Transfusion-requirements in Septic Shock Trial (TRISS)

Effects of Red Blood Cell Transfusion on Mortality and Morbidity in Patients With Septic Shock

Patients with blood poisoning - sepsis - often receive blood transfusions in the intensive care unit. The evidence that blood transfusion leads to improved outcome is limited and the blood may be harmful to some of these patients. To bridge the gap between clinical practice and evidence, a large randomised clinical trial is needed to document the efficacy and safety of RBC transfusion in these very sick patients

Study Overview

• Status: Completed
• Conditions: Septic Shock
• Intervention / Treatment: Biological: SAGM (Saline-Adenine-Glucose-Mannitol) blood transfusion; Biological: SAGM (Saline-Adenine-Glucose-Mannitol) blood transfusion

Detailed Description

Background Septic patients often receive red blood cell (RBC) transfusions in the intensive care unit. The evidence that RBC transfusion leads to improved outcome is limited and the intervention may be harmful to some of these patients. In contrast, current guidelines recommend restrictive transfusion of RBC for critical ill patients without septic shock. To bridge the gap between clinical practice and evidence, a large randomised clinical trial is needed to document the efficacy and safety of RBC transfusion in patients with septic shock

Design Pragmatic, multicenter, randomised, outcome assessment-blinded trial of patients with septic shock to RBC transfusion at haemoglobin (Hb) transfusion trigger of 7 g/dl (4.4 mM) or 9 g/dl (5.6 mM), stratified by the presence of haematological malignancy and centre.

Inclusion and exclusion criteria:

To increase the validity of the trial inclusion criteria will be broad with few exclusions

Outcome measures The outcome measures will mainly be patient-important but ICU- and hospital length of stay will also be assessed

Trial size 2 x 500 patients will be needed to show a 9% absolute risk difference in 90-day mortality (baseline mortality of 45%, relative risk reduction 20% (from septic patients in the TRICC trial), alpha of 0.05 (two-sided) and a beta of 0.20 that is a power of 80% (1-beta).

An interim-analysis will be performed after 500 patients. The Data Safety and Monitoring Board (DMSC) will recommend that the trial is stopped if a group-difference in 90-day mortality with p<0.001.

Time Line The first patient is expected to be randomised December 1st 2011 and the trial database is expected to be closed early 2014. The main manuscript will be submitted shortly thereafter.

Funding The trial is publicly funded by the Danish Strategic Research Council

• Study Type: Interventional
• Enrollment (Actual): 1005
• Phase: Phase 3

Contacts and Locations

Study Locations

• Denmark
  • Aarhus, Denmark
    • Aarhus University Hospital, Skejby
  • Aarhus, Denmark
    • Aarhus University Hospital, NBG
  • Copenhagen, Denmark
    • Rigshospitalet
  • Copenhagen, Denmark
    • Bispebjerg Hospital
  • Copenhagen, Denmark
    • Hvidovre Hospital
  • Copenhagen, Denmark
    • Glostrup Hospital
  • Gentofte, Denmark
    • Gentofte Hospital
  • Herning, Denmark
    • Herning Hospital
  • Hjørring, Denmark
    • Hjørring Hospital
  • Holbæk, Denmark
    • Holbæk Hospital
  • Horsens, Denmark
    • Horsens Hospital
  • Kolding, Denmark
    • Kolding Hospital
  • Køge, Denmark
    • Køge Hospital
  • Næstved, Denmark
    • Næstved Hospital
  • Randers, Denmark
    • Randers Hospital
  • Slagelse, Denmark
    • Slagelse Hospital
  • Sønderborg, Denmark
    • Sønderborg Hospital
  • Vejle, Denmark
    • Vejle Hospital
  • Ålborg, Denmark
    • Ålborg university Hospital
• Finland
  • Helsinki, Finland
    • Helsinki University Hospital
  • Joensuu, Finland
    • Joensuu Hospital
  • Tampere, Finland
    • Tampere University Hospital
• Norway
  • Bergen, Norway
    • Haukeland University Hospital
  • Oslo, Norway
    • Akershus University Hospital
  • Stavanger, Norway
    • Stavanger University Hospital
  • Ålesund, Norway
    • Ålesund Hospital
• Sweden
  • Halmstad, Sweden
    • Halmstad Hospital
  • Helsingborg, Sweden
    • Helsingborg Hospital
  • Stockholm, Sweden
    • Sodersjukhuset
  • Stockholm, Sweden
    • Karolinska Hospital, Huddinge
  • Stockholm, Sweden
    • Karolinska Institutet Solna
  • Växjö, Sweden
    • Växjö Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patient in the ICU AND
• Fulfil the criteria for septic shock AND
• Have haemoglobin of 9.0 g/dl (5.6 mM) or less AND
• Consent obtainable from patient or proxy or national law allows delayed consent

