Bleeding & Anemia: Compensatory Mechanisms Philippe Van der - - PowerPoint PPT Presentation

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Bleeding & Anemia: Compensatory Mechanisms

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

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Fees for lectures, advisory board and consultancy: Janssen-Cilag, Fresenius Kabi GmbH B-Braun Medical SA CSL 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.

29/11/2013 6 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

• n 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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Transfusion Thresholds & Other Strategies for Guiding Allogeneic 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

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

19 trials –

• ver 6,000 patients

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Transfusion Thresholds & Other Strategies for Guiding Allogeneic 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.

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

19 trials –

• ver 6,000 patients

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Transfusion Thresholds & Other Strategies for Guiding Allogeneic 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.

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

19 trials –

• ver 6,000 patients

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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.

2 4 6 8 10 Average units/patient 5 10 15 20 10 9 30-day mortality (%) 5 10 15 20 Multiple organ dysfunction 5 10 15 20 ICU LOS (days)

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

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Transfusion Thresholds & Other Strategies for Guiding Allogeneic RBC Transfusion

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

N=25 N=22 N=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
• f 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 supernant

Increased 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 outcomes

Vamvakas EC. Transfusion 50:600-10, 2010.

No definitive argument to support the superiority of fresh over

• lder RBCs for transfusion

Lelubre 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 ill

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

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Transfusion Medicine

Goodnough 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 Thresholds

Barr PJ, Bailie KEM NEJM 365; 26: 2532-3, 2011. « The decision to transfuse should be guided by an assessment

• f 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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20 40 60 80 100 120 140 HR (b.min-1) MAP (mmHg) CO (L.min-1) Hb (g.dL-1) 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 BL 3500 ml BL ES 1 h PO 2 h PO 4 h PO 8 h PO

Critical Level of Anemia in Anesthetized Man

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100 200 300 400 20 40 60 80 100 120

DO2 (ml/min.m²) VO2 (ml/min.m²)

PvO2 : 33 mmHg SvO2: 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

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 (%) 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

• 20

40 20

• 20

7.2 6.0 5.1 7.2 40 20

• 20

7.2 6.0 5.1 7.2 40 20

• 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
• f 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 of Critically Ill Patients to Anemia

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Hemodilution & Cardiac Output

FLOW RAP CONTROL

• 0 +

A NORMAL FUNCTION B HEMODILUTION C HYPOVOLEMIA

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O2 Demand Variations in ICU

500 450 400 350 300 250 200 150 100 50 250 225 200 175 150 125 100 75 50 25 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

2 4 6 8 10

Bleeding Time at 35°C (min) Apheresis:

RBCs Platelets Hct (%) 41 35 40 40 Plts (/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 surgery

Burns ER et al. JTCS, 1986 Mohr et al. JTCS, 1986 Pillgram-Larsen et al.Scand JTCS , 1986 Ramsey G et al. JTCS, 1983 Rocha E et al. Circulation, 1988 Simon TL et al. Ann Thorac Surg, 1984 Weksler BB et al. N Engl J Med , 1983. prospective prospective prospective retrospective prospective prospective prospective 43 65 101 92 100 28 28 No No No No No No No

Non cardiac surgery

Amrein 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. prospective retrospective prospective prospective prospective prospective 1941 101 52 139 282 No No No No No No

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 (rotational thromboelstometry): isolated reduction in hematocrit does not 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 patients

Median sample size: 30 Mean blood volume collected: 936 ml

ANH:

Reduced the likelihood of exposure to at least 1 of allogeneic RBC Reduced the units of allogeneic blood transfused

(-2,2 U; 95% CI -3,57, -0,86)

ANH & Perioperative Allogeneic Blood Transfusion

• 300
• 200
• 100

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 patients

Sample size: 16 - 168 patients Blood 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

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

• nly 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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Thank you for your attention