Cardiovascular Phenotypes in Sepsis

Overview

This prospective observational study will investigate cardiovascular phenotypes in adults with sepsis and hemodynamic instability. Approximately 400 patients requiring vasopressor support will be enrolled across multiple hospital sites. Within 72 hours of admission, participants will undergo peripheral vascular assessments, echocardiography, and blood sampling for cardiac, endothelial, and inflammatory biomarkers. Patients will be classified according to the presence or absence of peripheral vascular dysfunction and cardiac dysfunction. The primary aim is to examine the association between these cardiovascular phenotypes and one-year mortality. Secondary aims include evaluating biomarker profiles, characterizing myocardial injury, and assessing cardiac function at a 3-month follow-up. The study seeks to improve understanding of sepsis-related cardiovascular dysfunction and support development of more individualized management strategies.

Detailed description

Sepsis is frequently accompanied by myocardial injury, myocardial dysfunction, and peripheral circulatory abnormalities, all of which contribute to hemodynamic instability and increased mortality. Despite their clinical importance, distinct cardiovascular phenotypes in sepsis have not been clearly defined, and no established guidelines exist for evaluating or managing sepsis-related myocardial dysfunction. This study aims to characterize cardiovascular phenotypes based on peripheral vascular function and cardiac performance, and to assess their association with clinical outcomes.

This is a prospective, multicenter observational cohort study enrolling 400 adults with suspected sepsis and hemodynamic instability requiring vasopressor support. Eligible patients will be included within 72 hours of admission to an Intermediate Care Unit, Intensive Care Unit, Cardiac Care Unit, or Acute Care Unit. After enrollment, participants will undergo standardized assessments of peripheral endothelial function using the EndoPAT device and capillary refill time measurement. A comprehensive echocardiographic evaluation will be performed to assess biventricular function and left-a dn right ventricular-arterial coupling. Blood samples will be collected and stored for analysis of cardiac biomarkers (including high-sensitivity cardiac troponin and NT-proBNP), as well as inflammatory, endothelial, glycocalyx, and thrombotic biomarkers.

Participants will be classified into cardiovascular phenotypes: ; i) peripheral vascular dysfunction, ii) cardiac dysfunction, iii) a combination of peripheral vascular dysfunction and cardiac dysfunction or iv) no dysfunction. The primary objective is to evaluate the association between these phenotypes and one-year all-cause mortality using survival analysis methods such ax Cox regression. Secondary objectives include examining biomarker patterns associated with cardiovascular dysfunction, assessing the severity and progression of myocardial injury, and evaluating changes in cardiac function at a three-month follow-up visit where repeat EndoPAT testing, capillary refill time assessment, echocardiography, and blood sampling will be performed.

Long-term clinical outcomes, including cardiovascular events and mortality, will be obtained through the electronic health register. The study aims to improve understanding of the interplay between microcirculatory dysfunction, myocardial injury, and cardiac performance in sepsis, and to support development of individualized risk stratification and future clinical management strategies.

Primary outcome measures

• Association between cardiovascular phenotypes and one-year mortality in sepsis [Time frame: Up to 1 year after admission to the Intermediate Care Unit (IMCU), Intensive Care Unit (ICU) or Cardiac Care Unit (CCU).]

Secondary outcome measures (4)

• Association between cardiovascular phenotypes and in-hospital mortality in sepsis [Time frame: From admission to the IMCU, ICU, or CCU (baseline) until the date of in-hospital death or hospital discharge, whichever occurs first, assessed up to 90 days.]
• Change in echocardiographic indices of acute ventricular function and ventriculo-arterial coupling from baseline to 3 months [Time frame: Baseline (within 72 hours of admission to the IMCU/ICU/CCU) to 3 months after baseline.]
• Association of integrated cardiovascular biomarkers with one-year and in-hospital mortality in sepsis [Time frame: Up to 1 year after admission to the IMCU/ICU/CCU (baseline)]
• Association between emerging cardiovascular biomarkers and myocardial injury severity in sepsis [Time frame: 0-72 hours after admission to the IMCU/ICU/CCU]

