Multimodal Vasopressor Strategy in Septic Shock

Phase 2

Recruiting

• Conditions: Shock, Septic
• Interventions: Other: Simultaneous administration of vasopressors; Other: Successive administration of vasopressors

• Registration Number: NCT06155812
• Lead Sponsor: University Medical Centre Maribor

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.

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, methylene blue, dobutamine, or dopamine) 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, AT II will be administered at maximum dose of 100ng/kg/min).

Study Timeline

• Study First Submitted: 2023-11-09
• Study First Submitted QC: 2023-12-02
• Study First Posted: 2023-12-04
• Study Start: 2023-12-23
• Status Verified: 2025-03
• Last Update Submitted: 2025-03-18
• Last Update Posted: 2025-03-21
• Primary Completion: 2025-12
• Study Completion: 2026-11

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 80

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
BALANCED MULTIMODAL VASOPRESSOR SEPTIC SHOCK MANAGEMENT	Simultaneous administration of vasopressors	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).
STEPWISE VASOPRESSOR SEPTIC SHOCK MANAGEMENT	Successive administration of vasopressors	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, methylene blue, angiotensin II, dobutamine, or dopamine) as per clinical team decision.

Primary Outcome Measures

Name	Time	Method
Rate of change in renin levels	72 hours	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.
Compare lactate levels	72h	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.

Secondary Outcome Measures

Name	Time	Method
Compare Δ Sequential Organ Failure Assessment (SOFA) score	72 hours	The purpose is to monitor the rate of organ dysfunction. Score ranges from 0 (best) to 24 (worst) points.
Compare acute kidney injury rate	72 hours	The purpose is to monitor acute kidney injury based on Improving Global Outcomes (KDIGO) definition and staging system.

Trial Locations

Locations (2)

University Hospital Centre Zagreb; 🇭🇷 Zagreb, Croatia

Medical intensive care unit UMC Maribor; 🇸🇮 Maribor, Slovenia