Vasopressin Hemodynamic Response as a Septic Shock Subphenotype Indicator

The goal of this observational study is to learn about blood pressure response to the vasopressor drug vasopressin in people with septic shock.

The main questions it aims to answer are:

• Are the levels of molecules showing communication between cells different between people whose blood pressure improves and people whose blood pressure does not improve when given a vasopressor medication?
• Are measurements found on echocardiography (heart ultrasound) different between people whose blood pressure improves and people whose blood pressure does not improve when given a vasopressor medication?
• Are measurements of blood oxygen in tissues just below the skin different between people whose blood pressure improves and people whose blood pressure does not improve when given a vasopressor medication?

Participants will be asked to contribute one or two blood samples. Participants who are ordered the drug vasopressin will contribute two blood samples. Both samples will be about two tablespoons for a total of about four tablespoons. One sample will be drawn before starting vasopressin infusion and the second sample will be drawn between one and six hours after starting the vasopressor drug infusion. At the same time points, advanced echocardiography pictures and measurements of oxygen in tissues from a sensor placed on one of the hands will be taken. Participants who are not ordered the drug vasopressin and only ordered the drug norepinephrine will contribute only one blood sample. At the time the sample is collected, advanced echocardiography pictures and measurements of oxygen in tissues from a sensor placed on one of the hands will be taken. This research also involves analyzing data obtained during the participant's hospital stay.

Study Overview

• Status: Terminated
• Conditions: Shock, Septic
• Intervention / Treatment: Drug: Vasopressin

Detailed Description

Septic shock mortality remains high at 33% in North America; current clinical predictors of poor outcomes in septic shock are suboptimal. In addition to antibiotics and intravenous fluids, vasoactive agents are initiated to restore effective tissue perfusion. Norepinephrine (NE) is the recommended first-line vasopressor, but adjunctive arginine vasopressin is used in over one-third of patients to improve blood pressure or decrease NE dosage. However, less than half of vasopressin recipients have a clinically-apparent hemodynamic response (defined as a decrease in NE dosage at 6 hours after vasopressin initiation). Vasopressors, particularly norepinephrine, are known to be immune modulators. Further, each vasopressor has its own unique effect on a patient's hemodynamic profile as assessed by echocardiography and microcirculation measurements. In the current study, the investigators seek to clarify the link between vasopressin, immune response, hemodynamic profile, and microcirculatory measurments. The central goal of this proposal is to identify "vasopressin response" as an easily-identifiable bedside indicator of a distinct septic shock subphenotype.

• Study Type: Observational
• Enrollment (Actual): 2

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Main Campus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Adult patients with septic shock are eligible for this study. Patients ordered vasopressin as an adjunct to norepinephrine as part of routine care comprise the primary cohort of interest. An active control cohort of patients who are only receiving norepinephrine will also be enrolled.

Description

Inclusion Criteria:

• Adult patients (≥18 years old)
• Septic shock (as defined by Sepsis-3)
• Receiving norepinephrine
• Admitted to a medical, surgical, NeuroSciences, or mixed intensive care unit
• Central venous catheter in place
• Ordered fixed-dose vasopressin as an adjunct to norepinephrine by the primary care team (unless in active control cohort)

Exclusion Criteria:

• Vasopressin ordered for an indication other than septic shock
• Vasopressin initiated at another institution
• Receiving a primary vasopressor other than norepinephrine (eg, phenylephrine)
• Positive test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within the preceding 28 days
• Blood hemoglobin concentration <7 g/dL
• Primary treatment team determines that vasopressin initiation is emergent
• Patient or their legal authorized representative opts to not participate in the study

