Ré-évaluation du seuil transfusionnelRé-évaluation du seuil transfusionnel

Philippe Van der Linden MD, PhDCHU Brugmann-HUDERF, Université Libre de Bruxelles

Blood Transfusion Practice in Patients Undergoing Cesarean Section

Clinical scenario30-year-old womanCesarean section accompanied by profuse bleedingHemodynamically stable after crystalloid resuscitationEvidence of a slow ongoing blood loss

QuestionsAt what hemoglobin concentration would you transfuse the patient ?

At this threshold, how many units of RBCs would you transfuse?Would you measure Hb concentration before transfusing?

From Matot I et al. Am J Obstet Gynecol 190:462-7, 2004.P VdL

Blood Transfusion Practice in Patients Undergoing Cesarean Section

From Matot I et al. Am J Obstet Gynecol 190:462-7, 2004.

Gynecologists Anesthesiologists6 6,5 7 7,5 8 8,5 9 9,5 10

0

10

20

30

40

50

Transfusion threshold (g/dl)

% Responders

1 2 3 40

20

40

60

80

100

PRBCs units to be transfused

% Responders

p<0.01 p<0.05

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Anemia & Blood Transfusion in Critical Care

From Vincent JL et al. JAMA 288:1499-1507, 2002.

E.U. prospective study (1999)146 units; 3534 patients

Hb < 10 g/dl at admission: 29%

0

2

4

6

8

10

12

14

Hemoglobin (g/dl)

Pretransfusion Hb

0

10

20

30

40

50

Patients (%)

ICU transfusion rate

37

Higher transfusion rate:older patients, longer ICU stay

RBC transfusion associated with:decreased organ function, mortality

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Anemia & Blood Transfusion in Critical Care

From Vincent JL et al. JAMA 288:1499-1507, 2002.

0 10 20 30 40 50 60

Transfusions (%) Pre-transfusion Hb (g/dl)

Acute bleeding 55

Physiologic reserves

Altered tissue perfusion

CAD

Other indications

28

17

8

11

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Risks associated with anemia

Risks associatedwith

blood transfusion

Effectivenessof

blood transfusion

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Patient Outcome With Very Low Hb Level

Retrospective cohort studySurgery from 1981 to 1994Postop Hb level: 8 g/dl or less

1° outcome: 30-day mortality2° outcome: 30-day morbidity

From Carson JL et al. Transfusion 42:812-818, 2002.

0

2

4

6

8

10

12

9,4

7,46,6

1,2 1,6

Complications (%)

Congestive heart failureArrhythmiaPneumoniaWound infectionMyocardial infarction

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Postoperative Hb (g/dl)

30-day mortality or morbidity (%)0 20 40 60 80 100

9,4

22

28,6

57,7

52,6

91,7

7.1 - 8.0

6.1 - 7.0

5.1 - 6.0

4.1 - 5.0

3.1 - 4.0

2.1 - 3.0

From Carson JL et al. Transfusion 42:812-818, 2002.

Patient Outcome With Very Low Hb Level

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Patient Outcome With Very Low Hb Level

Retrospective cohort studySurgery from 1981 to 1994Postop Hb level: 8 g/dl or less

1° outcome: 30-day mortality2° outcome: 30-day morbidity

From Carson JL et al. Transfusion 42:812-818, 2002.

0

2

4

6

8

10

12

9,4

7,46,6

1,2 1,6

Complications (%)

Congestive heart failureArrhythmiaPneumoniaWound infectionMyocardial infarction

After adjusting for age, CVD,& APACHE II score,the OR of death for each gram decrease Hb

was 2.1 (95% CI 1.7-2.6)

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Hemoglobin and Surgical Outcome

Independent predictor of mortality

Sepsis

Bleeding + Hb < 4.0 g/dL

Hb when <3.0 g/dL

Probability of survival less than 1% if Hb <3.0 g/dL + O2ER > 50%

O2ER (%)0

10

20

30

40

50

Alive (N=29) Dead (N=18)

From Spence RK et al. Am Surg 58(2): 92-95, 1992.

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Anemia, Cardiovascular Disease (CVD), and Surgical Mortality

Adjusted odds ratio for mortality by CVD and preop Hb

Preoperative hemoglobin (g/dl)

From Carson JL et al. Lancet 348:1055-1060, 1996.