Eligibility criteria

Inclusion criteria

• Age 18 years or older
• Suspected sepsis based on clinical evaluation and supporting laboratory findings
• Hemodynamic instability, defined as mean arterial pressure < 65 mmHg despite adequate fluid resuscitation
• Requirement for vasopressor support
• Inclusion within 72 hours of admission to an Intermediate Care Unit (IMCU), Intensive Care Unit (ICU), Cardiac Care Unit (CCU), or Acute Care Unit (ACU)

Exclusion criteria

• Lack of informed consent
• Advanced peripheral arterial disease, including: subclavian artery occlusion with vertebrobasilar symptoms, critical hand ischemia with tissue loss or non-healing wounds, multilevel occlusive disease affecting upper-extremity arteries, upper limb surgery or significant upper limb trauma within 30 days prior to admission, technical limitations preventing proper placement of the EndoPAT device (e.g., finger amputation, severe rheumatologic deformity, or marked extremity edema).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

Center list to be confirmed — check the primary protocol.

Publications

• Frencken JF, van Smeden M, van de Groep K, Ong DSY, Klein Klouwenberg PMC, Juffermans N, Bonten MJM, van der Poll T, Cremer OL; MARS Consortium. Etiology of Myocardial Injury in Critically Ill Patients with Sepsis: A Cohort Study. Ann Am Thorac Soc. 2022 May;19(5):773-780. doi: 10.1513/AnnalsATS.202106-689OC. PMID 34784496
• Tyden H, Lood C, Jonsen A, Gullstrand B, Kahn R, Linge P, Kumaraswamy SB, Dahlback B, Bengtsson AA. Low plasma concentrations of apolipoprotein M are associated with disease activity and endothelial dysfunction in systemic lupus erythematosus. Arthritis Res Ther. 2019 May 2;21(1):110. doi: 10.1186/s13075-019-1890-2. PMID 31046824
• De Backer D, Donadello K, Sakr Y, Ospina-Tascon G, Salgado D, Scolletta S, Vincent JL. Microcirculatory alterations in patients with severe sepsis: impact of time of assessment and relationship with outcome. Crit Care Med. 2013 Mar;41(3):791-9. doi: 10.1097/CCM.0b013e3182742e8b. PMID 23318492
• Landesberg G, Jaffe AS, Gilon D, Levin PD, Goodman S, Abu-Baih A, Beeri R, Weissman C, Sprung CL, Landesberg A. Troponin elevation in severe sepsis and septic shock: the role of left ventricular diastolic dysfunction and right ventricular dilatation*. Crit Care Med. 2014 Apr;42(4):790-800. doi: 10.1097/CCM.0000000000000107. PMID 24365861
• Vallabhajosyula S, Kumar M, Pandompatam G, Sakhuja A, Kashyap R, Kashani K, Gajic O, Geske JB, Jentzer JC. Prognostic impact of isolated right ventricular dysfunction in sepsis and septic shock: an 8-year historical cohort study. Ann Intensive Care. 2017 Sep 7;7(1):94. doi: 10.1186/s13613-017-0319-9. PMID 28884343
• Sanfilippo F, Corredor C, Fletcher N, Landesberg G, Benedetto U, Foex P, Cecconi M. Diastolic dysfunction and mortality in septic patients: a systematic review and meta-analysis. Intensive Care Med. 2015 Jun;41(6):1004-13. doi: 10.1007/s00134-015-3748-7. Epub 2015 Mar 24. PMID 25800584
• Vallabhajosyula S, Pruthi S, Shah S, Wiley BM, Mankad SV, Jentzer JC. Basic and advanced echocardiographic evaluation of myocardial dysfunction in sepsis and septic shock. Anaesth Intensive Care. 2018 Jan;46(1):13-24. doi: 10.1177/0310057X1804600104. PMID 29361252
• Jentzer JC, Lawler PR, Van Houten HK, Yao X, Kashani KB, Dunlay SM. Cardiovascular Events Among Survivors of Sepsis Hospitalization: A Retrospective Cohort Analysis. J Am Heart Assoc. 2023 Feb 7;12(3):e027813. doi: 10.1161/JAHA.122.027813. Epub 2023 Feb 1. PMID 36722388

Identifiers

NCT: NCT07442032 · CaPS · Dnr 2025-04572-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