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Transfusion triggers: Going beyond the TRICC trial
Paul Hebert MD MHSc
University of Ottawa Centre for Transfusion Research, Ottawa Health Research Institute and the Ottawa Hospital
Historical RBC transfusion trigger
Lundy. Surg Gynecol Obstet 1954; 74: 1011
“This condition, owing to the lowered oxygen carrying capacity of the blood interferes with the adequate transportation of oxygen to the tissues. When the concentration of hemoglobin is less than 8-10 gm per 100 cc of whole blood it is wise to give blood transfusion
Study design: Multicentre RCTSetting: 25 ICUs across CanadaStudy Population: Included Hgb< 90 g/l within 72 hrs
and excluded patients with active blood loss (30 g/l decrease or >3 unit transfusion in 12 hrs)
Intervention: 70 g/L vs 100 g/L hemoglobin triggerOutcomes: 30 day all-cause mortality and organ failure
Study Design
Hebert et al. NEJM 321: 151-156, 1999
Study design: Multicentre RCTSetting: 25 ICUs across CanadaStudy Population: Included Hgb< 90 g/l within 72 hrs
and excluded patients with active blood loss (30 g/l decrease or >3 unit transfusion in 12 hrs)
Intervention: 70 g/L vs 100 g/L hemoglobin triggerOutcomes: 30 day all-cause mortality and organ failure
Study Design
Hebert et al. NEJM 321: 151-156, 1999
Hemoglobin over time
0 5 10 15 20 25 30
Time (Days)
0102030405060708090
100110120
Hem
oglo
bin
(g/L
)
Liberal strategy
Restrictive strategy
p<0.01
Hebert et al. NEJM 321: 151-156, 1999
Hemoglobin over time
0 5 10 15 20 25 30
Time (Days)
0102030405060708090
100110120
Hem
oglo
bin
(g/L
)
Liberal strategy
Restrictive strategy
p<0.01
Hebert et al. NEJM 321: 151-156, 1999
2.6 units
5.4 units
Survival of all patients over 30 days
0 5 10 15 20 25 30
Time (Days)
50
60
70
80
90
100
Sur
viva
l (%
)
Restrictive strategy
Liberal strategy
p=0.10
Hebert et al. NEJM 321: 151-156, 1999
Survival of all patients over 30 days
0 5 10 15 20 25 30
Time (Days)
50
60
70
80
90
100
Sur
viva
l (%
)
Restrictive strategy
Liberal strategy
p=0.10
Hebert et al. NEJM 321: 151-156, 1999
18.7%
23.3%
RBC transfusion cause harm?
• Are findings consistent within study?• Do findings agree with other studies?• Are findings generalizable to other patient
groups?
Spurious result or true finding?
Can we trust these studies?
Inferences weakened due to:• Logic of transfusions always being harmful??• Retrospective studies - limited data collection• Minimal adjustment for confounding factors• Timing of RBCs unknown• Trigger unknown…admission hematocrit/nadir
hematocritMain culprit: “Confounding by Indication”• higher acuity → more aggressive care
RCTs of Red Cell Transfusion Triggers Author Year N Setting Hgb trigger (g/dL)
Topley 1956 22 Trauma 11.3 vs 15.6
Blair 1986 50 GI Bleed 2 U vs 8U
Fortune 1987 25 Trauma 10.0 vs 13.0
Weisel 1992 27 CABG 10.0 vs 12.0
Johnson 1992 39 CABG 8.3 vs 10.7
Hebert 1995 69 ICU 7.0 -9.0 vs 10.0 -12.0
Bush 1997 99 Vascular 9.0 vs 10.0
Carson 1998 84 Hip Fx 10.0 vs symptoms
Bracey 1999 428 CABG 8.0 vs.9.0/symptoms
Hebert 1999 838 ICU 7.0 vs 10.0
Carson. Trans Med Reviews 2002
RCTs of Red Cell Transfusion Triggers Author Year N Setting Hgb trigger (g/dL)
Topley 1956 22 Trauma 11.3 vs 15.6
Blair 1986 50 GI Bleed 2 U vs 8U
Fortune 1987 25 Trauma 10.0 vs 13.0
Weisel 1992 27 CABG 10.0 vs 12.0
Johnson 1992 39 CABG 8.3 vs 10.7
Hebert 1995 69 ICU 7.0 -9.0 vs 10.0 -12.0
Bush 1997 99 Vascular 9.0 vs 10.0
Carson 1998 84 Hip Fx 10.0 vs symptoms
Bracey 1999 428 CABG 8.0 vs.9.0/symptoms
Hebert 1999 838 ICU 7.0 vs 10.0
Carson. Trans Med Reviews 2002
Purpose: To determine if a restrictive red cell
transfusion strategy will reduce red cell exposure without worsening organ dysfunction in pediatric critical care patients.
Lacroix. NEJM 2007; 356: 1609.
