Multimodal Vasopressor Strategy in Septic Shock

NCT06155812 | Completed Phase 2 DMC

• 1 other identifier: IRP-2023/01-03
• Study Type: interventional
• Target: 79
• Locations: 2 countries
• Sites: 2

Brief Summary

The goal of this prospective randomized controlled trial is to compare the effects of classic stepwise vs. early balanced multimodal vasopressor strategies in septic shock.

Conditions

Shock, Septic

Keywords

Vasopressor agents; Angiotensin II; Vasopressin; Norepinephrine; Renin; Lactate

Outcome Measures

Primary Outcomes (1)

• Rate of change in renin levels

  There is an increasing amount of data that renin is the best marker of tissue hypoperfusion and predictor of ICU mortality in patients with sepsis and septic shock, even outperforming lactate. Renin increased between the first and third day in non-survivors, but dropped in survivors. The rate of change in renin concentration but not lactate concentration in ICU patients over first 72 hours is associated with in hospital mortality.

  72 hours

Secondary Outcomes (3)

• Compare lactate levels

  72h

• Compare Δ Sequential Organ Failure Assessment (SOFA) score

  72 hours

• Compare acute kidney injury rate

  72 hours

Other Outcomes (5)

• Survival to ICU discharge

  From date of ICU admission until date of ICU discharge or death during ICU stay whichever came first, assessed up to 8 weeks

• 28-day mortality

  28 days after first admission to the ICU

• Renal replacement therapy requirement during ICU stay.

  From date of ICU admission until date of ICU discharge or death during ICU stay whichever came first, assessed up to 8 weeks

Study Arms (2)

STEPWISE VASOPRESSOR SEPTIC SHOCK MANAGEMENT

ACTIVE COMPARATOR

Regimen: Norepinephrine increases of 0.05-0.1 mcg/kg/min up to 0.5 mcg/kg/min, followed by vasopressin (administered at a fixed dose of 0.03 IE/min). If MAP remains \< 65 mmHg, norepinephrine will be titrated above dose of 0.5 mcg/kg/min until MAP ≥ 65 mmHg. Maximum norepinephrine dose as per clinical team decision. Initiation of additional vasoactive drugs (epinephrine, Ang II methylene blue or dopamine) as per clinical team decision. Initiation of inotropes (dobutamin, levosimendan, milrinone) as per clinical team decision.

Other: Successive administration of vasopressors

BALANCED MULTIMODAL VASOPRESSOR SEPTIC SHOCK MANAGEMENT

EXPERIMENTAL

Regimen: Simultaneous administration of norepinephrine, angiotensin II and vasopressin at equivalent starting doses (equivalent to approximately 0.05 mcg/kg/min of norepinephrine). Increments of 0.05 mcg/kg/min of equivalent doses of all three vasopressors every 3-5 min until MAP ≥ 65 mmHg is reached (vasopressin will be administered at a maximum dose of 0.03 IE/min, AT II will be administered at a maximum dose of 100 ng/kg/min). Initiation of additional vasoactive drugs (epinephrine, methylene blue or dopamine) as per clinical team decision. Initiation of inotropes (dobutamin, levosimendan, milrinone) as per clinical team decision.

Other: Simultaneous administration of vasopressors

Interventions

Simultaneous administration of vasopressors OTHER

Early, simultaneous administration of norepinephrine, angiotensin II, and vasopressin.

BALANCED MULTIMODAL VASOPRESSOR SEPTIC SHOCK MANAGEMENT

Successive administration of vasopressors OTHER

Administration and titration of norepinephrine and vasopressin. Administration of additional vasoactive drugs (epinephrine, methylene blue, angiotensin II or dopamine) as per clinical team. Initiation of inotropes (dobutamin, levosimendan, milrinone) as per clinical team decision.

STEPWISE VASOPRESSOR SEPTIC SHOCK MANAGEMENT

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adult patients (≥18 years).
• Sepsis (an acute change in total Sequential Organ Failure Assessment (SOFA) score ≥2 points consequent to infection) with persisting hypotension requiring vasopressors to maintain MAP ≥65 mm Hg and having a serum lactate level \>2 mmol/L despite adequate volume resuscitation (20-30ml/kg in 3 hours).
• Vasopressor requirement of ≥0,15 μg/kg/min equivalent of norepinephrine base.
• Patients are required to have central venous access and an arterial line present, and these are expected to remain present for at least the initial 72 hours of study.
• Patients are required to have an urinary catheter present, and it is expected to remain present for at least the initial 72 hours of study.
• Patients must have cardiac index (CI) \>2.3 L/min/m2 (measured by bedside echocardiography, pulse contour cardiac output (PiCCO) or Swan-Ganz catheter).

You may not qualify if:

• Death expected \<24 hours.
• Pregnancy (suspected or confirmed).
• Surgery expected for source of infection.
• Inter-hospital transfer expected during first 72 hours of hospitalization.
• Liver failure with a Model for End-Stage Liver Disease (MELD) score of ≥30.
• Patients with acute mesenteric ischemia or a history of mesenteric ischemic.
• Patients with Raynaud's phenomenon, systemic sclerosis or vasospastic disease.
• Patients with active bleeding and an anticipated need (within 48 hours of initiation of the study) for transfusion of \>4 units of packed red blood cells.
• Patients with a known allergy to mannitol.
• Patients on veno-arterial (VA) ECMO.

Sponsors & Collaborators

• University Medical Centre Maribor: lead

Study Sites (2)

University Hospital Centre Zagreb

Zagreb, Croatia

Location

Medical intensive care unit UMC Maribor

Maribor, 2000, Slovenia

Location

Related Publications (1)

• Kalamar Z, Gorenjak M, Landoni G, Markota A. Early multimodal vasopressor strategy in septic shock (TRICYCLE)-Study protocol for a randomized controlled clinical trial. PLoS One. 2025 Aug 29;20(8):e0331304. doi: 10.1371/journal.pone.0331304. eCollection 2025.

  PMID: 40880376 DERIVED

MeSH Terms

Conditions

Shock, Septic; Diabetes Insipidus

Condition Hierarchy (Ancestors)

Sepsis; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Shock; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Pituitary Diseases; Endocrine System Diseases

Study Officials

• Žiga Kalamar, MD

  University Medical Centre Maribor

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: Vasopressors will be administered successively in the control group. In the experimental group norepinephrine, angiotensin II, and vasopressin will be administered simultaneously.

Study Record Dates

• First Submitted: November 9, 2023
• First Posted: December 4, 2023
• Study Start: December 23, 2023
• Primary Completion: December 31, 2025
• Study Completion: February 1, 2026
• Last Updated: March 31, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF
• Time Frame: After November 2026

Locations

SL (1); CR (1)