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
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.
Case 1
Hebert, Crit Care Med 2005; 33; 7.
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
RBC Transfusions in Critical Care and Cardiac Surgery in Canada, 1998-2000
Hutton et al. CJA 2005
Purpose of an RBC transfusion
Increase O2 delivery and consumption.
Increase hemoglobin levels.
Decrease morbidity and mortality.
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)
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
Oxygen Delivery and Consumption following RBC transfusion
Suttner et al. Anesth Analg 2004; 99: 2-11
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
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
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
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%
Survival of patients < 55 years of age
Hebert et al. NEJM 321: 151-156, 1999
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
Case 1
Hebert, Crit Care Med 2005; 33; 7.
ICU Responses 1997 and 2003
Hebert, Crit Care Med 2005; 33; 7.
RBC transfusions and risk of death
Marik and Corwin, CCM 2008;36:2667
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
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
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
Case 3
Hebert, Crit Care Med 2005; 33; 7.
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
Goal Directed Therapy in Early Sepsis
Rivers et al. NEJM 2004; 345: 1368
Goal Directed Therapy in Early Sepsis
Rivers et al. NEJM 2004; 345: 1368
Case 3
ICU Responses 1997 and 2003
Hebert, Crit Care Med 2005; 33; 7.
Case 2
Hebert, Crit Care Med 2005; 33; 7.
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
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
RBC transfusions in acute MI
Wu. NEJM 2001; 345: 1230.
RBC transfusion in ACS
• Transfused patients were older, had more co-morbidities and higher mortality rates
Rao. NEJM 2001; 345: 1230.
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.
Case 2
Hebert, Crit Care Med 2005; 33; 7.
ICU Responses 1997 and 2003
Hebert, Crit Care Med 2005; 33; 7.
Case 4
Walsh, Transf 2009; epub.
TRICC and mechanical ventilation
Hebert et al. NEJM 321: 151-156, 1999
Case 4
Walsh, Transf 2009; epub.
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 ?
Alternatives to Red Cell Transfusions
• Erythropoietin
• Iron replacement
• Folate
Other– Factor VIIa for bleeding– Reduce phlebotomy – pediatric tubes
EPO in Critical Care – Part 1
Corwin, JAMA 2002; 288: 2827.
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
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.
EPO in Critical Care – part II
Thrombosis
Mortality
Corwin, NEJM 2007; 357: 965.
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”
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