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With particular thanks to Dr James Isbister of Sydney, Australia

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John FreedmanDirector, Transfusion Medicine

St Michael’s HospitalUniversity of Toronto

Blood Transfusion: An expensive & potentially hazardous alternative to

Blood Management

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I won’t keep you long

As Henry VIII said to each of his 6 wives

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Objectives of this presentationTo gain an understanding of:

Risks of allogeneic transfusion Infectious Immunologic (TRALI, immunomodulation) Errors

Blood conservation/transfusion alternatives

An Ontario approach to blood conservation

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Blood will immerse you in a world of horror unlike any you've experienced before. Brace yourself for a nightmarish battle against the bloodthirsty minions of an ancient, forgotten god bent on wiping humanity from the face of the earth

With thanks toDr James Isbister, Sydney, SABM 2005

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כי נפש הבשר בדם הוא

Leviticus 17 ויקרא (‘the life/soul of the flesh is in the blood’)

1:18,000 units to wrong pt

Blood transfusion: other than as a scarce and expensive resource, who cares?

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Blood transfusion Patients think blood transfusion is

special and beneficial, but have difficulty accepting small risks they can’t control.

Blood Donors believe their contribution is a gift to the community that will be used appropriately and safely

Clinicians think blood is ordinary, take blood transfusion for granted, benefit is assumed and risks regarded as minimal.

Governments view blood as a commodity and transfusion medicine as an expensive support service which should be regulated and funded in a cost-effective manner.

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• 1997 Krever Commission: Recommendation #9:

“It is recommended that ….. promote appropriate use of, and alternatives to, blood components and blood products.”

• 1996 Gallup Poll indicates that only 7% of respondents would want to receive donated blood; 82% think patients should have the right to make final decision

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Residual risk

HIV 1:10 million

HCV 1:3 million

HBV 1:72,000 (no NAT)

HTLV 1:1.1 million

Virus TTI

Per unit

MVA 1: 9,000

Home accident 1: 10,000

Murdered in Canada 1: 85,000

General anaesthesia 1: 20-50,000

Lightning 1: 3,000,000

Risk of death from:

(actuarial tables)

Chiavetta et al, CMAJ, 169:67-73, 2003

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Standard collection pouchStandard collection pouch

Skin fragment

Bacterial contamination

bacterialcontamination

bacterialcontamination

bacterial survival in component

bacterial survival in component

febrilereactionfebrile

reactionsevere

reactionsevere

reactionfatalityfatality

103103102102104104

105105106106

0

2

4

6

8

10

12

1 2 3 4 5

Days of storage

Lo

g C

FU

/ml

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Bacterial contamination of platelets

N plt type % positive

Blajchman (1995) 15,838 RDP 0.04%

Risk of receiving BCP 50-250-fold > combined risk from virus TTI.

Estimated that BCP kill ≈15 Canadians/yr

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The BSE threat, vCJD & transfusion

UK

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vCJD (variant Creutzfeldt-Jakob)

First case in UK in 1996; annual increase; ? peaked

167 cases of vCJD worldwide; 1 in Canada

Human cases about 5 yrs after BSE epidemic

Growth hormone, corneas, ---

?No transfusion-transmitted cases

Currently no screening test for vCJD

Geographic exclusion criteria for donor exclusionLlewelyn et al: Lancet 363:417-421, 2004

Peden et al: Lancet 364:527-529, 2004

1994 2003

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TRALI: Transfusion-related acute lung injury

leading cause of transfusion-related death

Anti-leukocyte antibody, usually in the donor blood product

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TRALI cases: Canada

• Age – median 68 years, range 16-94 years

• Sex – female 45%, male 55%

• Blood pressure – 30% hypotension, 24% hypertension,

• 75% perioperative (CVS), haem/onc, trauma patients

TRALI cases per year

1998

-200

020

0120

0220

0320

0420

050

10

20

30

40

50

60

70

80

Nu

mb

er

of

ca

se

s

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New acute lung injury; bilateral pulmonary infiltrates

• Within 6 hours of plasma-containing transfusion

• Acute respiratory distress

TRALI:

• Fever (1 to 2 oC)

• No evidence of circulatory overload

. ● HypoxemiaPaO2 of 30 – 50 torr;

PaO2/FIO2 <300 mm Hg;

O2 saturation < 90% on room air

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TRALI:often difficult to know if X-ray image that of noncardiogenic pulmonary edema

• Rales and diminished breath sounds

• Normal jugular venous pressure

• Normal/low pulmonary wedge pressure

• Does not respond to diuretics

• Hypotension does not respond to intravenous fluids

• Absent S3

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TRALI patients

• 17% died

• 48% mechanical ventilation (70% of those who died)

• Donor α-leukocyte antibodies in 63%

α-PMN in 54% of those who died vs in 25% of patients who recovered;

sicker patients also frequently received components containing α-HLA,

particularly class II

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Donors • Overall, 18 % of donors had anti-HLA

(29% female vs 7% male)

• 9 % of donors had anti-PMN (equal frequency female & male)

• ?? Remove suspect donors from the donor pool;

• ?? Remove female blood donors

• Many donors implicated had donated many times before (in one case >200 times) without a previously reported TRALI reaction

Frequency of antibodies in donors

-HLA

clas

s I

clas

s II

clas

s I +

II

-PM

N

0

5

10

15

20

25

30 FemalesMales

perc

ent

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Donor blood products with α-leukocyte antibodies implicated in TRALI cases

