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Red Cell Transfusion in Critical Care Patients
Alan Tinmouth, MD MSc
University of Ottawa Centre for Transfusion Research,
Ottawa Health Research Institute and the Ottawa Hospital
November 2009
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Objectives
• Review the seminal observational and randomized clinical trials evaluating red cell transfusions in the critically ill.
• Understand the limitations of the current evidence surrounding red cell transfusions.
• Understand the limits and benefits of alternatives / strategies to reduce the need for red cell transfusions.
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Case 1
Hebert, Crit Care Med 2005; 33; 7.
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Anemia in the critically ill is very common
• 95% anemic by 3rd day in ICU
• 40 – 45% of patients will receive RBCs
• Average = 5 units RBC
Vincent et al, JAMA 2002; Corwin et al, CCM 2004
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RBC Transfusions in Critical Care and Cardiac Surgery in Canada, 1998-2000
Hutton et al. CJA 2005
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Purpose of an RBC transfusion
Increase O2 delivery and consumption.
Increase hemoglobin levels.
Decrease morbidity and mortality.
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The Role of Hemoglobin in O2 Delivery
(1) DO2 = CO x (%sat x 1.39 x Hb)
(2) CO = HR x stroke volume
DO2 = O2 Delivery (ml/L)
CO = Cardiac output(L/min)
%Sat = % saturation of Hb
Hb = Hemoglobin (g/L)
1.39 = O2 carried in blood (ml/L)
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Oxygen Delivery and RBC Transfusion
VO2
Delivery IndependentDelivery Dependent
Critical DO2
DO2
• At least 19 clinical studies evaluating impact RBCs on oxygen kinetics in humans
• Uniform increase in DO2 but not VO2
Hebert et al, CMAJ, 1997
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Oxygen Delivery and Consumption following RBC transfusion
Suttner et al. Anesth Analg 2004; 99: 2-11
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Transfusion Requirements in Critical Care (TRICC)
Hebert PC, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical
care. N Engl J Med. 1999;340(6):409-17
Purpose:To determine if a restrictive and liberal red cell transfusion strategy are equivalent in terms of effects on mortality and morbidity in volume resuscitated critically ill patients
Hebert et al. NEJM 321: 151-156, 1999
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Study design: Multicentre RCT
Setting: 25 ICUs across Canada
Study Population: Included Hb< 9.0 g/dl within 72 hrs and excluded patients with active blood loss (3.0 g/dl decrease or >3 unit transfusion in 12 hrs)
Intervention: 7.0 g/dl vs 10.0 g/dl hemoglobin trigger
Outcomes: 30 day all-cause mortality and organ failure
TRICC Study
Hebert et al. NEJM 321: 151-156, 1999
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Hemoglobins over time
0 5 10 15 20 25 30
Time (Days)
0102030405060708090
100110120
Hem
ogl
obin
(g/
L)
Liberal strategy
Restrictive strategy
p<0.01
Hebert et al. NEJM 321: 151-156, 1999
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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%
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Survival of patients < 55 years of age
Hebert et al. NEJM 321: 151-156, 1999
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TRICC – Mortality and MODS
Outcomes Liberal Restrictive P-Value
(n=420) (n=418)
Mortality No.(%)
30-day 98 (23.3) 78 (18.7) 0.11
60-day 111(26.5) 95(22.8) 0.23
ICU 68 (16) 56 (13) 0.29
Hospital 118(28.1) 93(22.3) 0.05
Organ Dysfunction
MODS 8.8 ± 4.4 8.3 ± 4.6 0.10
MODS* 11.8 ± 7.7 10.7 ± 7.5 0.03
Change in MODS 1.26 ± 4.30 0.79 ± 4.26 0.15
Hebert et al. NEJM 321: 151-156, 1999
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Case 1
Hebert, Crit Care Med 2005; 33; 7.
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ICU Responses 1997 and 2003
Hebert, Crit Care Med 2005; 33; 7.
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RBC transfusions and risk of death
Marik and Corwin, CCM 2008;36:2667
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Can we trust these studies? Inferences from these studies are weakened because:• Logic of transfusions always being harmful??• Retrospective with limited data• Minimal adjustment for confounding factors• Timing of RBCs unknown• Trigger unknown…admission hematocrit/nadir
hematocrit• Main culprit: “Confounding by Indication”
– higher acuity → more aggressive care
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Adverse Effects Associated with Transfusion
FeverNeutrophilia
FlushingProinflammatory
Capillary leakTRALI / ARDS
MOF
Other adverse effects of leukocytes
Thrombosis
Impaired O2 deliveryAcidosis
K+, Na+, NH4+Hypothermia
GlucosePlasticisers
Jaundice
Thrombosis? ARDS
RES BlockadeMicrovascular Pathology
HypotensionFlushingAnxiety
GIT SymptomsPain
Proinflammatory
PLASMACleavage / activation of
Plasma proteins
BUFFY COAT
RED CELLS
1. Impaired RBC survival2. Reduced efficacy3. Adverse effects
Chemical,Metabolic
&Physical
HaemolysisBillirubin
LDHIron
Cytokines
KininsComplement
Histimine
Microaggregates
Procoagulants
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Consequences of Biochemical and BioMechanical Changes in Stored RBCs• Left shift of oxygen-
hemoglobin dissociation curve
• Loss of red blood cell deformability
• Increased RBC aggregation
• Increased RBC adhesion to endothelial cells
• Release of hypercoagulable microvessicles
• Increased NO scavenging
• Accumulation of cytokines
Tinmouth. Transfusion 2006
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Case 3
Hebert, Crit Care Med 2005; 33; 7.