Exclusion Criteria:

• Documented wish against transfusion OR
• Previous serious adverse reaction with blood product OR
• Acute coronary syndrome OR
• Life-threatening bleeding OR
• RBC transfusion during current ICU admission OR
• Withdrawal from active therapy or brain death OR
• Lack of informed consent (depending on national law) OR
• Acute burn injury regardless of degree and burn surface area

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Liberal blood transfusion; Blood transfusion at haemoglobin 9.0 g/dl (5.6 mM) or less	Biological: SAGM (Saline-Adenine-Glucose-Mannitol) blood transfusion; One unit prestorage, leuko-depleted SAGM blood at haemoglobin at 9.0 g/dl (5.6 mM) or less at point-of-care testing; Other Names: Liberal red blood cell (RBC) transfusion; Biological: SAGM (Saline-Adenine-Glucose-Mannitol) blood transfusion; One unit prestorage, leuko-depleted SAGM blood at haemoglobin 7.0 g/dl (4.3 mM) or less at point-of-care testing; Other Names: Restrictive red blood cell (RBC) transfusion
ACTIVE_COMPARATOR: Restrictive blood transfusion; Blood transfusion at haemoglobin 7.0 g/dl (4.3 mM) or less	Biological: SAGM (Saline-Adenine-Glucose-Mannitol) blood transfusion; One unit prestorage, leuko-depleted SAGM blood at haemoglobin at 9.0 g/dl (5.6 mM) or less at point-of-care testing; Other Names: Liberal red blood cell (RBC) transfusion; Biological: SAGM (Saline-Adenine-Glucose-Mannitol) blood transfusion; One unit prestorage, leuko-depleted SAGM blood at haemoglobin 7.0 g/dl (4.3 mM) or less at point-of-care testing; Other Names: Restrictive red blood cell (RBC) transfusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality	All cause 90 day mortality	90 day

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Days alive and out of hospital		90 days
Persistent organ failure	Defined as need for ventilation, vasopressor/inotrope infusion or renal replacement therapy	Day 5
Persistent organ failure	Defined as need for ventilation, vasopressor/inotrope infusion or renal replacement therapy	Day 14
Persistent organ failure	Defined as need for ventilation, vasopressor/inotrope infusion or renal replacement therapy	Day 28
Anaphylactic/allergic reactions	Defined by the clinician on the basis of mucocutaneous signs and symptoms (e.g. urticaria, pruritus, localised angio- oedema).	Followed up until ICU discharge; an expected average of one week
Haemolytic complications after transfusion of RBC	Defined by the clinician on the basis of haemoglobinuria or increased free plasma haemoglobin.	Followed up until ICU discharge; an expected average of one week
Transfusion associated acute lung injury (TRALI)	TRALI defined as: I. Acute or worsening hypoxaemia ((PaO2/FiO2 < 40 (PaO2 in kPa) or <300 (PaO2 in mmHg) regardless of PEEP) OR > 50% relative increase in FiO2. AND II. Occurrence within 6 hours after RBC transfusion AND III. Acute or worsening pulmonary infiltrates on frontal chest x-ray OR clinical signs of overt pulmonary oedema	Followed up until ICU discharge; an expected average of one week
Transfusion associated circulatory overload (TACO)	TACO defined as: I. Acute or worsening hypoxaemia ((PaO2/FiO2 < 40 (PaO2 in kPa) or <300 (PaO2 in mmHg) regardless of PEEP) OR > 50% relative increase in FiO2. AND II. Occurrence within 6 hours after RBC transfusion AND III. Acute or worsening pulmonary infiltrates on frontal chest x-ray OR clinical signs of overt pulmonary oedema AND IV. Increased blood pressure AND VI. Positive fluid balance	Followed up until ICU discharge; an expected average of one week
Ischaemic events	Defined as either myocardial, cerebral, intestinal or acute limb ischaemia	Followed up until ICU discharge; an expected average of one week
Days alive without life support	Life support defined as need for ventilation, vasopressor/inotrope infusion or renal replacement therapy. Days alive without each of these interventions will be reported	90-days
Mortality within the whole observation period	Mortality within the whole observation period reported at day 28, six-month and 1 year after randomisation of the last patient.	One year after randomisation of the last patient
Health-related quality of life	Physical and mental component summary scores of SF 36	1 year