16

13

10

7

4

16 7 8 9 10 11 12+

1981-1994

All surgeries except open-heart procedures (N=1958)

No CVD CVD

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No CVD

CVD

0 20 40 60 80 100

9,8

7,1

22,5

20

23,5

40

50

75

42,9

80

88,9

100

Postoperative Hb (g/dl)

30-day mortality or morbidity (%)

From Carson JL et al. Transfusion 42:812-818, 2002.

Patient Outcome With Very Low Hb Level

7.1 - 8.06.1 - 7.05.1 - 6.04.1 - 5.03.1 - 4.02.1 - 3.0

7.1 - 8.06.1 - 7.05.1 - 6.04.1 - 5.03.1 - 4.02.1 - 3.0

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Observational study

Healthy volunteers (N=9: 29 ± 5 years)

Verbal memory & standard computerized neuropsychologic tests:

Before and after acute isovolemic hemodilutionAfter re-transfusion of autologous bloodOn a separate day, wirhout alteration of hemoglobin

Isovolemic Anemia and Human Cognitive Function

From Weiskopf RB et al. Anesthesiology 92:1646-52, 2000.

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Isovolemic Anemia and Human Cognitive Function

60

40

20

0

-20

40

20

0

-20

7.2 6.0 5.1 7.2

40

20

0

-20

7.2 6.0 5.1 7.2

40

20

0

-20

Hemoglobin (g/dL)Hemoglobin (g/dL)

Horizontal addition (% changes) Immediate memory (% changes)

Digit-symbol substitution (% changes) Delayed memory (% changes)

From Weiskopf RB et al. Anesthesiology 92:1646-52, 2000.

****

** **

*

*p<0.05 vs Hb 14 g/dL

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Influence of Hemodilution on Outcome After Hypothermic Cardiopulmonary Bypass

Score

140

120

100

80

60

PsychomotorDev index(N=109)

MentalDev index(N=112)

p=0.008 p=0.36

From Jonas RA et al. J Thorac Cardiovasc Surg 126:1765-1774, 2003.

RCT: infants < 9 months- Hct 21.5 ± 2.9 % (N=74)- Hct 27.8 ± 3.2 % (N=73)

Blood product use: similarFluid balance:519 ± 343 vs 337 ± 222 ml p<0.001

60 min after CPBLower nadir CIHigher lactate

in the low hct group

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O2 ExtractionCardiac Output

Tissue O2 Demand

Acute Normovolemic Anemia

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Hematocrit Variations:Coronary Hemodynamics and O2 Utilization

From Jan K-M and Chien S. Am J Physiol 233:H106-H113, 1977. P VdL

Decreased cardiac output response

- hypovolemia- altered myocardial function- coronary artery disease- valvular disease...

Decreased O2ER response - impaired regional distribution of blood flow- microvascular disturbances- left shift of the O2Hb dissociation curve

Arterial hypoxemia - altered pulmonary gas exchange

Increased tissue O2 demand - hypermetabolic processes- stress, pain- emergence from sedation- rewarming- chest physiotherapy

Factors That May Reduce Patient's Tolerance to Anemia

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Risks associated with anemia

Risks associatedwith

blood transfusion

Effectivenessof

blood transfusion

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Transfusion Triggers: a Systematic Review

10 randomized trials comparing the effects of "liberal" vs

"restrictive" transfusion strategy based on a specified

hemoglobin (or hematocrit) concentration on short-term

outcome (N=1780 patients)

Surgical patients (N=5)

Acute blood loss (N=3)

ICU patients (N=2)

Transfusion triggers: hemoglobin between 7 and 10 g/dl

From Carson JL et al. Transfus Med Rev 16:187-199, 2002.

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Transfusion Triggers: a Systematic Review

In the restrictive groups:

Probability to receive a transfusion reduced by 42% (RR 0.58:

0.47-0.51)

volume of red cell transfused reduced by 0.93 units (0.36 - 1.5)

Mortality, morbidity, rates of cardiac events and length of

hospital stay unaffected by the transfusion strategy

From Carson JL et al. Transfus Med Rev 16:187-199, 2002.

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Blood Transfusion and The Heart

Systematic review of studies evaluating transfusion trigger10 studies, 1780 patients

Patients with cardiovascular disease: N=892

From Carson JL et al. Transfus Med Rev 16:187-199, 2002.

