In Search of the Transfusion Trigger

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In Search of the Transfusion Trigger

• Jeffrey L. Carson, M.D.
• Richard C. Reynolds Professor of Medicine
• Chief, Division of General Internal Medicine
• Robert Wood Johnson Medical School
• New Brunswick, New Jersey, USA

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Presentation Outline

• Framework for transfusion decision
• Improving Safety
• Viral infections
• Trali
• Medical error
• Immunomodulation
• Effect of anemia on mortality and morbidity
• Experimental and human data
• Effect of blood transfusion on mortality and
  morbidity
• Systematic review of literature and meta-analysis
• Effect of blood transfusion on functional
  recovery
• Summary

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Case 1

• 80 year old women 2 days postop for hip fracture
  repair.
• PMH- hypertension, DM, Hx of MI 3 years ago
• Symptoms- tired and weak
• Exam ok
• Hgb 8.5
• Transfuse?

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Case 2

• 66 year old male postop total hip replacement
• Hx of hypertension and gout
• Asymptomatic
• Hgb 8.1
• Transfuse?
• Hgb 7.5
• Transfuse?

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The Transfusion Decision
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The Transfusion Decision
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Risks of Transfusion
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Current Safety EstimatesRisk of Infection

• HBV 1205,000-488,000
• HCV 11,935,000
• HIV 12,135,000

Dodd et al, Transfusion, 2002
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Risk of CJD from Allogeneic Blood Transfusion

• Driving important blood policies
• Donors who lived in UK cannot donate blood
• In February 2004, first case of possible
  transfusion transmitted case of vCJD

Llewelyn et al. Lancet 2004
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Reports of Death or Major Complications
SHOT Initiative. Williamson BMJ 1999
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Transfusion-Related Acute Lung Injury (TRALI)

• Acute lung injury defined as acute hypoxemia with
  PaO2/FIO2 ratio of 300 mm Hg
• Bilateral infiltrates
• Absence of left atrial hypertension (i.e.,
  circulatory overload)
• Within 6 hours of receipt of plasma-containing
  blood and blood components. Typically within 2
  hours
• Packed cells, fresh frozen plasma, platelet
  concentrates, granulocytes, and, rarely,
  intravenous immunoglobulin and cryoprecipitate
• Incidence unclear estimated 15000

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Proposed Causes of TRALI

• Anti-leukocyte antibodies and the concentration
  of bioactive lipid factors in the donor product
• Association between infusion of plasma from
  female donors
• The United Kingdom blood system recently
  eliminated female donors from the production of
  high plasma volume products (FFP)

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Immunomodulation

• Transfused WBCs are implicated to lead to
  immunosuppresion by producing cytokines
• Remove WBCs at the time of processing might
  reduce rate of infections.
• Many observational studies show association
  between transfusion and infection

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Mortality and Leukodepletion
van de Watering, Circulation 199897562-568.
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Summary- Risks of Transfusion

• Risks of blood from known problems is very low
• Risk of HIV and Hepatitis C about 12 million
• Hepatitis B has highest residual risk
• TRALI may be a common serious effect of blood
• It is uncertain if allogeneic blood transfusion
  has a clinically significant immunomodulating
  effect that leads to bacterial infections
• Human error appears to be responsible for the
  most frequent serious adverse effects of blood

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The Transfusion Decision
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Anemia in Animals
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Isovolemic Hemodilution in Human Volunteers
First tested at 7 g/dL 3 of 55 Subjects
Toy, Weiskopf, Leung Anesthesiology and
Transfusion 2000
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Effect of Anemia and CVD on Surgical Mortality
and Morbidity

• Retrospective cohort study of patients who refuse
  blood transfusion for religious reasons
• Outcome-30-day mortality or morbidity
• CVD - patient with history of MI, angina, CHF,
  or PVD
• 1,958 patients age 18 or older
• Carson JL, et al. Lancet 19963481055-60.