Product transfused Percentage

Packed red blood cells 31 %

Random donor platelets 29 %

Fresh frozen plasma 18 %

Whole blood 4 %

Apheresis platelets 3 %

Cryosupernatant plasma 1 %

Cryoprecipitate 1 %

Not reported 13 %

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Capillary leak syndrome

Pulmonary damage

Pulmonary endothelial damage

Susceptible patient• Sepsis• Surgery (CPB)• Trauma

Transfusion:BRMs:• Lipids (Lyso-PCs)• Cytokines• Antibodies

Activation of EC

chemokines

PMN primed

primed PMN sequester on EC, adhere, cytoskeletal change, rigid, trapped in microvasculature

Hyper-reactive PMN

Release enzymes

1 2

TRALI

adhesion molecules

Antibody to WBC

Ag/Ab reaction

C’ activation

Leukosequestration

Silliman et al: Non-immunogenic TRALI. 2 stage process.

i. Susceptible patient: sepsis, surgery, trauma,

ii. Transfusion

Immunogenic TRALI: Classical theory, anti-leukocyte antibody, but antibody not always found.

Pulmonary endothelium

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1 Susceptible pt: sepsis, surgery, trauma

Activated EC ChemokinesAdhesion molecules on EC

2 Transfusion (BRM)Lipids (lyso-PCs)

Cytokines

(antibodies, microvesicles, cell fragments)

O2-

Attraction Tethering

Capillary leak

Lung damageTRALI

Pulmonary endothelium

Primed PMN

Rigid

Trapped . in mv

Hyper-reactive

enzymes

Firm Adhesion Activation EC damage

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Transfusion-induced immunomodulation

Renal allograft survival [Opelz & Terasaki, 1981]

Graft one year survival rates

23% in patients not transfused

87% in patients receiving > 10 transfusions

transfusion-induced immunosuppression (allogeneic leukocytes)

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Transfusion-induced immunomodulation(due to allogeneic leukocytes)

Some potential mechanisms:

• Clonal deletion or anergy (of CTLs)

• Induction of suppressor cells

• Production of antiidiotypic antibody

• Suppression of NK cell activity

• Polarization of cytokine response

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10/16 observational studies and 4/5 randomized trials showed statistically significant reduction in postoperative infections with autologous versus allogeneic transfusions.

Infections & perioperative transfusion

Even more true for no transfusion versus allogeneic transfusion

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In various surgical settings, no variable was moreconsistently associated with postoperative infection

than was perioperative allogeneic transfusion

For each allogeneic RBC unit given, 1.5 fold increase in nosocomial infection.

Translates into potential morbidity, mortality and LOS.

(Koval et al, J Orthop Trauma, 1997, 11:260)

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IBCT (213) 67.6%

ATR (37) 11.7%

DTR (40) 12.7%

TTI (6) 1.9%

PTP (3) 1.0%

TRALI (15) 4.8%

TA-GVHD (1) 0.3%

SHOT, UK, annual report 2000-01Adverse effects of transfusion

Incorrect blood component transfused (IBCT): “Wrong blood” is, without exception, an

avoidable error

IBCT 67.6%Acute HTR 11.7%

Delayed HTR 12.7%

TTI 1.9%TRALI 4.8%

PTP 1.0%TA-GvHD 0.3%

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SHOT 1996/97 to 2001/01

• Blood centre 2%

• Transfusion laboratory 28%

• Collection, administration 55%

• Prescription, sampling, request 13%

• Other 1%

• Unknown <1%

.

68% Wards

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CBS Projections: Collections vs Demands

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Cost of Blood Transfusion (in US$, 1998)

• Overhead = facility cost• Variable direct labour = lab technologists,

phlebotomists, nurses

• Fixed direct labour = administrators, etc.• Direct material = supplies, blood, tests

.

Cremieux P-Y, Barrett B, Anderson K, Slavin MB. J Clin Oncol 18:2755, 2000

Fixed DirectLabour 18%

Overhead46%

Variable Direct Labour 17%

Direct Material

19%

Mean Overall Cost: $491-$545 per unit.

Ontario blood budget: $420 million per year

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Costs incurred in provision of blood

• Recruitment and collections

• Infectious disease testing

• Manufacturing, shipping, handling, labelling

• Pre-transfusion testing

• Transfusion costs

• Post-transfusion sequelae

• Regulatory and legal costs

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Hospital charges• Blood type ABO $ 156• Blood type Rh 85• Antibody screen 182• Crossmatch, immediate spin 350• Crossmatch, antiglobulin (Coombs) 391• Red cell antigen screening, per antigen 108• Fresh frozen plasma thawing 156• Crypoprecipitate pooling 43• Handling 86• Surcharge 15%

Zeger, Jabbour (USC): Transfusion-free medicine and surgery, 2005, Blackwell

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COSTS: Adult open heart surgeryProduct Number Product

fee/unit ($)

Hospital fee/unit ($)

Total ($)

Red cells 6 276 477 4520

FFP 5 53 250 1515

Platelets 1 500 200 1400

ABO type 1 156 185

Rh type 1 85 85

Antibody screen

1 182 182

Total $ 7,887

Jabbour, 2005

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It is clear that:

1) the demand for blood outweighs the supply

2) there are real risks associated with blood transfusion

3) blood is not ‘free’

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Blood transfusion is a lot like marriage. It should not be entered into lightly,

unadvisedly or wantonly,or more often

than is absolutely necessary.

[Beal RW: Aust N Z J Surg 46:309, 1976]

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Blood is Good?????

