Anemia in the ICU:
An Evidence Based Approach
Andrew F. Shorr, MD, MPH
Walter Reed Army Medical Center
Overview
•
•
•
•
What is current transfusion practice?
What are the risks of transfusion?
Is there an optimal hemoglobin?
Are there alternatives to the use of pRBCs?
Transfusion in the U.S.
• 12 million units given each year
• Common indications
–
–
–
–
Bleeding
Ischemia
Resuscitation
? Any indication
Costs of Transfusion
• Some estimates range from $100-$150/ unit
• Earlier studies fail to account for
– Costs of nursing time
– Costs of additional testing
– Costs of reactions
• More recent estimates:
– $250-$300/ unit pRBC
Cantor, et al. Blood 1998; 16: 2364.
Cost of Transfusion
• Cost of pRBCs changing
– Leukoreduction
– Nucleic Acid Testing (NAT)
• Estimated increase in cost over next several
years: $50-$100/unit
• New total cost to healthcare system --> at
least $60 million
Transfusion in the ICU
•
•
•
•
Retrospective review of patients in ICU > 1 week
85% received pRBCs
Average transfusion: 9.5 units
Indications for transfusion
– No clear indication:
– Low Hct:
29%
19%
• Average daily blood loss from phlebotomy: 70
ml/day
Corwin, et al. CHEST 1995; 108: 767.
Transfusion in the ICU
• Practice survey in Canada
• 76% of all Canadian CCM MD participated
• Queried regarding
– Current transfusion practice in ICU
– Presented with hypothetical cases
Hebert, et al. Crit Care Med 1998; 26: 482.
Transfusion in the ICU
Scenario
24 yo trauma victim
Mean (range) Hgb
Threshold
8.25 g/dl (5.0 – 12.0)
70 yo with GIB
9.48 g/dl (7.0 – 12.0)
45 yo alcoholic with sepsis
8.69 g/dl (6.0 – 12.0)
55 yo with post-op MI
9.24 g/dl (7.0 – 12.0)
Academic physicians had a lower threshold
than non-academic MDs (p<0.001)
Once a threshold was reached,
> 90% of MDs transfused 2 units
Transfusion in the ICU
• On average, pRBCs used in the ICU
–
–
–
–
Are at least 2 weeks old
Lack sufficient 2,3 DPG
Have diminished O2 carrying capacity
Remain in the circulation for only a short time
Risks of Transfusion
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•
•
•
Infection
Transfusion reaction
Immunomodulatory
Volume-related
Blood Borne Infections
Infection
HIV
Hepatitis B
Hepatitis C
Estimated rate/ unit
transfused
1:420,000
1: 37,000
1: 62,000
Blood and the Immune System
• Despite filters, WBCs remain in pRBCs
• Transfusion promotes cytokine release
• Alters cellular immunity:
– Decreased: CD4 cells, NK cells, IL-2
production
– Increases: B cells, CD8 suppressor cells, PGE2
Blood and the Immune System
• Design: Prospective, observational study
• Subjects: CABG patients
• Comparisons: transfused vs. no transfusion
intraoperatively
• Measurements: IL-6, BPI
• n=136
Fransen et al. CHEST 1999; 116: 1233.
Blood and the Immune System
1000
IL-6 (ng/ml)
800
600
No Transfusion
Transfusion
400
200
0
Pre
X-on
0
0.5
4
Reperfusion (hrs)
8
18
Do the immune effect of blood have
clinical implications?
Transfusion and Outcomes
Colorectal Cancer
•
•
•
•
•
Design: Retrospective
Subjects: Colorectal cancer resection
Comparison: transfused vs. non-transfused
Endpoints: hospital charges and LOS
Controlled for multiple confounders
(comorbidity, age, gender, ICU admission, etc)
• n=487
Vamvakas et al, Arch Pathol Lab Med 1998; 122: 145.
Transfusion and Outcome
Transfused
Not
p
Transfused
19.0%
0.0004
Post-op
Infection
LOS (days)
34.2%
16.7
10.3
0.0001
Charges ($)
28,101
15,978
0.0001
After controlling for confounders, each unit transfusion
increased charges by 2.0% (p <0.001)
Transfusion and Outcome
Nosocomial pneumonia after pRBC in CABG
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•
•
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Design: Case-control
Subjects: s/p CABG
Endpoints: Nosocomial pneumonia
n= 45 cases and 90 controls
Leal-Noval, et al. Crit Care Med 2000; 28: 935
Transfusion and Outcome
Varaible
Adjusted
95%
Odds Ratio Confidence
Interval
Reintubation
62.5
8.1-480
Transfusion
> 4 units
Previous
Abx
p
0.01
12.8
2.0-82
0.01
6.6
1.2-36.8
0.02
Transfusion and Outcomes
Ischemia post-CABG
• Design: Prospective, multicenter,
observational study
• Subjects: CABG patients
• Measurement: Initial ICU Hct
• Endpoints: MI, need for IABP for CHF, all
adverse outcomes
• n=2,202
Spiess et al. J Thorac CV Sgy 1998;116: 460.