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Preop Hgb and Mortality
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Preop Hgb by Cardiovascular Disease Interaction
P0.03
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Postop Hgb Level and Mortality in Patients with
Hgb lt 8 g/dL
Carson et al. Transfusion 2002
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Conclusions-Risk of Anemia

• Mortality rises as preoperative hemoglobin falls
• A postoperative hemoglobin below 5-6 g/dL was
  associated with very high mortality
• Animal and human data suggest that patients with
  CVD may be less tolerant of anemia than patients
  without CVD

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The Transfusion Decision
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Efficacy of Transfusion Systematic Review

• Clinical Trials

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All Cause 30 Day Mortality
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Transfusion in Critical Care

• Clinical trial in consecutive ICU patients with
  Hgb lt 9.0 g/dl and euvolemia
• Restrictive blood given when Hgb lt 7.0 g/dl and
  maintained between 7-9 g/dl
• Liberal blood given when Hgb lt 10 g/dl and
  maintained between 10-12 g/dl
• Primary outcome 30 day mortality
• Hebert et al N Engl J Med 1999

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Outcomes TRICC Trial
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Subanalysis TRICC TrialIschemic Heart Disease
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Morbidity Outcomes in TRICC
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Summary-Clinical Trial Data

• There is only one adequately powered clinical
  trial in the world literature evaluating
  transfusion thresholds
• Study suggests 7 g/dL is as safe 10g/dL threshold
  in ICU patients
• Subanalysis in patients with ischemic heart
  disease found non significant lower mortality in
  patients transfused gt 10 g/dL.

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Effect of Transfusion Systematic Review

• Observational Studies

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Surgical Blood Transfusion

• Determine effect of transfusion on mortality,
  morbidity by comparison with similar patients not
  receiving transfusion
• 9,958 patients with hip fracture
• Age 60 or older
• Outcomes Mortality and Morbidity
• Carson, et al. JAMA 1998279199-295.

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Effect of Postoperative Transfusion on 30 Day
Mortality
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Other Observational Studies

• ICU study mortality lower in patients receiving
  transfusion
• Hebert et al. Am J Resp Critical Care Med 1997
• CABG mortality higher in patients receiving
  transfusion
• Speiss et al. J Thorac Cardiovasc Surg 1998
• ICU mortality higher in patients receiving
  transfusion
• Vincent et al. JAMA 2002

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Anemia and CVD

• Vascular surgery patients with Hct lt 28 had
  cardiac events
• Nelson, et al. Critical Care Med 1993
• Hct lt 28 in radical prostectomy patients
  associated with had cardiac events
• Hogue et al. Transfusion 1998

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Transfusion and MI

• Cohort study in 78,974 Medicare patients 65 years
  of age or older
• Mortality at 30 days compared in patients
  transfused vs not transfused
• Stratified by admission Hct level
• Adjusted for co-morbidity
• Many exclusions

Wu et al. N Engl J Med 20013451230-6.
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Impact of Transfusion on 30 Day Mortality
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Transfusion in Acute Coronary Syndrome

• Combined results from 3 large clinical trials of
  patients with acute coronary syndrome
• Examined the association in patients with
  bleeding and nadir Hgb.
• Primary outcome was 30-day all cause mortality
  and secondary outcome 30-day all cause mortality
  or MI.

Rao et al. JAMA 2004
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Association with Transfusion and ACS
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Summary-Observational Studies

• Results from observational studies are
  inconsistent
• Several studies suggest that higher Hgb levels
  are needed in patients with CVD
• Unclear if results of observational studies are
  valid

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The Transfusion Decision
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The Transfusion Decision
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Anemia and Function

• Fatigue, weakness, and diminished physical
  performance are widely accepted signs of anemia
• Treadmill testing correlates with hemoglobin
  concentration and exercise capacity improves
  with when hemoglobin increases with EPO in end
  stage renal failure and patients undergoing
  cancer chemotherapy
• No data with blood transfusion

