This document provides an overview of red cell transfusions in critically ill patients. It discusses the history of blood transfusions, reasons for anemia in ICU patients, physiological effects of red blood cells, technical aspects of blood compatibility testing and storage, hazards of transfusions, and evidence from studies on restrictive vs liberal transfusion thresholds. The TRICC study found no significant difference in mortality between restrictive and liberal transfusion strategies, though subgroups with lower illness severity saw benefits with restriction. Overall the document examines the risks and benefits of red cell transfusions in critical care.

1. Red Cell Transfusions in the Critically Ill
Bharath Kumar TV
Critical Care, Fortis Hospitals

2. Overview
• History
• Anemia in the ICU
• Physiology
• Technical Issues- Compatibility testing and Storage
• Hazards of transfusion
• The Evidence
• Guideline based approach

3. History
• The first recorded successful transfusion-1665
• English Physician- Richard Lower
• 1658: Red cells observed and described-Jan
Swammerdam
• First successful human blood transfusion: 1818
• British Obstetrician James Blundell for PPH

4. History
• Karl Landsteiner discovered the blood groups-1901
• 1907: First transfusion using blood typing and cross
matching- Reuben Ottenberg
• 1914: Long term anticoagulants to preserve blood
• 1939-40: Rh factor; Karl Landsteiner, Alexander Weiner,
Philip Levine and RE Stetson

5. 195 years later transfusion is still
controversial

6. Epidemiology
• Up to 25% of patients admitted to ICU have a
Hb‹9gm/dl*
• More pronounced in septic patients
• Frequent sampling may contribute(may avg.40ml/day)
• Anemia in the critically ill is multi-factorial
• Rivers in EGDT was one of the first to advocate the PRBC
transfusion
*Walsh et al. Intensive Care Med 2006;32:100-109

7. Reasons for anemia in the critically ill
• Obvious/occult source of bleeding
• Sampling
• Hemodilution secondary to fluid resuscitation
• Blunted EPO production
• Abnormalities in iron metabolism
• Altered proliferation and differentiation of precursors

8. Physiological functions of the RBC
• Major role in oxygen transport
• Profound anemia(‹5g/dl) risk factor for mortality
• Systemic O2 delivery influenced by the Hb level
• ↑Systemic delivery does not translate into
improvements in regional DO2
• Data on regional DO2 is inconsistent

10. So what’s all the fuss about?
• RBC transfusions increase the blood viscosity
• Microcirculatory stasis and impaired tissue DO2
• Activation of WBCs and release of cytokines may have
microcirculatory effects
• Cytokines mediate vasoconstriction and thrombosis
• Many countries routinely use leukocyte-reduced PRBCs
• Evidence that transfusion can cause vasoconstriction
• Decrease in the 2,3DPG in stored blood
• Hemolysis in stored blood can also contribute to
vasoconstriction

11. SYSTEMIC DO2 IS NOT EQUAL TO REGIONAL DO2

12. Serious Hazards
• Infectious hazards
• Non-infectious hazards
- TRALI
- TRIM
- TACO
- Hemolytic Reactions
- Incompatibility
- Anaphylaxis

13. Tolerance to Anemia
• Depends on volume status, physiological reserve and
dynamics of the anemia
• Normovolemic hemodilution well tolerated
• Compensatory mechanisms such as increases in CO
• Increased adrenergic drive, blood flow redistribution
• Increased oxygen extraction ratio
• These mechanisms are obtunded/exhausted
• Critical patients have very low reserves
• Myocardial demand-supply ratios are usually on the
edge

14. Technical Aspects- Boring, but a necessary evil!

15. Compatibility Testing
• Includes ABO-Rh typing, cross matching and antibody
screening
• To demonstrate harmful Ag-Ab reactions in-vitro
• ABO-Rh typing:
- reason for most serious and tragic reactions
- reactions due to naturally occurring antibodies
- anti A or B antibodies formed when the individual lacks
either or both of the A and B antigens
- performed by testing the RBCs for antigens and the
serum for antibodies

16. • Rh testing:
- 85% of the individuals possess the antigen D
- Normally there is no AntiD in the Rh negative individual
- after ABO, most likely to produce immunization
• Donor blood groups that patients can receive:Donor Recipient
O O, A, B, AB
A A, AB
B B, AB
AB AB

