Personalized Hemodynamic Resuscitation Targeting Capillary Refill Time in Early Septic Shock: The ANDROMEDA-SHOCK-2 Randomized Clinical Trial.
ANDROMEDA-SHOCK-2 Investigators for the ANDROMEDA Research Network, Spanish Society of Anesthesiology, Reanimation and Pain Therapy (SEDAR), and Latin American Intensive Care Network (LIVEN), Hernandez G, Ospina-Tascón GA, Kattan E, Ibarra-Estrada M, Ramasco F, Orozco N, Ramos K, Aldana JL, Ferri G, Hamzaoui O, De Backer D, Teboul JL, Vieillard-Baron A, Petri Damiani L, García-Gallardo GA, Morales S, Carmona Garcia P, Mendez R, Hernandez-Gilsoul T, Pérez-Nieto OR, Olea Vielba C, Ramos S, Dominguez D, Bruna M, David S, Wendel-Garcia PD, Galiana-Ivars M, Myatra SN, Messina A, Cecconi M, Pozo M, Amthauer M, Higuera E, Al Duhalib Z, Rico-Feijoo J, Ferrer-Gómez C, Pérez-Carbonell A, Martinez-Castro S, Redondo Calvo FJ, Vives M, Sanchez HF, Bilbao I, Fernandez P, Al-Fares A, Benitez-Cano A, Gonzalez C, Reyes LF, Rodriguez-Guillen JH, Cristino AV, Pendino JC, Ortiz G, Alonso-Gonzalez MC, Murias G, Aguirre-Ávalos G, Hernández L, Calderón Barajas ZA, Zarragoikoetxea I, Monnet X, Goury A, Mendonça Dos Santos T, Vallecilla L, Martins de Lima L, Sady E, Alegria L, Ostermann M, Bakker J, Biasi Cavalcanti A
- DOI
- 10.1001/jama.2025.20402
- Record issued
- 2026-08-15
- Engine
- 7.39.0
- Exported
- 2026-09-20
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How this rating was calculated
- IntegrityIntegrity concern ×2−1★
- StatisticsStatistic did not reproduce−0.5★
- StatisticsPrinted percentage does not match its own count (capped) ×2−0.25★
- ReportingData & code availability partially met−0.25★
- The numeric-impossibility checks (GRIM/GRIMMER/DEBIT/SPRITE) did not run: 4 reported means were read, and their group size is not stated where the values are printed (this source has no machine-readable table structure). These checks need the count the mean was averaged over, so none was performed.
- No data or code availability links were detected to verify.
- 01Printed percentage does not match its own count
51% does not match the reported count 314/628
“314/628 (51.0)”
Table 1 - 02Printed percentage does not match its own count
15% does not match the reported count 111/720
“111 of 720 (15%)”
Results - 03Printed percentage does not match its own count
6% does not match the reported count 44/720
“44 of 720 patients (6%)”
Results
This Kaimen Rigor review uses Kaimen Rigor reviewers trained on a curated corpus of high-fidelity and retracted papers, with expert supervision and curation. It can still make mistakes; verify each finding against the source before relying on it.
This is a well-conducted multicenter RCT with rigorous design, clear reporting, and appropriate statistical methods. The main weakness is the vague data availability statement, which lacks a concrete access route. Minor copyedit issues exist in the abstract and results sections.
Both reviewers agreed on study type (interventional) and on all dimension statuses except minor sub-criterion disagreements (limitations addressed, outlier handling, regulatory compliance) which were resolved by weighing the evidence. The statistics verification covered only a subset of tests; the 3 inconsistent results were not specified, so no specific errors were confirmed. The citation check found no retracted or unresolved references.
Numerical inconsistencies
3 findings · worst highValues that contradict each other or are impossible for the stated sample: recomputed p-values and test statistics, GRIM/GRIMMER checks on summary numbers, percentages against their own counts, totals against their parts, and estimates against their own confidence intervals.
- Summary statistic impossible for the stated N (GRIM/GRIMMER)Recomputed
- Printed percentage does not match its own countRecomputed
- Internal contradictions in the reported numbersAssessed
Recomputed 2 tests: 2 consistent, 0 inconsistent; 2 via agent-written checks. 1 reported summary statistic mathematically impossible for the stated N (PERCENT). 2 printed percentages that do not match their own count.
- PERCENT15% does not match the reported count 111/720
“111 of 720 (15%)”
Results - PERCENT6% does not match the reported count 44/720
“44 of 720 patients (6%)”
Results - PERCENT51% does not match the reported count 314/628
“314/628 (51.0)”
Table 1
- CONSISTENTreported p = .910 · recomputed p = .922Reviewers 1, 2Recompute p-value for mortality hazard ratio from CI.
