target, fluid-sparing). However, the assertion of its role in "endothelial protection" is currently indirect, based on mitigating fluid overload. The mention of potential catecholamine-induced glycocalyx shedding [87] is a valid concern. This section should be balanced by acknowledging that the direct endothelial effects of NE in this context are complex and not uniformly protective; its primary proposed benefit here is functional (pressure restoration and fluid minimization) rather than direct cellular protection. 4 The framework relies on serial measurements of IVAM, lactate, and non-invasive SVR. A brief discussion on the practical feasibility, required frequency of monitoring, and the limitations of non-invasive hemodynamic monitoring techniques (e.g., impedance cardiography) in diverse clinical settings (ED, ward, ICU) would add depth. What is the proposed "monitoring bundle" and its expected turnaround time? 5 The discussion of the ARISS trial is appropriate. It could be strengthened by more explicitly contrasting ARISS's "static concentration target" approach with the proposed dynamic, physiology-guided strategy. This directly highlights the manuscript's core argument: it's not about if albumin is given, but when, to whom, and based on what physiological state. 6 The manuscript effectively argues for albumin's potential endothelial-stabilizing and oncotic effects in the pre-leak state. To avoid ambiguity, explicitly state that in the proposed active leak phase ("dynamic exclusion zone"), albumin is not recommended for volume or oncotic support, as it would extravasate. Its role is confined to the pre-leak or recovery windows. Minor Points 1 Figure 1 and the associated text in Section 3.2 describe a "triphasic sequence." Ensure the labels in the text (Hyperinflammatory activation, Glycocalyx injury..., Clinical expression...) perfectly match the boxes in the figure for clarity. 2 Page 2, line 48: "transcapillary escape rate of albumin increases" - consider specifying "in sepsis" or "in critical illness" for immediate context. 3 The conclusion is robust. Consider adding one sentence reiterating that this is a hypothesis-generating framework awaiting prospective validation.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

All comments have been corrected, and the article's content has been aligned with the requirements.

Comments on the Quality of English Language

Several sentences require refinement to make them clearer and more academic. Careful revision of the English text is recommended. Reword long or ambiguous sentences.