Frequency (%)
Transfusion and Outcome
20
18
16
14
12
10
8
6
4
2
0
<24%
25%-33%
>34%
Q Wave M
Severe LV
Dysfunction
Adverse Ischemic
Outcome
Transfusion and Outcomes
• Multivariate analysis to control for
confounders
– Association with higher risk with higher Hct
consistent
– Initial Hct most significant predictor of adverse
outcome (OR 2.22)
• Conclusion
– “There is no rationale for transfusion to an
arbitrary level after CABG.”
Transfusion and Outcomes
19801985
19901995
p
CVA/MI
6.6%
5.5%
<0.001
Age
65.9
70.4
<0.001
ASA > 3
79.2%
93.6% <0.001
% AODM
9.0%
14.8% 0.003
% CAD
36.0%
42.2% 0.04
% Transfused
72.9%
8.7%
<0.001
pRBC units
transfused
1.10
0.27
<0.001
• Carotid
Endarterectomy
• Evaluated impact of
transfusion on
ischemic events
(Stroke and MI)
• n=1114
Kober et al. Mayo Clin Proc 2001; 76: 369-376.
Transfusion and Outcome
Trauma
• Design: Prospective observational study
• Subjects: Trauma patients at major trauma
center
• Controlled for ISS, GCS, age, gender, race
• Measurements: SIRS, ICU admission,
death
• n=9,539
Malone, et al. SCCM 2001, A138.
Transfusion and Outcome
Outcome
(Transfused vs. not)
Odds
Ratio
CI
p
SIRS
5.74
3.91-8.40
<0.001
ICU admission
2.89
2.09-4.19
<0.001
Death
10.33 4.84-18.80 <0.001
Transfusion and Outcome
• Use of pRBCs alters immune system
• Immune dysregulation has significant
clinical correlates
• Multiple endpoints adversely affected by
use of pRBCs
• But why are we transfusing anyway?
Optimal Hemoglobin
• Hemoglobin crucial for oxygen delivery
• O2 Delivery =
C.O. x Sa02 x Hgb x 1.34 x 10
• Originally thought that increasing delivery
would improve outcomes (Shoemaker 1988)
• Multiple studies evaluated
– Increasing CO with dobutamine
– Increasing O2 carrying capacity with transfusion
Supraphysiologic O2 Delivery
Author
n
Control
Group
Mortality (%)
34
Treatment
Group
Mortality (%)
34
p
100 44
34
54
0.04
Gattinoni 762 67
1995
48
52
0.64
Yu 1993 67
Hayes
1994
Proportion
achieving
goal (%)
60
0.99
Transfusion and Oxygen Delivery
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•
•
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Subjects: 23 patients with septic shock
Intervention: transfusion of 3u pRBCs
Measurements: O2 uptake and gastric tonometry
Results
– No increase in O2 uptake with transfusion
– Inverse association between gastric pH and age of
blood (r=-0.71, p < 0.001)
– No beneficial impact of transfusion in sepsis but at cost
of splanchnic ischemia
Marik P, et al. JAMA 1993; 269: 3024.
DPG and O2 Carrying
ml )2/100 ml blood
12
Fresh Blood
10
8
1-Week-Old Blood
Activated Blood
6
4
2
0
0
5
10
15
20
25
2,3 DPG (mmol/g Hb)
Hamasaki et al. Vox Sang 2000; 79:191-197.
Optimal Hemoglobin
• No evidence that increasing O2 delivery
changes mortality in general ICU
population
• May actually be harmful
• ATS position statement:
– “We conclude that continued aggressive
attempts to increase O2 delivery are
unwarranted.”
Optimal Hemoglobin
• Clearly higher Hgb achieved via transfusion
is not helpful and may be harmful
• Is there a lower threshold?