“there was no significant difference in 28-day mortality between the CRT-PHR and usual care groups (26.5% vs 26.6%; hazard ratio, 0.99 [95% CI, 0.81-1.21]; P = .91)”
Taken as given: The hazard ratio is log-normally distributed.; The 95% CI is two-sided.Method: Compute p-value from log hazard ratio and its 95% CI using normal approximation.How we recomputed it: pCI(0.99, 0.81, 1.21, 1) - CONSISTENTreported p = .040 · recomputed p = .028Reviewer 2Recompute the p-value for the primary win ratio from the reported win ratio and 95% CI.
“yielding a stratified win ratio of 1.16 (95% CI, 1.02-1.33; P = .04)”
Taken as given: The win ratio is a ratio estimate, so log=1.; The CI is a 95% confidence interval.; The p-value is two-sided.Method: Used pCI function to derive p-value from the estimate and 95% CI on the log scale.How we recomputed it: pCI(1.16, 1.02, 1.33, 1)
- lowinternal contradictionThe abstract reports '131 131 wins (48.9%)' and '112 787 (42.1%)', but the sum of these percentages (48.9% + 42.1% = 91.0%) plus ties (9.0%) equals 100%, which is consistent. However, the number '131 131' appears with a space, which may be a typographical error.
“There were 131 131 wins (48.9%) in the CRT-PHR group vs 112 787 (42.1%) in the usual care group”
Abstract - lowinternal contradictionThe abstract reports 1501 randomized patients, but the results section states 744 randomized to CRT-PHR and 757 to usual care, which sums to 1501. However, the figure shows 757 randomized to usual care and 744 to CRT-PHR, consistent. No contradiction found.
“From 1501 randomized patients, 1467 were included in the primary analysis”
Abstract
Overstated conclusions
None foundConclusions that reach past what the paper's own results support — including a significance claim that no longer holds when the statistic is recomputed, and efficacy resting on an unvalidated surrogate endpoint.
Checked — nothing surfaced.
4 major claims checked against the paper's own evidence: all adequately supported.
- supportedReviewers 1, 2A personalized hemodynamic resuscitation protocol targeting capillary refill time was superior to usual care for the primary composite outcome.The primary outcome analysis shows a win ratio of 1.16 with 95% CI excluding 1 and p=0.04, supporting superiority.Evidence: Stratified win ratio 1.16 (95% CI, 1.02-1.33; P = .04).
“a personalized hemodynamic resuscitation protocol targeting capillary refill time was superior to usual care for the primary composite outcome”
Abstract - supportedReviewers 1, 2The effect was primarily due to a lower duration of vital support.The individual wins for duration of vital support were higher (26.4% vs 21.1%) compared to death and length of stay, supporting the claim.Evidence: Individual wins for death were 19.1% vs 17.8%; duration of vital support, 26.4% vs 21.1%; and length of hospital stay, 3.4% vs 3.2%.
“primarily due to a lower duration of vital support”
Abstract - supportedReviewers 1, 2The CRT-PHR strategy improved patient-centered outcomes in early septic shock.The primary composite outcome improved, and secondary outcomes showed no harm, supporting the claim.Evidence: Primary outcome win ratio 1.16; secondary outcomes showed no significant difference in mortality but more organ support-free days.
“A personalized hemodynamic resuscitation strategy targeting capillary refill time normalization improves patient-centered outcomes in early septic shock.”
Key Points - supportedReviewer 2The trial had a power of 88% to show superiority in the hierarchical composite outcome.The power calculation is described with assumptions and sample size, supporting the claim.Evidence: Statistical Analysis section.
Using the win ratio method with these 3 components and with 1500 patients enrolled, the trial had a power of 88% to show superiority in the hierarchical composite outcome for a 2-sided α of .05.
Statistical analysisreviewer’s wording
Efficacy claim is anchored to an adequate endpoint and a meaningful effect.
- ADEQUATESurrogate endpointThe primary outcome is a hierarchical composite of mortality, duration of vital support, and length of hospital stay, which are hard clinical outcomes. The intervention targets capillary refill time (CRT) normalization, but the primary endpoint is not solely a surrogate; it includes mortality and clinical events. The paper also demonstrates target engagement by showing higher CRT normalization in the intervention group (85.9% vs 61.7%) and cites prior evidence linking CRT to outcomes (ANDROMEDA-SHOCK trial).
“The primary outcome was a hierarchical composite outcome: (1) all-cause mortality within 28 days, (2) duration of vital support ... and (3) length of hospital stay truncated at day 28.”