Collaborators and Investigators

• Sponsor: Scandinavian Critical Care Trials Group
• Collaborators: Rigshospitalet, Denmark; University of Copenhagen; Copenhagen Trial Unit, Center for Clinical Intervention Research
• Investigators: Principal Investigator: Anders Perner, MD, PhD, Dept. of Intensive Care, Rigshospitalet / SCCTG

Publications and helpful links

General Publications

• Holst LB, Haase N, Wetterslev J, Wernerman J, Aneman A, Guttormsen AB, Johansson PI, Karlsson S, Klemenzson G, Winding R, Nebrich L, Albeck C, Vang ML, Bulow HH, Elkjaer JM, Nielsen JS, Kirkegaard P, Nibro H, Lindhardt A, Strange D, Thormar K, Poulsen LM, Berezowicz P, Badstolokken PM, Strand K, Cronhjort M, Haunstrup E, Rian O, Oldner A, Bendtsen A, Iversen S, Langva JA, Johansen RB, Nielsen N, Pettila V, Reinikainen M, Keld D, Leivdal S, Breider JM, Tjader I, Reiter N, Gottrup U, White J, Wiis J, Andersen LH, Steensen M, Perner A. Transfusion requirements in septic shock (TRISS) trial - comparing the effects and safety of liberal versus restrictive red blood cell transfusion in septic shock patients in the ICU: protocol for a randomised controlled trial. Trials. 2013 May 23;14:150. doi: 10.1186/1745-6215-14-150.
• Holst LB, Haase N, Wetterslev J, Wernerman J, Guttormsen AB, Karlsson S, Johansson PI, Aneman A, Vang ML, Winding R, Nebrich L, Nibro HL, Rasmussen BS, Lauridsen JR, Nielsen JS, Oldner A, Pettila V, Cronhjort MB, Andersen LH, Pedersen UG, Reiter N, Wiis J, White JO, Russell L, Thornberg KJ, Hjortrup PB, Muller RG, Moller MH, Steensen M, Tjader I, Kilsand K, Odeberg-Wernerman S, Sjobo B, Bundgaard H, Thyo MA, Lodahl D, Maerkedahl R, Albeck C, Illum D, Kruse M, Winkel P, Perner A; TRISS Trial Group; Scandinavian Critical Care Trials Group. Lower versus higher hemoglobin threshold for transfusion in septic shock. N Engl J Med. 2014 Oct 9;371(15):1381-91. doi: 10.1056/NEJMoa1406617. Epub 2014 Oct 1.
• Carson JL, Stanworth SJ, Dennis JA, Trivella M, Roubinian N, Fergusson DA, Triulzi D, Doree C, Hebert PC. Transfusion thresholds for guiding red blood cell transfusion. Cochrane Database Syst Rev. 2021 Dec 21;12(12):CD002042. doi: 10.1002/14651858.CD002042.pub5.

Study record dates

Study Major Dates

• Study Start: November 1, 2011
• Primary Completion (ACTUAL): March 1, 2014
• Study Completion (ACTUAL): April 1, 2014

Study Registration Dates

• First Submitted: November 30, 2011
• First Submitted That Met QC Criteria: December 2, 2011
• First Posted (ESTIMATE): December 5, 2011

Study Record Updates

• Last Update Posted (ESTIMATE): October 3, 2014
• Last Update Submitted That Met QC Criteria: October 2, 2014
• Last Verified: October 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Shock, Septic; Shock; Physiological Effects of Drugs; Natriuretic Agents; Diuretics, Osmotic; Diuretics; Mannitol
• Other Study ID Numbers: H-3-2011-114