Splenic Doppler Velocity–Time Integral as a Dynamic Marker of Visceral Perfusion in Adults with Septic Shock: A Prospective Pilot Feasibility Study

Splenic Doppler Velocity–Time Integral as a Dynamic Marker of Visceral Perfusion in Adults with Septic Shock: A Prospective Pilot Feasibility Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Splenic Doppler Velocity–Time Integral as a Dynamic Marker of Visceral Perfusion in Adults with Septic Shock: A Prospective Pilot Feasibility Study Santiago Beltramino, Agustín Manchado, Fernanda Coñequir, Diego Arufe This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8245171/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: In septic shock, restoring macrohemodynamics does not guarantee microcirculatory recovery. Capillary refill time (CRT) is a simple, guideline-endorsed bedside marker; however, its accuracy can be confounded by edema, temperature, and skin pigmentation.Regarding visceral perfusion, traditional splenic Doppler indices (RI and PI) primarily reflect vascular resistance and vasomotor tone, failing to reliably predict relevant clinical outcomes. Conversely, the velocity–time integral (VTI) is a quantitative correlate of blood flow volume. We therefore hypothesized that splenic VTI (s-VTI) could serve as a superior, real-time bedside signal of organ perfusion Methods: Prospective within-patient paired analysis conducted in a tertiary ICU. Adults with septic shock (n = 16) underwent splenic pulsed-wave Doppler in two clinically adjudicated states (worse→better), defined by a pre-specified bedside hierarchy of improvement (CRT → norepinephrine → MAP). Doppler data were not used for adjudication. The primary outcome was the paired change in splenic velocity–time integral (Δs-VTI = s-VTI_better − s-VTI_worse); secondary outcomes were changes in RI and PI. Analyses were descriptive and hypothesis-generating. Results: Δs-VTI was > 0 in 16/16 pairs (exact sign test one-sided p < 0.001). Median s-VTI_worse was 16.6 cm (IQR 11.1–18.7) vs s-VTI_better 32.1 cm (IQR 23.9–38.3); the median paired change was +15.8 cm (IQR 9.0–23.1), corresponding to a +93.8% increase from the worse state (IQR 59.5–204.8%). CRT moved in the expected direction (median 7.2 → 2.0 s; Δ −5.25 s, IQR −8.0 to −3.4), with normalization <3 s in 13/16 better states. RI/PI showed limited and variable directional behavior: RI_worse 0.64 (IQR 0.57–0.70) vs RI_better 0.60 (IQR 0.55–0.66), with concordant decrease in 9/16 pairs (56.3%); PI_worse 1.28 (IQR 0.89–1.35) vs PI_better 1.11 (IQR 0.84–1.30), concordant in 8/16 (50.0%). Conclusions: In this prospective within-patient case series, s-VTI increased in the clinically adjudicated better vs worse state in all 16pairs, nearly doubling in the median. s-VTI behaved as an organ-level flow marker with consistent directional behavior, likely reflecting the re-expansion of the splenic volume reservoir, potentially complementing CRT in bedside perfusion assessment, whereas RI and PI proved inconsistent, providing limited directional information under vasoplegic sepsis. These hypothesis-generating findings warrant prospective validation to confirm reproducibility and define actionable thresholds. Ultrasonography Doppler Splenic Artery Regional Blood Flow Hemodynamics Shock Septic Critical Care Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Septic shock is a life-threatening condition characterized by circulatory and metabolic failure with tissue hypoperfusion and multiorgan dysfunction ( 1 ) . Resuscitation targets often focus on macrocirculatory variables, mean arterial pressure (MAP) and cardiac output, yet these targets may not secure adequate tissue perfusion ( 2 ) . Current guidelines endorse bedside assessment of perfusion with capillary refill time (CRT) ( 3 ) . CRT is a simple bedside marker associated with short-term outcomes, although its reliability may be limited by vascular disease, skin factors, temperature, and vasoactive drugs ( 4 , 5 ) . Other surrogates, such as lactate, the venous–arterial CO₂ difference, and sublingual microcirculation, are constrained by delayed kinetics or limited availability ( 6 , 7 ) . Point-of-care ultrasound (POCUS) is widely used in septic shock to guide resuscitation by estimating cardiac output and assessing pulmonary and venous congestion, yet it is seldom applied to monitor organ-specific perfusion, where few validated bedside tools provide real-time assessment of visceral blood flow. Splenic Doppler has shown potential for splanchnic flow assessment and fluid responsiveness outside sepsis ( 8 ) . However, in septic shock, studies of splenic doppler resistive index (RI) and pulsatility index (PI) have not demonstrated consistent incremental value for hemodynamic monitoring, and no sepsis-specific thresholds have been established ( 9 ) . By contrast, the velocity-time integral (VTI) measured at left ventricular outflow is validated for cardiac stroke-volume estimation and kidney VTI has shown promise for predicting acute kidney injury ( 10 ) . These observations, together with the spleen’s role as a hemodynamic reservoir under sympathetic control, where volume contraction (and subsequently lower flow) is expected during hypoperfusion and splenic re-expansion (higher flow) during adequate resuscitation, support the conceptual rationale for a splenic velocity–time integral (s-VTI) as a directional, organ-level flow signal that may track splanchnic perfusion at the bedside ( 11 , 12 , 13 ) . We hypothesized that, in septic shock, s-VTI integrating the forward velocity–time signal would be higher in a clinically adjudicated better than worse state and behave more directionally than RI/PI. Methods Design and setting Prospective exploratory case series with a structured within-patient paired analysis conducted in a single tertiary-care ICU. Sixteen consecutive adult patients with septic shock (Sepsis-3 criteria) were included, and one healthy volunteer was examined as a technical reference but was not included in inferential analyses. Data were obtained during routine clinical care; no study-specific interventions were performed. Written informed consent was obtained from each participant or their legal representative. Splenic Doppler acquisition Bedside splenic Doppler ultrasound was performed using a Mindray Consona M6 Pro system (Mindray, Shenzhen, China) equipped with a phased-array P4-2s transducer (1–5 MHz) under the “Abdomen” preset. Patients were examined in a supine or slight right-lateral position. The splenic artery was visualized longitudinally at the hilum, and pulsed-wave Doppler sampling was placed within the splenic parenchyma, 1–2 cm distal to the hilum, corresponding to an intraparenchymal arterial branch. At each time-point, two acquisitions were initially obtained in separate parenchymal branches, and the most stable trace was selected for serial comparison. When feasible, the same intraparenchymal branch was re-identified in follow-up scans to maintain internal consistency. Each measurement comprised three consecutive cardiac cycles. Recorded parameters included s-VTI (cm), PSV (peak systolic velocity), EDV (end-diastolic velocity), MV (mean velocity), RI, and PI, all obtained from the same Doppler envelope. Scans were