- ADEQUATEEffect sizeThe primary effect is a win ratio of 1.16 (95% CI, 1.02-1.33; P = .04) for the hierarchical composite outcome, which is statistically significant. The effect is anchored to clinical meaningfulness as it reflects a reduction in mortality, duration of vital support, and hospital stay. The win ratio is a clinically meaningful measure of benefit, and the paper discusses the clinical relevance of reduced organ support duration.
“a stratified win ratio of 1.16 (95% CI, 1.02- 1.33; P = .04)”
Data authenticity concerns
None foundAn adversarial read for patterns associated with data that may not be genuine: results that look too clean, implausibly large effects, duplicated data or images, and methods that do not match the results reported.
Checked — nothing surfaced.
Reporting gaps
1 finding · worst mediumRequired detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.
- Data/code availability incompleteAssessed
The introduction cites prior trials (liberal vs restrictive fluids, high vs low MAP targets) and the ANDROMEDA-SHOCK trial, acknowledging their limitations and the need for personalized approaches. The rationale linking CRT-targeted resuscitation to improved outcomes is well articulated, and the study objectives follow logically from the cited evidence.
Randomization used a web-based system with permuted blocks and stratification by center, ensuring allocation concealment. The trial was unblinded, which is acknowledged as a limitation. A power analysis was performed using the win ratio method with 88% power. Inclusion/exclusion criteria were defined, and the analysis population (ITT) was pre-specified. Outlier handling is addressed through the ITT analysis and missing data approach.
“The trial was unblinded to patients and clinicians.”
“The trial was unblinded to patients and clinicians.”
The paper reports sex (female/male percentages), age (median and IQR), weight, and various comorbidities in Table 1. Since both sexes are enrolled, sex_justified is not applicable. Demographics are adequately reported for a clinical trial.
“Sex, No. (%) Female 302 (41.9) 334 (44.7) Male 418 (58.1) 413 (55.3)”
“Age, median (IQR), y 66.0 (52.0-74.0) 65.0 (51.0-76.0)”
“Comorbidities Chronic hypertension 162/705 (23.0) 179/730 (24.5)”
“Female 302 (41.9) 334 (44.7)”
“Age, median (IQR), y 66.0 (52.0-74.0) 65.0 (51.0-76.0)”
The trial was approved by the institutional review board at each participating site, and written informed consent was obtained from patients or legal representatives. Regulatory compliance is implied through adherence to CONSORT and local regulations.
“The trial was approved by the institutional review board at each participating site.”
“Written informed consent was obtained from patients or their legal authorized representatives according to local regulations.”
“The trial is reported in accordance with the 2025 Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines.”
“The trial was approved by the institutional review board at each participating site.”
“Written informed consent was obtained from patients or their legal authorized representatives according to local regulations.”
The trial uses a protocol-based intervention rather than a drug or device, but the protocol is described in sufficient detail. The statistical software (R version 4.2.3) is identified. No antibodies, cell lines, or other biological reagents are used, so those criteria are not applicable.
The primary analysis uses the stratified win ratio method, and secondary outcomes use appropriate models (Cox, cumulative logistic, GAMLSS). Effect sizes are reported with 95% CIs. Exact p-values are provided for the primary outcome and mortality. Software is identified. Data presentation includes per-group n and appropriate figures.
“SWR, 1.16 (1.02 to 1.33)”
“HR, 0.99 (0.81 to 1.21)”
The paper states 'Data Sharing Statement: See Supplement 4.' This is vague and does not specify a concrete access route. Since the trial involves patient data, repository deposit and accession numbers are not applicable, but the data availability statement is inadequate.
“Data Sharing Statement: See Supplement 4.”
“Data Sharing Statement: See Supplement 4.”
The trial is registered (NCT05057611), reported per CONSORT, and all outcomes are reported. Limitations are extensively discussed. Conclusions are proportional to the evidence. Funding and conflicts of interest are disclosed.
“TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT05057611”
“The trial is reported in accordance with the 2025 Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines.”
“This study has limitations. First, it was unblinded.”
“TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT05057611”
“The trial is reported in accordance with the 2025 Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines.”
“This study has limitations. First, it was unblinded.”
Registered (1 ID: ClinicalTrials.gov). Reporting guideline cited: CONSORT.
Broken references and links
None found · partly checkedReferences checked against Crossref, OpenAlex and Retraction Watch for retractions and resolvability, plus declared data and code links probed for whether they resolve to content matching the paper.
Nothing surfaced — but not everything feeding this category ran (missing: data/code link verification), so read this as a partial clean bill.
Checked 38 references by DOI: 38 verified.
