Multimodal Vasopressor Strategy in Septic Shock

Sponsor

University Medical Centre Maribor (Other)

Overall Status

Recruiting

CT.gov ID

NCT06155812

Collaborator

(none)

Enrollment

Location

Arms

35.9

Anticipated Duration (Months)

2.2

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Shock, Septic	Other: Simultaneous administration of vasopressors Other: Successive administration of vasopressors	Phase 2/Phase 3

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, angiotensin II, 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).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

80 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

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

Masking:

Single (Investigator)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Nov 3, 2023

Anticipated Primary Completion Date :

Dec 1, 2025

Anticipated Study Completion Date :

Nov 1, 2026

Arms and Interventions

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, methylene blue, angiotensin II, dobutamine, or dopamine) as per clinical team decision.	Other: Successive administration of vasopressors Administration and titration of norepinephrine and administration of additional vasoactive drugs (epinephrine, methylene blue, angiotensin II, dobutamine, or dopamine) as per clinical team.
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).	Other: Simultaneous administration of vasopressors Early, simultaneous administration of norepinephrine, angiotensin II, and vasopressin.

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, methylene blue, angiotensin II, dobutamine, or dopamine) as per clinical team decision.

Other: Successive administration of vasopressors

Administration and titration of norepinephrine and administration of additional vasoactive drugs (epinephrine, methylene blue, angiotensin II, dobutamine, or dopamine) as per clinical team.

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).

Other: Simultaneous administration of vasopressors

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

Outcome Measures

Primary Outcome Measures

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.

Secondary Outcome Measures

Compare lactate levels [72 hours]
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.
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.

Other Outcome Measures

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Adult patients (≥ 18 years)
Sepsis (an acute change in total 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
Patients must have a Cardiac Index (CI) >2.3 L/min/m2 (measured by bedside echocardiography, PiCCO catheter, or Swan-Ganz catheter)

Exclusion Criteria:

Death expected < 24 hours
Pregnancy (suspected or confirmed)
Surgery is expected for the source of the infection
Inter-hospital transfer is expected during the first 72 hours of hospitalization
Liver failure with a Model for End-Stage Liver Disease (MELD) score of ≥ 30 (3 months observed mortality at 52.6 %)
Patients on VA-ECMO
Known allergy to mannitol
Patients with systemic sclerosis or Raynaud syndrome