Targeted Tissue Perfusion Versus Macrocirculatory-guided Standard Care in Patients With Septic Shock (TARTARE-2S)

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

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:

1. Intervention group- Targeted tissue perfusion guided (TTP) - care.
2. 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.

Study Overview

• Status: Completed
• Conditions: Critical Illness; Shock; Septic
• Intervention / Treatment: Other: Hemodynamical treatment TTP; Other: Hemodynamical treatment MCG

Detailed Description

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

1. capillary refill time (CRT) / <3 sec/ every hour
2. skin mottling / absent / every hour
3. arterial lactate / <2.0 mmol/l/ per 2hr
4. peripheral temperature/ warm /every hour
5. urine output/ ≥0.5 mL/kg per hour/ every hour

6. 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
7. Continuous mixed venous saturation (SvO2) >65%, if available

Control group - Macrocirculatory targets guided (MCG) standard care Primary targets

1. 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)

2. 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
3. Urine output ≥ 0.5 mL/kg/h/ hourly Secondary target
4. Continuous SvO2 >65%, if available

• Study Type: Interventional
• Enrollment (Actual): 200
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Finland
  • Helsinki, Finland, 00029
    • Helsinki University Hospital
• Switzerland
  • Bern, Switzerland
    • Inselspital, Bern University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Septic shock defined as

  1. Septic infection AND
  2. systemic mean blood pressure > 65 mmHg requiring any dose of vasopressors (norepinephrine, vasopressin) despite adequate fluid resuscitation (minimum of 20 ml/kg crystalloids) AND
  3. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Helsinki University Central Hospital
• Collaborators: University Hospital Inselspital, Berne
• Investigators: Principal Investigator: Ville Pettilä, Prof, Helsinki University Hospital/ Bern University Hospital; Principal Investigator: Stephan Jakob, Prof, Dr, Bern University Hospital

Publications and helpful links

General Publications

• Varis E, Pettila V, Poukkanen M, Jakob SM, Karlsson S, Perner A, Takala J, Wilkman E; FINNAKI Study Group. Evolution of Blood Lactate and 90-Day Mortality in Septic Shock. A Post Hoc Analysis of the FINNAKI Study. Shock. 2017 May;47(5):574-581. doi: 10.1097/SHK.0000000000000772.
• Pettila V, Merz T, Wilkman E, Perner A, Karlsson S, Lange T, Hastbacka J, Hjortrup PB, Kuitunen A, Jakob SM, Takala J. Targeted tissue perfusion versus macrocirculation-guided standard care in patients with septic shock (TARTARE-2S): study protocol and statistical analysis plan for a randomized controlled trial. Trials. 2016 Aug 2;17:384. doi: 10.1186/s13063-016-1515-x.

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2016
• Primary Completion (Actual): December 1, 2022
• Study Completion (Actual): December 31, 2022

Study Registration Dates

• First Submitted: October 15, 2015
• First Submitted That Met QC Criteria: October 16, 2015
• First Posted (Estimate): October 19, 2015

Study Record Updates

• Last Update Posted (Actual): March 1, 2023
• Last Update Submitted That Met QC Criteria: February 28, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: septic shock; mean arterial pressure; tissue perfusion; macrocirculatory; vasopressor use; days alive free of organ support
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Disease Attributes; Sepsis; Shock, Septic; Shock; Critical Illness
• Other Study ID Numbers: TARTARE-2S-01

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No