Multimodal Vasopressor Strategy in Septic Shock

Simultaneous Administration of Norepinephrine, Angiotensin II, and Vasopressin in Septic Shock Patients

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.

Study Overview

• Status: Completed
• Conditions: Shock, Septic
• Intervention / Treatment: Other: Simultaneous administration of vasopressors; Other: Successive administration of vasopressors

Detailed Description

CONTROL GROUP(Classic stepwise vasopressor administration):

Patients will be started on norepinephrine with 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. Initiation of additional vasoactive drugs (epinephrine, Ang II, methylene blue or dopamine) as per clinical team decision. Initiation of inotropes (dobutamine, milrinone, levosimendan) as per clinical team decision.

EXPERIMENTAL GROUP(Balanced multimodal vasopressor administration):

Early, simultaneous start 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, Ang II will be administered at maximum dose of 100ng/kg/min). Initiation of additional vasoactive drugs (epinephrine, methylene blue or dopamine) as per clinical team decision. Initiation of inotropes (dobutamine, milrinone, levosimendan) as per clinical team decision.

• Study Type: Interventional
• Enrollment (Actual): 79
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Croatia
  • Zagreb, Croatia
    • University Hospital Centre Zagreb
• Slovenia
  • Maribor, Slovenia, 2000
    • Medical intensive care unit UMC Maribor

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• 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).

Exclusion Criteria:

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: STEPWISE VASOPRESSOR SEPTIC SHOCK MANAGEMENT; 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; 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.
Experimental: BALANCED MULTIMODAL VASOPRESSOR SEPTIC SHOCK MANAGEMENT; 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; Early, simultaneous administration of norepinephrine, angiotensin II, and vasopressin.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Compare Δ Sequential Organ Failure Assessment (SOFA) score	The purpose is to monitor the rate of organ dysfunction. Score ranges from 0 (best) to 24 (worst) points.	72 hours
Compare acute kidney injury rate	The purpose is to monitor acute kidney injury based on Improving Global Outcomes (KDIGO) definition and staging system.	72 hours
Compare lactate levels	In critically ill patients, plasma lactate is commonly used to guide hemodynamic resuscitation. Hyperlactatemia has been widely recognized as a marker of tissue hypoxia/hypoperfusion but it can also result from increased or accelerated aerobic glycolysis during the stress response and may represent an important energy source in critically ill patients. Resuscitation to normalize lactate levels could worsen physiological status.	72h

Other Outcome Measures

Outcome Measure	Time Frame
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
Vasopressor cumulative dose requirement.	72 hours
Quality of life assessment 90 days after ICU admission (using EQ-5D standardized questionnaire).	90 days after ICU admission if alive

Collaborators and Investigators

• Sponsor: University Medical Centre Maribor
• Investigators: Principal Investigator: Žiga Kalamar, MD, University Medical Centre Maribor

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): December 23, 2023
• Primary Completion (Actual): December 31, 2025
• Study Completion (Actual): February 1, 2026

Study Registration Dates

• First Submitted: November 9, 2023
• First Submitted That Met QC Criteria: December 2, 2023
• First Posted (Actual): December 4, 2023

Study Record Updates

• Last Update Posted (Actual): March 31, 2026
• Last Update Submitted That Met QC Criteria: March 29, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Norepinephrine; Vasopressin; Lactate; Renin; Angiotensin II; Vasopressor agents
• Additional Relevant MeSH Terms: Urogenital Diseases; Endocrine System Diseases; Pathologic Processes; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Infections; Sepsis; Systemic Inflammatory Response Syndrome; Inflammation; Pituitary Diseases; Shock; Pathological Conditions, Signs and Symptoms; Shock, Septic; Diabetes Insipidus; Vasoconstrictor Agents
• Other Study ID Numbers: IRP-2023/01-03

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All of the individual participant data collected during the trial, after deidentification.
• IPD Sharing Time Frame: After November 2026
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

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