performed by two attending intensivists (> 5 years of POCUS experience) following a brief calibration session; inter-operator reproducibility was not formally assessed. VTI values were obtained by manual tracing of the Doppler envelope using the system’s built-in software. Clinical states and timing Each patient contributed two bedside states, worse and better, adjudicated by a pre-specified hierarchy without using Doppler data: primary—CRT (longer = worse) measured concurrently with Doppler; if CRT was unreliable, norepinephrine (NE) dose (higher = worse); if tie, mean arterial pressure (MAP) ( 65 mmHg, was adjudicated as worse → better because CRT is the primary determinant and improvement was accompanied by vasopressor withdrawal. Doppler metrics were not used to define states. In the expanded cohort, most paired assessments were obtained during clinical recovery, with bedside adjudication indicating improvement in 14/16 state transitions and deterioration in 2/16 according to the predefined hierarchy, irrespective of acquisition order. Sensitivity analyses were performed by repeating the primary within-patient paired analysis using alternative adjudication criteria based on (i) norepinephrine dose only and (ii) MAP only. Results of these sensitivity analyses were consistent with the primary paired findings. Outcomes Primary (within-patient dynamic change). For each patient we computed a single paired change in splenic VTI: Δs\text{-VTI} = s\text{-VTI}_{\text{better}} − s\text{-VTI}_{\text{worse}} \ (\mathrm{cm}), testing whether s-VTI is higher in the better state across patients. Secondary (exploratory): Directional concordance between the change in s-VTI and CRT (shorter = better). Paired behavior of RI and PI across states, classified as concordant or paradoxical relative to s-VTI. Statistical analysis Given the case-series design and modest sample, analyses were descriptive and hypothesis-generating. Paired observations were defined by perfusion state (better vs worse) using pre-specified bedside criteria (shorter CRT, lower norepinephrine dose, higher MAP), irrespective of temporal order. Continuous variables are summarised as median (IQR) and categorical variables as n/N (%) with exact binomial 95% CIs. No multiplicity adjustment was applied and no imputation was performed. Primary inference. We tested whether Δs-VTI > 0 across patients using an exact sign test (one-sided directional hypothesis; two-sided p-values also reported). We report the median (IQR) Δs-VTI and the percent change from the worse state. As sensitivity analyses, we present the exact Wilcoxon signed-rank test (Pratt method for ties) and the Hodges–Lehmann paired median difference with exact 95% CI. Secondary summaries. CRT: ΔCRT = CRT_better − CRT_worse summarized as median (IQR); among better states, the proportion with CRT normalization < 3 s is reported with exact binomial 95% CIs. No formal hypothesis testing was pre-specified for CRT. RI/PI: state-paired comparisons reported as medians (IQR) for RI_worse, RI_better, PI_worse, PI_better. Within each patient we classified the Doppler response as concordant (higher in worse, lower in better) or paradoxical (opposite), and summarized n/N with exact binomial 95% CIs. Given heterogeneity and sample size, no hypothesis tests were planned for RI/PI. Per-patient ΔRI and ΔPI are provided in Table 1/Supplement. Norepinephrine and MAP were collected to adjudicate perfusion states and were not analyzed as endpoints. Software. Analyses were conducted in Python 3.11. The sign test was implemented as an exact binomial test with ties (Δ = 0) excluded. The Hodges–Lehmann estimator for paired differences and a distribution-free 95% CI for the median of differences (from sign-test order statistics) were computed from the empirical distributions. Exact binomial CIs for proportions used the Clopper–Pearson method. Results Patients and measurements Sixteen adult ICU patients with septic shock and one healthy volunteer were included. The healthy volunteer provided a technical benchmark (s-VTI ≈ 39 cm, RI ≈ 0.52, PI ≈ 0.79). For each patient, two perfusion states were captured within the same ICU stay (worse and better) based on bedside criteria, irrespective of temporal order. Fourteen transitions represented clinical improvement and two deterioration according to the predefined hierarchy. In one patient receiving routine hemodialysis, an ultrafiltration session (standard care) defined the worse time-point (norepinephrine uptitration and CRT prolongation). Primary within-patient change in s-VTI All sixteen patients had higher s-VTI in the clinically adjudicated “better” than in the paired “worse” state (Δs-VTI > 0 in 16/16; exact sign test one-sided p < 0.001). Median s-VTI_worse was 16.6 cm (IQR 11.1–18.7) and median s-VTI_better was 32.1 cm (IQR 23.9–38.3) (Figs. 1 – 2 ). The median paired change was + 15.8 cm (IQR 9.0–23.1), corresponding to a + 93.8% increase relative to the worse state (IQR 59.5–204.8%). Secondary CRT CRT moved in the expected direction alongside perfusion changes and Δs-VTI. Across all pairs, CRT was higher in the worse state and lower in the better state: CRT_worse median 7.2 s (IQR 5.5–10.0) vs CRT_better median 2.0 s (IQR 1.15–2.4); ΔCRT (better − worse) median − 5.25 s (IQR − 8.0 to − 3.4). CRT shortened in 16/16 pairs, with normalization < 3 s in 13/16 better states and persistent prolongation in 3/16 despite normal MAP and the absence of vasopressors in most cases. Doppler indices (RI/PI), paired by perfusion state RI (n = 16). RI_worse median 0.64 (IQR 0.57–0.70) vs RI_better 0.60 (IQR 0.55–0.66). A concordant response (higher in worse, lower in better) occurred in 9/16 (56.3%); a paradoxical or flat response in 7/16 (43.7%). Median values overlapped substantially between states (Fig. 3 – 4 ) PI (n = 16). PI_worse median 1.28 (IQR 0.89–1.35) vs PI_better 1.11 (IQR 0.84–1.30). A concordant decrease occurred in 8/16 (50.0%), while a paradoxical or flat pattern occurred in 8/16 (50.0%). Only 2/16 patients reached PI ≥ 1.7 at their worst state ( Fig. 5 – 6 ) Per-patient paired values for s-VTI, CRT, RI, and PI are provided in Table 1 /Supplement. Norepinephrine and MAP were recorded for state adjudication and were not analyzed as endpoints. Discussion In this prospectively collected within-patient case series, s-VTI behaved as a dynamic perfusion marker. Across all sixteen patients, s-VTI was higher in the clinically adjudicated “better” than in the paired “worse” state (Δs-VTI > 0 in 16/16; exact sign test p < 0.001). The median s-VTI increased from 16.6 cm (IQR 11.1–18.7) to 32.1 cm (IQR 23.9–38.3), yielding a within-patient median change of + 15.8 cm (IQR 9.0–23.1), equivalent to a relative increase of + 93.8% (IQR 59.5–204.8%) compared with the worse state. This substantial relative increase strongly supports the concept of the spleen acting as an active blood reservoir under sympathetic control ( 13 ) . In the clinically "worse" state, the observed low median s-VTI likely reflects maximal splenic contraction and volume expulsion, a well-known physiological response to shock. The near doubling of s-VTI during clinical improvement is consistent with the organ's re-expansion as sympathetic tone decreases and