17. Cross-Matching
• Essentially a transfusion reaction in a test tube
• Between donor RBCs and recipient serum
• Takes 45-60minutes
• Three phases- immediate, incubation and antiglobulin
• Immediate:
- detects ABO incompatibilities and those due to MN, P
and Lewis systems
- takes 1-5minutes to complete

18. • Incubation:
- incubate the first phase reactions at 37 degrees in albumin or low-
ionic strength salt solution
- detects incomplete antibodies or those that are able to attach to a
specific antigen, but unable to cause agglutination
- takes 30-45minutes in albumin and 10-20 in low ionic strength salt
solution
• Antiglobulin test:
- addition of antiglobulin sera
- helps in confirming the presence of the incomplete Ab
- detects most Ab including the Rh, Kell, Kidd and Duffy

19. • Antibody Screen:
- also carried out in three phases
- trial transfusion between recipient’s serum and
commercially supplied RBCs
- screening also done in the donor serum to look for
unexpected antibodies
• Type and Screen:
- Only ABO-Rh typing and antibody screening
- Skips cross matching
- less than ideal; for emergencies
- can add the immediate phase of cross match

20. Emergency Tranfusion: A simplified
approach

21. Storage of Blood
• Most common preservative- CPDA-1
• Citrate for anticoagulation, phosphate as buffer,
dextrose as energy source and adenine to replenish ATP
• 35days shelf life; preserved at 1-6degrees C
• Can be extended up to 42 days with certain special
preservatives(adsol, nutricel and optisol)
• Duration of storage: based on 70% of transfused cells
surviving at least 24hrs post transfusion

22. Blood product separation

23. What happens with storage?
• Also called the ‘Storage Lesion’
• Decreases in the 2,3DPG
• Membrane changes:
- lipid peroxidation
- decreased deformability
- membrane vesiculation
• Changes in storage medium
- decreased pH
- increased potassium
- release of proinflammatory cytokines

24. • Increased tendency to adhere to endothelium
• Promote vasoconstriction
• Microcirculatory dysfunction and tissue hypoxia
• Some studies have shown adverse outcomes with
increased age of RBCs
• Studies to watch out for:
- ABLE: age of blood evaluation RCT
- Date collection completed in April
- RECESS: The Red Cell Storage Duration Study
- Estimated completion date: October 2013

25. Should we leukoreduce?
• Many adverse effects related to co-infusion of white cells
• Process where WBCs are reduced in number by centrifugation
or filtration
• Removes 99.995% of the white cell load
• Decreases febrile non-hemolytic reactions
• Decreases transmission of EBV, CMV, parasites, prions
• Decreased TRALI
• Decreases RBC storage lesions

26. Does the theory translate into practice?

27. • Hebert and colleagues:
- Before and after study
- cardiac surgery, hip fracture repair, surgical patients
requiring intensive care
- 1% decrease in mortality following implementation of
universal leukoreduction practices in Canada
• Blumberg and colleagues:
- Meta-analysis of nine RCTs
- surgical population of 3093 patients
- reduced the odds of postoperative infection
Herbert et al. JAMA 2003;289:1941-49
Blumberg et al. Transfusion 2007;47:573-81

28. Hazards of transfusion

30. Infectious
• Previously HIV and Hepatitis were dominant concerns
• Decreased risk in the recent past due to better pathogen
detection and reduction systems
• HIV- 1 in 4million transfusions
HCV- 1 IN 2.8million transfusions
• Newer infectious agents have however emerged
• Dengue and Babesia
• Human variant of Creutzfedlt Jakob disease
• EBV in children

31. Non-infectious serious hazards of
transfusion
• The NISHOTs

32. NISHOTs
• TRALI:
- Conventionally a new ALI developing within 6hrs
- presence of leukocyte Ag or neutrophil Ab suggestive
- newer definitions suggest onset anytime up to 72hrs
- this form of delayed onset TRALI-25% of ICU patients
- TARD: Transfusion associated respiratory distress
- presents at hypoxemia, dyspnoea, cyanosis
- bilateral pulmonary infiltrates
- Mechanisms- Immune and Non immune
- 70% require mech.ventilation and fatality is 6-10%

33. • Transfusion associated GVHD:
- decreased in view of implementation of leucodepletion
- usually in immunocompromised
- 90% fatality
- donor leucocytes mount an immune response
- maculopapular rash, abdominal pain, diarrhoea
- altered LFTs
- destruction of bone marrow stem cells with
pancytopenia
- irradiation of blood