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1960

1971

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EnoughEnough In the right placeIn the right place At the right timeAt the right time And not too muchAnd not too much

Most people in this room will depart Most people in this room will depart Earth as a result of not maintaining Earth as a result of not maintaining one or more of these functions of the one or more of these functions of the bloodblood

Blood

J Isbister, SABM 2005

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• Allogeneic transfusion avoidance

• Transfusion reduction

Blood Conservation: AimsManagement

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Goals: Minimize Anemia and Avoid Allogeneic Blood Transfusion.

Anemia(Reduced

Hematocrit)

Allogeneic Transfusion

Risk

Transfusion has risks,but bleeding to death is fatal !

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In the ICU, most patients anemic at time of admission.

Hb typically declines by at least 0.5 g/dL/day in first 3 d of ICU stay. Continues to decline if sepsis/severe illness.

These patients particularly may be at risk from anemia (cardiovascular, respiratory, metabolic compromise).

Etiology of anemia multifactorial:phlebotomy, GI bleeding, coagulopathy, blood loss from vascular procedures, renal failure, nutritional deficiencies, marrow suppression, impaired erythropoietin response, etc

Anemia is common: 30% patients preop

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“I need you to find a radically innovative new way to keep

everything exactly the same”

Office of the Director of Medical

Services

BloodConservation?

?

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Blood conservation approaches in surgery

Autologous blood (PAD, cell salvage, ANH) Erythropoietin (EPO, Eprex) Other pharmacologics (e.g. antifibrinolytics) Fibrin glues (e.g. Tisseel) Hemostatic/harmonic scalpels Blood substitutes Controlled hypotension; positioning Minimally invasive surgery Transfusion trigger (level of Hb) rFVIIa

etc

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Preoperative Autologous Donation (PAD) in primary hip surgery:

No PAD, 29% had allogeneic transfusionPAD, 6% had allogeneic transfusion

(B Feagan; 2001/2002); 28 Ontario sites; 3352 pts

Is blood conservation approach effective in avoiding allogeneic transfusion?

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Pre-operative EPO for Orthopaedic SurgeryFeagan BG et al. Ann Intern Med 133:845-854, 2000.

Allogeneic Blood Transfusions 45% in placebo group 23% in low dose EPO (p<0.003) 11% in high dose EPO (p< 0.001)

Significant requirement for supplemental iron Monitor serum ferritin, transferrin saturation

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Hb pre-op % transfused< 130 53 %> 130 20 %

But, ifHb done in PAF < 130 > 130

Initial Hb level predictive of transfusion.

EPOIronB12, folate

BC Capital Health Region

15%

5%

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Operative mortality increases with untreated anemia.Preop Hb Mortality

< 60 g/L 62%

61 - 80 33%

81 - 100 0%

> 100 7%

Carson, Am J Surg 170:6A:32S, 1995

Adjusting for APACHE II score: Post-op, 2.5X increase in odds of death for each 10 g/L decrease in Hb below 80 g/L

Transfusion trigger: How much Hb do you need?

(Carson et al: Transfusion 42:812, 2002)

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.

Crude in-hospital survival rate of patients with different preoperative haemoglobin concentrations

.Lancet, Vol 369, May 18, 2002

Preoperative haemoglobin >100g/L

Preoperative haemoglobin ≤100g/L

.

So level of Hgb important, but at what trigger should one transfuse?

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So how many red cells do you need?

“The bad news is, you have only one red blood cell.The good news is, he’s a workaholic!”

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Hébert et al; NEJM 340:409, 1999: ICU patients (TRICC)

Transfusion trigger randomized by Hb (70 vs 100 g/L)restrictive liberal

Units transfused 2.6 5.4

Mean Hb values 85 107

Hospital morbidity 22% 28%

ICU mortality 14% 16%

30 day mortality 19% 23%

Organ failure score 8.3 8.8

Trend to improved survival in restricted group (p=0.10)

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1940’s – 80’s: Hb 100g/L

1980’s – 2005: Hb 80g/L70g/L60g/L70g/L

Transfusion Transfusion triggertrigger

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WHAT HGB LEVEL?WHAT HGB LEVEL?

• SAFE PREOPERATIVE SAFE PREOPERATIVE HGB WILL VARY FROM HGB WILL VARY FROM ONE PATIENT TO THE ONE PATIENT TO THE NEXT, NEXT, ANDAND

• SAFE PREOPERATIVE SAFE PREOPERATIVE HGB WILL VARY FOR HGB WILL VARY FOR THE THE SAMESAME PATIENT PATIENT DEPENDING ON DEPENDING ON CLINICAL CLINICAL CIRCUMSTANCESCIRCUMSTANCES

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When Does Anemic Organ Injury Occur?

70 g.L-1 100 g.L-1

Hemoglobin Concentration

30 g.L-1 90 g.L-1

Clinical Evidence Of Harm

Tissue Hypoxia

Activation of Protective Mechanisms

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What is the Optimal Transfusion Threshold ?

70 g.L-1 100 g.L-1

Hemoglobin Concentration

30 g.L-1 90 g.L-1

No Co-Morbidities

Co-Morbidities

????

AnaerobicMetabolism

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Adjusted odds ratio for mortality according to preoperative hemoglobin concentration in patients refusing red blood cell (RBC) transfusions.

While cardiovascular disease (CVD) increases the risk of mortality, increased blood loss during surgery (resulting in a decrease in Hb) are also associated with an important rise in the risk of death.

Adapted from Carson JL et al. Lancet 348: 1055, 1996.

.

.

.

