Aryeh Shander, MD,FCCM, FCCP

Surgical Bleeding and Transfusions: The Issues in 2004

Chief, Dept of Anesthesiology, Critical Care and Hyperbaric Medicine Englewood Hospital & Medical Center and Associate Clinical Professor,

Mount Sinai School of Medicine

Objectives

Risks of bleeding, subsequent hypovolemia, and acute anemia

– Compensatory mechanisms Macrocirculation Microcirculation

– Morbidity & mortality Risks of transfusions

Surgical BleedingVessel interruption

Surgical repairBleeding contained

No need for further action

Delay in repair Bleeding stops

Surgical repair Clotting

Factor consumption

Impaired clottingTransfusion of blood products

SIRSTransfusion relatedcomplications

Consequences of untreated Hypovolemia

American College of Surgeons (ACS)

Advance Trauma Life Support (ATLS)

Society of Critical Care Medicine (SCCM)

Failure of the circulatory system to maintain adequate cellular perfusionFailure of the circulatory system to maintain adequate cellular perfusion

Bleeding and Hemorrhage

•Macrocirculation Compensation Shifting of blood flow

•Microcirculatory response Cellular adaptation Phenotype survival SIR

MACMACROCIRCULATIONROCIRCULATION

MICMICROCIRCULATIONROCIRCULATION

PLASMAPLASMA

Baseline Delta max0

100

200S

ysto

lic B

P (

mm

Hg

)

Human Hemorrhage and Blood Pressure

25-30% bleed25-30% bleed(n=6)(n=6)

Hamilton-Davies C et al, Hamilton-Davies C et al, Intensive Care Med 1997;23:276-81Intensive Care Med 1997;23:276-81

Baseline Delta max0

20

40

60

80H

eart

Rat

e

Human Hemorrhage and Heart Rate

25-30% bleed25-30% bleed(n=6)(n=6)

Hamilton-Davies C et al, Hamilton-Davies C et al, Intensive Care Med 1997;23:276-81Intensive Care Med 1997;23:276-81

Baseline Delta max0.0

0.5

1.0

1.5

2.0

2.5

im-a

CO

2 ga

p (k

Pa)

25-30% bleed25-30% bleed(n=6)(n=6)

p=0.002p=0.002

Human Hemorrhage and Gastric Perfusion

Hamilton-Davies C et al, Hamilton-Davies C et al, Intensive Care Med 1997;23:276-81Intensive Care Med 1997;23:276-81

Deliberate perioperative increase of DO2 >600 ml/min/m2 using volume loading and dopexamine in RCT

Protocol (dopexamine) group had higher DO2 preop and postop (p<0.001)

Boyd O. JAMA 1993;270:2699-2707.

(n=107) Dopexamine Control P Complications 0.68±0.16 1.35±0.02 0.008 Mortality 5.7% 22% 0.015

“Fluid” + Dobutamine / High Risk Surgery

“Fluid” + Dobutamine / High Risk Surgery

0

10

20

30

40

50

60

70

80

28 d Mortality pOP Complications

Control (n=18)Protocol (n=19)

%

Lobo et al, Crit Care Med 2000;28:3396-3404.

*

* p<0.05

*

Surgery, trauma and the inflammatory response

Surgical trauma: hyperinflammation versus immunosuppression? Menger MD, Vollmar B.Langenbecks Arch Surg 2004;389:475-84.

– Surgery Vs. Trauma effect on ICAM and VCAM

– Local (surgery) Vs. Systemic (trauma) Pro and inflammatory response

The role of interleukin-10 in the regulation of the systemic inflammatory response following trauma-hemorrhage Schneider CP et al, Biochim Biophys Acta 2004;1689:22-32.

– Protective role

– Damaging role

Risks of Anemia

Anemia in CVD

Hgb = Mortality in CVDCarson/Gould – 300 Pts with Hgb <8

gm/dL - StratifiedCarson JL et al, Lancet

1996;348:1055-60

Hgb < 9.5 g/dL = high risk with CVD

Hebert PC at al, Am J Respir Crit Care Med 1997;155:1618-23

Hgb < 7.0 g/dL acceptable with normal coronary circulation

Low Hct and Adverse Outcome

Lowest CPB HCT of <14% in low risk patients and <17% in high risk patients associated with doubling of mortality risk (Fang WC, Circulation 1997)

Below 23%, CPB HCT is inversely related to mortality (Defoe GR, Ann Thorac Surg 2001)

In postop cardiac surgical pts, inverse relationship exists between hemoglobin and major morbidity (Hardy JF, Br J Anaesth 1998)

Perioperative vital organ dysfunction, short- and intermediate-term mortality increased with lowest HCT <22% (Habib RH, J Thorac Cardiovasc Surg 2003)

Blood transfusion in Elderly Patients with Acute Myocardial

InfarctionWu WC et al, NEJM 2001;345:1230-36

Cooperative Cardiovascular Project– 234,769 total patients 78,974 (33.6%) included– CMS ICD-9 discharge code for MI and anemia– Anemia – WHO definition Hct of 39% or less– Hct in the first 24 hrs– 30 day mortality

3324 (4.2%) had Hct less than 30%– These patients had more trauma, surgery,

internal bleeding, coexisting diseases, DNR, shock and less treatments (β blockers ASA etc.)