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Vasopressin plus norepinephrine; Patients with septic shock ordered vasopressin as an adjunct to norepinephrine	Drug: Vasopressin; Fixed dosage vasopressin ordered as an adjunctive vasopressor to norepinephrine; Other Names: antidiuretic hormone (ADH); arginine vasopressin (AVP)
Norepinephrine; Active control cohort of patients with septic shock who are only receiving norepinephrine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ratio of plasma interleukin-10 (IL-10) to tumor necrosis factor-α (TNF-α)	Compare baseline ratio of plasma concentrations of interleukin-10 (IL-10) to tumor necrosis factor-α (TNF-α) in vasopressin responders vs. non-responders. The active control cohort of patients who are only receiving norepinephrine will serve as a control for this analysis.	Baseline (before vasopressin initiation and within 45 minutes of order placement).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Left ventricular ejection fraction (LVEF)	Compare baseline left ventricular ejection fraction (LVEF) in vasopressin responders vs. non-responders. The active control cohort of patients who are only receiving norepinephrine will serve as a control for this analysis.	Baseline (before vasopressin initiation and within 45 minutes of order placement).
Ratio of ratio of arterial elastance (Ea) to left ventricular end-systolic elastance (Ees)	Compare left ventricular-arterial coupling (ratio of arterial elastance [Ea] to left ventricular end-systolic elastance [Ees]) over time in vasopressin responders vs. non-responders. The active control cohort of patients who are only receiving norepinephrine will serve as a control for this analysis.	Baseline (before vasopressin initiation and within 45 minutes of order placement) through one to six hours after vasopressin initiation.
Lipopolysaccharide-stimulated monocyte TNF-α secretion	Compare lipopolysaccharide-stimulated monocyte TNF-α secretion over time in vasopressin responders vs. non-responders. The active control cohort of patients who are only receiving norepinephrine will serve as a control for this analysis.	Baseline (before vasopressin initiation and within 45 minutes of order placement) through one to six hours after vasopressin initiation.
Monocyte adhesion	Compare monocyte adhesion over time in vasopressin responders vs. non-responders. The active control cohort of patients who are only receiving norepinephrine will serve as a control for this analysis.	Baseline (before vasopressin initiation and within 45 minutes of order placement) through one to six hours after vasopressin initiation.
Plasma renin concentration	Compare plasma renin concentration over time in vasopressin responders vs. non-responders. The active control cohort of patients who are only receiving norepinephrine will serve as a control for this analysis.	Baseline (before vasopressin initiation and within 45 minutes of order placement) through one to six hours after vasopressin initiation.
Plasma angiopoietin-2 concentration	Compare plasma angiopoietin-2 concentration over time in vasopressin responders vs. non-responders. The active control cohort of patients who are only receiving norepinephrine will serve as a control for this analysis.	Baseline (before vasopressin initiation and within 45 minutes of order placement) through one to six hours after vasopressin initiation.
StO2 recovery slope (%/min)	Compare tissue oxygenation (StO2) recovery slope, during the reperfusion phase of a vascular occlusion test (VOT), over time between vasopressin responders vs non-responders. The active control cohort of patients who are only receiving norepinephrine will serve as a control for this analysis.	Baseline (before vasopressin initiation and within 45 minutes of order placement) through one to six hours after vasopressin initiation.
Difference in StO2 (%)	Compare the difference between maximum tissue oxygenation (StO2) and minimum StO2, during the reperfusion phase of a vascular occlusion test (VOT), over time between vasopressin responders vs non-responders. The active control cohort of patients who are only receiving norepinephrine will serve as a control for this analysis.	Baseline (before vasopressin initiation and within 45 minutes of order placement) through one to six hours after vasopressin initiation.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma interleukin-1β (IL-1β) concentration	Compare plasma interleukin-1β (IL-1β) concentration over time in vasopressin responders vs. non-responders. The active control cohort of patients who are only receiving norepinephrine will serve as a control for this analysis.	Baseline (before vasopressin initiation and within 45 minutes of order placement) through one to six hours after vasopressin initiation.
Plasma interleukin-6 (IL-6) concentration	Compare plasma interleukin-6 (IL-6) concentration over time in vasopressin responders vs. non-responders. The active control cohort of patients who are only receiving norepinephrine will serve as a control for this analysis.	Baseline (before vasopressin initiation and within 45 minutes of order placement) through one to six hours after vasopressin initiation.