Hb decrease 2 – 3.9 g/dLHb decrease > 4 g/dL

Hb decrease 2-3.9 g/dL + CVD

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Blood ManagementBlood Managementis all aboutis all about

OxygenOxygen HemostasisHemostasis

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J Isbister, SABM 2005

Tour de France

Arsenal FC

Modified from James Isbister, SABM 2005

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ATPATPCO2

O2

HbO2

HbO2

Hemoglobin

Hemoglobin

O2

HbO2

O2

MyoglobinO2

O2

O2

Co

nsu

mp

tio

nO2 Delivery DO2

Inspired PO2

Lung Fn (Diffusion)

Red Cell& Hb Function Cardiac &

Vascular Fn Red Cell, HbEndothelial Fn Interstitial

Space

TissueMetabolism

With thanks to James Isbister, SABM 2005 (modified)

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Limit transfusion to appropriate need. Transfuse unit by unit.There is no single Hb value optimal for all patients:

consider factors such as:Cardiac output

Heart rate, stroke volume, contractilityPeripheral vascular resistance

Increased O2 release from red cellDecreased blood viscosity

Dilution

Assessing Efficacy• Red cell survival• Hemoglobin level• Patient symptoms• Doctor feels better

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DEVELOPING A NETWORK of ONTARIO TRANSFUSION COORDINATORS

Enhance transfusion practice outside of the Blood Bank* ‘clinical bridge’ between Transfusion Service & rest of hospital

Interact with physicians, nurses & patients to promote . blood conservation & alternatives to allogeneic transfusion

Anticipated a 5 to 10% reduction in red cell use

.

MOH

Susan Gagne; Niagara Health System; 905-684-7271 ext 46570

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Pre-operative approach

assess at pre-admission clinic (3-5 weeks before surgery)

identify patients at risk of transfusion ahead of surgery

discuss informed consent and transfusion alternatives

investigate, diagnose and treat anemia

(family doctor, surgeon, anesthetist, hematologist)

erythropoietin and / or iron

predonation of autologous blood (with hematinics + EPO)

stop anticoagulants/antiplatelet drugs if safe to do so

minimize blood taken for lab testing

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Progress

• At specific time periods, collect detailed anonymized patient information for a defined number of all consecutive patients admitted for the designated procedures

• Evaluations: Baseline (Jan 2002), 12, 18 & 24 months

• Aggregate data for Ministry of Health of Ontario; Site-specific

data for each institution

[Guelph General Hospital, Hamilton Health Sciences Centre, Hospital for Sick Children (Toronto), Kingston General Hospital, Lakeridge Health (Oshawa), London Health Science Centre, Mt Sinai Hospital (Toronto), Niagara Health System, North Bay General Hospital, Peterborough Regional Health Centre, Sault Area Hospitals (Sault St Marie), Scarborough General Hospital, St Joseph’s Health Centre (Toronto), St Mary’s General Hospital (Kitchener), St Michael’s Hospital (Toronto), Sudbury Regional Hospital, Sunnybrook & Women’s College Health Sciences Centre (Toronto), The Ottawa Hospital, Toronto East General Hospital, Trillium Health Centre (Mississauga), University Health Network (Toronto), Windsor Regional Hospital]

10

10

HSC, MSH, UHN, TEGH, SJH, SWCHC, SMH, BrH, Tr,

23 hospitals chosen based on blood utilization & geography

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0

20

40

60

80

100

Per

cen

tag

e o

f ho

spita

ls

White = pre-ONTraCBlue = at 6 mosYellow = at 16 mosRed = at 24 mos

Education in-services in previous 6 mos:Pre-Ontrac = < 20At 6 mos = > 140At 16 mos = > 250At 24 mos = > 290

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Knee arthroplasty:

19 hospitals; 1150 patients at each time point

AAA surgery:

17 hospitals; 300 patients at each time point

CABG surgery (primary):

4 hospitals; 300 patients at each time point

Three targeted surgical procedures

674

Proportion of knee surgery patients (N=1119)who received allogeneic blood

ALL 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 230

10

20

30

40

50

60

70

80

90

100

X X X X

Site number

Pe

rcen

t tr

an

sfu

sed

one knee

Revisionknees

Bilateralknees

BASELINE

At baseline, marked variation across province in likelihood of receiving a transfusion 4

Mean for:

Aggr

685

One Knee: % With Allogeneic Transfusion Baseline vs 12 Months, by site

0

20

40

60

80

100

All 1 2 3 4 5 6 8 9 10 11 12 14 15 16 17 18 19 20 21 22

Site Number

% A

l l o

g e

n e

i c

AAAs: % With Allogeneic Transfusion (Baseline vs 12 Months) by site

0102030405060708090

100

2 3 4 7 8 9 10 11 12 14 15 16 17 18 19 21 22 23

Site Number

% A

llo

Baseline

12 Month

CABGs: % With Allogeneic Transfusion

0

20

40

60

80

100

All 4 7 18 23

Site Number

% A

lloge

neic Baseline

12 Month

All

All

Blue baselineRed 12 months

urgent

elective

At 12 months, most, but not all, hospitals showed a reduction in the proportion of patients transfused with allogeneic RCC

Baseline vs 12 months; % receiving allogeneic transfusion

One knee

AAA CABG

5

695

One Knee: % With Allogeneic Transfusion Baseline vs 12 Months, by site

0

20

40

60

80

100

All 1 2 3 4 5 6 8 9 10 11 12 14 15 16 17 18 19 20 21 22

Site Number

% A

l l o

g e

n e

i c

AAAs: % With Allogeneic Transfusion (Baseline vs 12 Months) by site

0102030405060708090

100

2 3 4 7 8 9 10 11 12 14 15 16 17 18 19 21 22 23

Site Number

% A

llo

Baseline

12 Month

CABGs: % With Allogeneic Transfusion

0

20

40

60

80

100

All 4 7 18 23

Site Number

% A

lloge

neic Baseline

12 Month

All

All

Blue baselineRed 12 months

urgent

elective

At 12 months, most, but not all, hospitals showed a reduction in the proportion of patients transfused with allogeneic RCC

