Targeted Tissue Perfusion Versus Macrocirculatory-guided Standard Care in Patients With Septic Shock

Study Overview
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Brief Summary
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Background: The recommended monitoring and target levels in septic shock (SSC Guidelines 2012) including mean arterial pressure (MAP) target are not based on robust clinical data. Objective: To test, if in patients with septic shock, tissue perfusion guided (TPG) treatment strategy leads to a faster resolution of hypoperfusion than the macrocirculatory target guided standard care. Design: A prospective phase II two-parallel-group open-label randomized controlled trial Interventions: Intervention group- Targeted tissue perfusion guided (TTP) - care. Control group - Macrocirculatory - guided (MCG) care. Randomization: 1:1 stratified according to the site and presence or absence of known hypertension. Trial size: 200 randomised patients in 4 ICUs.

Detailed Description
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Study hypothesis: Targeting at clinical tissue perfusion (in the TTP arm) will decrease the use and untoward effects of vasopressors, and result in more days alive in 30-days without vasopressor or inotropic support and without lactatemia, in comparison with standard clinical care with preference of macrocirculatory targets (MCG arm). Intervention group - Targeted tissue perfusion (TTP) care: Primary targets /registration period capillary refill time (CRT) / <3 sec/ every hour skin mottling / absent / every hour arterial lactate / <2.0 mmol/l/ per 2hr peripheral temperature/ warm /every hour urine output/ ≥0.5 mL/kg per hour/ every hour mean arterial pressure (MAP) 50-65 mmHg (minimum as a safety limit)/ continuous if previous hypertension 65- 70 mmHg if oliguria 2-hour trial 75-80 mmHg (If diuresis better, continue 2hr and re-evaluate) Secondary target Continuous mixed venous saturation (SvO2) >65%, if available Control group - Macrocirculatory targets guided (MCG) standard care Primary targets Mean arterial pressure (MAP) 65-75 mmHg /continuous ** if previous hypertension 75-80 mmHg *** if oliguria < 0.3 ml/kg, 2-hour trial 85-90 mmHg (If diuresis better, continue 2hr and re-evaluate) Central venous pressure (CVP)/hourly, Adequate fluid therapy is indicated to restore clinical hypovolemia up to the recommended CVP-level of 8-12 mmHg, if needed Urine output ≥ 0.5 mL/kg/h/ hourly Secondary target Continuous SvO2 >65%, if available

Official Title
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Targeted Tissue Perfusion Versus Macrocirculatory-guided Standard Care in Patients With Septic Shock [TARTARE-2S]- A Multicentre Randomized Controlled Trial

Conditions
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Shock; Septic, Critical Illness

Intervention / Treatment
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* Other: Hemodynamical treatment TTP
* Other: Hemodynamical treatment MCG


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Septic shock defined as Septic infection AND systemic mean blood pressure > 65 mmHg requiring any dose of vasopressors (norepinephrine, vasopressin) despite adequate fluid resuscitation (minimum of 20 ml/kg crystalloids) AND Elevated lactate ≥ 3.0 mmol/L with suspected hypoperfusion Exclusion Criteria: aged less than 18 or over 80 years any other probable condition than sepsis affecting or expected to affect the central nervous system including post cardiac arrest present or suspected myocardial ischemia acute pulmonary embolism terminal illness and not considered for full intensive care support use of extra-corporeal membrane oxygenation (ECMO) known liver disease - Child-Pugh -Class B or C confirmed chronic kidney disease known on admission known to be pregnant or lactating more than 4 hours from fulfilled inclusion criteria to randomization another probable cause of hyperlactatemia patients transferred from another ICU patients with active haematological malignancy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Targeted tissue perfusion guidance (TTP)<br>TTP-guidance based on clinical signs of peripheral perfusion. | Other: Hemodynamical treatment TTP<br>* Based on capillary refilling time, peripheral temperature, mottling, diuresis, MAP safety limit monitoring<br>|
| Active Comparator: Macrocirculatory - guidance (MCG)<br>MCG-guidance based on recommended macrocirculatory parameters. | Other: Hemodynamical treatment MCG<br>* Based on MAP, CVP, urine output monitoring<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Days alive in 30 days- without vasopressors/ inotropes or hyperlactatemia | • Days alive in 30 days with normal arterial blood lactate ( first confirmed value of < 2 mmol/L) AND without any inotropic or vasopressor agent | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to normalization of arterial blood lactate |  | 30 days | 
| Days alive with normal arterial blood lactate in 30 days |  | 30 days | 
| Days alive without any inotropic or vasopressor agent in 30 days |  | 30 days | 
| Days alive without renal replacement therapy (RRT) in 30 days |  | 30 days | 
| Days alive without mechanical ventilation in 30 days |  | 30 days | 
| Days alive without any organ support (mechanical ventilation, renal-replacement therapy, vasopressor/ inotropic agents) in 30 days |  | 30 days | 
| New acute kidney injury (AKI) (Kdigo stages I-III) |  | 30 days | 
| Days alive outside hospital in 90 days |  | 90 days | 
| Total amount of norepinephrine given up to day 5 |  | 5 days | 
| Number/ total number of the following adverse reactions | ventricular tachycardia/ fibrillation , atrial fibrillation , myocardial infarction , skin necrosis , stroke , secondary bowel ischemia, limb ischemia, numbers of serious adverse events | 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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septic shock, tissue perfusion, macrocirculatory, mean arterial pressure, vasopressor use, days alive free of organ support