Plasma interferon-gamma (IFN-γ) concentration	Compare plasma interferon-gamma (IFN-γ) concentration over time in vasopressin responders vs. non-responders. The active control cohort of patients who are only receiving norepinephrine will serve as a control for this analysis.	Baseline (before vasopressin initiation and within 45 minutes of order placement) through one to six hours after vasopressin initiation.
Plasma C-X-C motif chemokine ligand 10 (CXCL10, also known as interferon gamma-induced protein 10 [IP-10]) concentration	Compare plasma C-X-C motif chemokine ligand 10 (CXCL10, also known as interferon gamma-induced protein 10 [IP-10]) concentration over time in vasopressin responders vs. non-responders. The active control cohort of patients who are only receiving norepinephrine will serve as a control for this analysis.	Baseline (before vasopressin initiation and within 45 minutes of order placement) through one to six hours after vasopressin initiation.
Plasma granulocyte-colony stimulating factor (G-CSF) concentration	Compare plasma granulocyte-colony stimulating factor (G-CSF) concentration over time in vasopressin responders vs. non-responders. The active control cohort of patients who are only receiving norepinephrine will serve as a control for this analysis.	Baseline (before vasopressin initiation and within 45 minutes of order placement) through one to six hours after vasopressin initiation.
Plasma E-selectin concentration	Compare plasma E-selectin concentration over time in vasopressin responders vs. non-responders. The active control cohort of patients who are only receiving norepinephrine will serve as a control for this analysis.	Baseline (before vasopressin initiation and within 45 minutes of order placement) through one to six hours after vasopressin initiation.
Plasma vasopressin concentration	Evaluate the association of plasma vasopressin concentration with ratio of plasma interleukin-10 (IL-10) to tumor necrosis factor-α (TNF-α) over time. The active control cohort of patients who are only receiving norepinephrine will serve as a control for this analysis.	Baseline (before vasopressin initiation and within 45 minutes of order placement) through one to six hours after vasopressin initiation.
Plasma copeptin concentration	Compare plasma copeptin concentration over time in vasopressin responders vs. non-responders. The active control cohort of patients who are only receiving norepinephrine will serve as a control for this analysis.	Baseline (before vasopressin initiation and within 45 minutes of order placement) through one to six hours after vasopressin initiation.
Left ventricular ejection fraction (LVEF) change	Compare left ventricular ejection fraction (LVEF) over time in vasopressin responders vs. non-responders. The active control cohort of patients who are only receiving norepinephrine will serve as a control for this analysis.	Baseline (before vasopressin initiation and within 45 minutes of order placement) through one to six hours after vasopressin initiation.
Stroke volume (SV) by echocardiography	Compare stroke volume (SV) over time in vasopressin responders vs. non-responders. The active control cohort of patients who are only receiving norepinephrine will serve as a control for this analysis.	Baseline (before vasopressin initiation and within 45 minutes of order placement) through one to six hours after vasopressin initiation.
Tricuspid annular plane systolic excursion (TAPSE)	Compare tricuspid annular plane systolic excursion (TAPSE) over time in vasopressin responders vs. non-responders. The active control cohort of patients who are only receiving norepinephrine will serve as a control for this analysis.	Baseline (before vasopressin initiation and within 45 minutes of order placement) through one to six hours after vasopressin initiation.
Tricuspid annular systolic plane velocity (TAPSV, also known as RV S')	Compare tricuspid annular systolic plane velocity (TAPSV, also known as RV S') over time in vasopressin responders vs. non-responders. The active control cohort of patients who are only receiving norepinephrine will serve as a control for this analysis.	Baseline (before vasopressin initiation and within 45 minutes of order placement) through one to six hours after vasopressin initiation.
Venous-arterial carbon dioxide tension gradient (Pva-CO2)	Compare venous-arterial carbon dioxide tension gradient (Pva-CO2) over time in vasopressin responders vs. non-responders. The active control cohort of patients who are only receiving norepinephrine will serve as a control for this analysis.	Baseline (before vasopressin initiation and within 45 minutes of order placement) through one to six hours after vasopressin initiation.
Central venous oxygen saturation (ScvO2)	Compare central venous oxygen saturation (ScvO2) over time in vasopressin responders vs. non-responders. The active control cohort of patients who are only receiving norepinephrine will serve as a control for this analysis.	Baseline (before vasopressin initiation and within 45 minutes of order placement) through one to six hours after vasopressin initiation.