Baseline vs 12 months; % receiving allogeneic transfusion

One knee

AAA CABG

5

70

Percent transfused with allogeneic RCC

05

10

1520

2530

354045

5055

60baseline

12 mos

18 mos

24 mos

pe

rce

nt

Non-autologous pts Autologous pts

71

10

knee CABG AAA0

10

20

30

40

per

cen

t re

du

ctio

nProjected % reduction from baseline in allogeneicRCC use for province for the 3 targeted procedures

At 12 mos

At 18 mos RCC use 2003 vs 2002

Ontario ONTraC -2.5

-2.0

-1.5

-1.0

-0.5

0.0

0.5

1.0

1.5

2.0

2.5

yes no

otherprovinces

pe

rce

nt

ch

an

ge

RCC used 2003 vs 2002

• Reduction in allogeneic transfusion markedly exceeds the anticipated 5-10%• Historically, Ontario had the highest annual rate of increase in RCC use;• 2003, Ontario had lower increase (net decrease) in RCC use than other provinces; • ONTraC hospitals had lower increase in RCC use than non-ONTraC hospitals

.

7210

knee CABG AAA0

10

20

30

40

per

cen

t re

du

ctio

nProjected % reduction from baseline in allogeneicRCC use for province for the 3 targeted procedures

At 12 mos

At 18 mos RCC use 2003 vs 2002

Ontario ONTraC -2.5

-2.0

-1.5

-1.0

-0.5

0.0

0.5

1.0

1.5

2.0

2.5

yes no

otherprovinces

pe

rce

nt

ch

an

ge

RCC used 2003 vs 2002

• Reduction in allogeneic transfusion markedly exceeds the anticipated 5-10%• Historically, Ontario had the highest annual rate of increase in RCC use;• 2003, Ontario had lower increase (net decrease) in RCC use than other provinces; • ONTraC hospitals had lower increase in RCC use than non-ONTraC hospitals

Fresh Component UseOntario Compared to the Rest of Canada

500,000

550,000

600,000

650,000

700,000

750,000

800,000

850,000

1999/2000 2000/2001 2001/2002 2002/2003 2003/2004

All Canada (except QC & ON) Ontario

Ontario Compared to Canada

73

Red Cells

24.0

26.0

28.0

30.0

32.0

34.0

36.0

1999/2000 2000/2001 2001/2002 2002/2003 2003/2004 2004/2005 2005/2006

Canada (except ON & QC) Ontario

Red Cells Issues - Ontario Compared to Rest of Canada (excl. QC)(per 1,000 population) 1999-2000 to 2005-2006

74

0

2

4

6

8

10

12

14

16

1 2 3

Allogeneic

No Tx

p<.05p<.001p<.01

5.445.332.25No Tx

11.6614.935.58Allogeneic

Rate of Infection (%)

CABGAAAKnee

Transfusion-induced immunomodulation: infection rate Infection defined by symptoms + pos culture

6

%

75

J Surg Research 2002;102:237-244

Prospective data from 6301 non-cardiac surgical procedures 1995-2000

Transfusion PRBCs > 4 units

Odds Ratio:Death 2.84 Infection 9.28

P<0.001 for both

767

baseline 12 months0

1

2

3

4

5

6

7

8

9no transfusionallogeneic transfusion

ALOS (mean + SEM) for no transfusion vs allogeneic transfusion

*For all comparisons of no transfusion vs allogeneic transfusion, P < 0.0001

knees AAA CABG knees AAA CABG

*

**

*

*

*

AL

OS

(da

ys)

IN MULTIVARIATE ANALYSIS, ALLOGENEIC TRANSFUSION WAS AN INDEPENDENT PREDICTOR FOR LOS

VARIABLES EVALUATED: Co-morbidities; Initial, pre-op, nadir & discharge hemoglobin levels; Postoperative infection; Age; Sex; Number of units of blood transfused; Any blood conservation measure (PAD, EPO, cell saver, controlled hypotension, fibrin glue, DDAVP, antifibrinolytics)

Average length of stay (ALOS; days) (mean SEM)

7

baseline 12 months0

1

2

3

4

5

6

7

8

9

no transfusionallogeneic transfusion

ALOS (mean + SEM) for no transfusion vs allogeneic transfusion

*For all comparisons of no transfusion vs allogeneic transfusion, P < 0.0001

knees AAA CABG knees AAA CABG

*

**

*

*

*

AL

OS

(da

ys

)

baseline 12 months0

2

4

6

8

10

12

14

16

no transfusionallogeneic transfusion

*For all comparisons of no transfusion vs allogeneic transfusion, P < 0.0001

knees AAA CABG knees AAA CABG

*

**

*

*

*

AL

OS

(da

ys

)

Average length of stay (ALOS; days) (mean ± SEM)

77

0

2

4

6

8

10

one knee

No transfusion Autologous Allogeneic

Average length of stay (ALOS; days) (mean + SEM)

AL

OS

(d

ay

s)

78

P < 0.0001

Pre-op Hb

Pre-op Hb (g/L)

Pre-op Hb Mean Pre-op Hb

Pre-op Hb versus number of units transfused

79

Compared to NO transfusion:

Knee CABG AAAEvery ↓ in pre-op Hb of 10 g/L increases chance of allogeneic transf by 1.839 (84%) 1.847