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Summary-Anemia and Function

• Limited studies linking anemia and function
• No clinical trials that demonstrate that higher
  blood transfusion thresholds improves functional
  recovery

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The Transfusion Decision
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Specific Aims

• To compare the effect of symptomatic
  transfusion to 10 g/dl threshold transfusion on
  functional recovery, mortality, and morbidity

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Study Population

• 2,000 hip fracture patients
• Cardiovascular disease
• CAD, CHF, PVD, Stroke
• Cardiovascular risk factors
• DM, hypertension, tobacco use, hyperlipidemia.
  chronic renal insufficiency
• Postop hemoglobin lt 10 g/dL within 3 days of
  surgery

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Outcomes

• Ability to walk independently at 60 days
• Death or myocardial infarction
• Morbidity
• MI, thromboembolism, pneumonia, stroke
• Nursing home placement at 60 days
• Functional status

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Two Transfusion Strategies

• Symptomatic transfusion
• Transfusion for symptoms from anemia
• Cardiac chest pain
• Congestive heart failure
• Orthostatic hypotension or unexplained
  tachycardia
• Transfusion permitted (but not mandatory) if Hgb
  lt 8
• Transfusion given to relieve symptoms or keep Hgb
  over 8 g/dl
• Blood sparing strategy

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Two Transfusion Strategies-2

• 10 g/dl threshold transfusion
• Transfusion for Hgb lt 10 g/dl
• Transfuse 1 unit of packed red cells
• Transfuse enough blood to keep Hgb gt10

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Symptomatic Transfusion

• Widely recommended
• Transfuse for symptoms
• Consistent with TRICC trial
• Reduce blood use Save money ?
• Reduce risk of transfusion
• Safest blood transfusion is one never given

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10 g/dl Threshold Transfusion

• JW data suggests mortality begins to rise below
  10 g/dl
• Several observational studies suggest patients
  with CVD benefit from higher transfusion
  thresholds
• Patient has more energy
• Better rehabilitation and functional status
• Fewer go to nursing home Save money
• Less pneumonia, thromboembolism
• Shorter length of stay Save money
• Fewer MI and CHF
• Blood safe Why wait for symptoms?

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Logistics

• Patients consented preop
• Hgb checked in recovery room and daily for 3
  days.
• If Hgb lt 10 g/dL, check with clinicians if OK to
  enter patient into trial
• Randomize patient
• Follow Hgb days 1, 2, 4 and 7
• Transfuse as per protocol

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Detection of MI

• Troponin performed by Troponin Core Laboratory
• ECG interpreted by ECG Core Laboratory
• Clinical narrative
• Central classification by ECG Core Laboratory

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Cases
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Case 1

• 80 year old women 2 days postop for hip fracture
  repair.
• PMH- hypertension, DM, Hx of MI 3 years ago
• Symptoms- tired and weak
• Exam ok
• Hgb 8.5
• Transfuse?

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Case 2

• 66 year old male postop total hip replacement
• Hx of hypertension and gout
• Asymptomatic
• Hgb 8.1
• Transfuse?
• Hgb 7.5
• Transfuse?

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Transfusion Recommendations

• Pending additional clinical trials, the best data
  suggests that a restrictive transfusion trigger
  (7 g/dL) should be used
• The appropriate transfusion threshold in patients
  with cardiovascular disease is unknown
• Careful assessment of the need for transfusion in
  each patient should be made

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• Status as of May 2007

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Status of FOCUS

• Enrolled 965 patients
• Target 2000 patients
• 35 sites in US and Canada
• Recruitment accelerating
• Projected to complete enrollment September 2008
• 15 cases per week
• Adherence to protocol is not good enough

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We Need Your Help

• Inform your patients (families) that FOCUS is
  recruiting at UAB
• Inform that research staff will visit to tell
  them about the trial and ask consider
  participating
• After enrollment into the trial, adhere to
  protocol

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