Management of Massive Bleeding in the ICU Ibrahim Al-Sanouri, MD, FCCP, FAAAAI

Key Discussion Points Definition Complications of massive transfusion: coagulopathy. Therapy goals Haemostatic resuscitation Introduction of Massive Transfusion (MMT) protocol and RBC:FFP:Plts ratio.

Bleeding in the ICU Bleeding in the ICU: massive or not massive. Mucosal or several. Immediate or delayed. GI bleed, Trauma or post surgical intervention Massive blood transfusion: control the source

Definition of Massive Transfusion

Importance of Massive Transfusion 39% of trauma related deaths – uncontrollable bleeding (Leading cause of preventable death) 2% of trauma patients – need massive transfusion Bleeding 2 main causes Vascular injury (surgical) Coagulopathy (non-surgical)

Massive Blood Transfusion complications Fluid overload Thrombocytopnea Hypocalcemia Decreased oxygen release by transfused red cells due to 2,3-bisphosphoglycerate (2,3-BPG) levels (left shift in Hg-O2 curve). Hypothermia

Coagulopathy in massive bleeding:

Complications of massive transfusion

Massive Blood Transfusion Management Haemostatic Resuscitation Fluid management Metabolic acid base correction Normal temperature Calcium management

Therapeutic goals: Maintenance of tissue perfusion and oxygenation by restoration of blood volume and haemoglobin. Arrest of bleeding by treating any traumatic, surgical or obstetric source Judicious use of blood component therapy to correct coagulopathy

Massive bleeding management Treating team Blood products supplying service services Lab

1-Restore circulating volume: Insert wide bore peripheral or central cannulae Give pre-warmed crystalloid or colloid as needed, keep patient warm. Avoid hypotension or urine output <0.5 ml/kg/h Concealed blood loss is often underestimated

2- Contact key personnel A named senior person must take responsibility for communication and documentation. Consultant anaesthetist Blood transfusion Biomedical Scientist Haematologist Arrange Intensive Care Unit bed

3- Stop the bleeding: Early surgical or obstetric intervention Interventional radiology

4-Labs investigation: CBC, PT, APTT, Thrombin time, Fibrinogen, DIC profile. Blood gases and pulse oximetry Ensure correct sample identification Repeat tests after blood component infusion Results may be affected by colloid infusion May need to give components before results available

5-Maintain Hb> 8 g.dl Assess degree of urgency Employ blood salvage to minimize allogeneic blood use Give red cells Group O Rh D negative In extreme emergency Until ABO and Rh D groups known Use blood warmer and/or rapid infusion device if flow rate >50 ml/kg/h in adult

6- Maintain adequate coagualtion Anticipate platelet count <50 after 2 blood volume replacement. Maintain PT & APTT < 1.5 · mean control Give FFP 12–15 ml/kg guided by tests Anticipate need for FFP after 1–1.5 blood volume replacement Allow for 30 min thawing time

6-Maintain adequate coagulation Maintain Fibrinogen > 1.0 g/l If not corrected by FFP give cryoprecipitate (Two packs of pooled cryoprecipitate for an adult) Allow for 30 min thawing time Keep ionised Ca2+ > 1Æ13 mmol/l

7-Hospital protocol: Multidisplinary services: Hospital Transfusion Committee. Improve awareness and confidence and ensure that the blood transfusion chain works efficiently. Rapid communication cascade. Safe and jusdicious use of blood components.

What is Haemostatic Resuscitation? Prevents post massive transfusion coagulopathy. Aims to reduce use of blood products in the intensive care phase. With 5-7 unitis PRBC’s Plt count decreases to less than 50 % With 5 units PRBC PT is increased to more than 1.5 control.

Haemostatic Resuscitation: RBC Erythrocytes promote marginalization of platelets so the platelet concentrates along the endothelium and remains almost seven times that of the average blood concentration Erythrocytes support thrombin generation by activating platelets by liberating ADP. Oxygenation delivery.

Haemostatic Resuscitation: FFP It remains controversial when and in what dose plasma should be transfused to massively bleeding trauma patients. The optimal ratio of FFP to RBCs remains to be established: FFP:RBC ratio greater than 1:2 is associated with improved survival compared to one lower than 1:2.

