## Protocol Section
### Identification Module
**NCT ID:** NCT06426407

**Brief Title:** Vasopressin Hemodynamic Response as a Septic Shock Subphenotype Indicator

**Official Title:** Vasopressin Hemodynamic Response as a Septic Shock Subphenotype Indicator

#### Organization Study ID Info
**ID:** 21-047
#### Organization
**Class:** OTHER
**Full Name:** The Cleveland Clinic
### Status Module
#### Completion Date
**Date:** 2026-01

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-05-23

**Type:** ACTUAL

**Last Update Submit Date:** 2024-05-17

**Overall Status:** NOT_YET_RECRUITING

#### Primary Completion Date
**Date:** 2026-01

**Type:** ESTIMATED

#### Start Date
**Date:** 2024-06

**Type:** ESTIMATED

**Status Verified Date:** 2024-05

#### Study First Post Date
**Date:** 2024-05-23
**Type:** ACTUAL
**Study First Submit Date:** 2024-02-16
**Study First Submit QC Date:** 2024-05-17
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** OTHER

**Name:** The Cleveland Clinic

#### Responsible Party

**Investigator Affiliation:** The Cleveland Clinic

**Investigator Full Name:** Seth Bauer

**Investigator Title:** Principal Investigator

**Type:** PRINCIPAL_INVESTIGATOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

**Oversight Has DMC:** False

### Description Module

**Brief Summary:** 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?

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 will be taken. Participants who are not ordered the drug vasopressin and only ordered the drug norepinephrine will contribute only one sample. At the time the sample is collected, advanced echocardiography pictures will be taken. This research also involves analyzing data obtained during the participant's hospital stay.

**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. In the current study, the investigators seek to clarify the link between vasopressin, immune response, and hemodynamic profile. The central goal of this proposal is to identify "vasopressin response" as an easily-identifiable bedside indicator of a distinct septic shock subphenotype.

### Conditions Module

**Conditions:**

- Shock, Septic

### Design Module

#### Bio Spec

**Description:** Blood collected into EDTA test tubes

**Retention:** SAMPLES_WITHOUT_DNA

#### Design Info

**Observational Model:** COHORT

**Time Perspective:** PROSPECTIVE

#### Enrollment Info

**Count:** 48

**Type:** ESTIMATED

**Study Type:** OBSERVATIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** Patients with septic shock ordered vasopressin as an adjunct to norepinephrine

**Intervention Names:**

- Drug: Vasopressin

**Label:** Vasopressin plus norepinephrine

#### Arm Group 2

**Description:** Active control cohort of patients with septic shock who are only receiving norepinephrine

**Label:** Norepinephrine

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Vasopressin plus norepinephrine

**Description:** Fixed dosage vasopressin ordered as an adjunctive vasopressor to norepinephrine

**Name:** Vasopressin

**Other Names:**

- antidiuretic hormone (ADH)

- arginine vasopressin (AVP)

**Type:** DRUG

### Outcomes Module

#### Other Outcomes

**Description:** 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.

**Measure:** Plasma interleukin-1β (IL-1β) concentration

**Time Frame:** Baseline (before vasopressin initiation and within 30 minutes of order placement) through one to six hours after vasopressin initiation.

**Description:** 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.

**Measure:** Plasma interleukin-6 (IL-6) concentration

**Time Frame:** Baseline (before vasopressin initiation and within 30 minutes of order placement) through one to six hours after vasopressin initiation.

**Description:** 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.

**Measure:** Plasma interferon-gamma (IFN-γ) concentration

**Time Frame:** Baseline (before vasopressin initiation and within 30 minutes of order placement) through one to six hours after vasopressin initiation.

**Description:** 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.

**Measure:** Plasma C-X-C motif chemokine ligand 10 (CXCL10, also known as interferon gamma-induced protein 10 [IP-10]) concentration

**Time Frame:** Baseline (before vasopressin initiation and within 30 minutes of order placement) through one to six hours after vasopressin initiation.

**Description:** 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.

**Measure:** Plasma granulocyte-colony stimulating factor (G-CSF) concentration

**Time Frame:** Baseline (before vasopressin initiation and within 30 minutes of order placement) through one to six hours after vasopressin initiation.

**Description:** 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.

**Measure:** Plasma E-selectin concentration

**Time Frame:** Baseline (before vasopressin initiation and within 30 minutes of order placement) through one to six hours after vasopressin initiation.