adequate perfusion is restored, thereby providing the physiological explanation for the remarkable directional consistency observed. The “better-state” median s-VTI (≈ 32 cm) approximated the healthy reference (≈ 39 cm), offering physiological context rather than inferential comparison. Because absolute s-VTI values depend on insonation angle, vessel caliber, and branch geometry, defining a universal threshold for normal s-VTI is unlikely to be reliable. In contrast, proportional changes within the same patient, measured at a stable angle and site, reduce geometric variability and likely capture true physiological shifts in organ blood flow. Furthermore, the median relative Δs-VTI was + 93.8% (IQR 59.5–204.8%), far exceeding the 10–15% thresholds commonly cited for fluid responsiveness in central or carotid Doppler studies. This magnitude, aligned with concurrent improvement in CRT and reduced vasopressor requirements, strongly supports the clinical relevance of s-VTI as a marker of comprehensive resuscitation. Relationship of S-VTI with CRT CRT evolved in the expected direction with the clinical changes, prolonging in clinically worse states and shortening in better states. Across all 16 state pairs, CRT decreased from a median 7.2 s (IQR 5.5–10.0) to 2.0 s (IQR 1.15–2.4), with normalization < 3 s in 13/16 better states. A minority of patients thus maintained CRT prolongation despite adequate MAP and the absence of escalating vasopressor support, consistent with macro–microcirculatory uncoupling in sepsis ( 14 – 15 ) and with the attenuated diagnostic performance of CRT beyond the acute phase ( 16 – 17 ) . CRT can also be affected by edema, peripheral vascular disease, skin temperature or pigmentation, and vasoactive drugs ( 18 – 20 ) . In this context, using s-VTI in conjunction with CRT may refine bedside assessment of tissue perfusion and help avoid over-resuscitation. Limitations of RI and PI in sepsis Compared with s-VTI, RI again showed a less consistent and more variable directional behavior. In the expanded within-patient paired analysis, RI was concordant in 9 of 16 pairs and paradoxical or flat in 7 of 16, with substantial overlap between state distributions (RI_worse 0.64 [IQR 0.57–0.70] vs RI_better 0.60 [IQR 0.55–0.66]). The trauma-derived threshold of 0.65 ( 21 ) fell within both distributions, limiting its discriminatory value in septic shock. For reference, the healthy volunteer had an RI of 0.52, meaning several patients remained above that value even after clinical recovery. Together with the paradoxical responses, these findings suggest that RI is an unreliable directional marker under vasoplegic conditions, whereas s-VTI remained consistently concordant with the clinical perfusion state. Similarly, PI showed minimal separation and frequent paradoxical responses. In the state-paired view (worse → better), PIworse​ and PIbetter​ distributions were again closely overlapping (1.28 [IQR 0.89–1.35] vs 1.11 [IQR 0.84–1.30]). Notably, apparent paradoxical patterns—PI increasing or remaining elevated while CRT shortened—were observed in half of the cohort (8/16). In patients with early septic shock, Brunauer et al. reported only a moderate correlation between visceral PI and CRT (r = 0.32,p = 0.007) ( 9 ) . In that series, median PI values were approximately 1.75 when CRT > 3 s and 1.50 when CRT ≤ 3 s, with about 25% of patients maintaining PI ≥ 1.7 despite CRT normalization, interpreted as a potential “regional–systemic perfusion mismatch.” In our cohort, however, only 2/16 patients reached PI ≥ 1.7 at their worst state, and in all such paradoxical cases, s-VTI improved alongside CRT. These findings suggest that what appears to be a discrepancy may reflect changes in vasomotor tone that transiently alter the PI, rather than a true dissociation of perfusion. Vasoplegia likely explains the apparent dissociation between indices. RI and PI mainly describe waveform morphology and vascular compliance rather than forward flow. When vasodilation reduces both systolic and diastolic velocities in parallel, these ratio-based indices change little or may even fall, remaining within “normal” ranges despite low perfusion—an effect documented in experimental, neonatal, and microcirculatory data ( 22 – 23 ) . In contrast, s-VTI integrates the entire forward velocity–time signal, decreasing proportionally with reduced velocities or shorter ejection, providing a magnitude-sensitive estimate of time-averaged flow, similar to volumetric Doppler quantification used in carotid perfusion studies ( 24 ) . This physiological distinction also clarifies why, in vasoconstricted states such as hemorrhagic or cardiogenic shock, preserved systolic peaks with diminished diastolic flow yield higher RI and PI values (25–27) , which in that context behave as more faithful markers of perfusion impairment. Altogether, these observations suggest that s-VTI may capture complementary physiological information compared with traditional indices. Limitations This series has several important limitations. First, its observational design and limited sample size (16 patients) restrict the generalizability of our findings and preclude formal statistical validation; thus, the data remains hypothesis-generating. Furthermore, we did not assess interobserver variability for splenic VTI measurements, leaving the reproducibility of the technique untested. Relatedly, we have not yet defined rigorous cut-off values for s-VTI to distinguish hypoperfusion from adequate flow, and any thresholds proposed here require prospective validation. Second, s-VTI is an angle-dependent measurement that requires optimal Doppler alignment, and absolute VTI values may technically differ between splenic branches due to variations in vessel diameter or resistance. However, serial measurements obtained in the same intraparenchymal branch remain internally consistent and suitable for directional assessment. Moreover, this technical weakness must be balanced against the physiological limitations of angle-independent indices: RI and PI are inherently less sensitive to changes in forward flow, which ultimately affects their utility as markers of perfusion compared to s-VTI. Conclusion In this prospective, within-patient case series, s-VTI varied dynamically with the bedside hemodynamic state, lower in clinically worse and higher in better states across all 16 pairs, consistent with an organ-level flow marker showing robust directional behavior that may complement CRT in bedside assessment of perfusion. In contrast, RI and PI showed limited and variable directional behavior under vasoplegic sepsis. These hypothesis-generating findings warrant larger prospective studies to confirm directionality, estimate effect size, establish reproducibility and technical quality, assess responsiveness to interventions, define actionable thresholds, and benchmark s-VTI against CRT, RI/PI, and microcirculatory or biochemical surrogates linked to patient-centered outcomes. Declarations Ethical Approval and Patient Consent This exploratory case series was conducted as an initial feasibility phase of a larger prospective study approved by the Institutional Ethics Committee of Fundación Favaloro (protocol No. 15186). All procedures