29/11/2013 More pharmaceuticals and less plasma? “Severe bleeding: from basics to practice” Brussels, Thursday 28 November Niels Rahe-Meyer Clinic for Anaesthesiology and Intensive Care Medicine 1
29/11/2013 Conflict of interest Research Support / PI CSL Behring, MSD Employee No relevant COI Consultant No relevant COI Stockholder No relevant COI Speakers Bureau No relevant COI Scientific Advisory Board CSL Behring, MSD Franziskus Hospital | Hannover Medical School Niels Rahe-Meyer 2013 2
29/11/2013 Kozek-Langenecker SA. et al., Eur J Anaesth 2013;30 Spahn DR. et al., Crit Care 2013;17(2):R76 Grading of Recommendation Assessment, Development and Evaluation (GRADE) system 1 2 Strong Weak A C High Low Franziskus Hospital | Hannover Medical School Niels Rahe-Meyer 2013 3
29/11/2013 PRBC:FFP:platelet (1:1:1) improves early mortality N=157, patients with trauma requiring massive transfusion 50 Patients mortality at 24 hours 40 p=0.008 36 30 (%) 20 17 10 Use of PRBC:FFP:platelets (1:1:1) reduced 24-hour mortality in patients with trauma 0 PRBC:FFP:platelet (n=73) Historical control (n=84) FFP, fresh frozen plasma; PRBC, packed red blood cell. Dente CJ. e t al. , J. Trauma 2009 Franziskus Hospital | Hannover Medical School Niels Rahe-Meyer 2013 4
29/11/2013 PRBC:FFP:platelet (1:1:1) does not improve 28- day mortality Prospective RCT, n=78, patients with trauma requiring massive transfusion; control = laboratory-results-guided transfusion protocol 50 Patients mortality at 28 40 days (%) 30 32 RR 2.27 (95% CI 0.98 to 9.63) 20 14 10 No significant advantage of 1:1:1 ratio in 28-day mortality 0 PRBC:FFP:platelet (n=40) Control (n=35) CI, confidence interval; FFP, fresh frozen plasma; PRBC, packed red blood cell; RR, relative risk Nascimento B. e t al. , CMAJ 2013 Franziskus Hospital | Hannover Medical School Niels Rahe-Meyer 2013 5
29/11/2013 Fresh frozen plasma (FFP) “We recommend the initial administration of plasma (FFP) … in patients with massive bleeding” ( Grade 1B) Spahn DR. et al., Crit Care 2013 Franziskus Hospital | Hannover Medical School Niels Rahe-Meyer 2013 6
29/11/2013 Platelets Prospective study, N=41, patients likely to be massively transfused Predictors of diffuse microvascular bleeding Predictive value Sensitivity Specificity Positive Negative (%) (%) (%) (%) Platelet count 89 93 73 96 ≤ 50x10 9 /L or fibrinogen ≤ 0.5 g/L A platelet count ≤ 50x10 9 /L or a fibrinogen level ≤ 0.5 g/L were the most sensitive laboratory predictors of microvascular bleeding Ciavarella D. et al., Br J Haematol 1987, 67 (3):365–368. Franziskus Hospital | Hannover Medical School Niels Rahe-Meyer 2013 7
29/11/2013 Platelets “We recommend that platelets be administered to maintain a platelet count above 50x10 9 /L ” (Grade 1C ) “We suggest maintenance of a platelet count above 100x10 9 /L in patients with ongoing bleeding and/or traumatic brain injury” (Grade 2C ) “We suggest an initial dose of 4–8 single platelet units or one aphaeresis pack” (Grade 2C ) Spahn DR. et al., Crit Care 2013; 17(2):R76 Franziskus Hospital | Hannover Medical School Niels Rahe-Meyer 2013 8
29/11/2013 Cryoprecipitate “We suggest that the indication for cryoprecipitate is lack of available fibrinogen concentrate for the treatment of bleeding and hypofibrinogenaemia”(Grade 2C ) 1 “We recommend treatment with fibrinogen concentrate or cryoprecipitate in the continuing management of the patient if significant bleeding is accompanied by thromboelasto- metric signs of a functional fibrinogen deficit or a plasma fibrinogen level of less than 1.5-2.0 g/L” (Grade 1C ) 2 1. Kozek-Langenecker SA. et al., Eur J Anaesthesiol 2013; 2. Spahn DR. et al., Crit Care 2013 Franziskus Hospital | Hannover Medical School Niels Rahe-Meyer 2013 9
29/11/2013 Contents DDAVP FXIII rFVIIa Tranexam Fibrinogen PCC Franziskus Hospital | Hannover Medical School Niels Rahe-Meyer 2013 10
29/11/2013 Desmospressin vs control for non exposure to allogeneic blood Meta-analysis,19 RCTs, N=1387, patients undergoing surgery RR = 0.96; 95% CI 0.87-1.06 The use of DDAVP did not reduce the risk of exposure to allogeneic RBC transfusion compared with control CI, confidence interval; DDVAP, desmopressin; RBC, red blood cell; RR, risk ratio Carless PA et al., Cochrane Database Syst Rev 2004;1:CD001884 Franziskus Hospital | Hannover Medical School Niels Rahe-Meyer 2013 11