**Description:** 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.

**Measure:** Plasma vasopressin concentration

**Time Frame:** Baseline (before vasopressin initiation and within 30 minutes of order placement) through one to six hours after vasopressin initiation.

**Description:** 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.

**Measure:** Plasma copeptin concentration

**Time Frame:** Baseline (before vasopressin initiation and within 30 minutes of order placement) through one to six hours after vasopressin initiation.

**Description:** 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.

**Measure:** Left ventricular ejection fraction (LVEF) change

**Time Frame:** Baseline (before vasopressin initiation and within 30 minutes of order placement) through one to six hours after vasopressin initiation.

**Description:** 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.

**Measure:** Stroke volume (SV) by echocardiography

**Time Frame:** Baseline (before vasopressin initiation and within 30 minutes of order placement) through one to six hours after vasopressin initiation.

**Description:** 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.

**Measure:** Tricuspid annular plane systolic excursion (TAPSE)

**Time Frame:** Baseline (before vasopressin initiation and within 30 minutes of order placement) through one to six hours after vasopressin initiation.

**Description:** 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.

**Measure:** Tricuspid annular systolic plane velocity (TAPSV, also known as RV S')

**Time Frame:** Baseline (before vasopressin initiation and within 30 minutes of order placement) through one to six hours after vasopressin initiation.

**Description:** 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.

**Measure:** Venous-arterial carbon dioxide tension gradient (Pva-CO2)

**Time Frame:** Baseline (before vasopressin initiation and within 30 minutes of order placement) through one to six hours after vasopressin initiation.

**Description:** 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.

**Measure:** Central venous oxygen saturation (ScvO2)

**Time Frame:** Baseline (before vasopressin initiation and within 30 minutes of order placement) through one to six hours after vasopressin initiation.

**Description:** 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.

**Measure:** Dynamic arterial elastance (Eadyn, the ratio of pulse pressure variation to stroke volume variation)

**Time Frame:** Baseline (before vasopressin initiation and within 30 minutes of order placement) through one to six hours after vasopressin initiation.

**Description:** Compare the ordinal outcome clinical trajectory (comprised of rapid recovery, chronic critical illness, and early recovery) between vasopressin responders vs. non-responders.

**Measure:** Clinical trajectory

**Time Frame:** Baseline (before vasopressin initiation and within 30 minutes of order placement) through the sooner of intensive care unit discharge or 14 days.

**Description:** Compare the incidence of hospital mortality in vasopressin responders vs. non-responders.

**Measure:** Incidence of in-hospital mortality

**Time Frame:** Baseline (before vasopressin initiation and within 30 minutes of order placement) through hospital discharge.

**Description:** Compare intensive care unit length of stay in vasopressin responders vs. non-responders.

**Measure:** Intensive care unit length of stay

**Time Frame:** Baseline (before vasopressin initiation and within 30 minutes of order placement) through intensive care unit discharge.

#### Primary Outcomes

**Description:** 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.

**Measure:** Ratio of plasma interleukin-10 (IL-10) to tumor necrosis factor-α (TNF-α)

**Time Frame:** Baseline (before vasopressin initiation and within 30 minutes of order placement).

#### Secondary Outcomes

**Description:** 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.

**Measure:** Left ventricular ejection fraction (LVEF)

**Time Frame:** Baseline (before vasopressin initiation and within 30 minutes of order placement).

**Description:** 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.

**Measure:** Ratio of ratio of arterial elastance (Ea) to left ventricular end-systolic elastance (Ees)

**Time Frame:** Baseline (before vasopressin initiation and within 30 minutes of order placement) through one to six hours after vasopressin initiation.

**Description:** 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.

**Measure:** Lipopolysaccharide-stimulated monocyte TNF-α secretion

**Time Frame:** Baseline (before vasopressin initiation and within 30 minutes of order placement) through one to six hours after vasopressin initiation.

**Description:** 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.

**Measure:** Monocyte adhesion

**Time Frame:** Baseline (before vasopressin initiation and within 30 minutes of order placement) through one to six hours after vasopressin initiation.

**Description:** 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.

**Measure:** Plasma renin concentration

**Time Frame:** Baseline (before vasopressin initiation and within 30 minutes of order placement) through one to six hours after vasopressin initiation.

