Clinical trial NCT02579525: Targeted Tissue Perfusion Versus Macrocirculatory-guided Standard Care in Patients With Septic Shock
Official title: Targeted Tissue Perfusion Versus Macrocirculatory-guided Standard Care in Patients With Septic Shock [TARTARE-2S]- A Multicentre Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Shock; Septic
Critical Illness
Keywords: septic shock
tissue perfusion
macrocirculatory
mean arterial pressure
vasopressor use
days alive free of organ support
Lead sponsor: Helsinki University Central Hospital
Sponsor class: OTHER
Collaborators: name: Insel Gruppe AG, University Hospital Bern
First posted: 2015-10-19
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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

Eligibility criteria: 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

Primary outcomes:
measure: Days alive in 30 days- without vasopressors/ inotropes or hyperlactatemia
timeFrame: 30 days
Secondary outcomes:
measure: Time to normalization of arterial blood lactate
timeFrame: 30 days
measure: Days alive with normal arterial blood lactate in 30 days
timeFrame: 30 days
measure: Days alive without any inotropic or vasopressor agent in 30 days
timeFrame: 30 days
measure: Days alive without renal replacement therapy (RRT) in 30 days
timeFrame: 30 days
measure: Days alive without mechanical ventilation in 30 days
timeFrame: 30 days
measure: Days alive without any organ support (mechanical ventilation, renal-replacement therapy, vasopressor/ inotropic agents) in 30 days
timeFrame: 30 days
measure: New acute kidney injury (AKI) (Kdigo stages I-III)
timeFrame: 30 days
measure: Days alive outside hospital in 90 days
timeFrame: 90 days
measure: Total amount of norepinephrine given up to day 5
timeFrame: 5 days
measure: Number/ total number of the following adverse reactions
timeFrame: 30 days
Other outcomes:
Locations:
city: Helsinki
country: Finland
facility: Helsinki University Hospital
city: Bern
country: Switzerland
facility: Inselspital, Bern University Hospital
Study officials:
affiliation: Helsinki University Hospital/ Bern University Hospital
name: Ville Pettilä, Prof
role: PRINCIPAL_INVESTIGATOR
affiliation: Bern University Hospital
name: Stephan Jakob, Prof, Dr
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.