3680 (4.7%) of the cohort received transfusions

Low Hct and Adverse Outcome

Retrospective database reviews

These studies did not assess impact of transfusion or preoperative hematocrit

Lowest HCT groups were transfused at a significantly higher rate

Prospective, randomized trial results supporting these conclusions not available

Risks of Blood Transfusions

Blood Transfusion:The Global Picture

>82,000,000 units donated per annum world wide

In the US, ~12,500,000 units of RBCs transfused

That’s one unit every 25 seconds!

WHO 2003

Risk and Prevention of Bloodborne Diseases

43% of WHO participating countries (191) test their blood for HIV HCV HBV

13,000,000 units per annum are not tested!

20% of the world’s population uses 80% of the safe blood supply

WHO 2003

Risks Associated With Blood Transfusions

Clerical error

Transfusion reactions

Viral/bacterial infection

Immunomodulation

DHHS Jan, 2002

SHOT - Serious Hazards Of Transfusions

366 Reported"Complications"

Blood Delivery

Error

52%

Acute Reaction

15%

Delayed

Reaction

14%

GVHD

2%

TRALI

8%

Purpura

6%

Disease

3%

LM Williamson et al,BMJ 1999;319:16-19

• ABO – clerical associated complications 1:16,0001

Krombach J et al, Human Error: The Persisting Risk of Blood Transfusion.

Anesth Analg 2002;94:154-156

Transfusion Safety in Hospitals

• Linden JV et al. A report of104 transfusion errors in NY State. Transfusion 1992;32:601-6 1:12,000

• Robillard P et al. ABO incompatible transfusions, acute and delayed hemolytic reaction in Quebec. Transfusion 2002;42:25s 1:13,000

• Baele PL et al. Bedside transfusion errors. A prospective survey by the Belgium SAnGUIS group. Vox Sang 1994;66:117-21 1:400

Decline in HIV, HBV, and HCV Risks of Transmission Through

Transfusion

Adapted from Busch MP et al, JAMA 2003;289:959-62.Aubuchon JP, Transfusion 2004;44:1377-1383.

Ris

k o

f In

fect

ion

per

R

isk

of

Infe

ctio

n p

er

Un

it T

ran

sfu

sed

Un

it T

ran

sfu

sed

1:100

1:1000

1:10,000

1:100,000

1:1,000,000

1:10,000,0001983 1985 1987 1989 1991 1993 1995 1997 1999

2001YearYearRevised Donor

Deferral CriteriaNon-A, Non-B

Hepatitis Surrogate Testing

HIV AntibodyScreening

HCV AntibodyScreening

p24 AntigenTesting

HCV and HIVNucleic Acid

Testing

HIVHCV

HBV

Clerical 1:12,000

Bacteria 1:2,000

TRALI 1:5,000

Potential Risks to the Blood supply

• Simian Foamy Virus (SFV)

• West Nile virus

• vCJD

• Trypanosoma Cruzi

TRALI1:2000 transfused patients

FDA reports as the third most prevalent transfusion related mortality, after hemolysis and sepsis

Associated with: whole blood, RBC, platelets, FFP and cryo.

CHF – ARDS, fleeting or devastating

Two prominent theories HLA class I and possible II, and monocyte antigens 20% of women with multiple gestations carry class I

antigens Mixture of predisposition and infusion of blood

related lipid derived mediators

Risks of Allogeneic Blood

‘TRIM’Transfusion Related Immune

Modulation

Immune Effects of Blood

Immunologic effects of autologous/allogenic blood Tx

Decreased T-cell proliferation Decreased CD3, CD4, CD8 T-cells Increased soluble cytokine receptor

– sTNF-R, sIL-2R Increased serum neopterin Increased cell-mediated lympholysis Increased TNF-alfa Increased suppressor T-cell activity Reduced natural killer cell activity

McAlister FA et al, Br J Surg 1998;85:171-8.Innerhofer P et al, Transfusion 1999;39:1089-96.