Using meta-analytic techniques, there were no differences in the combined odds ratio of death or cardiac eventsusing restrictive strategiescompared with more liberal approaches

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Blood Transfusion and The Heart

Retrospective analysis (N=78974)Blood transfusion decreased 30-day mortality in elderly patients

with a primary diagnosis of AMIif their admission hematocrit was less than 33%(Wu WC et al. N Engl J Med 345:1230-1236, 2001)

Observational study using prospectively collected data (N=24111)Blood Transfusion in the setting of acute coronary syndrome is not associated

with improved survival when nadir hematocrit values are 20-25%(Rao SV et al. JAMA 292:1555-1562, 2004)

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Effects of Blood Transfusion on Survival

From Lackritz EM et al. Lancet 340:524-528, 1992.

1.0

0.8

0.6

0.4

0.2

00 1 2 3 4 5

Probability of mortality

Admission hemoglobin (g/dl)

Transfused on day of admission vs not transfused

Threshold Hb: 3.9 g/dl

For Hb< 3.9 g/dl For Hb> 3.9 g/dl

n=194 n=149OR: 0.30 (0.14-0.61) OR: 1.88 (0.51-6.84)

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Blood Transfusion For Severe Anemic Children

Observational study (N=9968)Severely anemic children: 13%

Transfused: 65% (984/1516)

Mortality (multiple logistic regression)prostration OR: 7.4 (4.2-13.1)respiratory distress: OR: 4.1 (2.2-7.4)profound anemia: OR: 2.5 (1.4-4.5)

blood transfusion: OR: 0.28 (0.15-0.53)

0

20

40

60

80

10089

23

Mortality (%)

Not transfused Transfused

Children with prostration,respiratory distress and

Hb < 4 g/dl

From English M et al. Lancet 359:494-495, 2002.

p=0.0002

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Transfusion Strategy in Preterm Infants

Preterm infants with birth weight 500-1300 gExclusion criteria

Congenital heart disease or major birth defect requiring surgeryAllo-immune hemolytic diseaseChromosomic abnormalityImminent death

Subjects stratified by birth weight (500-750g; 751-1000g; 1001-1300g)

From Bell EF et al. Pediatrics 115:1685-1691, 2005.

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Within each birth weight stratum, infants were assigned randomly to the liberal or the restrictive transfusion group.The transfusion threshold consisted of 3 steps according to clinical condition based on respiratory status

Liberal Restrictive

Tracheally intubated for assisted ventilation 46% 34%

Nasal CPAP or supplemental O2 38% 28%

Neither positive pressure, nor O2 30 % 22 %

From Bell EF et al. Pediatrics 115:1685-1691, 2005.

Transfusion Strategy in Preterm Infants

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From Bell EF et al. Pediatrics 115:1685-1691, 2005.

Transfusions (nb)

Donor exposure

No transfusion (%)

Age at 1st transfus

0 2 4 6 8 10 12 14

Liberal Restrictive

p=0.006

Transfusion Strategy in Preterm Infants

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From Bell EF et al. Pediatrics 115:1685-1691, 2005.

Transfusion Strategy in Preterm Infants

Intravent hhageor periventricular

leukomalacia

Subjects with> 1 apnea / day

0

10

20

30

40

50

0

20

12

43

p=0.012

p=0.017%

Liberal Restrictive

Beforetransfusion

Aftertransfusion

0,4

0,6

0,8

1

1,2

1,4

1,6

Apnea episodes in 24 hours

NS

p=0.003

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Effects of Allogeneic Blood Transfusion on VO2

17 studies

Sepsis - septic shock: N=9

blood transfusion increases VO2: 2 studies

Acute respiratory failure: N=4

blood transfusion increases VO2: 2 studies

Postoperative - post-trauma: N=4

blood transfusion increases VO2: 1 study

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RBC Transfusion Increases DO2 but not VO2

No O2 deficit

Whole body VO2 measurements

Methodological problems

Changes in tissue O2 demand

Indirect vs direct VO2 measurements

Microcirculatory alterations

Abnormal RBC function

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Blood Transfusion: "Storage Effects"

Decreased 2, 3 - diphosphoglycerate (~ 0 after 15 days)Increased affinity of hemoglobin for oxygen

Decreased in red blood cell ATPchange in RBC shape (discoid to spherocytic)

reduced cellular deformability

Decreased tissue oxygen availability

endothelial swelling and tissue edema in sepsisreduce capillary luminal diameter

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Double-blind RCT

Euvolemic anemic (8.5 ± 0.8 g/dl) critically ill patients

LD RBC transfusion: 2 U

- "fresh" blood: 2 days (2 - 3); N=10

- "old" blood: 28 days (22 - 32); N=12

No difference in any globaloxygenation parameters

RBC Transfusion and Tissue Oxygenation: Effects of Storage Time

From Walsh TS et al. Crit Care Med 32:364-371, 2004.

