•
Anemia, Oxygen Delivery
– Physiology
– Clinical evidence for RBCs
– Sepsis, CAD/ACS, Trauma
•
Coagulopathy
– Physiology
– Clinical evidence for FFP use
– Liver disease
•
Thrombocytopenia
– Evidence-based use of Platelets
– Uremia

Translate what you learn today to our trainees and
change the transfusion culture in Colorado

Help practitioners/educators:
 Develop a framework for performing risk/benefit
analysis for each transfusion decision
 To understand the clinical and physiologic
evidence behind those decisions
 To challenge dogmatic transfusion practices
based on new evidence
Risk
Febrile transfusion reactions
Allergic reaction
Anaphylaxis
HIV
Hepatitis B




Terrible T’s
TRIM
TRALI
TACO
Incidence
<1 in 100
2-3 in 100
2 in 100,000
1 in 2,000,000
1 in 150,000

TRIM (transfusion-related immunomodulation)
 Reduce rejection (kidney transplants 1960s)
 Increased incidence of nosocomial bacterial infections
Marik; CCM, 2008
Transfusion
TRALI
Other
12%
Trauma
7%
Pneumonia
35%
Aspiration
11%
NonPulmonary
Sepsis
35%
-6
hours
0



13% of all transfused MICU patients
Mortality-8-9%
Differentiating TACO and TRALI
 BNP
 Hypertension vs. Hypotension
 Leukopenia or fever (TRALI)

Diurese to low pulmonary venous pressures
 Trial of diuresis Hypoperfusion  TRALI
 Trial of diuresis Resolution  TACO


RBC (acquisition cost) ~$200 per unit
RBC (total cost) ~$1400-$2400 per unit
 Higher if you factor in care for probable
complications
▪ TRALI (8% incidence in ICU)
▪ Nosocomial infection (10% increase per unit)
Transfusion
TRALI
Other
12%
Trauma
7%
Pneumonia
35%
Aspiration
11%
NonPulmonary
Sepsis
35%
-6
hours
0
Red Blood
Cell Transfusion
1) Physiologic
2) Hard outcome
3) Symptom?
Transfusion reactions
TRALI
TACO (hydrostatic edema)
TRIM (nosocomial infection)
Cost ($ and Human)

76YM w/ HTN, CAD (Hx MI) admitted to the ICU with
pneumonia severe sepsis

Quickly improved with IVF (5L), oxygen, antibiotics
overnight- transferred to floor

BP- 110/50 (140/90), HR 110, Temp-100.8

SPO2 90% on 4LNCO2

Lactate-4.8 2.8, Hgb 9.67.6, Creatinine 1.81.4 (0.8)
BP- 110/50 (140/90)
HR 110, Temp-100.8
1) Physiologic
SPO2 90% on 4LNCO2
2) Hard outcome
3) Symptom?
Lactate-4.8 2.8
Creatinine- 1.81.4 (0.8)
Transfusion reactions
TRALI
TACO (hydrostatic edema)
TRIM (post-transfusion
infection)
Cost ($ and Human)
Hgb 9.27.6
Physiologic benefit RBCs
SPO2 x Hgb x CO (SV x HR)
Hgb=3.5
Heart rate (beats/min) = 116 - 4.0 x Hgb (g/dL)
Zimmerman; Critical Care Med, 2004

1st case- Epi Q’s re: anemia and transfusion
 Need hospital transfusion numbers

2nd case: Sepsis: APACHE II<20, 52YM,
increase O2 delivery?, Improve outcome
benefit? When?
 Harm?
 Leukoreduction?

3rd case: Post-op knee 55YM: AF w/ RVR,
known CAD, improve myocardial O2 delivery?
rehab potential? ADLs?