Every extracted reference resolved against Crossref/OpenAlex with no retraction flags.
Copyediting
3 minorWording, consistency and formatting errors that need correcting before submission.
No major wording or formatting errors. 3 minor suggestions below.
3 copyedit issues flagged: mostly typo, consistency.
- MINORtypoAbstract, Results“There were 131 131 wins (48.9%) in the CRT-PHR group vs 112 787 (42.1%) in the usual care group”→ Consider using commas for large numbers (e.g., 131,131) for readability.Spacing in large numbers is unusual but not incorrect.
- MINORtypoAbstract, Results“There were 131 131 wins (48.9%)”→ Remove the space between '131' and '131' to read '131,131'.The number is written with a space instead of a comma, which is a formatting inconsistency.
- MINORconsistencyResults, Protocol Interventions“In the usual care group, 62% of patients had fluid responsiveness assessed at any time point, while 68% had basic echocardiography assessments.”→ Consider adding the denominator for clarity, e.g., '62% (n=...) of patients'.Percentages are given without denominators, which is a minor reporting inconsistency.
The published work is robust and well-reported, with only minor reporting gaps. An informed reader should weigh the vague data sharing statement and the unblinded design as limitations. No erratum is warranted based on the identified issues, but the authors should consider clarifying data access and addressing the minor copyedit inconsistencies.
- 1.HIGHdata codeIn the Data Sharing Statement (Article Information), provide the actual data availability statement in the main text, including the access mechanism (e.g., data access committee, platform) and conditions, rather than only referencing Supplement 4.The current statement is vague and does not provide a concrete route for data access, which is a reporting gap that reviewers and readers will notice.
- 2.HIGHdata codeIn the Data Sharing Statement, specify whether individual participant data will be deposited in a repository or made available through a managed-access process, and provide a contact or URL.A clear data access route is essential for reproducibility and transparency in a clinical trial.
- 3.HIGHdata codeIn the Methods or Data Sharing Statement, state whether the analysis code is available and where (e.g., a public repository), or explain why it is not shared.Sharing analysis code facilitates replication and is increasingly expected for clinical trials.
- 4.MEDIUMethicsIn the Methods, explicitly state the regulatory framework (e.g., Declaration of Helsinki) under which the trial was conducted.Explicitly naming the regulatory framework strengthens the regulatory compliance statement.
- 5.MEDIUMrigorIn the Methods, describe how outliers or extreme values were handled in the analysis, or state that no outliers were excluded.Explicitly addressing outlier handling clarifies the analysis approach and addresses a reviewer concern.
- 6.MEDIUMdata codeIn the Data Sharing Statement, provide a timeline for data availability and the process for requesting access.A timeline and process make the data sharing statement more concrete and actionable.
- 7.LOWcopyeditIn the Abstract, Results, change '131 131' to '131,131' and '112 787' to '112,787' for readability.The spacing in large numbers is unusual and may be a typographical error.
- 8.LOWcopyeditIn the Results, Protocol Interventions, add denominators to the percentages (e.g., '62% (n=...)') for clarity.Providing denominators improves the clarity and completeness of the reported percentages.
The star rating is the report’s one-glance summary. Every paper starts at 5★ and loses stars for the concrete problems the review finds — so a rating is never a vague average, it’s a running total you can read line by line under “How this rating was calculated.”
- Reporting — 8 dimensionseach dimension that fully fails−½★
- each dimension partially met−¼★
- Statistics · Integrity · Claimseach serious problem−1★
- each medium problem−½★
- Citationseach retracted or unverifiable reference−¼★
- Copyeditonly when the manuscript needs a full edit−½★
The rating never drops below 1★, and a demonstrable critical failure (an impossible statistic, a proven ethics violation) caps it at 1★ on its own — so the stars can never look healthy when the verdict is CRITICAL.
The rating draws on a panel of agents. Three independent Kaimen Rigor reviewers grade the eight dimensions below across several independent passes (the shown verdict is their majority vote — steadier than any single run), isolate the paper’s major claims and check its own evidence backs them, and flag integrity concerns. Alongside them, a citation agent resolves every reference against Crossref, OpenAlex, and Retraction Watch; a statistics agent recomputes reported tests; and rule-based checks verify that declared data/code links actually resolve. Full text is required — an abstract-only submission is not analyzed.
Graded against NIH, MDAR, ARRIVE 2.0, CONSORT, EQUATOR, and RRID guidelines. A dimension that doesn’t apply to the study type is skipped, never penalized.
This Kaimen Rigor review is model-assisted and is not a substitute for formal expert review. It complements human evaluation by surfacing potential methodological concerns — verify each finding against the source.