Red Cell Transfusion in Critical Care Patients

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 (%

)


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


ICU Responses 1997 and 2003


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


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


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


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



Case 2


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




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”

Documents

Red Cell Transfusion in Critical Care Patients