**Description:** 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.

**Measure:** Plasma angiopoietin-2 concentration

**Time Frame:** Baseline (before vasopressin initiation and within 30 minutes of order placement) through one to six hours after vasopressin initiation.

### Eligibility Module

**Eligibility Criteria:** 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

**Minimum Age:** 18 Years

**Sampling Method:** NON_PROBABILITY_SAMPLE

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

**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.

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** bauers@ccf.org

**Name:** Seth Bauer, PharmD

**Phone:** 2169522553

**Role:** CONTACT

#### Overall Officials

**Official 1:**

**Affiliation:** The Cleveland Clinic

**Name:** Seth Bauer, PharmD

**Role:** PRINCIPAL_INVESTIGATOR

### IPD Sharing Statement Module

**Access Criteria:** Individual participant data may be available through reasonable request to the study principal investigator and completion of a data use agreement.

**Description:** Individual participant data may be available through reasonable request to the study principal investigator and completion of a data use agreement.

**Info Types:**

- STUDY_PROTOCOL

- SAP

- ICF

- CSR

- ANALYTIC_CODE

**IPD Sharing:** YES

**Time Frame:** Study data will become available at the time of initial manuscript publication and remain available for 5 years after initial manuscript publication.

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000010335

- Term: Pathologic Processes

- ID: D000018805

- Term: Sepsis

- ID: D000007239

- Term: Infections

- ID: D000018746

- Term: Systemic Inflammatory Response Syndrome

- ID: D000007249

- Term: Inflammation

### Condition Browse Module - Browse Branches

- Abbrev: BC23

- Name: Symptoms and General Pathology

- Abbrev: All

- Name: All Conditions

- Abbrev: BC01

- Name: Infections

### Condition Browse Module - Browse Leaves

- ID: M15577

- Name: Shock

- Relevance: HIGH

- As Found: Shock

- ID: M15580

- Name: Shock, Septic

- Relevance: HIGH

- As Found: Shock, Septic

- ID: M20864

- Name: Sepsis

- Relevance: LOW

- As Found: Unknown

- ID: M16869

- Name: Toxemia

- Relevance: LOW

- As Found: Unknown

- ID: M10283

- Name: Infections

- Relevance: LOW

- As Found: Unknown

- ID: M6368

- Name: Communicable Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M16355

- Name: Syndrome

- Relevance: LOW

- As Found: Unknown

- ID: M20818

- Name: Systemic Inflammatory Response Syndrome

- Relevance: LOW

- As Found: Unknown

- ID: M10293

- Name: Inflammation

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000012772

- Term: Shock, Septic

- ID: D000012769

- Term: Shock

### Intervention Browse Module - Ancestors

- ID: D000045505

- Term: Physiological Effects of Drugs

- ID: D000006490

- Term: Hemostatics

- ID: D000003029

- Term: Coagulants

- ID: D000014662

- Term: Vasoconstrictor Agents

- ID: D000050034

- Term: Antidiuretic Agents

- ID: D000045283

- Term: Natriuretic Agents

### Intervention Browse Module - Browse Branches

- Abbrev: All

- Name: All Drugs and Chemicals

- Abbrev: NaAg

- Name: Natriuretic Agents

- Abbrev: VaCoAg

- Name: Vasoconstrictor Agents

- Abbrev: Coag

- Name: Coagulants

- Abbrev: AA

- Name: Amino Acids

### Intervention Browse Module - Browse Leaves

- ID: M9789

- Name: Hormones

- Relevance: LOW

- As Found: Unknown

- ID: M17414

- Name: Vasopressins

- Relevance: HIGH

- As Found: Contained

- ID: M4437

- Name: Arginine Vasopressin

- Relevance: HIGH

- As Found: Contained

- ID: M12575

- Name: Norepinephrine

- Relevance: LOW

- As Found: Unknown

- ID: M17409

- Name: Vasoconstrictor Agents

- Relevance: LOW

- As Found: Unknown

- ID: M9576

- Name: Hemostatics

- Relevance: LOW

- As Found: Unknown

- ID: M6259

- Name: Coagulants

- Relevance: LOW

- As Found: Unknown

- ID: T1

- Name: Arginine

- Relevance: HIGH

- As Found: 6 hours

### Intervention Browse Module - Meshes

- ID: D000014667

- Term: Vasopressins

- ID: D000001127

- Term: Arginine Vasopressin

### Misc Info Module

- Version Holder: 2024-05-31