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TRICC and acuity of illness
0 5 10 15 20 25 30
Time (Days)
50
60
70
80
90
100
Su
rviv
al (
%)
APACHE II > 20
Restrictive strategy
Liberal Strategy
p=0.54
0 5 10 15 20 25 30
Time (Days)
50
60
70
80
90
100
Su
rviv
al (
%)
Liberal strategy
Restrictive strategy
p = 0.02
APACHE II =< 20
Hebert et al. NEJM 321: 151-156, 1999
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Goal Directed Therapy in Early Sepsis
Rivers et al. NEJM 2004; 345: 1368
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Goal Directed Therapy in Early Sepsis
Rivers et al. NEJM 2004; 345: 1368
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Case 3
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ICU Responses 1997 and 2003
Hebert, Crit Care Med 2005; 33; 7.
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Case 2
Hebert, Crit Care Med 2005; 33; 7.
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0 5 10 15 20 25 30
Time (Days)
50
60
70
80
90
100
Surv
ival
(%)
p = 0.30
Liberal Restrictive
TRICC – Cardiovascular DiseasePatients with Ischemic Heart
Disease (n=257)
0 5 10 15 20 25 30
Time (Days)
50
60
70
80
90
100
Surv
ival (
%)
p = 0.95
Liberal Restrictive
Patients with cardiovascular diseases (n=357)
Hebert et al. NEJM 321: 151-156, 1999
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Complications during the ICU Stay
Complication Liberal(n=420)
Restrictive(n=418)
P Values
Cardiac No. (%) 88 (21.0) 55 (13.2) <0.01
Myocardial Infarction 12 (2.9) 3 (0.7) 0.02
Pulmonary Edema 45 (10.7) 22 (5.3) <0.01
Angina 9 (2.1) 5 (1.2) 0.28
Cardiac Arrest 33 (7.9) 29 (6.9) 0.6
Pulmonary No. (%) 122 (29.1) 106 (25.4) 0.22
ARDS 48 (11.4) 32 (7.7) 0.06
Pneumonia 86 (20.5) 87 (20.8) 0.92
Hebert et al. NEJM 321: 151-156, 1999
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RBC transfusions in acute MI
Wu. NEJM 2001; 345: 1230.
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RBC transfusion in ACS
• Transfused patients were older, had more co-morbidities and higher mortality rates
Rao. NEJM 2001; 345: 1230.
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RBC transfusion in ACS
• Adjusted analysis showed higher mortality rate associated with transfusions– No associated with harm for nadir hct of 0.20-0,25– Increased mortality for nadir hct > 0.30
Rao. NEJM 2001; 345: 1230.
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Case 2
Hebert, Crit Care Med 2005; 33; 7.
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ICU Responses 1997 and 2003
Hebert, Crit Care Med 2005; 33; 7.
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Case 4
Walsh, Transf 2009; epub.
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TRICC and mechanical ventilation
Hebert et al. NEJM 321: 151-156, 1999
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Case 4
Walsh, Transf 2009; epub.
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Case 5
• 28 year old Jehova Witness. Peripartum hemorrage taken to OR and hysterectomy performed. Bleeding now controlled. Admitted to ICU post-op with Hgb 28 g/L.
Treatment recommendations ?
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Alternatives to Red Cell Transfusions
• Erythropoietin
• Iron replacement
• Folate
Other– Factor VIIa for bleeding– Reduce phlebotomy – pediatric tubes
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EPO in Critical Care – Part 1
Corwin, JAMA 2002; 288: 2827.
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EPO in Critical Care – Part 1
• EPO raised hemoglobin (13.2 g/L vs. 9.4 g/L)• EPO resulted in 19% reduction in number of
units RBCs transfused
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EPO in Critical Care – part II
• EPO raised increased hemoglobin (16 g/L vs. 12 g/L, p < 0.001) and resulted in higher hemoglobin levels.
• No difference in transfusion rates with restrictive transfusion policy
Corwin, NEJM 2007; 357: 965.
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EPO in Critical Care – part II
Thrombosis
Mortality
Corwin, NEJM 2007; 357: 965.
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Conclusions
• In critical care patients, restrictive RBC transfusion strategy is not worse than liberal transfusion strategy– Patients not likely to benefit from RBC transfusion are
only likely to be harmed
• Results of TRICC not generalizable to all critically ill patients– e.g. cardiac and bleeding patient
• Alternatives to transfusions also have adverse effects– “best transfusion is not simply transfusion not given”