were conducted in accordance with institutional ethical standards and the Declaration of Helsinki, with written informed consent obtained from each participant or their legal representative. Conflict of Interest Statement The authors declare that they have no conflicts of interest related to this work.. Author Contribution Author Contributions StatementS.B. was responsible for the conceptualization of the study, methodology design, formal analysis, and drafting the original manuscript. S.B. performed Doppler data acquisition and served as the principal investigator. A.M. and F.C. contributed to patient recruitment, clinical data acquisition, and review and editing of the manuscript. D.A. contributed to the conceptualization, project administration, and performed critical review and editing of the manuscript. All authors read and approved the final manuscript. Data Availability The datasets generated and analyzed during the current study (comprising the clinical and Doppler ultrasound measurements shown in Table 1) are available from the corresponding author, S.B. (Santiago Beltramino), on reasonable request. 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Corradi F, Tavazzi G. The Doppler combined assessment of splanchnic perfusion and congestion in cardiogenic shock: a physiological approach. Intensive Care Med. 2025;51(6):1168-71. doi: 10.1007/s00134-025-07855-8 . PMID: 40140096. Additional Declarations No competing interests reported. Supplementary Files Supplementaryinformation.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8245171","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":556578090,"identity":"5e015c22-e99d-40ea-86b9-478480bc89de","order_by":0,"name":"Santiago 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ICU","correspondingAuthor":false,"prefix":"","firstName":"Agustín","middleName":"","lastName":"Manchado","suffix":""},{"id":556578092,"identity":"39c2ff7a-b7a5-44a3-bfe3-9aba0162dfc6","order_by":2,"name":"Fernanda Coñequir","email":"","orcid":"","institution":"ICU Staff Physician, ITAC","correspondingAuthor":false,"prefix":"","firstName":"Fernanda","middleName":"","lastName":"Coñequir","suffix":""},{"id":556578093,"identity":"079d28e7-2679-45ce-84c5-1225987a36d6","order_by":3,"name":"Diego Arufe","email":"","orcid":"","institution":"Head of Liver Transplantation, Sanatorio Sagrado Corazón","correspondingAuthor":false,"prefix":"","firstName":"Diego","middleName":"","lastName":"Arufe","suffix":""}],"badges":[],"createdAt":"2025-12-01 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12:48:42","extension":"xml","order_by":28,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":77990,"visible":true,"origin":"","legend":"","description":"","filename":"27cb6a2c711246b2924ffa264a60421b1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8245171/v1/94ddb5e2e4b1e3dabcd04ca9.xml"},{"id":97894866,"identity":"6337e2df-b1ba-4d84-8b04-85f834507fd3","added_by":"auto","created_at":"2025-12-10 15:33:10","extension":"html","order_by":29,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":95684,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8245171/v1/d7a49ce88e01a071a5566b3d.html"},{"id":97894973,"identity":"6b13f2af-7a54-4df2-b261-63c4aa17659b","added_by":"auto","created_at":"2025-12-10 15:33:17","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":87207,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eWithin-patient trajectories of splenic VTI (worse→better): increased in 16/16; median Δ+15.8 cm (IQR 9.0–23.1).\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8245171/v1/6374cbd7189a6768bb77ea94.jpeg"},{"id":97704465,"identity":"1231bf01-1d36-4717-bfd9-d10fafda2400","added_by":"auto","created_at":"2025-12-08 12:48:42","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":37572,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003ePaired distributions of splenic VTI (worse vs better): medians 16.6 vs 32.1 cm; median Δ+15.8 cm (IQR 9.0–23.1).\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8245171/v1/bba226a5dd485ebc261e75ae.jpeg"},{"id":97704468,"identity":"ab0988a2-df4f-4af9-a9f9-a3b1e2a62f93","added_by":"auto","created_at":"2025-12-08 12:48:42","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":39376,"visible":true,"origin":"","legend":"\u003cp\u003eMedian Splenic RI paired by perfusion state (worse→better):\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8245171/v1/f4d7c9ad12bd747bd1bfd3c4.jpeg"},{"id":97894826,"identity":"47cac185-1c80-4955-baba-67644edf026f","added_by":"auto","created_at":"2025-12-10 15:33:03","extension":"jpeg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":89080,"visible":true,"origin":"","legend":"\u003cp\u003eWithin-patient paired evolution of RI (worse → better). Concordant decrease occurred in 9/16 pairs, with a paradoxical or flat response in the remaining 7/16 (Descriptive analysis).\u003c/p\u003e","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8245171/v1/49c448fff0886cd78d909e58.jpeg"},{"id":97894480,"identity":"c28e2dad-78ab-462f-bdfa-9f6c308a68b9","added_by":"auto","created_at":"2025-12-10 15:32:35","extension":"jpeg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":40242,"visible":true,"origin":"","legend":"\u003cp\u003eMedian\u003cstrong\u003e \u003c/strong\u003e\u0026nbsp;Splenic pulsatility index (PI) paired by perfusion state (worse→better):\u003c/p\u003e","description":"","filename":"floatimage5.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8245171/v1/52881d50b52e389c667125c4.jpeg"},{"id":97704475,"identity":"0a9bc34e-a634-4ecc-a61c-78bb7a7f40c3","added_by":"auto","created_at":"2025-12-08 12:48:42","extension":"jpeg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":90820,"visible":true,"origin":"","legend":"\u003cp\u003eWithin-patient paired evolution of PI (worse → better). Concordant decrease occurred in 8/16 pairs, with a paradoxical or flat response in the remaining 8/16 (Descriptive analysis).\u003c/p\u003e","description":"","filename":"floatimage6.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8245171/v1/89202f7d1174e79745ecc9ac.jpeg"},{"id":98628158,"identity":"aa1b6e1e-84ee-4edb-8b0e-9aa98751b08d","added_by":"auto","created_at":"2025-12-19 17:11:04","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":982061,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8245171/v1/23ee68b0-2a97-4119-9c79-1a3e531c4359.pdf"},{"id":97893485,"identity":"d7c834ba-a7fb-4c5e-a252-dcdb02a21d25","added_by":"auto","created_at":"2025-12-10 15:30:32","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1795740,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementaryinformation.docx","url":"https://assets-eu.researchsquare.com/files/rs-8245171/v1/198de846a8506992feee0583.