bleeding & anemia: compensatory mechanisms - belgium · does bleeding time predict surgical...

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Bleeding & Anemia: Compensatory Mechanisms

Philippe Van der Linden MD, PhDCHU Brugmann-HUDERF, Free University of Brussels

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Fees for lectures, advisory board and consultancy: Janssen-Cilag,

Fresenius Kabi GmbHB-Braun Medical SACSL Behring GmbH

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Post-traumatic Coagulopathy:The STOP the Bleeding Campaign

From Rossaint R et al. Crit Care 2013 Apr 26; 17:136.

Traumatic injuries worldwide are responsible for over 5 million deaths annually.

Bleeding caused by traumatic injury-associated coagulopathy is the leading cause of potentially preventable death among trauma patients.

The campaign aims to reduce the number of patients who die from exsanguination within 24 hours after arrival in the hospital by a minimum of 20% within the next 5 years.

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Management of Massive Bleeding

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Massive Transfusion During Elective Surgery or Major Trauma

Elective Surgery

Major Trauma

Tissue trauma Controlled Uncontrolled

Initiation of transfusion No delay Variable

Volume status Normovolemia Hypovolemia

Temperature Normothermia Hypothermia

Hemostasis monitoring Ongoing Late

Coagulopathy factors Complex

From Hardy JF et al. Can J Anesth 53:S40-S58, 2006.

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Kozek-Langenecker S et al. Eur J Anaesthesiol 30:270-382, 2013.

Spahn DR et al. Crit Care 17:R76, 2013.

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Transfusion Thresholds & Other Strategies for Guiding Allogeneic

RBC Transfusion

RCTs assessing the effects of transfusion thresholds (based

on Hb or Hct) on RBC transfusion rate and clinical outcomes• Major surgery: 10 trials – 4319 patients

• Gastrointestinal bleeding: 2 studies – 264 patients

• Trauma: 3 studies – 77 patients

• ICU: 3 studies – 1544 patients (637 children)

• Medical: 1 study – 60 patients

From Carson JL et al. Cochrane Database of Systematic Review, 2012, Issue 4, CD002042.

19 trials – 6,264 patients

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RBC Transfusion

Results: restrictive transfusion strategies• risk of receiving RBC transfusion (RR: 0.61; 95% CI: 0.52-0.72)

• volume of transfused RBCs (1.19; 95% CI: 0.53-1.85)

• in hospital mortality (RR: 0.77; 95% CI: 0.62-0.95)

• No impact on 30-day mortality (RR:0.85; 95% CI: 0.70-1.03)

• No impact on the rate of adverse events, ICU and in-hospital

length of stay


19 trials – over 6,000 patients

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RBC Transfusion

Conclusions:• The existing evidence support the use of restrictive transfusion triggers

in most patients, including those with pre-existing cardiovascular disease.

• In countries with inadequate screening of donor blood, the data may

constitute a stronger basis for avoiding allogeneic RBC transfusion.



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RBC Transfusion

Implications for research:• Further large trials on transfusion triggers should include patients with

acute coronary syndrome, elderly patients recovering from acute illness,

patients with gastro-intestinal bleeding, coagulopathy or hemorrhagic

shock and patients with traumatic injury.



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Transfusion Strategies for Acute Upper Gastrointestinal Bleeding

From Villanueva C et al. N Engl J Med 368:1:11-21, 2013.

Prospective randomized controlled trial: • Restrictive transfusion strategy: Hb < 7 g/dl (N=461)• Liberal transfusion strategy: Hb < 9 g/dl (N=460)

1 outcome: 45-day mortality

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Transfusion Strategy in Critically Ill Trauma patients

Post-hoc analysis of the TRICC trial

Critically ill trauma patients with Hb < 9 g/dL within 72 hours of ICU admission (N=203)

Restrictive (Hb: 7 g/dL) or liberal (Hb: 10 g/dL) transfusion strategy

From McIntyre L et al. J Trauma 57:563-568, 2004.

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Transfusion Strategy in Critically Ill Trauma Patients

From McIntyre L et al. J Trauma 57:563-568, 2004.

0

2

4

6

8

10Average units/patient

0

5

10

15

20

10 9

30-day mortality (%)

0

5

10

15

20Multiple organ dysfunction

0

5

10

15

20ICU LOS (days)

Restrictive: 8.3 ± 0.6 g/dl (N=100) Liberal 10.4 ± 1.2 g/dl (N=103)

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RBC Transfusion


N=25N=22N=30

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Efficacy of RBC Transfusion in The Critically Ill: A Systematic Review

• Systematic review of the literature to determine the association between RBC transfusion , and morbidity and mortality in high-risk hospitalized patients

• Cohort studies that assessed the independent effect of RBC transfusion on patient outcomes

• 571 articles screened: 45 met inclusion criteria (N=272,596)

From Marik PE et al. Crit Care Med 36:2267-74, 2008.

