title: 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.
abstract: Septic shock has a 90-day mortality risk of up to 50 %. The hemodynamic targets, including mean arterial pressure (MAP) are not based on robust clinical data. Both severe hypotension and high doses of vasopressors may be harmful. Hence, re-evaluation of hemodynamic targets in septic shock is relevant.
  
  
  
  The targeted tissue perfusion versus macrocirculation-guided standard care in patients with septic shock (TARTARE-2S) trial is a prospective, two-parallel-group, randomized, open-label, multicenter trial with assessor-blinded outcome evaluation. We will randomize at least 200 patients with septic shock in four European intensive care units (ICUs) to test whether a tissue perfusion-guided treatment strategy based on capillary refill time, peripheral temperature, arterial lactate concentrations, and accepting lower MAP levels, leads to a faster resolution of shock than macrocirculation target-guided standard care. The primary outcome measure is days alive in 30 days with normal arterial blood lactate (first value of <2 mmol/L) and without any inotropic or vasopressor agent. Secondary outcomes include individual components of the primary outcome, days alive without renal replacement, days alive without mechanical ventilation in 30 days, and new acute kidney injury. The sample size enables detection of a 13.5-h difference in the primary outcome with a type 1 error of 5 % and power of 80 %, assuming 25 % mortality and a mean of 650 h (SD 30) among the 30-day survivors. After 150 included patients the statistician masked for allocation group will recalculate the sample size potentially increasing the sample up to 300. The Data Safety and Monitoring Board (DSMB) will review the safety data after 100 patients.
  
  
  
  The TARTARE-2S trial will provide important clinical data on treatment targets in septic shock, evaluating the impact of clinical tissue perfusion-guided hemodynamic treatment on a surrogate outcome combining resolution of shock (hyperlactatemia and vasopressors/inotropes), and 30-day mortality.
  
  
  
  ClinicalTrials.gov: NCT02579525 . Registered on 19 October 2015.
authors.affiliation: Department of Intensive Care Medicine, Bern University Hospital (Inselspital), University of Bern, Bern, Switzerland. ville.pettilae@insel.ch.|Division of Intensive Care Medicine, Department of Perioperative, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. ville.pettilae@insel.ch.
authors.forename: Ville
authors.initials: V
authors.lastname: Pettilä
authors.affiliation: Department of Intensive Care Medicine, Bern University Hospital (Inselspital), University of Bern, Bern, Switzerland.
authors.forename: Tobias
authors.initials: T
authors.lastname: Merz
authors.affiliation: Division of Intensive Care Medicine, Department of Perioperative, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Erika
authors.initials: E
authors.lastname: Wilkman
authors.affiliation: Department of Intensive Care, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.|CRIC, Center of Research for Intensive Care, Copenhagen, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Perner
authors.affiliation: Department of Intensive Care, Tampere University Hospital, Tampere, Finland.
authors.forename: Sari
authors.initials: S
authors.lastname: Karlsson
authors.affiliation: CRIC, Center of Research for Intensive Care, Copenhagen, Denmark.|Section of Biostatistics, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Theis
authors.initials: T
authors.lastname: Lange
authors.affiliation: Division of Intensive Care Medicine, Department of Perioperative, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Hästbacka
authors.affiliation: Department of Intensive Care, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Peter Buhl
authors.initials: PB
authors.lastname: Hjortrup
authors.affiliation: Department of Intensive Care, Tampere University Hospital, Tampere, Finland.
authors.forename: Anne
authors.initials: A
authors.lastname: Kuitunen
authors.affiliation: Department of Intensive Care Medicine, Bern University Hospital (Inselspital), University of Bern, Bern, Switzerland.
authors.forename: Stephan M
authors.initials: SM
authors.lastname: Jakob
authors.affiliation: Department of Intensive Care Medicine, Bern University Hospital (Inselspital), University of Bern, Bern, Switzerland.
authors.forename: Jukka
authors.initials: J
authors.lastname: Takala
mesh_terms: D062186:Arterial Pressure / Q000187:drug effects; D015415:Biomarkers / Q000097:blood; D002316:Cardiotonic Agents / Q000627:therapeutic use; D002317:Cardiovascular Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002985:Clinical Protocols; D003131:Combined Modality Therapy; D003627:Data Interpretation, Statistical; D005060:Europe; D005240:Feasibility Studies; D005440:Fluid Therapy / Q000009:adverse effects / Q000401:mortality; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D019344:Lactic Acid / Q000097:blood; D008833:Microcirculation / Q000187:drug effects*; D015233:Models, Statistical; D011446:Prospective Studies; D012039:Regional Blood Flow; D017582:Renal Replacement Therapy / Q000009:adverse effects / Q000401:mortality; D012107:Research Design; D012121:Respiration, Artificial / Q000009:adverse effects / Q000401:mortality; D018401:Sample Size; D012772:Shock, Septic / Q000175:diagnosis / Q000401:mortality / Q000503:physiopathology / Q000628:therapy*; D013997:Time Factors; D016896:Treatment Outcome; D014662:Vasoconstrictor Agents / Q000627:therapeutic use
chemical_list: D015415:Biomarkers; D002316:Cardiotonic Agents; D002317:Cardiovascular Agents; D014662:Vasoconstrictor Agents; D019344:Lactic Acid
keywords: Critical illness; Lactate; Mortality; Septic shock; Tissue perfusion; Vasopressor