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Splenic Doppler Velocity–Time Integral as a Dynamic Marker of Visceral Perfusion in Adults with Septic Shock: A Prospective Pilot Feasibility Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSeptic shock is a life-threatening condition characterized by circulatory and metabolic failure with tissue hypoperfusion and multiorgan dysfunction \u003csup\u003e(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/sup\u003e. Resuscitation targets often focus on macrocirculatory variables, mean arterial pressure (MAP) and cardiac output, yet these targets may not secure adequate tissue perfusion \u003csup\u003e(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/sup\u003e. Current guidelines endorse bedside assessment of perfusion with capillary refill time (CRT) \u003csup\u003e(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/sup\u003e. CRT is a simple bedside marker associated with short-term outcomes, although its reliability may be limited by vascular disease, skin factors, temperature, and vasoactive drugs \u003csup\u003e(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e)\u003c/sup\u003e. Other surrogates, such as lactate, the venous\u0026ndash;arterial CO₂ difference, and sublingual microcirculation, are constrained by delayed kinetics or limited availability \u003csup\u003e(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e)\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003ePoint-of-care ultrasound (POCUS) is widely used in septic shock to guide resuscitation by estimating cardiac output and assessing pulmonary and venous congestion, yet it is seldom applied to monitor organ-specific perfusion, where few validated bedside tools provide real-time assessment of visceral blood flow. Splenic Doppler has shown potential for splanchnic flow assessment and fluid responsiveness outside sepsis \u003csup\u003e(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e)\u003c/sup\u003e. However, in septic shock, studies of splenic doppler resistive index (RI) and pulsatility index (PI) have not demonstrated consistent incremental value for hemodynamic monitoring, and no sepsis-specific thresholds have been established \u003csup\u003e(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/sup\u003e. By contrast, the velocity-time integral (VTI) measured at left ventricular outflow is validated for cardiac stroke-volume estimation and kidney VTI has shown promise for predicting acute kidney injury \u003csup\u003e(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThese observations, together with the spleen\u0026rsquo;s role as a hemodynamic reservoir under sympathetic control, where volume contraction (and subsequently lower flow) is expected during hypoperfusion and splenic re-expansion (higher flow) during adequate resuscitation, support the conceptual rationale for a splenic velocity\u0026ndash;time integral (s-VTI) as a directional, organ-level flow signal that may track splanchnic perfusion at the bedside \u003csup\u003e(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/sup\u003e. We hypothesized that, in septic shock, s-VTI integrating the forward velocity\u0026ndash;time signal would be higher in a clinically adjudicated better than worse state and behave more directionally than RI/PI.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\"\u003e\n \u003ch2\u003eDesign and setting\u003c/h2\u003e\n \u003cp\u003eProspective exploratory case series with a structured within-patient paired analysis conducted in a single tertiary-care ICU. Sixteen consecutive adult patients with septic shock (Sepsis-3 criteria) were included, and one healthy volunteer was examined as a technical reference but was not included in inferential analyses. Data were obtained during routine clinical care; no study-specific interventions were performed. Written informed consent was obtained from each participant or their legal representative.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eSplenic Doppler acquisition\u003c/h3\u003e\n\u003cp\u003eBedside splenic Doppler ultrasound was performed using a Mindray Consona M6 Pro system (Mindray, Shenzhen, China) equipped with a phased-array P4-2s transducer (1\u0026ndash;5 MHz) under the \u0026ldquo;Abdomen\u0026rdquo; preset. Patients were examined in a supine or slight right-lateral position. The splenic artery was visualized longitudinally at the hilum, and pulsed-wave Doppler sampling was placed within the splenic parenchyma, 1\u0026ndash;2 cm distal to the hilum, corresponding to an intraparenchymal arterial branch.\u003c/p\u003e\n\u003cp\u003eAt each time-point, two acquisitions were initially obtained in separate parenchymal branches, and the most stable trace was selected for serial comparison. When feasible, the same intraparenchymal branch was re-identified in follow-up scans to maintain internal consistency. Each measurement comprised three consecutive cardiac cycles.\u003c/p\u003e\n\u003cp\u003eRecorded parameters included s-VTI (cm), PSV (peak systolic velocity), EDV (end-diastolic velocity), MV (mean velocity), RI, and PI, all obtained from the same Doppler envelope. Scans were performed by two attending intensivists (\u0026gt;\u0026thinsp;5 years of POCUS experience) following a brief calibration session; inter-operator reproducibility was not formally assessed. VTI values were obtained by manual tracing of the Doppler envelope using the system\u0026rsquo;s built-in software.\u003c/p\u003e\n\u003ch3\u003eClinical states and timing\u003c/h3\u003e\n\u003cp\u003eEach patient contributed two bedside states, worse and better, adjudicated by a pre-specified hierarchy without using Doppler data: primary\u0026mdash;CRT (longer\u0026thinsp;=\u0026thinsp;worse) measured concurrently with Doppler; if CRT was unreliable, norepinephrine (NE) dose (higher\u0026thinsp;=\u0026thinsp;worse); if tie, mean arterial pressure (MAP) (\u0026lt;\u0026thinsp;65 mmHg\u0026thinsp;=\u0026thinsp;worse). For example, a patient with CRT 12 s on 0.5 \u0026micro;g/kg/min NE and later CRT 4 s off NE, with stable MAP\u0026thinsp;\u0026gt;\u0026thinsp;65 mmHg, was adjudicated as worse \u0026rarr; better because CRT is the primary determinant and improvement was accompanied by vasopressor withdrawal. Doppler metrics were not used to define states.\u003c/p\u003e\n\u003cp\u003eIn the expanded cohort, most paired assessments were obtained during clinical recovery, with bedside adjudication indicating improvement in 14/16 state transitions and deterioration in 2/16 according to the predefined hierarchy, irrespective of acquisition order. Sensitivity analyses were performed by repeating the primary within-patient paired analysis using alternative adjudication criteria based on (i) norepinephrine dose only and (ii) MAP only. Results of these sensitivity analyses were consistent with the primary paired findings.\u003c/p\u003e\n\u003ch3\u003eOutcomes\u003c/h3\u003e\n\u003cp\u003ePrimary (within-patient dynamic change). For each patient we computed a single paired change in splenic VTI:\u003c/p\u003e\n\u003cp\u003e\u0026Delta;s\\text{-VTI} = s\\text{-VTI}_{\\text{better}} \u0026minus; s\\text{-VTI}_{\\text{worse}} \\ (\\mathrm{cm}),\u003c/p\u003e\n\u003cp\u003etesting whether s-VTI is higher in the better state across patients.\u003c/p\u003e\n\u003cp\u003eSecondary (exploratory):\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\n \u003cp\u003eDirectional concordance between the change in s-VTI and CRT (shorter\u0026thinsp;=\u0026thinsp;better).\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003ePaired behavior of RI and PI across states, classified as concordant or paradoxical relative to s-VTI.