1.433Every ↓ in nadir Hb of 10 g/L increases chance of allogeneic transf by 4.31 (430%) 4.502

3.534

As age increases by 10 yrs, the odds of an allogeneic transfusion by 1.515 1.558 1.818As BSA decreases by -0.25, the odds of an allogeneic transfusion by 1.466 2.288 1.598Being female increases the odds of receiving allogeneic transfusion by 1.445 6.820 1.987

Having an allogeneic transfusion odds of postoperative infection by 2.653 2.681 1.950

Each additional allogeneic unit the chance of infection by a factor of 1.587 1.524 1.488

80

1.3381.79

2.395

3.205

1.524

2.323

3.54

5.394

1.312

1.721

2.258

2.963

1

2

3

4

5

6

Odds Ratio Compared to

having 0 Units

transfused

One Knee CABG AAA

# of Allogeneic Units Transfused

1

2

3-5

6+

1.102

1.214

1.338

1.475

1.109

1.23

1.364

1.513

1.074

1.153

1.239

1.331

1

1.2

1.4

1.6

1.8

2

Odds Ratio Compared to

having 0 units

Transfused

One Knee CABG AAA

# of Allogeneic Units Transfused

1

2

3-5

6+

Increased risk

of LOS per allogeneic units RCC transfused

Increased risk of

postoperative infection per allogeneic units RCC transfused

81

At 12 months, For Ontario, estimate for the 3 targeted procedures only:

• Red cell product (at $400/unit) 8,640,000

• Reduced LOS 5,300,000

• Reduced work in hospitals 650,000

Total savings per year: $14,950,000

• In addition: greater patient satisfaction and safety

Cost of program per year: $ 1,800,000

Expansion to other procedures & other conservation measures should result in even greater savings

82

DEMANDDEMAND SUPPLY

SUPPLY

What’s best for the What’s best for the blood supply?blood supply?

What’s best for the What’s best for the patient?patient?

83

V x=

Formula for “Scientific” Medical Formula for “Scientific” Medical OpinionOpinion

T4

AG

Volume of hot air

Academic rank (Professor =1 , Lecturer = 4)

Years from graduation

Distance from regular patient contact

J Isbister, SABM, 2005

84

Evidence Based Medicine

Minimal variation inclinical practice with people perpetuating

the mistakes of others

Clinical ExperienceRepeating one’s

own mistakes with increasing

confidence over time

Nothing is black and white, medicine ispracticed in the context of constant

uncertainty

CLINICAL DECISION MAKING

85

LawLaw

PoliticPoliticss

PerceptiPerceptionon

PracticPracticee

EvidenEvidencece

SciencSciencee

J Isbister

86

Thomas S. Kuhn 1922-1996

Relace transfusion with

• Blood conservation =• Bloodless medicine =• Bloodless surgery =• Blood management

87

Ott DA, Cooley DA. Cardiovascular surgery in Jehovah's Witnesses. Report of 542 operations without blood transfusion. JAMA 238:1256-8, 1977.

Jehovah's Witnesses who require operation represent a challenge to the physician because of the patients' refusal to accept blood transfusion. We report a 20-year experience with a consecutive series of 542 Jehovah's Witness patients ranging in age from 1 day to 89 years who underwent operation. Early mortality (within 30 days after operation) was 9.4%. In 362 patients requiring temporary cardiopulmonary bypass, early mortality was 10.7%. Mortality was 13.5% among 126 patients who had single- or double-valve replacement. The only deaths among patients who had aortic valve replacement or repair of a ventricular septal defect occurred in those who had some serious complication before operation. Preoperative or postoperative anemia was a contributing factor in 12 deaths, and loss of blood was the direct cause of three deaths. Cardiovascular operations can be performed safely without blood transfusion.

Bloodless Bloodless SurgerySurgery

88

89

• Blood transfusion is risk factor for:– Mortality– ICU admission– ICU length of stay– Hospital length of stay

90

Why “bloodless medicine”…?

There are many bloodless medicine programs …and the number is growing. Even in remote areas of Siberia, physicians and patients know about bloodless medicine.

If one types “bloodless medicine” into an internet search engine, > 12,000 hits are obtained.…

[from T Kickler, Johns Hopkins, Transfusion 43:550, May 2003]

91

Bloodless medicine (or blood conservation)Requires coordination of services across a variety of departments….cooperation between outpatient scheduling, surgical and anesthesia physicians and their clinic personnel, operating room scheduling, intensivists and hematologists to get the patient prepared, …the billing office….

This is in contrast to a transfusion, which can usually be accomplished with one phone call….

[from T Kickler, Johns Hopkins, Transfusion 43:550, May 2003]

92

Some institutions market their bloodless medicine programs by pointing out the complications and adverse effects of allogeneic transfusion, as a way to lower hospital expenses or length of hospital admissions.

May be so, but careful outcomes research needed before making this the only argument to establish bloodless medicine program.

The strongest argument for having a bloodless medicine program is to respect the rights of patients…. based on the ethical value of autonomy or self-determination, and medical institutions have a responsibility to respond to this need.

A plethora of new techniques and therapies are available …and their relative merits, alone and in combination, still needs to be investigated, but it is becoming standard of practice.

93

3 year renewable contract signed; to 2009

5 new coordinators; 3 new sites

New targeted procedures

94

Radical prostatectomy

0

5

10

15

20

25

30

35

40p

erce

nt

rece

ivin

g a

llog

enei

c tr

ansf

usi

on Individual sites

Aggr

mean

95

One knee: mean nadir Hb

60

65

70

75

80

85

90

Hb

(g

/L)

CABG: mean nadir Hb

60

65

70

75

80

85

90

baseline12 months18 months

Hb

(g

/L)

• Nadir hemoglobins higher for autologous than for allogeneic transfusions• Progressive reduction in hemoglobin level trigger for transfusions• Trigger hemoglobin higher in knee surgery than in CABG !!