34. • TRIM:
- Modulation of immune system in recipients
- Evidence: prolonged survival of renal allografts
- increases post-op infections, tumor recurrences
- activates latent viral infections
- mechanism is multi-factorial
- decreased activation of NK cells, macrophages
- decreased IL-2 production and CD4/CD8 ratio

35. • TACO:
- underreported complication
- rapid/massive transfusion, reduced cardiac reserve
- severe anemia(Hb‹5), age
- respiratory distress, tachycardia, hypertension, hypoxemia
- slow transfusion(‹1ml/kg/hr) in at risk patients

36. Other Hazards
• Hypocalcemia:
- citrate binds and causes hypocalcemia
- more of a problem with FFPs and platelets
- hypotension, flat ST segments and prolonged QT
• Hyperkalemia:
- potassium concentration increases during storage
- usually not a problem unless coexistent
acidosis/hypothermia
• Hypothermia
• Acid-base abnormalities

37. To transfuse or not to transfuse is the question
(A walk through the maze of evidence)

38. • “RBC transfusion in the ICU. Is there a reason?”
• Corwin and colleagues
• Retrospective chart review in a multidisciplinary ICU
• 85% of patients with LOS›1week transfused
• In 29% of cases, no clear indication
• Most of those transfused had a phlebotomy volume of
61-70ml/day
Corwin et al. Chest 1995;108(3):767-71

39. • “Transfusion requirements in Critical Care”-TRICC study
• To determine if a restrictive approach(7-9) is equivalent
to a more liberal approach(10-12) in euvolemia
• Multicentric RCT
• Primary outcome: 30day mortality
• Secondary outcome: 60day all cause mortality, ICU
mortality and hospital mortality
• Measures of organ failure and dysfunction also studied
• 838 patients; 418 R and 420 L
• Mortality: 18.7% R and 23.3%L

40. • ICU mortality: 13.9 R vs 16.2 L
• Similarly hospital and 60day mortality also lesser with R
• None of these differences reached significance though
• Subgroup of APACHE 2‹20 and age‹55yrs
• Here differences were significant
Hebert et al. N Eng J Med 1999;340:409-417

41. • “RBC transfusion does not increase oxygen consumption
in critically ill septic patients”
• Fernandes and colleagues
• Small study
• 15 septic patients on mech.ventilation
• Hb‹10
• 10 patients received PRBC and 5 albumin
• No change in O2 utilization and delivery parameters
• Increase in PVR in the PRBC group
Fernandes et al. Critical Care 2001;5:362-67

42. • The ‘CRIT’ study
• Corwin and colleagues
• Prospective multicentre observational cohort study
• 4892 patients enrolled from 284 ICUs
• Primary endpoint: quantify the RBC transfusions
• Secondary endpoint: clinical outcomes and
complications
• 44% of patients received one or more trasnsfusions
• Mean time to first transfusion was 2.3±1.7days
• Longer the stay, the more the transfusions

43. • Number of transfusions independent marker of ICU stay
• Independent marker of mortality
• 10% for those without transfusions
• 25% for those with 6 or more transfusions
• Independent marker for complications
Corwin et al. Critical Care Med 2004;32(1):39-52

44. • “Red cell transfusions and the risk of ARDS among
critically ill patients”
• Zilberberg and colleagues
• Cohort study within CRIT
• 67% of cases developing ARDS had exposure to RBCs
• Independent relationship noted even after adjustment
for other factors such as age, severity of illness etc
Zilberberg et al. Critical Care 2007

45. • “Efficacy of red cell transfusion in the critically ill: A systematic
review”
• MEDLINE, EMBASE and COCHRANE
• Cohort studies that independently assessed the effect of RBC
transfusion on outcomes
• 45 studies with 272596 patients
• Mortality, Infection, MODS and ARDS
• In 42 of 45 studies risks outweighed the benefits
• In 17 of 18 studies looking at mortality showed RBC
transfusion to be an independent predictor
• Increased risk and independent predictor of infection/MODS
and ARDS
Marik et al. Crit Care Med 2008;36:2667-74

46. • “Red cell transfusions and outcomes in patients with ALI,
sepsis and shock”
• Parsons et al
• Secondary analysis of new onset ALI patients enrolled in
the ARDS network fluid and catheter treatment
trial(FACTT)
• 285 subjects with ALI, sepsis and shock
• Patients met shock criteria(MAP‹60 or vasopressor)
• Primary end point: association between PRBC and
outcome
• Secondary end points: 90 day mortality and VFD