PgCO2 -PaCO2(kPa)

pHi

Lactate(mM/l)

-1 -0,5 0 0,5 1

RBC< 5 days

RBC > 20 days

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"Fresh" Vs "Old" RBC Transfusion in Cardiac Surgery

Double-blind multicenter randomized controlled pilot studyBlood transfusion:- "Fresh": median storage time: 4 days- "Old": median storage time: 19 days

Units transfused:- "Fresh": 5.5 ± 8.4 units- "Old" : 3.3 ± 3.3 units

0

5

10

15

20

25

30

35

27

13

Death or life-threatening complication (%)

"Fresh" (N=26) "Old" (N=31)

Overall, 73% of patients received RBCs with storage times thatcorresponded to the treatment allocation more than 90% of the time

Hébert PC et al. Anesth Analg 100:1433-8, 2005.

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Preoperative Optimization of DO2 in Major Elective Surgery

RCT with double blinding between treatment groups

Treatment groups:Invasive monitoringFluids (PAOP 12 mmHg)Hb > 11 g/dlSaO2 > 94%Adrenaline or Dopexamine for DO2 >600 ml/min.m

0 20 40 60 80 100 1200

100

90

80

Survival (%)

Days after surgery

Adrenaline

Dopexamine

Control

Fisher's test for combined treatmentgroups vs control p=0007

2

N=138

From Wilson J et al. BMJ 318:1099-103,1999.P VdL

Early Goal-Directed Therapy (EGDT) in The Treatment of Severe Sepsis and Septic Shock

Treatment before ICU admission: (6 h)

Control (N =133)EGDT (N= 130)

EGDT patients (7-72 h interval):higher ScvO2

lower lactatelower base deficitlower APACHE II scores

in-hospital 28-day 60-day0

10

20

30

40

50

60

70

46,549,2

56,9

30,533,3

44,3

Mortality (%)

Control EGDT

p=0.009p=0.01

p=0.03

From Rivers E et al. N Engl J Med 345:1368-1377, 2001.P VdL

Supplemental O2 - mechanical ventilationCentral venous & arterial cathetterization

Sedation - paralysis (if intubated) or both

CVP

MAP

ScvO2

Goals achieved

ICU admission

8 - 12 mm Hg

65 - 90 mm Hg

> 70%

< 8 mm Hg

< 65 mm Hg> 90 mm Hg

< 70%RBC transfusion for hct > 30%Inotropic agents

Crystalloids - colloids

Vasoactice agents

Early Goal-Directed Therapy (EGDT) in The Treatment of Severe Sepsis and Septic Shock

From Rivers E et al. N Engl J Med 345:1368-1377, 2001.

No Yes

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TRANSFUSION MEDICINEGoodnough LT et al, NEJM 340:438-444,1999.

"It is unlikely that any level of hemoglobin can be used as a universal threshold for transfusion.

The advent of a very safe blood supply suggests that outcomes should now be monitored to identify

patients in whom transfusion may be underused in addition to identifying patients who receive

unnecessary transfusions."

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Transfusion Triggers

Dyspnea

Tachycardia

Hypotension

ST-T Abnormalities

PvO2, SvO2, O2ER

Others (lactate) ?

Central venous O2 saturation ?

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Transfusion Triggers:Logistical & Geographical Factors

Logistical factors

Available monitoring

Knowledge and availability of physician and nurse staff

Time required for blood products to be delivered

Safety of local transfusion services

Geographical factors:

high vs medium and low HDI countries

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Perioperative Transfusion Trigger

Transfusion (%)

100

0> 30%Hematocrit< 20%

Preoperative periodDefinition of anemiaSurgical riskPatient's clinical status

Peroperative periodVolemiaBlood lossesHemodynamic response

Postoperative periodMetabolic needsComplications

Logistical and geographical factors

Adapted from Janvier G et Annat G. Ann Fr Anesth Réanim 14:9-20, 1995.

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Conclusions

Humans exhibit a high tolerance to acute anemia, providing that "normovolemia" is maintained.

It is unlikely that any level of hemoglobin can be used as a universal threshold for transfusion.

Don't treat numbers, but patients using the available monitoring AND your clinical judgment

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Blood Transfusion Requirements

Red Cell Transfusion Strategies

Administer transfusion(s) on a unit-by-unit basis

Evaluate the patient after each unit

Standardized multidisciplinary approach!!!

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