Multimodal Vasopressor Strategy in Septic Shock

Study Overview
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Brief Summary
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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
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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).

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

Conditions
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Shock, Septic

Intervention / Treatment
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* Other: Simultaneous administration of vasopressors
* Other: Successive administration of vasopressors


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Vasopressors will be administered successively in the control group. In the experimental group norepinephrine, angiotensin II, and vasopressin will be administered simultaneously.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: STEPWISE VASOPRESSOR SEPTIC SHOCK MANAGEMENT<br>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<br>* Administration and titration of norepinephrine and administration of additional vasoactive drugs (epinephrine, methylene blue, angiotensin II, dobutamine, or dopamine) as per clinical team.<br>|
| Experimental: BALANCED MULTIMODAL VASOPRESSOR SEPTIC SHOCK MANAGEMENT<br>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<br>* Early, simultaneous administration of norepinephrine, angiotensin II, and vasopressin.<br>|

What is the study measuring?
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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 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. | 72 hours | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vasopressor agents, Angiotensin II, Vasopressin, Norepinephrine, Renin, Lactate