4th case: NSTEMI (HCT 25), AF w/ RVR, No
EKG changes, transitions to STEMI
 Age of blood?
Everything else is extrapolation from these studies
Do summary slide here of key points (with pictures)

Incidence: X% at 3 days

Mechanisms (non-bleeding)
 Loss (phlebotomy)
▪ Sepsis; X% total hgb drop
 Suppression (TNF, IL-1, IL-6)
▪ ↓ Epo + Epo receptor
▪ Induce apoptosis of erythroblasts
▪ Decreased availability of Iron
 Destruction-RES system
 Dilution
Epidemiology of Transfusion in the
Critically Ill
Napolitano; Critical Care, 2004
PROPENSITY MATCHED
30 DAY MORTALITY
Adj 30d Mort: 1.65, p< 0.001
ABC Study Outcomes (Europe)
Difference in Mortality by Number of Units Transfused.
Vincent, J. L. et al. JAMA 2002;288:1499-1507
Copyright restrictions may apply.
ABC Study Outcomes
Survival Analysis by Transfusion Status Among Propensity-Matched Patients.
28-day mortality
23% vs. 17%, p=0.05
Vincent, J. L. et al. JAMA 2002;288:1499-1507
Copyright restrictions may apply.
Transfusion
TRALI
Other
12%
Trauma
7%
Pneumonia
35%
Aspiration
11%
NonPulmonary
Sepsis
35%
-6
hours
0
 Multicenter RCT, Canada, n=838
 Hgb 7 vs. 10
 Who: non-bleeding, CAD (600 ex)
 Ischemic heart disease (n=257)
 Outcomes
 30d Mortality 18% vs. 23%, p=.10
 Hospital Mort 22% vs. 28%,p=.05
 Subgroups
 APACHE II < 20
 (9% vs 16%, p=.03)
 Age < 55
 (5.7% vs. 13%, p=.02)
Hebert; NEJM, 1999
 Complications
▪ ARDS or pulmonary edema
(8% vs. 14%, p<.01)
▪ MI (0.7% vs 2.9%), p=.02
 Multicenter RCT, US/Canada, n=2016




Hgb 7 vs. 10
Who: age> 50, Hip repair
Clinical evidence/RF Heart disease
Hgb <10 w/in 3d surgery
 Outcomes
 60d mort/10 ft: 35% vs. 35%, p=.90
 MI/UA/Death: No difference
 Discharge Location
 Functional outcomes (Fatigue, ADL)
 Notes
 2 units. vs. 0 units
 1.3 g/dL difference nadir hgb
Carson, NEJM, 2012
 Complications
▪ No differences in 20+
transfusion outcomes
DO2 = CO x (SPO2 x hgb)

Oxygen kinetics?

Will ↑RBCs ↑O2 utilization
 Assumptions: transfused RBCs
▪ Don’t alter the flow (CO)
▪ No alteration inO2 kinetics

↑DO2 ≠ ↑VO2
1) delivery dependent hypoxia
2) microvascular delivery
3) 0xygen kinetics maintained

Transfused RBCs :
 Greedy
 Flow, O2 kinetics
 Fragile
 Autoregulation, plugging
 Sticky
 adhesionshunting
 microvesicles

16 pt- Septic Shock and hgb <10g/dl
 1) Dobutamine 10mcg  800cc RBCs (3 units)
 2) 800cc RBCs (3 units)  Dobutamine 10mcg

DO2 (jncreases in both scenarios)
 Dobutamine 48.5 (± 6.9)
 PRBCs 21.3 (± 4.3)

VO2 increased only with Dobutamine
 21.7 (Dobutamine) vs. 2.2 (PRBCs)

Conclusion: In septic patients with delivery (DO2) dependent
decreases in VO2, RBC transfusion does not improve VO2.
Lorente; Critical Care Med, 1993
Zimmerman; Critical Care Med, 2004

The storage lesion (average US age=17 days)
 ↓deformability, ↑ fragility
 Loss of antioxidantsHgbMethemoglobin
 Lose 2,3 DPG (7-14 days), ATP, NO
 WBC may accelerate storage lesion
▪ ↑ IL-1, IL-8, TNF, bioactive lipids, HLA-ag

Epidemiology (all RBCs>14d)
 ↑ PNA, infxn, MOF, LOS in TRAUMA
 ↑ Morbidity/Mortality in Cardiac Surgery
▪ 2 RCTs ongoing (10/14d vs. 21)