TRIPICU studyStudy design: Multicentre RCTSetting: 19 ICUs in Canada, EuropeStudy Population: Age 3 days – 14 yrs and hb < 95
g/L within 7 days of PICU admission. Stable, no acute blood loss and no cardiac disease
Intervention:Restrictive (70 g/L) vs. liberal (95 g/L) hemoglobin trigger
Outcomes: Death, new or progressive multiorgan dysfunction.
Lacroix. NEJM 2007; 356: 1609.
TRIPICU – Hemoglobin levels
Lacroix. NEJM 2007; 356: 1609.
4.00
6.75
9.50
12.25
15.00
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
Low
est H
b (g
/dL)
Length of stay post-randomization (day)
RestrictiveLiberal
Average Hb : 87±4.0 vs. 108±5.0 g/L (δ: 21±2.0).
TRIPICU - Outcomes
Restrictive group Liberal group
Total # of patients 320 317
Non-transfused (n)174
(54.4%)7
(2.2%)
No. of transfusions 301 542
New or progressive MODS (n) 38 39
New or progressive MODS (%) 11.9(95% CI 8.5-15.9)
12.3(95% CI 8.9-16.4)
Lacroix. NEJM 2007; 356: 1609.
Study Patients: 263 patients with EARLY sepsis and septic shockSetting: Single Centre study conducted in large city hospitalStudy design: open-labeled randomized trialIntervention: Early Goal-directed therapy using ScvO2 guided
care vs standard of careOutcome: in-hospital mortality and other mortality rates
Outcome Control Treatment RR (95% C.I.) P-value
In-hospital 46.5 30.5 0.58 (0.38-0.87) 0.009
28-day Mortality 49.2 33.3 0.58 (0.39 – 0.87) 0.01
60-day Mortality 56.9 44.3 0.67 (0.46-0.96) 0.03
Rivers et al NEJM 2001;345:1368
Mortality Rates in 263 Septic Shock Patients
Outcome Control Treatment RR (95% C.I.) P-value
In-hospital 46.5 30.5 0.58 (0.38-0.87) 0.009
28-day Mortality 49.2 33.3 0.58 (0.39 – 0.87) 0.01
60-day Mortality 56.9 44.3 0.67 (0.46-0.96) 0.03
Rivers et al NEJM 2001;345:1368
Cardiovascular Disease
Patients with ischemic heart disease (n=257)
Patients with cardiovascular diseases (n=357)
Hebert et al. NEJM 321: 151-156, 1999
Cardiovascular Disease
Patients with ischemic heart disease (n=257)
Patients with cardiovascular diseases (n=357)
Hebert et al. NEJM 321: 151-156, 1999
Effect of anemia on mortality in cardiac disease
1.00
4.04
7.08
10.12
13.16
16.20
6 7 8 9 10 11 12+
Odd
s R
atio
Preoperative Hgb (g/dl)
Healthy (No IHD) Ischemic Heart Disease
P=0.03
Carson JL, et al. Lancet 1996;348:1055-60.
• Retrospective cohort of patients who refuse blood transfusion
• CVD definition - History of MI, angina, CHF, or PVD.
• 1,958 patients age 18 or older.• Undergo surgical procedure in OR.• Outcome-30-day mortality or morbidity.
Adjusted OR of death in transfused versus not transfused patients
Hct OR (95% CI)*
*Wu. NEJM 2001; 345: 1230.
RBCs Kill
RBCs save lives
Copyright restrictions may apply.
Rao, S. V. et al. JAMA 2004;292:1555-1562.
Nadir Hematocrit, % Adjusted OR 95% CI __________________________________________
35 291.64 10.28-8273.85
30 168.64 7.49-3797.69
25 1.13 0.70-1.82 20 1.59 0.95-2.66 __________________________________________
RiskofDeathin24,112transfusedversus
non-transfusedfrom3RCTs
Functional outcomes in cardiovascular patients undergoing surgical hip fracture repair (FOCUS)
Design: Multicentre RCT in 47 North American centresStudy Population: 2016 hip fracture patients undergoing
surgical repair with a Hb < 100 g/L within 3 days fo surgeryIntervention:• Liberal Strategy: transfusion trigger of 100 g/L• Restrictive Strategy: transfusion for symptomatic anemia Outcomes:• Primary: functional recovery (ability to walk 10 feet without
human assistance 60 days post-op)• Long term survival, nursing home placement, post-op
complications (MI and infection)
Carson. Transfusion 2006; 46 2192
FOCUS study
• Results yet to be published• Lower pre-transfusion hemoglobin with
symptomatic transfusions (79 g/L vs 92 g/L)• Early report: No difference in mortality and
cardiac outcomes
Carson. AABB & ASH Annual Meetings 2009
Overall recommendations
• Adopt a transfusion threshold of 70 g/L and maintain critically ill children and adults between 70 and 90 g/L
• Transfuse one RBC unit at a time.• Patients with acute coronary syndrome and
septic shock may benefit from Hb> 80 g/L • Further trials are especially focused on patients
with cardiac disease• For peri-operative care await results of FOCUS
study soon to be published