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.

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.

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.

All of the individual participant data collected during the trial, after deidentification.

After November 2026