\u003c/p\u003e\n \u003c/li\u003e\n\u003c/ul\u003e\n\u003cdiv id=\"Sec7\"\u003e\n \u003ch2\u003eStatistical analysis\u003c/h2\u003e\n \u003cp\u003eGiven the case-series design and modest sample, analyses were descriptive and hypothesis-generating. Paired observations were defined by perfusion state (better vs worse) using pre-specified bedside criteria (shorter CRT, lower norepinephrine dose, higher MAP), irrespective of temporal order. Continuous variables are summarised as median (IQR) and categorical variables as n/N (%) with exact binomial 95% CIs. No multiplicity adjustment was applied and no imputation was performed.\u003c/p\u003e\n \u003cp\u003ePrimary inference. We tested whether \u0026Delta;s-VTI\u0026thinsp;\u0026gt;\u0026thinsp;0 across patients using an exact sign test (one-sided directional hypothesis; two-sided p-values also reported). We report the median (IQR) \u0026Delta;s-VTI and the percent change from the worse state. As sensitivity analyses, we present the exact Wilcoxon signed-rank test (Pratt method for ties) and the Hodges\u0026ndash;Lehmann paired median difference with exact 95% CI.\u003c/p\u003e\n \u003cp\u003eSecondary summaries.\u003c/p\u003e\n \u003cul\u003e\n \u003cli\u003e\n \u003cp\u003eCRT: \u0026Delta;CRT\u0026thinsp;=\u0026thinsp;CRT_better\u0026thinsp;\u0026minus;\u0026thinsp;CRT_worse summarized as median (IQR); among better states, the proportion with CRT normalization\u0026thinsp;\u0026lt;\u0026thinsp;3 s is reported with exact binomial 95% CIs. No formal hypothesis testing was pre-specified for CRT.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eRI/PI: state-paired comparisons reported as medians (IQR) for RI_worse, RI_better, PI_worse, PI_better. Within each patient we classified the Doppler response as concordant (higher in worse, lower in better) or paradoxical (opposite), and summarized n/N with exact binomial 95% CIs. Given heterogeneity and sample size, no hypothesis tests were planned for RI/PI. Per-patient \u0026Delta;RI and \u0026Delta;PI are provided in Table 1/Supplement.\u003c/p\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\u003c/table\u003e\n \u003cp\u003e\u003c/p\u003e\n \u003c/li\u003e\n \u003c/ul\u003e\n \u003cp\u003eNorepinephrine and MAP were collected to adjudicate perfusion states and were not analyzed as endpoints.\u003c/p\u003e\n \u003cp\u003eSoftware. Analyses were conducted in Python 3.11. The sign test was implemented as an exact binomial test with ties (\u0026Delta;\u0026thinsp;=\u0026thinsp;0) excluded. The Hodges\u0026ndash;Lehmann estimator for paired differences and a distribution-free 95% CI for the median of differences (from sign-test order statistics) were computed from the empirical distributions. Exact binomial CIs for proportions used the Clopper\u0026ndash;Pearson method.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003ePatients and measurements\u003c/h2\u003e\u003cp\u003eSixteen adult ICU patients with septic shock and one healthy volunteer were included. The healthy volunteer provided a technical benchmark (s-VTI\u0026thinsp;\u0026asymp;\u0026thinsp;39 cm, RI\u0026thinsp;\u0026asymp;\u0026thinsp;0.52, PI\u0026thinsp;\u0026asymp;\u0026thinsp;0.79). For each patient, two perfusion states were captured within the same ICU stay (worse and better) based on bedside criteria, irrespective of temporal order. Fourteen transitions represented clinical improvement and two deterioration according to the predefined hierarchy. In one patient receiving routine hemodialysis, an ultrafiltration session (standard care) defined the worse time-point (norepinephrine uptitration and CRT prolongation).\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003ePrimary within-patient change in s-VTI\u003c/h3\u003e\n\u003cp\u003eAll sixteen patients had higher s-VTI in the clinically adjudicated \u0026ldquo;better\u0026rdquo; than in the paired \u0026ldquo;worse\u0026rdquo; state (Δs-VTI\u0026thinsp;\u0026gt;\u0026thinsp;0 in 16/16; exact sign test one-sided p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Median s-VTI_worse was 16.6 cm (IQR 11.1\u0026ndash;18.7) and median s-VTI_better was 32.1 cm (IQR 23.9\u0026ndash;38.3) (Figs.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The median paired change was +\u0026thinsp;15.8 cm (IQR 9.0\u0026ndash;23.1), corresponding to a\u0026thinsp;+\u0026thinsp;93.8% increase relative to the worse state (IQR 59.5\u0026ndash;204.8%).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eSecondary\u003c/h2\u003e\u003cdiv id=\"Sec12\" class=\"Section3\"\u003e\u003ch2\u003eCRT\u003c/h2\u003e\u003cp\u003eCRT moved in the expected direction alongside perfusion changes and Δs-VTI. Across all pairs, CRT was higher in the worse state and lower in the better state: CRT_worse median 7.2 s (IQR 5.5\u0026ndash;10.0) vs CRT_better median 2.0 s (IQR 1.15\u0026ndash;2.4); ΔCRT (better\u0026thinsp;\u0026minus;\u0026thinsp;worse) median \u0026minus;\u0026thinsp;5.25 s (IQR \u0026minus;\u0026thinsp;8.0 to \u0026minus;\u0026thinsp;3.4). CRT shortened in 16/16 pairs, with normalization\u0026thinsp;\u0026lt;\u0026thinsp;3 s in 13/16 better states and persistent prolongation in 3/16 despite normal MAP and the absence of vasopressors in most cases.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eDoppler indices (RI/PI), paired by perfusion state\u003c/h2\u003e\u003cp\u003eRI (n\u0026thinsp;=\u0026thinsp;16). RI_worse median 0.64 (IQR 0.57\u0026ndash;0.70) vs RI_better 0.60 (IQR 0.55\u0026ndash;0.66). A concordant response (higher in worse, lower in better) occurred in 9/16 (56.3%); a paradoxical or flat response in 7/16 (43.7%). Median values overlapped substantially between states (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003ePI (n\u0026thinsp;=\u0026thinsp;16). PI_worse median 1.28 (IQR 0.89\u0026ndash;1.35) vs PI_better 1.11 (IQR 0.84\u0026ndash;1.30). A concordant decrease occurred in 8/16 (50.0%), while a paradoxical or flat pattern occurred in 8/16 (50.0%). Only 2/16 patients reached PI\u0026thinsp;\u0026ge;\u0026thinsp;1.7 at their worst state ( Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003ePer-patient paired values for s-VTI, CRT, RI, and PI are provided in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e/Supplement. Norepinephrine and MAP were recorded for state adjudication and were not analyzed as endpoints.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this prospectively collected within-patient case series, s-VTI behaved as a dynamic perfusion marker. Across all sixteen patients, s-VTI was higher in the clinically adjudicated \u0026ldquo;better\u0026rdquo; than in the paired \u0026ldquo;worse\u0026rdquo; state (Δs-VTI\u0026thinsp;\u0026gt;\u0026thinsp;0 in 16/16; exact sign test p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The median s-VTI increased from 16.6 cm (IQR 11.1\u0026ndash;18.7) to 32.1 cm (IQR 23.9\u0026ndash;38.3), yielding a within-patient median change of +\u0026thinsp;15.8 cm (IQR 9.0\u0026ndash;23.1), equivalent to a relative increase of +\u0026thinsp;93.8% (IQR 59.5\u0026ndash;204.8%) compared with the worse state.