48. • Subset analysis: in subjects meeting pre-specified transfusion
criteria
• Hb‹10.2,CVP›8, ScVo2‹70%, MAP‹60 and vasopressor
• No independent association between transfusion and 28day
mortality
• No independent association to ventilator free days or 90 day
mortality
• In the subset also, no independent association to mortality or
VFDs
• No benefit or harm in conclusion
Parsons et al. Critical Care 2011;15:R221

50. Does transfusion improve oxygen and tissue dynamics?

51. • Dietrich et al
- Improved delivery
- No improvement in consumption or lactic acidosis
• Silverman and Tuma
- Looked at gastric mucosal tonometry
- Transfusion did not improve mucosal pH
• Marik et al
- No improvement in oxygen delivery
Dietrich et al. Crit Care Med 1990;18:940-44
Silverman et al. Chest 1992;102:184-88
Marik et al. JAMA 1993;269:3024-30

52. Does it increase infections?

53. • Taylor et al
- 1717patients in a mixed medical-surgical ICU
- 15.38% infection versus 2.92%
- Dose response relationship noted as well
• Claridge et al
- 1593 adult patients admitted to a level 1 trauma unit
- 33% versus 7.6%
- Also reported a strong dose response relationship
Taylor et al. Crit Care Med. 2002;30:2249-54
Claridge et al. Am Surg. 2002;68:566-72

54. • Shorr et al
• Prospective observational study
• 4892 patients in 284 adult ICUs
• Screened for BSI at time of admission and 48hrs later
• Total of 3.3% had ICU acquired infection
• Three variables associated with infection
• Baseline treatment with cephalosporins
• Higher sequential organ failure assessment score
• PRBC transfusions
Shorr et al. Chest 2005;127:1722-28

55. Red cell transfusions for patients with cardiac disease-A much
glorified myth?

56. • Hebert et al
- Subgroup analysis of “TRICC”
- 357 total cardiac patients; 257 with IHD
- Liberal group had higher organ dysfunction
- No difference in 30 day, 60 day or ICU mortality
• Rao and colleagues
- Metaanalysis of data collected from 3 major trials
- PURSUIT, GUSTO 2b, PARAGON
- Involved patients with ACS
- 24000 patients; 2401 received PRBCs
- 30 day mortality, MI all higher in transfused group
Rao et al. JAMA 2004;292:1555-1562

57. • Yang et al
- Transfusion and outcomes in patients with ACS
- NSTEMI
- 74000 patients
- After adjustment for age and comorbidities
- Transfused group had higher death rates
- Higher re-infarction rates
Yang et al. J Am Coll Cardiol. 2005;46:1490-95

58. • Singla et al
- Transfusion in patients with ACS
- Significant increase in 30 day mortality and recurrent
MI
- Adjusting for univariate predictors, relationship still
persisted
Singla et al. American Journal of Cardilogy. 2007;99(8):1119-21

59. • Silvain and colleagues
- Tried to understand the mechanisms leading on to increased
mortality and re-infarction in transfused patients
- In vitro transfusions
- Studied residual platelet aggregation and MPA
- Transfusions increased RPA and MPA
- Possibly explaining the reasons for poor outcome
Silvain et al. European Heart Journal 2010;31:2816-21

61. Downside
• Not all were RCTs
• Not all were good quality studies
• Too many confounders
• Patients were otherwise sick
• Against intuitive sense
• Evidence burdened medicine?
• Near unanimity however, that RBC transfusions are
harmful

62. For those who would say, “ Frankly I don’t care. Just tell
me what I need to do!!”
GUIDELINES

69. Summary
• A Hb less than 9 is very common at ICU admission
• Sampling may be one of the commonest causes
• Systemic O2 delivery is not equal to regional DO2
• More serious hazards in the ICU include TRIM, TRALI, TACO
and TRGVH
• Leucoreduction, though attractive may not be cost-effective

70. • Transfusions are independently associated with poor
outcomes
• Near unanimity that transfusions are bad although quality of
evidence is variable
• For every unit that you transfuse, keep asking yourself- Does
the patient really need it?
• Good clinical sense may be the only guide

71. THANK YOU

72. ?