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Efficacy of RBC Transfusion in The Critically Ill: Association Between Transfusion & The Risk of Death

From Marik PE et al. Crit Care Med 36:2267-74, 2008.

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Changes occuring in the supernantIncreased K+, release of various proinflammatory cytokines and complement, biologically active lipids (such as PAF), free Hb, heme and iron with potential redox injuries, cytotoxicity and inflammation

RBC Storage Lesions

Adapted from Aubron C et al. Annals of Intensive Care 3:2, 2013.

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“Old” Vs. “Fresh” Red Blood Cells: Meta-analysis of clinical studies

Available data do not support that old RBCs are associated with common adverse morbidity and/or mortality outcomesVamvakas EC. Transfusion 50:600-10, 2010.

No definitive argument to support the superiority of fresh over older RBCs for transfusionLelubre et al. Crit Care 17:R66, 2013.

Need for large randomized controlled trials evaluating the clinical impact of transfusing fresh vs. old RBCs in the critically illAubron C et al. Annals of Intensive Care 3:2, 2013.

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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 ».

Transfusion ThresholdsBarr PJ, Bailie KEM NEJM 365; 26: 2532-3, 2011.

« The decision to transfuse should be guided by an assessment of individual patient on the basis of a combination of symptoms, signs, lab measures and not by a single hemoglobin level ».

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Maintenance of Tissue O2 Delivery during Normovolemic Anemia

Cardiac Output

Increased preload

Decreased afterload

Increased contractility

Increased heart rate

Tissue O2 Extraction

Regional blood flow redistribution

Microvascular adjustments

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Acute Anemia and - blockade

From Lieberman JA et al. Anesthesiology 92:407-13, 2000.

6.5

6.0

5.5

5.0

4.5

4.0

3.5

3.0

55

50

45

40

35

30

25

20

CI (l/min.m2) O2ER (%)

Baseline ANH Baseline ANH

N=8

Hb (g/dl) 12.5 ± 0.8 4.8 ± 0.2 * p<0.05 vs Baseline

*

*

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Acute Anemia and - blockade

6.5

6.0

5.5

5.0

4.5

4.0

3.5

3.0

55

50

45

40

35

30

25

20

CI (l/min.m2) O2ER (%)

Baseline ANH Esmolol Baseline ANH Esmolol

N=8

Hb (g/dl) 12.5 ± 0.8 4.8 ± 0.2 4.7 ± 0.2 * p<0.05 vs Baseline;# p<0.05 vs ANH

*

* #

*

* #

From Lieberman JA et al. Anesthesiology 92:407-13, 2000.

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0

20

40

60

80

100

120

140HR (b.min-1)MAP (mmHg) CO (L.min-1) Hb (g.dL-1)

0

2

4

6

8

10

12

From van Woerkens ECSM et al. Anesth Analg 75:818-821, 1992.

Preinduction

Postinduction

H1

H2

H3

1500 ml B

L

3500 ml B

L

ES

1 h PO

2 h PO

4 h PO

8 h PO

Critical Level of Anemia in Anesthetized Man

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0 100 200 300 4000

20

40

60

80

100

120

DO2 (ml/min.m²)

VO2 (ml/min.m²)

PvO2 : 33 mmHgSvO2: 57%O2ER: 48%Hb: 4.0 g/dL

Critical Level of Anemia in Anesthetized Man

From van Woerkens ECSM et al. Anesth Analg 75:818-821, 1992.

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Hemoglobin and Surgical Outcome

Independent predictor of mortality

SepsisBleeding + Hb < 4.0 g/dLHb 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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From Weiskopf RB et al. Anesthesiology 92:1646-52, 2000.

