Transfusion-requirements in Septic Shock Trial

Study Overview
=================
Brief Summary
-----------------
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

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

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

Conditions
-----------------
Septic Shock

Intervention / Treatment
-----------------
* Biological: SAGM (Saline-Adenine-Glucose-Mannitol) blood transfusion
* Biological: SAGM (Saline-Adenine-Glucose-Mannitol) blood transfusion


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Liberal blood transfusion<br>Blood transfusion at haemoglobin 9.0 g/dl (5.6 mM) or less | Biological: SAGM (Saline-Adenine-Glucose-Mannitol) blood transfusion<br>* One unit prestorage, leuko-depleted SAGM blood at haemoglobin at 9.0 g/dl (5.6 mM) or less at point-of-care testing<br>* Other names: Liberal red blood cell (RBC) transfusion;|
| Active Comparator: Restrictive blood transfusion<br>Blood transfusion at haemoglobin 7.0 g/dl (4.3 mM) or less | Biological: SAGM (Saline-Adenine-Glucose-Mannitol) blood transfusion<br>* One unit prestorage, leuko-depleted SAGM blood at haemoglobin 7.0 g/dl (4.3 mM) or less at point-of-care testing<br>* 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 |
| --- | --- | --- |
| 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 | 
| Days alive and out of hospital |  | 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 |