Transfusion Requirements in
Critical Care
• Multicenter, RCT
• Subjects
– Acutely ill in ICU, Hgb < 9.0
– Excluded if: chronic anemia, ongoing bleeding,
admission after CABG
Hebert et al. NEJM 1999; 340:409-17
Transfusion Requirements in
Critical Care
• Randomized to 2 strategies
• Liberal strategy:
– Maintain Hgb between 10-12
• Restrictive strategy:
– Maintain Hgb between 7-9
• Endpoints
– All cause mortality, MSOF
– Predefined subgroups: age > 55, CAD, APACHE II >
20
Transfusion Requirements in
Critical Care
Restrictive Liberal
p
(n=418) (n=420)
ICU mortality 13.4%
16.2% 0.29
Death (30d)
18.7%
23.3%
0.11
ICU LOS
11.0
11.5
0.53
MODS
8.3
8.8
0.10
0.7%
2.9%
0.02
MI
Transfusion Requirements in
Critical Care
Patients with APACHE II < 20
Survival (%)
100
90
Restrictive
Liberal
80
p=0.02
70
60
50
0
5
10
15
Days
20
25
30
Transfusion Requirements in
Critical Care
Patients Younger than 55
Survival (%)
100
90
Restrictive
Liberal
80
p=0.02
70
60
50
0
5
10
15
Days
20
25
30
Transfusion Requirements in
Critical Care
• Conclusions
– Lower transfusion threshold was as effective as
higher trigger
– Lower threshold superior in some subgroups
– Mechanism of worse outcomes with liberal
strategy unclear (? promotes cytokine cascade,
increased risk of ARDS)
Transfusion Requirements in
Critical Care
• Editorial comment in NEJM
“This study has made it clear that a single
threshold for transfusion in all patients is not
appropriate…… With this knowledge, more
physicians will be able to follow the dictum
“first do no harm,” and we will have a surplus
of blood rather than a shortage.”
Ely et al. NEJM 1999: 340: 468.
Alternatives to Transfusion
• Limited blood use policy
• Artificial hemoglobin
• Erythropoetin
Blood Policy (Police?)
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•
•
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•
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Enforce blood bank QA
Eliminate routine ordering of labs
Minimize frequency of lab testing
Employ iSTAT system
Attention to detail
With this may be able to eliminate 20% of
transfusions
Artificial Hemoglobin
• Several products
– Biopure
– HBOC
– DCLHBG
• Current focus on cross-linked products
– Increases half-life
– No excessive oncotic pressure
Artificial Hemoglobin
• Potential advantages
of cell-free HgB
– No antigenicity
– Unlimited supply
– No disease
transmission
– Long storage
– Better rheologic
properties
• Demonstrated in vitro
– Vasopressor
– Corrects acidosis
– Improves
microvascular
perfusion
– Increases O2 delivery
Artificial Hemoglobin
Author
n
Type of Patient Type of Study Effect
Reah
DCLHb
1997
Kasper
HBOC
1998
14
Septic Shock
Observational Decreased
NE dose
24
AAA Sgy
Randomized
Baron
209 CABG
DCLHb
1997
Gould
44 Trauma
polymerized
1998
Randomized
Randomized
Increased
BP,
worse O2
delivery
Less
transfusion
Less
transfusion
Artificial Hemoglobin
Potential Problems with Artificial Hemoglobin
--Pulmonary hypertension
--Excessive vasoconstriction
--Platelet activation
--Immunomodulation
--Increased risk of infection
--Interference with blood tests
Erythropoetin in Critical Illness
• Design: Prospective
• Subjects: MICU patients with and without
sepsis
• Measurement: EPO level
• n=36
Rogiers et al. Inten Care Med 1997; 159.
Erythropoetin in Critical Illness
Group
Control
No. of
measurements
18
EPO (IU/l) HCT
845
30.3
Sepsis no ARF
64
124
28.9
Sepsis with
ARF
Non-sepsis no
ARF
Non-sepsis
with ARF
43
136
28.2
36
199
29.8
14
103
32.4
Efficacy of EPO in the
Critically Ill Patient
• Multicenter DBRCT
• Subjects
– Critically ill adults
– Excluded if: underlying cancer, immunosuppressed,
MSOF
• Intervention
– rHuEPO vs placebo
– rHuEPO given for at least 2 weeks
– All subjects given FeSO4
Corwin et al. CCM 1999; 27:2346-50.
Efficacy of EPO in the
Critically Ill Patient
• Endpoints
– Cumulative blood use
– Ability to remain transfusion-free
• Indications for transfusion
– Left to primary MD
EPO in the ICU
Actual Transfusion Trigger
ARM
PRE-XFUSION
HCT
P
Placebo
27.0+4.0
NS
EPO
27.5+3.8
No difference in trigger when stratified by study center
Efficacy of EPO in the
Critically Ill Patient
ICU DX
Pneumonia
Post-op
respiratory failure
COPD
exacerbation
Trauma
Sepsis
Other
EPO
(n=80)
18
10
PLACEBO
(n=80)
20
8
18
16
12
3
19
12
3
21
Efficacy of EPO in the
Critically Ill Patient
EPO Placebo
p
Total units transfused 166
305
<0.002
Hct change
4.8
1.4
<0.001
Final Hct
35.1
31.6
<0.01
Mortality
30.0% 26.3%
NS
Efficacy of EPO in the
Critically Ill Patient
• Conclusions
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–
–
–
–
EPO effective in critically ill patients
EPO clearly safe in ICU subjects
Optimal dose unknown
May be cost neutral
Attractive alternative
Conclusions
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•
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Transfusions often over used
Blood is not benign
No clear transfusion trigger
New options available