\u003c/p\u003e\u003cp\u003eThis substantial relative increase strongly supports the concept of the spleen acting as an active blood reservoir under sympathetic control\u003csup\u003e(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/sup\u003e. In the clinically \"worse\" state, the observed low median s-VTI likely reflects maximal splenic contraction and volume expulsion, a well-known physiological response to shock. The near doubling of s-VTI during clinical improvement is consistent with the organ's re-expansion as sympathetic tone decreases and adequate perfusion is restored, thereby providing the physiological explanation for the remarkable directional consistency observed.\u003c/p\u003e\u003cp\u003eThe \u0026ldquo;better-state\u0026rdquo; median s-VTI (\u0026asymp;\u0026thinsp;32 cm) approximated the healthy reference (\u0026asymp;\u0026thinsp;39 cm), offering physiological context rather than inferential comparison. Because absolute s-VTI values depend on insonation angle, vessel caliber, and branch geometry, defining a universal threshold for normal s-VTI is unlikely to be reliable. In contrast, proportional changes within the same patient, measured at a stable angle and site, reduce geometric variability and likely capture true physiological shifts in organ blood flow. Furthermore, the median relative Δs-VTI was +\u0026thinsp;93.8% (IQR 59.5\u0026ndash;204.8%), far exceeding the 10\u0026ndash;15% thresholds commonly cited for fluid responsiveness in central or carotid Doppler studies. This magnitude, aligned with concurrent improvement in CRT and reduced vasopressor requirements, strongly supports the clinical relevance of s-VTI as a marker of comprehensive resuscitation.\u003c/p\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003eRelationship of S-VTI with CRT\u003c/h2\u003e\u003cp\u003eCRT evolved in the expected direction with the clinical changes, prolonging in clinically worse states and shortening in better states. Across all 16 state pairs, CRT decreased from a median 7.2 s (IQR 5.5\u0026ndash;10.0) to 2.0 s (IQR 1.15\u0026ndash;2.4), with normalization\u0026thinsp;\u0026lt;\u0026thinsp;3 s in 13/16 better states. A minority of patients thus maintained CRT prolongation despite adequate MAP and the absence of escalating vasopressor support, consistent with macro\u0026ndash;microcirculatory uncoupling in sepsis \u003csup\u003e(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e)\u003c/sup\u003e and with the attenuated diagnostic performance of CRT beyond the acute phase \u003csup\u003e(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e)\u003c/sup\u003e. CRT can also be affected by edema, peripheral vascular disease, skin temperature or pigmentation, and vasoactive drugs \u003csup\u003e(\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e)\u003c/sup\u003e. In this context, using s-VTI in conjunction with CRT may refine bedside assessment of tissue perfusion and help avoid over-resuscitation.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003eLimitations of RI and PI in sepsis\u003c/h2\u003e\u003cp\u003eCompared with s-VTI, RI again showed a less consistent and more variable directional behavior. In the expanded within-patient paired analysis, RI was concordant in 9 of 16 pairs and paradoxical or flat in 7 of 16, with substantial overlap between state distributions (RI_worse 0.64 [IQR 0.57\u0026ndash;0.70] vs RI_better 0.60 [IQR 0.55\u0026ndash;0.66]). The trauma-derived threshold of 0.65 \u003csup\u003e(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e)\u003c/sup\u003e fell within both distributions, limiting its discriminatory value in septic shock. For reference, the healthy volunteer had an RI of 0.52, meaning several patients remained above that value even after clinical recovery. Together with the paradoxical responses, these findings suggest that RI is an unreliable directional marker under vasoplegic conditions, whereas s-VTI remained consistently concordant with the clinical perfusion state.\u003c/p\u003e\u003cp\u003eSimilarly, PI showed minimal separation and frequent paradoxical responses. In the state-paired view (worse \u0026rarr; better), PIworse​ and PIbetter​ distributions were again closely overlapping (1.28 [IQR 0.89\u0026ndash;1.35] vs 1.11 [IQR 0.84\u0026ndash;1.30]). Notably, apparent paradoxical patterns\u0026mdash;PI increasing or remaining elevated while CRT shortened\u0026mdash;were observed in half of the cohort (8/16). In patients with early septic shock, Brunauer et al. reported only a moderate correlation between visceral PI and CRT (r\u0026thinsp;=\u0026thinsp;0.32,p\u0026thinsp;=\u0026thinsp;0.007) \u003csup\u003e(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/sup\u003e. In that series, median PI values were approximately 1.75 when CRT\u0026thinsp;\u0026gt;\u0026thinsp;3 s and 1.50 when CRT\u0026thinsp;\u0026le;\u0026thinsp;3 s, with about 25% of patients maintaining PI\u0026thinsp;\u0026ge;\u0026thinsp;1.7 despite CRT normalization, interpreted as a potential \u0026ldquo;regional\u0026ndash;systemic perfusion mismatch.\u0026rdquo; In our cohort, however, only 2/16 patients reached PI\u0026thinsp;\u0026ge;\u0026thinsp;1.7 at their worst state, and in all such paradoxical cases, s-VTI improved alongside CRT. These findings suggest that what appears to be a discrepancy may reflect changes in vasomotor tone that transiently alter the PI, rather than a true dissociation of perfusion.\u003c/p\u003e\u003cp\u003eVasoplegia likely explains the apparent dissociation between indices. RI and PI mainly describe waveform morphology and vascular compliance rather than forward flow. When vasodilation reduces both systolic and diastolic velocities in parallel, these ratio-based indices change little or may even fall, remaining within \u0026ldquo;normal\u0026rdquo; ranges despite low perfusion\u0026mdash;an effect documented in experimental, neonatal, and microcirculatory data \u003csup\u003e(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e)\u003c/sup\u003e. In contrast, s-VTI integrates the entire forward velocity\u0026ndash;time signal, decreasing proportionally with reduced velocities or shorter ejection, providing a magnitude-sensitive estimate of time-averaged flow, similar to volumetric Doppler quantification used in carotid perfusion studies \u003csup\u003e(\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e)\u003c/sup\u003e. This physiological distinction also clarifies why, in vasoconstricted states such as hemorrhagic or cardiogenic shock, preserved systolic peaks with diminished diastolic flow yield higher RI and PI values \u003csup\u003e(25\u0026ndash;27)\u003c/sup\u003e, which in that context behave as more faithful markers of perfusion impairment. Altogether, these observations suggest that s-VTI may capture complementary physiological information compared with traditional indices.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003eLimitations\u003c/h2\u003e\u003cp\u003eThis series has several important limitations. First, its observational design and limited sample size (16 patients) restrict the generalizability of our findings and preclude formal statistical validation; thus, the data remains hypothesis-generating. Furthermore, we did not assess interobserver variability for splenic VTI measurements, leaving the reproducibility of the technique untested. Relatedly, we have not yet defined rigorous cut-off values for s-VTI to distinguish hypoperfusion from adequate flow, and any thresholds proposed here require prospective validation.