Haemostatic Resuscitation: FFP Meta-analysis from 2010-2012: Patients undergoing massive transfusion, high FFP to RBC ratios was associated with a significant reduction in the risk of death (odds ratio (OR) 0.38 (95%CI 0.24-0.60) and multiorgan failure (OR 0.40 (95%CI 0.26-0.60). Murad MH, Stubbs JR, Gandhi MJ, Wang AT, Paul A, Erwin PJ, Montori VM, Roback JD: The effect of plasma transfusion on morbidity and mortality: a systematic review and meta-analysis. Transfusion 2010, 50:1370-1383

Haemostatic Resuscitation: FFP Meta-analysis from 2012 reports of reduced mortality in trauma patients treated with the highest FFP or PLT to RBC ratios. Johansson PI, Oliveri R, Ostrowski SR: Hemostatic resuscitation with plasma and platelets in trauma. A meta-analysis. J Emerg Trauma Shock 2012, 5:120-125.

Coagulopathy of Massive Transfusion Mortality Vs FFP/RBC ratio Retrospective review of 246 patients receiving a massive transfusion (> 10 units of blood) Borgman MA. et al. The ratio of blood products transfused affects mortality in patients receiving massive transfusions at a combat support hospital J trauma, 2007. 66:805-813

Haemostatic Resuscitation: Plts Platelets are also pivotal for hemostasis: low Plts increases mortality. The highest survival was established in patients who received both a high PLT:RBC and a high FFP:RBC ratio. Holcomb JB, Wade CE, Michalek JE, Chisholm GB, Zarzabal LA, Schreiber MA, Gonzalez EA, Pomper GJ, Perkins JG, Spinella PC, Williams KL, Park MS: Increased plasma and platelet to red blood cell ratios improves outcome in 466 massively transfused civilian trauma patients. Ann Surg 2008, 248:447-458.

Haemostatic Resuscitation: plt Retrospective study of massively transfused patients: As apharesis platelet to RBC ratio increased, a stepwise improvement in survival was seen and a high apheresis PLT:RBC ratio was independently associated with improved survival. Zink KA, Sambasivan CN, et al: A high ratio of plasma and platelets to packed red blood cells in the first 6 hours of massive transfusion improves outcomes in a large multicenter study. Am J Surg 2009, 197:565-570.

Massive transfusion protocols and ratios: 10 RBC, 4 FFP and 2 apheresis PLT for trauma patients. 211 trauma patients of who 94 received TEP and 117 were historic controls. The TEP patients received more RBC (16 vs. 11), FFP (8 vs. 4), and PLT (2 vs. 1) intraoperatively than the controls. The protocol group displayed lower 30-day mortality (51% vs. 66%). After controlling for age, sex, mechanism of injury, Trauma and Injury Severity Score (TRISS), and 24-hour blood product usage, a 74% reduction in the odds ratio of mortality was found among patients in the TEP group. Cotton BA, Gunter OL, Isbell J, Au BK, Robertson AM, Morris JA: St Jacques P, Young PP: Damage control hematology: the impact of a trauma exsanguination protocol on survival and blood product utilization. J Trauma 2008, 64:1177-1182.

Ratio 10-4-2: RBC-FFP-PLts Pre-defined Massive Transfusion Protocols are associated with REDUCTION of organ failure and post injury complication J Trauma 2009 Jan ; 66(1) 41-48 Ratio 10-4-2: RBC-FFP-PLts Pre-MMT (n-141) MMT (n=129) P-values 24hr survival (%) 61 69 0.185 30d survival (%) 37.6 56.8 0.001 Hospital length of stay d (+/-SD) 16.4(+/-12.1) 12 (+/-12.1) 0.049 ICU stay, (days) 6.6(+/-9.4) 5.0 (+/- 8.3) 0.239 Ventilator (days) 8.2 (+/-9.7) 5.7 (+/-7.2) 0.017 IO crystalloid, Litres 7L 4.8L <0.001 IO blood products units 11U 14.7U 24hr blood products 38.7U 31.2U 0.05

Complications comparison Pre-MMT (n-141) MMT (n=129) P-values Systemic inflammatory response syndrome SIRS (%) 55.3 52.8 0.682 Severe sepsis/septic shock (%) 19.8 10 0.019 Ventilator-dependent respiratory failure(%) 62.4 60.8 0.787 VAP(%) 39 27.2 0.041 Abdominal compartment syndrome(%) 9.9 <0.001 Open abdomen(%) 30.5 6.4 Need of Renal replacement therapy(%) 2.8 3.2 0.826 Pre-defined Massive Transfusion Protocols are associated with REDUCTION of organ failure and post injury complication J Trauma 2009 Jan ; 66(1) 41-48 Ratio 10-4-2: RBC-FFP-PLts