29/11/2013 Desmospressin “There is no convincing evidence that desmopressin minimises perioperative bleeding or perioperative allogeneic blood transfusion in patients without a congenital bleeding disorder” (Grade 2B ) 1 “We do not suggest that desmopressin be used routinely in the bleeding trauma patient” (Grade 2C ) 2 1. Kozek-Langenecker SA. et al., Eur J Anaesthesiol 2013; 2. Spahn DR. et al., Crit Care 2013 Franziskus Hospital | Hannover Medical School Niels Rahe-Meyer 2013 12
29/11/2013 Factor XIII vs placebo for transfusion avoidance RCT-DB, N=409, patients undergoing cardiopulmonary bypass 100 Odds ratio 1.05 95% CI 0.61–1.80 Patients avoiding blood Odds ratio 0.99 80 95% CI 0.57–1.72 transfusion (%) 65,9 60 64,8 64,3 40 Replenishment of FXIII levels after cardiopulmonary 20 bypass had no effect on transfusion avoidance 0 17.5 IU/kg FXIII… 35 IU/kg FXIII… Placebo… Karkouti KN. et al., J Thorac Cardiovasc Surg 2013;146(4):927–39 Franziskus Hospital | Hannover Medical School Niels Rahe-Meyer 2013 13
29/11/2013 Factor XIII concentrate “In case of ongoing or diffuse bleeding and low clot strength despite adequate fibrinogen concentrations, it is likely that FXIII activity is critically reduced. In cases of significant FXIII deficiency (i.e. <60%) , we suggest that FXIII concentrate (30 IU/kg) can be administered” (Grade 2C ) Kozek-Langenecker SA. et al., Eur J Anaesthesiol 2013;30:270–382 Franziskus Hospital | Hannover Medical School Niels Rahe-Meyer 2013 14
29/11/2013 rFVIIa vs placebo for exposure to allogeneic blood products RCT, N=301, trauma patients p=0.03 p=0.08 A significant reduction in RBC transfusion avoidance was observed with rFVIIa compared with placebo Boffard KD. et al., J Trauma 2005;59(1):8-15 Franziskus Hospital | Hannover Medical School Niels Rahe-Meyer 2013 15
29/11/2013 rFVIIa We suggest that off-label administration of rFVIIa can be considered for perioperative bleeding, which cannot be stopped by conventional, surgical or interventional radiological means and/or when comprehensive coagulation therapy fails (Grade 2C ) 1,2 1. Kozek-Langenecker SA. et al., Eur J Anaesthesiol 2013; 2. Spahn DR. et al., Crit Care 2013 Franziskus Hospital | Hannover Medical School Niels Rahe-Meyer 2013 16
29/11/2013 Tranexamic acid vs placebo for mortality risk RCT-DB, N=20,211, trauma patients with, or at risk of, significant bleeding 10 Patients who died due to p<0.0001 8 p=0.003 7,7 bleeding (%) 6 6,1 5,3 4,8 4 2 0 Treatment ≤ 1 h from injury Treatment 1–3 h from injury TXA (n=3747) Placebo (n=3704) Early treatment with TXA reduced the risk of death due to bleeding compared with placebo Roberts I et al., Lancet 2011;377:1096–1101 Franziskus Hospital | Hannover Medical School Niels Rahe-Meyer 2013 17
29/11/2013 Antifibrinolytic therapy “We recommend that TXA or -aminocaproic acid should be considered before coronary artery bypass graft surgery ” (Grade 1A ) 1 “We recommend that TXA be administered as early as possible to the trauma patient who is bleeding or at risk of significant haemorrhage…” (Grade 1A ) “We suggest that protocols for the management of bleeding patients consider administration of the first dose of TXA en route to the hospital” (Grade 2C ) 2 1. Kozek-Langenecker SA. et al., Eur J Anaesthesiol 2013; 2. Spahn DR. et al., Crit Care 2013 Franziskus Hospital | Hannover Medical School Niels Rahe-Meyer 2013 18
29/11/2013 Fibrinogen concentrate vs placebo for exposure to allogeneic blood products RCT-DB, N=61, patients undergoing cardiopulmonary bypass p<0.0001** 14 Units of blood components 12 10 8 6 Fibrinogen reduced the need for allogeneic blood 4 transfusion by 85%* 2 0 Placebo Fibrinogen Rahe-Meyer N. et al., Anaesthesiology 2013;118(1):40–50 * During the 24-hour period after the start of study medication ** Unstratified Hodges-Lehmann point estimate and corresponding non-parametric 95% confidence intervals Franziskus Hospital | Hannover Medical School Niels Rahe-Meyer 2013 19
29/11/2013 Fibrinogen concentrate We recommend treatment with fibrinogen concentrate if significant bleeding is accompanied by at least suspected low fibrinogen concentrations or function ” (Grade 1C ) 1,2 “We recommend that a plasma fibrinogen concentration <1.5 – 2.0 g/L or ROTEM/TEG signs of functional fibrinogen deficit should be triggers for fibrinogen substitution” (Grade 1C ) 1,2 “ We recommend that fibrinogen concentrate infusion guided by point-of-care viscoelastic coagulation monitoring should be used to reduce perioperative blood loss in complex cardiovascular surgery . ” (Grade 1B ) 1 1. Kozek-Langenecker SA. et al., Eur J Anaesthesiol 2013; 2. Spahn DR. et al., Crit Care 2013 Franziskus Hospital | Hannover Medical School Niels Rahe-Meyer 2013 20
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