Interventional Studies (MICU)
 Physiologic outcomes with inconsistent results
 ABLE (Age of Blood Evaluation) ICU Patients
▪ n=2510, 25 centers Canadian, double blind RCT
▪ Vent >48 hours, ICU, request for 1 RBC unit
▪ Fresh (<7d) vs. standard (15-20d)
▪ 90day mortality (power 25%20%)

Epidemiology
▪ Association with TRALI, infection, mortality



Universal leukoreduction- 2005 in US
No outcome benefit before and after studies
No benefit in recent RCTs (Trauma/Med/Surg)
 Mortality, Infection, TRALI
 Except CABG less post-op infection

Should we switch back to non-leukoreduced
blood?
 more economical
CAD/ACS




Myocardium oxygen extraction ratio- 55-70%
CAD or ACS flow limited
Do RBCs increase DO2 myocardial VO2?
Transfused RBCs
 NO sink, ↓ ATP, reduce microvascular flow
 Hypercoaguable, ↑platelet aggregation
 ↓worsening oxygen kinetics





24,112 patients from 3 ACS (NSTEMI) trials
10% (2401) transfused
Adjusted for 50+ co-morbidities and time from
admission
Grouped by nadir HCT; 20-25%, 25-30%, >30%
Adj. probability of death at 30d w/transfusion
Rao; JAMA, 2004

39, 922 pts, ACS (NSTEMI and STEMI)

STEMI- Improved outcomes when transfused
up to Hgb≥ 12 g/dL
NSTEMI- Worse outcomes when transfused
at any Hgb level!!


Registry: ACS patients: Worse CV outcome
and death with transfusion down to hgb < 9
g/dL (equivalent below 9 g/dL)
Sabatine; Circulation, 2005
Singla; Am J Card, 2007






TRICC-(357 -CV disease), (257-IHD)
Hgb-7 vs 10 g/dL
No difference in 30 day mortality (0.3%)
FOCUS- 2016 CAD or RF for CAD, Age>50
Hgb-7 vs 10 g/dL
No difference in mortality or functional
outcomes




STEMI Up to Hct 30% if active ischemia?
NSTEMI Up to Hct 20-25% if active ischemia??
CAD (no active ischemia) hgb 7mg/dL (FOCUS)
Alternatives to increase supply and reduce demand
Reverse or avoid inadequate
tissue oxygenation due to
inadequate delivery
Transfusion reactions
TRALI
TACO (hydrostatic edema)
TRIM (nosocomial infection)
Cost ($ and Human)
Risk
Febrile transfusion reactions
Allergic reaction
Anaphylaxis
HIV
Hepatitis B




Terrible T’s
TRIM
TRALI
TACO
Incidence
<1 in 100
2-3 in 100
2 in 100,000
1 in 2,000,000
1 in 150,000

TRIM (transfusion-related immunomodulation)
 Reduce rejection (kidney transplants 1960s)
 Increased incidence of nosocomial bacterial infections
Marik; CCM, 2008
Within 6 hours
ALI Dx criteria
1) Acute
2) Bilateral infiltrates
3) Hypoxemia
4) Not hydrostatic
edema (TACO)





Associated most commonly with platelets and plasma
Mortality 30-50% in ICU patients
Antibody mediated (Anti-HLA I or II, Anti-neutrophil)
Non immune mediated
Common-5-8% MICU pts transfused (29% bleeding liver disease)

Massive transfusion studies
 No analysis of FFP

Recent ALI association studies have identified FFP as an
independent risk factor (9 studies)
 Ruptured AAA repair(1) , MICU (3), trauma (2) mechanically ventilated
(2), Sepsis (1)
No association of RBCs and ALI when adjust for FFP
 FFP/Plts  most common causative agents TRALI in critically ill

MICU TRALI incidence:
5-8% transfused pts
Mortality- 41-53%
Benson, ICM, 2010
Vlaar, CCM, 2010
Gajic O, TRALI in the
Critically ill, AJRCCM
2007
Benson, ICM, 2010
Silliman C,
Blood 2003
Wallis JP,
Transfusion 2003



13% of all transfused MICU patients
Mortality-8-9%
Differentiating TACO and TRALI
 BNP
 Hypertension vs. Hypotension
 Leukopenia or fever (TRALI)