Fresh Whole Blood: Routine use of fresh whole blood (FWB) for resuscitation of bleeding patients was abandoned in the civilian setting. In the combat setting, however, FWB has been used. In a report of US military patients in Iraq and Afghanistan from January 2004 to October 2007, those with hemorrhagic shock, a resuscitation strategy that included FWB was associated with improved 30-day survival (95% vs. 82%, p=0.002). Spinella PC, Perkins JG, Grathwohl KW, Beekley AC, Holcomb JB: Warm fresh whole blood is independently associated with improved survival for patients with combat-related traumatic injuries. J Trauma 2009, 66:S69-S76.

Haemostatic Agents: Antifibrinolytis: Shakur H, et al: CRASH-2 Trial collaborators: Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant hemorrhage (CRASH-2): a randomized, placebo-controlled trial. Lancet 2010, 376:23-32. Recombinant factor VII: Hauser CJ at al: Results of the CONTROL trial: efficacy and safety of recombinant activated Factor VII in the management of refractory traumatic hemorrhage. J Trauma 2010, 69:489-500. Fibrinogen concentrate Prothrombin complex concentrate

Hospital Alert: Active Hemorrhage SBP < 90 HR > 100 Ph < 7.35 BE < - 2 Uncontrollable active bleeding Poor responder to fluid Activation of MMT by team leader only- Registrar or above.

Hb: 8-10 g/dl Platelets > 100 PT&APTT (INR)< 1.5 MANAGEMENT of MASSIVE TRANSFUSION (MMT) for TRAUMA PREVENT HYPOTHERMI A AC I DOS I S COAGULOPATHY Hospital MMT alert confirmation (patient requiring urgent transfusion) - SBP < 90, - HR > 100 - Ph < 7.35 - BE < - 2 - Obvious signs of uncontrollable active bleeding - Poor responder to fluid resuscitation (Trauma Team leader must declare MMT Activation to blood bank , Co-ordinate Porter urgently to standby for Collection of MMT pack one Pre-hospital MMT alert: Systolic BP < 90 Poor response to initial fluid resuscitation Suspected active haemorrhage If so activate MMT (match 3 of the ocriteria) MMT ACTIVATION For Trauma PATIENT ARRIVAL Take bloods (FBC, U&E, Clotting, fibrinogen and X-match and ABG) Send pink bottle with X-match form to blood bank urgently ( please obtain 2 samples for x-match at different time if possible) HAEMOSTASIS THERAPY TARGET end point: Hb: 8-10 g/dl Platelets > 100 PT&APTT (INR)< 1.5 Fibrinogen > 1.0 g/l Ca²⁺ > 1 mmol/l pH: 7.35-7.45 BE: ± 2 Tª > 36 °C MMT PACK 1 4 x O –ve RBC ( female) or O+ve(Male) 2 FFP (or Group specific if possible) HAEMORRHAGE CONTROL: Surgery Stabilize fractures Pelvic brace PREVENT HYPOTHERMIA Fail to reach targets RE-ASSESSMENT ABCDE If haemorrhage continue HAEMOSTATIC DRUGS: Consider the following if bleeding persist despite surgical interventions: Activated factor VII Beriplex (consider when patient who is on anti-coagulant) Antifibrinolitic agents Please discuss any of these therapeutic measures with Haematologist on call) Activate MMT PACK 2 Please, specify location of patient 2 x packs of Cryoprecipitate if Fibrinogen is < 1.0 g/l INTRA-OPERATIVE CELL SALVAGE: Transfuse 1 x FFP every 250 ml of blood Transfuse 1 x ATD platelets every 1000 ml of blood MMT PACK 2 1 pharased Platelets Once administered check: FBC, Clotting, fibrinogen and ABG 4 X RBC 4 X FFP When MMT stops Notify blood bank Return any unused products Resume standard ordering practices

Summery: Immediate labs service is important to identify coagulopathy, and guide ongoing transfusion therapy. Massive hemorrhage could results in serious life threatening complications Massive bleeding and massive transfusion could lead to severe coagulaopthy which tight a viscous cycle that could cause mortality

Summery: While resuscitation your patient keep patient warm with normal calcium level Identify and correct source of bleeding. Implementation of a homeostatic control resuscitation strategy to massively bleeding patients seems both reasonable and lifesaving.

Thank You! Questions? Ibrahim Al-Sanouri, MD.