29/11/2013 Bleeding & Anemia: Compensatory Mechanisms Philippe Van der Linden MD, PhD CHU Brugmann-HUDERF, Free University of Brussels 1
29/11/2013 Fees for lectures, advisory board and consultancy: Janssen-Cilag, Fresenius Kabi GmbH B-Braun Medical SA CSL Behring GmbH 2
29/11/2013 Post-traumatic Coagulopathy: The STOP the Bleeding Campaign 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. From Rossaint R et al. Crit Care 2013 Apr 26; 17:136. 3
29/11/2013 Management of Massive Bleeding 4
29/11/2013 Massive Transfusion During Elective Surgery or Major Trauma Elective Major Surgery Trauma Tissue trauma Controlled Uncontrolled Initiation of transfusion No delay Variable Volume status Normovolemia Hypovolemia Temperature Normothermia Hypothermia Hemostasis monitoring Ongoing Late factors Coagulopathy Complex From Hardy JF et al. Can J Anesth 53:S40-S58, 2006. 5
29/11/2013 Kozek-Langenecker S et al. Eur J Anaesthesiol 30:270-382, 2013. Spahn DR et al. Crit Care 17:R76, 2013. 6
29/11/2013 Transfusion Thresholds & Other Strategies for Guiding Allogeneic RBC Transfusion 19 trials – 6,264 patients 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. 7
29/11/2013 Transfusion Thresholds & Other Strategies for Guiding Allogeneic RBC Transfusion 19 trials – over 6,000 patients 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. 8
29/11/2013 Transfusion Thresholds & Other Strategies for Guiding Allogeneic RBC Transfusion 19 trials – over 6,000 patients 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. 9
29/11/2013 Transfusion Thresholds & Other Strategies for Guiding Allogeneic RBC Transfusion 19 trials – over 6,000 patients 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. 10
29/11/2013 Transfusion Strategies for Acute Upper Gastrointestinal Bleeding 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 From Villanueva C et al. N Engl J Med 368:1:11-21, 2013. 11
29/11/2013 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. 12
29/11/2013 Transfusion Strategy in Critically Ill Trauma Patients Average units/patient 30-day mortality (%) 10 20 8 15 10 9 6 10 4 5 2 0 0 Restrictive: 8.3 ± 0.6 g/dl (N=100) Liberal 10.4 ± 1.2 g/dl (N=103) Multiple organ dysfunction ICU LOS (days) 20 20 15 15 10 10 5 5 0 0 From McIntyre L et al. J Trauma 57:563-568, 2004. 13
29/11/2013 Transfusion Thresholds & Other Strategies for Guiding Allogeneic RBC Transfusion N=25 N=22 N=30 From Carson JL et al. Cochrane Database of Systematic Review, 2012, Issue 4, CD002042. 14
29/11/2013 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. 15
29/11/2013 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. 16
29/11/2013 RBC Storage Lesions 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 Adapted from Aubron C et al. Annals of Intensive Care 3:2, 2013. 17
29/11/2013 “ 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 older 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. 18
29/11/2013 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 of individual patient on the basis of a combination of symptoms, signs, lab measures and not by a single hemoglobin level ». 19
29/11/2013 Maintenance of Tissue O 2 Delivery during Normovolemic Anemia Cardiac Output Tissue O 2 Extraction Increased preload Regional blood flow redistribution Decreased afterload Microvascular adjustments Increased contractility Increased heart rate 20
29/11/2013 Acute Anemia and - blockade N=8 O 2 ER (%) CI (l/min.m2) 6.5 55 6.0 50 * 5.5 45 * 5.0 40 4.5 35 4.0 30 3.5 25 3.0 20 Baseline ANH Baseline ANH * p<0.05 vs Baseline Hb (g/dl) 12.5 ± 0.8 4.8 ± 0.2 From Lieberman JA et al. Anesthesiology 92:407-13, 2000. 21
29/11/2013 Acute Anemia and - blockade CI (l/min.m2) N=8 O 2 ER (%) 6.5 55 6.0 50 * * # 5.5 45 * 5.0 40 4.5 35 * # 4.0 30 3.5 25 3.0 20 Esmolol Esmolol Baseline ANH Baseline ANH 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. 22
29/11/2013 Critical Level of Anemia in Anesthetized Man 140 12 MAP (mmHg) HR (b.min-1) CO (L.min-1) Hb (g.dL-1) 120 10 100 8 80 6 60 4 40 2 20 0 0 Preinduction Postinduction 1500 ml BL 1 h PO 2 h PO 4 h PO 8 h PO H1 H2 H3 3500 ml BL ES From van Woerkens ECSM et al. Anesth Analg 75:818-821, 1992. 23
29/11/2013 Critical Level of Anemia in Anesthetized Man VO2 (ml/min.m²) 120 100 80 PvO2 : 33 mmHg 60 SvO2: 57% 40 O2ER: 48% Hb: 4.0 g/dL 20 0 0 100 200 300 400 DO2 (ml/min.m²) From van Woerkens ECSM et al. Anesth Analg 75:818-821, 1992. 24
29/11/2013 Hemoglobin and Surgical Outcome Independent predictor of 50 mortality 40 Sepsis Bleeding + Hb < 4.0 g/dL 30 Hb when <3.0 g/dL 20 10 Probability of survival less 0 than 1% if Hb <3.0 g/dL + O2ER (%) O 2 ER > 50% Alive (N=29) Dead (N=18) From Spence RK et al. Am Surg 58(2): 92-95, 1992. 25
29/11/2013 Isovolemic Anemia and Human Cognitive Function Horizontal addition (% changes) Immediate memory (% changes) * 60 40 * * 40 20 20 0 0 -20 -20 Digit-symbol substitution (% changes) Delayed memory (% changes) * 40 40 * * * 20 20 0 0 -20 -20 7.2 6.0 5.1 7.2 7.2 6.0 5.1 7.2 Hemoglobin (g/dL) Hemoglobin (g/dL) * p<0.05 vs Hb 14 g/dL From Weiskopf RB et al. Anesthesiology 92:1646-52, 2000. 26
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