Diurese to low pulmonary venous pressures
 Trial of diuresis Hypoperfusion  TRALI
 Trial of diuresis Resolution  TACO


RBC (acquisition cost) ~$200 per unit
RBC (total cost) ~$1400-$2400 per unit
 Higher if factor in care for probable complications
▪ TRALI (8% incidence in ICU)
▪ Nosocomial infection (10% increase per unit)
Reverse or Avoid
inadequate tissue
oxygenation due to
inadequate delivery
Transfusion reactions
TRALI
TACO (hydrostatic edema)
Infection (TRIM)
Cost ($ and Human)
Special Populations:
CAD/ACS
Sepsis
Trauma





All blood products associated with morbidity and
mortality in dose-dependent manner
 TRALI
 Infection
 MOF
Ratio debate: FFP:PRBC:Plts
Bleeding control?
Coagulopathy?
TRICC approach (hgb=7) safe and effective postresuscitation

Most hospital have a protocol
 RBCs:FFP~2:1

General measures:
 Ionized Calcium > 0.9 mmol/L
 pH >7.10
 Temperature > 34 degrees

Plug hole in vessel!!
 Pressure on hole (allow time for clotting)
 Change pressure gradient in vessel
▪ Embolization, lower driving pressure (hypotensive
resuscitation)
1.0
1.5
2.0
Reduce Bleeding
Transfusion
complications
3.0

1) Thoracentesis and elevated INR
(Coumadin)? LP?
 Go over pre-procedure prophylaxis data


2) Liver disease paracentesis
GI bleed (elevated INR)
 Dose (use of vit K), what if bleeding

3) Really (18) High INR on Coumadin
 Head bleed, Factor VIIa?


5) Uremia procedure- what to do?
6) PNA, malignancy- Plts 20k
1.5
3.0
Prevent Bleeding?
Stop Bleeding?
Transfusion
complications
Gajic; Critical Care Med, 2006

If Bleeding and Coagulopathy
 2010 AABB guidelines: consider FFP for:
 Yes:
▪ Massive transfusion < 1:3 ratio (moderate/low grade)
▪ Coumadin induced ICH (very low grade)
 Neutral
▪ Surgery/Trauma (no massive transfusion) (very low)
 NO
▪ Coumadin high INR No ICH (very low)
▪ All non-bleeding situations (silent on liver disease)




Central lines
Arterial Lines
Thoracentesis
Liver disease
 Paracentesis
 Percutaneous/Transjugular liver biopsy
 Prior to banding for nonbleeding varices
 Dental extraction (use DDAVP)

The INR=1.5 story
 Prothrombin time > 1.5 x upper limit normal:
▪ safe to perform surgery with normal hemostasis
 ISI developed to standardize tissue factor
 ISI in most labs was 1
 1:1 relationship btw PT > 1.5 x ULM and INR=1.5
 Now back calculation yield an INR-1.8-2.2
▪ normal hemostasis
Transfusing Platelets


44% of ICU patients thrombocytopenia
Transfusion Triggers:
 No bleeding RF: <10k; bleeding RF???: <20k
 Large vessel Bleeding: 50k -60k
 Diffuse microvascular bleeding: 100k
 Pre-procedural prophylaxis: 50k; Surgical
prophylaxis: 100k
 Measure plts 1 hour after to evaluate for
consumption/destruction

Main risk  TRALI (highest of all blood products)

Mechanism:
 Altered GP1B, ↓IIb/IIIa receptors (adhesion/aggregation)
 Dysfunctional vWF, Less functional factor VIII
 Plts↑ PGI2 levels, ↓plt TxA2, ADP
 Effects uremic toxins/anemia

Treatment: (BUN does not correlate)
 Dialysis
 **Desmopressin (48h) , *Cryoprecipitate (1 h onset)
 EPO/Transfuse to HCT=30
 Estrogen (0.6mg/kg IV QD x 5d)
134 trauma patients randomized to Novo
VIIa after 6 units of blood in 4 hours

ARDS 16% vs. 4%, p= .03
Boffard KD, J Trauma 2005