Dynamic arterial elastance (Eadyn, the ratio of pulse pressure variation to stroke volume variation)	Compare dynamic arterial elastance (Eadyn) over time in vasopressin responders vs. non-responders. The active control cohort of patients who are only receiving norepinephrine will serve as a control for this analysis.	Baseline (before vasopressin initiation and within 45 minutes of order placement) through one to six hours after vasopressin initiation.
Baseline tissue oxygenation (StO2)	Compare baseline tissue oxygenation (StO2) over time between vasopressin responders vs non-responders. The active control cohort of patients who are only receiving norepinephrine will serve as a control for this analysis.	Baseline (before vasopressin initiation and within 45 minutes of order placement).
Tissue oxygenation (StO2) deperfusion slope	Compare tissue oxygenation (StO2) deperfusion slope, during a vascular occlusion test, over time between vasopressin responders vs non-responders. The active control cohort of patients who are only receiving norepinephrine will serve as a control for this analysis.	Baseline (before vasopressin initiation and within 45 minutes of order placement) through one to six hours after vasopressin initiation.
Minimum tissue oxygenation (StO2)	Compare minimum tissue oxygenation (StO2), during a vascular occlusion test, over time between vasopressin responders vs non-responders. The active control cohort of patients who are only receiving norepinephrine will serve as a control for this analysis.	Baseline (before vasopressin initiation and within 45 minutes of order placement) through one to six hours after vasopressin initiation.
Tissue oxygenation (StO2) area under the curve (AUC)	Compare tissue oxygenation (StO2) area under the curve (AUC), during a vascular occlusion test, over time between vasopressin responders vs non-responders. The active control cohort of patients who are only receiving norepinephrine will serve as a control for this analysis.	Baseline (before vasopressin initiation and within 45 minutes of order placement) through one to six hours after vasopressin initiation.
Capillary refill time (CRT)	Compare capillary refill time (CRT) over time between vasopressin responders vs non-responders. The active control of cohort of patients who are only receiving norepinephrine will serve as a control for this analysis.	Baseline (before vasopressin initiation and within 45 minutes of order placement) through one to six hours after vasopressin initiation.
Clinical trajectory	Compare the ordinal outcome clinical trajectory (comprised of rapid recovery, chronic critical illness, and early recovery) between vasopressin responders vs. non-responders.	Baseline (before vasopressin initiation and within 45 minutes of order placement) through the sooner of intensive care unit discharge or 14 days.
Intensive care unit length of stay	Compare intensive care unit length of stay in vasopressin responders vs. non-responders.	Baseline (before vasopressin initiation and within 45 minutes of order placement) through intensive care unit discharge.
Incidence of in-hospital mortality	Compare the incidence of hospital mortality in vasopressin responders vs. non-responders.	Baseline (before vasopressin initiation and within 45 minutes of order placement) through hospital discharge.

Collaborators and Investigators

• Sponsor: The Cleveland Clinic
• Investigators: Principal Investigator: Seth Bauer, PharmD, The Cleveland Clinic

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2025
• Primary Completion (Actual): February 1, 2026
• Study Completion (Actual): February 1, 2026

Study Registration Dates

• First Submitted: February 16, 2024
• First Submitted That Met QC Criteria: May 17, 2024
• First Posted (Actual): May 23, 2024

Study Record Updates

• Last Update Posted (Actual): February 19, 2026
• Last Update Submitted That Met QC Criteria: February 17, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Sepsis; Systemic Inflammatory Response Syndrome; Inflammation; Shock; Pathological Conditions, Signs and Symptoms; Shock, Septic; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptide Hormones; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins; Pituitary Hormones, Posterior; Pituitary Hormones; Vasopressins; Arginine Vasopressin
• Other Study ID Numbers: 21-047

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data may be available through reasonable request to the study principal investigator and completion of a data use agreement.
• IPD Sharing Time Frame: Study data will become available at the time of initial manuscript publication and remain available for 5 years after initial manuscript publication.
• IPD Sharing Access Criteria: Individual participant data may be available through reasonable request to the study principal investigator and completion of a data use agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No