Nadir hemoglobin levels as surrogate measure of transfusion trigger

9

Radical prostatectomy:Non-autologous 83.29Autologous 89.47

96

Radical prostatectomy(N=863)

0

10

20

30

40

50

pe

rce

nt

20% of Pts had autologous blood collected, of whom 47% received their autologous blood; only 3.47% also received allogeneic blood.

42% of autologous units collected were transfused.

97

PatientPatientBlood Blood

ManagementManagement

Opinion Opinion LeaderLeader

SurgeonSurgeon

Anesthesi-Anesthesi-ologistologist

HematologistHematologistCooordinatorCooordinator

BureaucratBureaucratICU &ICU &WardsWards

98

Allogeneic blood transfusion should only be used as therapy when there is evidence for potential benefit, there are no alternatives, a quality product is available and the risks are appropriately considered and balanced against the benefits.

The best transfusion is the transfusion not given!

☺Thank you

99

100

percent of patients undergoing PAD

knee CABG AAA0

5

10

15

20 baseline12 months18 months

per

cen

t o

f p

atie

nts

Procedures employed:

• Increase in pre-operative autologous donation in CABG & AAA patients• Progressive increase in use of erythropoietin after first year

11

0

10

20

30

40

50

nu

mb

er

pa

tie

nts

pe

r m

on

th

Overall EPO use per month

PAD EPO

101

Procedures Utilized (% of patients)

0%

10%

20%

30%

40%

50%

60%

70%

OneKnee

AAA CABG OneKnee

AAA CABG

Cell Saver Antifibrinolytics

Procedure

Utiliz

ed

Baseline

12 Months

Procedures Utilized

0%

2%

4%

6%

8%

10%

OneKnee

AAA CABG OneKnee

AAA CABG OneKnee

AAA CABG

Fibrin Glue Hypotension DDAVP

Procedure

% U

tiliz

ed

Baseline

12 Months

Cell saver antifibrinolytics

Fibrin glue hypotension DDAVP

Limited use of other procedures; specific for type of surgery

Other blood conservation procedures (% of patients)

13

102

Miscellaneous slides

103

Pharmacologic agents: costs

» Cost per dose Cost per course

• Eprex 588 2,350• Darbopoietin 132 530• Amicar 18 46• Aprotinin 540 1,000• DDAVP 144• Tranexamic acid 73• rFVIIa 7,056 (4.8

mg)

Jabbour

104

Transfusion triggerRestrictive vs Liberal

105

106

107

108

Consider: PAD EPO cell saver

Hb > 130 g/L N/A

Hb >100 - <130 g/L N/A

Surgery 2 to 4 weeks away N/A

>10% likely to require transfusion Anticipated blood loss (units) 1-2 1-5 >1;

>20% BV

Need for Fe supplement

Not within 72 h of surgery

109

Factors to consider in the surgical transfusion decision

Clinical history

Cardiopulmonary disease

Existing coagulopathy

Anemia

Trauma classification (mechanism of injury)

Medications

Antiplatelet drugs; Anticoagulants

Clinical symptoms

Dyspnea on exertion; Angina

Hemoglobin/hematocrit level

Oxygen delivery/consumption

Surgical procedure (elective vs emergency; laparoscopic vs open)

Estimated blood loss

Jehovah’s Witness

110

Independent predictors for transfusion:

Preoperative factors: Red blood cell mass Type of operation Urgency of operation Number of diseased vessels Serum creatinine > 1.3 mg/dL Preoperative prothrombin time

Postoperative factors: Cardiopulmonary bypass time Three or fewer bypass grafts Lesser volume of ANH removed Total crystalloid > 2500 ml Moskowitz et al

111

24,509 consecutive adult surgical patients; 14 procedures (not neuro or cardiac)

• Type of procedure

• Age

• Sex

• Emergency surgery

• Preoperative autologous donation

• Preoperative hemoglobin level

Identifying patients for blood conservation strategies. Van Klei et al, Br J Surg 89:1176, 2002

Identifying patients for blood conservation strategies

112

Preoperative autologous donation (PAD)

Consider when:

Preoperative hemoglobin >130 g/L> 10% of patients undergoing procedure

require transfusion Elective surgery scheduled 2 to 4 weeks away

Patient on iron supplement Not within 72 h of surgery

no severe cardiovascular or hemodynamic problems

113

Autologous blood donation

Advantages Disadvantages

Prevents transfusion-transmitted disease No effect on risk of bacterial contamination

Prevents red cell alloimmunization No effect on risk of ABO incompatibility error

Supplements the blood supply Costs more than allogeneic blood?