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)

****

** **

*

*p<0.05 vs Hb 14 g/dL

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Decreased cardiac output response

- hypovolemia- altered myocardial function

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 Tolerance ofCritically Ill Patients to Anemia

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Hemodilution & Cardiac Output

FLOW

RAP

CONTROL

- 0 +

A

NORMAL FUNCTIONBHEMODILUTION

CHYPOVOLEMIA

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O2 Demand Variations in ICU

500

450

400

350

300

250

200

150

100

50

0

250

225

200

175

150

125

100

75

50

25

0

Withdrawal of sedation (Crit Care Med 22:1114,1994)

Rewarming (Circulation 68:1238,1983)

Chest Physiotherapy (Crit Care Med 22:1809, 1994)

Time (hours)0 1 2 3 4 5 6 7 8 9 10 12 before after

VO2 (ml/min) VO2 (ml/min.m²)

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Anemia & Hemostasis

Effects of erythrocytes• Rheological effect on platelet margination

• ADP release from dammaged red blood cells

• Direct platelet activation through interference with arachidonic

acid metabolism

• Thrombin generation through direct exposure of procoagulant

phospholipids at the outer surface of the erythrocytes’membrane

Effects of plasma substitutes• coagulation: colloids (except albumin) >> crystalloids

Ouaknine-Orlando B and Samama CM. Hémorragies et thromboses. Masson, 2000.

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Healthy blood donors:2 units RBCs apheresis (N=29)Plateletpheresis (N=28)

Return of the RBCs restore BT and shed blood thomboxane B2 level to normal

Anemia & Bleeding Time

0

2

4

6

8

10Bleeding Time at 35°C (min)

Apheresis: RBCs PlateletsHct (%) 41 35 40 40Plts (/mm3) 220 200 238 163

p<0.01

From Valeri CR et al. Transfusion 41:977-983, 2001.

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Type of study

N Correlation

Cardiac surgeryBurns ER et al. JTCS, 1986Mohr et al. JTCS, 1986Pillgram-Larsen et al.Scand JTCS , 1986Ramsey G et al. JTCS, 1983Rocha E et al. Circulation, 1988Simon TL et al. Ann Thorac Surg, 1984Weksler BB et al. N Engl J Med , 1983.

prospectiveprospectiveprospective

retrospectiveprospectiveprospectiveprospective

4365101921002828

NoNoNoNoNoNoNo

Non cardiac surgeryAmrein PC et al. JAMA, 1981.Barber A et al. Am J Med, 1985.Eika C et al. Scand J Haematol, 1978.Ferraris VA et al. Surg Gyn Obstet, 1983.Gorman M et al; Ophtal Surg, 1986.Rohrer MJ et al; Ann Surg, 1988.

prospectiveretrospectiveprospectiveprospectiveprospectiveprospective

194110152139282

NoNoNoNoNoNo

Does Bleeding Time Predict Surgical Bleeding ?

From Lind SE et al. Blood 77:2547-2552, 1991.

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Monitoring of Hemostasis During Massive Transfusion

TEG (thromboelastography) & ROTEM (rotationalthromboelstometry): isolated reduction in hematocrit doesnot compromise much in vitro blood coagulation.

Iselin BM et al. Br J Anaesth 2001.Bochsen L et al. Blood Coagul Fibrinolysis 2011.

Ogawa S et al. Anesth Analg 2012.Nagler M et al. Thrombosis Res 2013.

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24 RCTs - 1218 patientsMedian sample size: 30Mean blood volume collected: 936 ml

ANH:Reduced the likelihood of exposure to at least 1 of allogeneic RBCReduced the units of allogeneic blood transfused (-2,2 U; 95% CI -3,57, -0,86)

ANH & Perioperative Allogeneic Blood Transfusion

-300

-200

-100

0

100

Perioperative Blood Loss(weighted mean difference; 95% CI)

NS

From Bryson GL et al. Anesth Analg 86:9-15, 1998.

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ANH & Perioperative Allogeneic Blood Transfusion

42 RCTs - 2233 patientsSample size: 16 - 168 patientsBlood volume collected: 500 -2000 ml

ANH (compared to usual care):Did not reduce the risk of allogeneic transfusion (RR: 0.96; 95% CI: 0.90-1.01)Reduced the number of allogeneic blood units transfused (WMD: 303 ml; 95% CI: 55 - 555 ml)

From Segal JD et al. Transfusion 44:632-644, 2004.

-200

-150

-100

-50

0

50

Blood loss (ml)(pooled average difference; 95% CI)

Intraop Total

NS

p<0.001

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Bleeding & Anemia: Compensatory Mechanisms Conclusions

RBC transfusion threshold in the bleeding patient remains poorly defined. Recent guidelines recommend the maintenance of a Hb between 7and 9 g/dl. This recommendation is not supported by strong evidence.

RBC transfusion in the bleeding patient could not be based only on a Hb value but should take into account:

• Patient’s underlying clinical condition• Bleeding pathophysiological mechanism• Institutional logistic constraints• Safety of blood products

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bleeding & anemia: compensatory mechanisms - belgium · does bleeding time predict surgical...

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