Immune modulation

Allogeneic transfusion may enhance tumor recurrence following colorectal cancer resection (Heiss MM, J Clin Oncol 1994)

Allogeneic transfusion is associated with prolonged hospital LOS (Vamvakas EC, Transfusion 2000)

Allogeneic transfusion is associated with increased risk of bacterial infection (35%) and pneumonia (52%) (Carson JL, Transfusion 1999)

Length of storage of transfused RBCs was associated with postoperative pneumonia following CABG surgery, 5% per unit (Vamvakas EC, Transfusion 1999)

Donor Leukocytes

Persistence of donor WBCs in trauma patients for up to 1.5 years after an allogeneic blood transfusion

‘Survival of donor leukocyte subpopulations in immunocompetent transfusion recipients: frequent long-term microchimerism in severe

trauma patients’

2 x 109 WBCs in one unit of packed red blood cells

1 x 108 WBCs – centrifuged, buffy coat depleted

1–5 x 106 WBCs – leukocyte filter, leukocyte-depleted

Lee TH et al, Blood 1999;93:3127–3139

Leukocyte reduction results in a significant reduction of mortality in patients undergoing cardiac surgery

Mortality Rates Are Lower When Leukocyte-Reduced

Blood Is Used

0

2

4

6

8

10

Allogeneic Leukocyte Reduced

van de Watering LMG et al, Circulation 1998;97:562–568

Mort

ality

Rate

(%

)

7.8%

3.3%

n=914Bc=306Ff=305Sc=303

A prospective, randomized clinical trial of universal WBC

reduction

Men = 704 (49.4%)Age = 69.4 (39.8, 84.3)Surgical pts. (62%) Non-surg. pts. 542 (38%)

Men = 675 (49.8%)

Age = 69.6 (42.0, 84)

Surgical pts. (60.5%) Non-surg. pts. 535 (39.5%)

Control Leukoreduced

No demographic differences between groups

N=2780

Dzik WH et al, Transfusion 2002;42:1114-22.

Primary outcomes

In-hospital death 121 (8.5%)

LOS from the first transfusion avg. 10.6 days + 14.5

Total hospital cost avg. $29,800 + $33.2K

median = $19,500) Nonprophylactic

antibiotic use after transfusion (days) 5.1

In-hospital death 122 (9.0%) LOS from the first transfusion avg. 10.3 days + 13.7 Total hospital cost avg. $29,000 + $34K

(median = $19,200) Nonprophylactic antibiotic use after transfusion (days) 4.5

Control Leukoreduced

Dzik WH et al, Transfusion 2002;42:1114-22.

The Impact of PRBCs on Nosocomial Infection Rates

in ICU

Retrospective database study of 1,717 patients using Project IMPACT

NI rates of 3 groups were compared:

– Entire cohort

– Transfusion group

– Nontransfusion group

Patients stratified for age, gender, and probability

of survival using Mortality Prediction Model (MPM-0) scores

Taylor RW et al, Crit Care Med 2002;30:1-6.

5.9

15.4

2.9

0

2

4

6

8

10

12

14

16

18

Per

cen

t o

f P

atie

nts

All Patients

Transfused Patients

Non-transfusedPatients

N = 1,717 n = 416 n = 1,301

P < .05

Nosocomial Infection Rates in Critically Ill Patients

Adjusted for severity of illness using MPM-0 scores, age, gender (Project IMPACT).Taylor RW et al, Crit Care Med 2002;30:2249-54.

For each unit of PRBCs given, the odds of infection is increased by a factor of 1.5

13.6

24

10.2

0

5

10

15

20

25

Pe

rce

nt

of

Pa

tie

nts

All Patients

Transfused Patients

Non-transfusedPatients

N = 1,717 n = 416 n = 1,301

P < .05

Taylor RW et al, Crit Care Med 2002;30:2249-54.

Mortality Rates in Critically Ill Patients

Transfusion and Outcome

• Retrospective, database study of long-term outcome in 1,915 patients after primary CABG

• Excluded for death within 30 days of surgery

• 546 patients transfused during hospitalization were matched by propensity score (age, gender, size, LOS, perfusion time and STS risk) with patients not transfused and 5-year mortality compared

• 5-year mortality twice as high in transfused patients

• After correction for comorbidity, 5-year mortality remained 70%higher in transfused group (p<0.001)

Engoren et al, Ann Thorac Surg 2002;74:1180-6

Univariate association rates of stroke and death in CABG

with platelet transfusion

02468

10

PrimaryCABG

ReopCABG

PrimaryCABG

ReopCABG

PlatesNo Plates

Pat

ient

s (%

)

STROKE DEATH

Spiess BD et al, Transfusion 2004;44:1143-1148

N=1720/248 from 6 RCT for Aprotinin FDA approval

SummaryRisks

Infectious vs. non-infectious

Outcome data Morbidity

– Infection– MOF

Mortality –

Mechanism WBC mediated RBC mediated Platelet/plasma

Storage lesion

Combination