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: 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.

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

septic shock, tissue perfusion, macrocirculatory, mean arterial pressure, vasopressor use, days alive free of organ support

Based on capillary refilling time, peripheral temperature, mottling, diuresis, MAP safety limit monitoring

• Days alive in 30 days with normal arterial blood lactate ( first confirmed value of < 2 mmol/L) AND without any inotropic or vasopressor agent

Days alive without any organ support (mechanical ventilation, renal-replacement therapy, vasopressor/ inotropic agents) in 30 days

ventricular tachycardia/ fibrillation , atrial fibrillation , myocardial infarction , skin necrosis , stroke , secondary bowel ischemia, limb ischemia, numbers of serious adverse events

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

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.