\u003c/p\u003e\u003cp\u003eSecond, s-VTI is an angle-dependent measurement that requires optimal Doppler alignment, and absolute VTI values may technically differ between splenic branches due to variations in vessel diameter or resistance. However, serial measurements obtained in the same intraparenchymal branch remain internally consistent and suitable for directional assessment. Moreover, this technical weakness must be balanced against the physiological limitations of angle-independent indices: RI and PI are inherently less sensitive to changes in forward flow, which ultimately affects their utility as markers of perfusion compared to s-VTI.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn this prospective, within-patient case series, s-VTI varied dynamically with the bedside hemodynamic state, lower in clinically worse and higher in better states across all 16 pairs, consistent with an organ-level flow marker showing robust directional behavior that may complement CRT in bedside assessment of perfusion. In contrast, RI and PI showed limited and variable directional behavior under vasoplegic sepsis.\u003c/p\u003e\u003cp\u003eThese hypothesis-generating findings warrant larger prospective studies to confirm directionality, estimate effect size, establish reproducibility and technical quality, assess responsiveness to interventions, define actionable thresholds, and benchmark s-VTI against CRT, RI/PI, and microcirculatory or biochemical surrogates linked to patient-centered outcomes.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cdiv id=\"Sec3\"\u003e\u003cstrong\u003eEthical Approval and Patient Consent\u003c/strong\u003e\n \u003cp\u003eThis exploratory case series was conducted as an initial feasibility phase of a larger prospective study approved by the Institutional Ethics Committee of Fundaci\u0026oacute;n Favaloro (protocol No. 15186). All procedures were conducted in accordance with institutional ethical standards and the Declaration of Helsinki, with written informed consent obtained from each participant or their legal representative.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec7\"\u003e\u003cbr\u003e\u003c/div\u003e\u003ch2\u003eConflict of Interest Statement\u003c/h2\u003e\u003cp\u003eThe authors declare that they have no conflicts of interest related to this work..\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAuthor Contributions StatementS.B. was responsible for the conceptualization of the study, methodology design, formal analysis, and drafting the original manuscript. S.B. performed Doppler data acquisition and served as the principal investigator. A.M. and F.C. contributed to patient recruitment, clinical data acquisition, and review and editing of the manuscript. D.A. contributed to the conceptualization, project administration, and performed critical review and editing of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets generated and analyzed during the current study (comprising the clinical and Doppler ultrasound measurements shown in Table 1) are available from the corresponding author, S.B. (Santiago Beltramino), on reasonable request. Access to the full, anonymized dataset will be granted to researchers who meet the criteria for access to confidential data, as governed by the authors' institutional ethics board and data sharing policies.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBauer M, Gerlach H, Vogelmann T, Preissing F, Stiefel J, Adam D. 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PMID: 40140096.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Ultrasonography, Doppler, Splenic Artery, Regional Blood Flow, Hemodynamics, Shock, Septic, Critical Care","lastPublishedDoi":"10.21203/rs.3.rs-8245171/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8245171/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e In septic shock, restoring macrohemodynamics does not guarantee microcirculatory recovery. Capillary refill time (CRT) is a simple, guideline-endorsed bedside marker; however, its accuracy can be confounded by edema, temperature, and skin pigmentation.Regarding visceral perfusion, traditional splenic Doppler indices (RI and PI) primarily reflect vascular resistance and vasomotor tone, failing to reliably predict relevant clinical outcomes. Conversely, the velocity–time integral (VTI) is a quantitative correlate of blood flow volume. We therefore hypothesized that splenic VTI (s-VTI) could serve as a superior, real-time bedside signal of organ perfusion\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eProspective within-patient paired analysis conducted in a tertiary ICU. Adults with septic shock (n = 16) underwent splenic pulsed-wave Doppler in two clinically adjudicated states (worse→better), defined by a pre-specified bedside hierarchy of improvement (CRT → norepinephrine → MAP). Doppler data were not used for adjudication. The primary outcome was the paired change in splenic velocity–time integral (Δs-VTI = s-VTI_better − s-VTI_worse); secondary outcomes were changes in RI and PI. Analyses were descriptive and hypothesis-generating.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Δs-VTI was \u0026gt; 0 in 16/16 pairs (exact sign test one-sided p \u0026lt; 0.001). Median s-VTI_worse was 16.6 cm (IQR 11.1–18.7) vs s-VTI_better 32.1 cm (IQR 23.9–38.3); the median paired change was +15.8 cm (IQR 9.0–23.1), corresponding to a +93.8% increase from the worse state (IQR 59.5–204.8%). CRT moved in the expected direction (median 7.2 → 2.0 s; Δ −5.25 s, IQR −8.0 to −3.4), with normalization \u0026lt;3 s in 13/16 better states. RI/PI showed limited and variable directional behavior: RI_worse 0.64 (IQR 0.57–0.70) vs RI_better 0.60 (IQR 0.55–0.66), with concordant decrease in 9/16 pairs (56.3%); PI_worse 1.28 (IQR 0.89–1.35) vs PI_better 1.11 (IQR 0.84–1.30), concordant in 8/16 (50.0%).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e In this prospective within-patient case series, s-VTI increased in the clinically adjudicated better vs worse state in all 16pairs, nearly doubling in the median. s-VTI behaved as an organ-level flow marker with consistent directional behavior, likely reflecting the re-expansion of the splenic volume reservoir, potentially complementing CRT in bedside perfusion assessment, whereas RI and PI proved inconsistent, providing limited directional information under vasoplegic sepsis. These hypothesis-generating findings warrant prospective validation to confirm reproducibility and define actionable thresholds.\u003c/p\u003e","manuscriptTitle":"Splenic Doppler Velocity–Time Integral as a Dynamic Marker of Visceral Perfusion in Adults with Septic Shock: A Prospective Pilot Feasibility Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-08 12:48:37","doi":"10.21203/rs.3.rs-8245171/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4cb53d31-1e8e-43d6-b504-d24a3dcd5e30","owner":[],"postedDate":"December 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-27T13:23:31+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-08 12:48:37","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8245171","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8245171","identity":"rs-8245171","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}