Provides compatible blood for pts with alloabs Wastes blood not transfused

Prevents some adverse reactions Possible adverse reactions from donation

Reduces likelihood of allogeneic transfusion May subject patient to preoperative anemia

114

Autologous donation deferral

• evidence of infection or bacteremia

• severe aortic stenosis

• unstable angina

• myocardial infarction or cerebrovascular accident in past 6 months

• high grade left main coronary artery disease

• cyanotic heart disease

• active seizure disorder

• uncontrolled hypertension

Br J Anaesth 78:768, 1997

115

PAD

observational

42 studies

RR 0.31

[Carless et al

Transf Med 14:123, 2004]

116

PAD

randomized

8 studies

RR 0.37

117

Autologous Donation:

In contrast to autologous blood donation under standard

conditions, in “aggressive” autologous blood phlebotomy

(twice weekly for 3 weeks beginning 25-35 days before surgery)

endogenous erythropoietin levels do increase.*

Can be further stimulated by exogenous erythropoietin.**

* Goodnough et al: J Lab Clin Med 236:57, 1995

**Goodnough et al: N Engl J Med 336:933, 1997

118

Erythropoietin

Consider when:

Anticipated loss of two to five units Preoperative hemoglobin >100 to < 130 g/L

Elective surgery scheduled 2 to 4 weeks away Patient on iron supplement

119

Different Formulations of Recombinant Erythropoietin

Estimated total number of cases of PRCA is about 250Possibly related to formulation and increased incidence with sq administrationNever seen if EPO is administered IVSince 1998- 1.7/10,000 cases in France, 0.26/10,000 cases in Germany

120

121

Percent patients transfused with allogeneic blood

0

10

20

30

40

50

60p

erc

en

tCABG:

.

.

.

.

.

122

Cell Salvage

Consider when:

Blood loss likely >20% of blood volume > 10% of patients undergoing procedure

require transfusion Mean transfusion requirement exceeds one unit

123

ANH

Consider when:

Blood loss likely >20% of blood volume Preoperative hemoglobin >100 g/L Absence of severe cardiac disease

124

Before planned surgery:

• Assessment at preadmission clinic

• Correcting treatable anemia

• Stopping anticoagulants and antiplatelet drugs,

if safe to do so

• Erythropoietin and /or iron

• Pre-donation of blood, with hematinics + erythropoietin

• Minimizing blood taken for laboratory samples

125

During surgery:

• Losing less blood through optimal surgical & anesthetic technique

• Keeping patient warm

• Using measured hematocrit or blood loss as guide to red cell replacement

• Using rapid hemostasis testing to guide blood component replacement

• Antifibrinolytics to reduce bleeding in selected cases

• Intraoperative cell salvage

126

After surgery:

• Postoperative cell salvage

• Using a protocol to trigger re-exploration at a specified level of blood loss

• Use of a protocol to guide when hemoglobin should be checked

• Use of a protocol stating blood transfusion thersholds and targets

• Minimizing blood taken for laboratory samples

127

At surgery:

Meticulous dissection:

• Develop avascular planes

• Stop all small bleeders as encountered

Reduction of regional vascular pressure

• Appropriate patient position

• Blood inflow control

• Limb exsanguination & proximal tourniquet

Prevention of hypothermia

Optimal use of cell salvage-

128

“Haemostatic” dissecting instruments:

mechanism disadvantages applications

Monopolar diathermy heat transmission collateral thermal damage; most proceduresinterferes with pacemakers; ignition of flammable fluid/gas

Bipolar diathermy heat cannot “cut” tissues; where need ignition flammable gas/fluid precise dissection

Argon beam heat collateral thermal damage; hepatobiliaryinterferes with pacemakers; surgeryignition of flammable gas/fluid

Laser (e.g. Nd-YAG, CO2) heat as above according to laser type

Ultrasound dissector mechanical cost solid organ disruption; some heat surgery

Water-jet dissectormechanical cost solid organ surg

129

Key points:

surgical technique is most important determinant of blood loss

simple physical methods result in significant reduction in blood loss

minimally invasive surgery can contribute to blood conservation

modern ‘haemostatic’ surgical instruments can contribute to bloodless dissection, especially with solid organ surgery

topical haemostatic agents, particularly fibrin sealants, help when bleeding not controlled by more

straightforward means

130

Pharmacologics:

• High dose aprotinin reduces red cell and component use in cardiac, hepatic transplant and major orthopedic (but not vascular) surgery

• Tranexamic acid inconsistent in reduction of red cells and no effect on component use

• Tranexamic acid no proven benefit in patients taking antiplatelet drugs

• EACA does not reduce allogeneic transfusion

• DDAVP after cardiac surgery may be useful in proven platelet dysfunction

• rFactor VIIa: await evidence from randomized placebo-controlled studies

131

Potential difficulties:

• Clinical/diagnostic criteria not detailed enough

• Clinical information often missing/difficult to interpret

• Donor samples difficult to retrieve; donor recall delayed

• Shipping of samples: time, conditions

• Crossmatch samples availability rare

• Sensitivity of tests:

• inherent

• panel antigen coverage

• false positives and negatives

• technique specific

132

Factors to consider in the surgical transfusion decision

Clinical history

Cardiopulmonary disease

Existing coagulopathy

Anemia

Trauma classification (mechanism of injury)

Medications

Antiplatelet drugs; Anticoagulants

Clinical symptoms

Dyspnea on exertion; Angina

Hemoglobin/hematocrit level

Oxygen delivery/consumption

Surgical procedure (elective vs emergency; laparoscopic vs open)

Estimated blood loss

Jehovah’s Witness

133

24,509 consecutive adult surgical patients; 14 procedures (not neuro or cardiac)

• Type of procedure

• Age

• Sex

• Emergency surgery

• Preoperative autologous donation

• Preoperative hemoglobin level

Identifying patients for blood conservation strategies. Van Klei et al, Br J Surg 89:1176, 2002

Identifying patients for blood conservation strategies

134

K Sazama, Vox Sang 92:95-102, 2007.

135K Sazama, Vox Sang 92:95-102, 2007.

136

137Van der Linden P, Dierick A: Vox Sang 92:103-112, 2007.

138Van der Linden P, Dierick A: Vox Sang 92:103-112, 2007.

139Van der Linden P, Dierick A: Vox Sang 92:103-112, 2007.

140

141

142