Update on Hemostatic Resuscitation RAHUL J ANAND MOLLY FLANNAGAN DIVISION OF TRAUMA, CRITICAL CARE, AND EMERGENCY GENERAL SURGERY

Massive Transfusion Defined as transfusion of >10 U blood or Pt blood volume in 24 hrs Causes ◦Trauma ◦Emergency surgery ◦AAA repair ◦GI hemorrhage CHEST 2009; 136:1654 –1667

Massive transfusion in trauma Trauma patients with MT have high mortality (19 to 84%) Mortality Is directly related to number of PRBC units received CHEST 2009; 136:1654 –1667

Traditional Massive Transfusion Crystalloid fluid PRBC (lacking in clotting factors) Dilutional coagulopathy Hypothermia Acidosis Liver dysfunction due to shock

Hemostatic Resuscitation Traditional MT underestimates treatment needed to reverse coagulopathy Normalization of body temperature Hemorrhage control Transfusion with ◦FFP ◦Platelets ◦Cryoprecipitate

Hemostatic Resuscitation Emerging Consensus Expedite hemorrhage control Limit crystalloid resuscitation to prevent dilutional coagulopathy Transfuse PRBC:FFP:Plts in a 1:1:1 fashion Frequent lab monitoring ◦Lactate ◦Ionized calcium ◦Electrolytes ◦Platelets, Fibrinogen ◦TEG / ROTEM

So YOU have MASSIVE BLEEDING – now what? Secure Access ◦2 Large bore IV, or Central line or ◦Intra-Osseus line Begin Aggressive Resuscitation ◦(ATLS suggests 2 L or warmed crystalloid) STOP the bleeding

Damage Control Resuscitation FOCUSED SURGERY PERMISSIVE HYPOTENSION HEMOSTATIC RESUSCITATION

CHOICE OF RESUSCITATION FLUID

Choice of Crystalloid No real difference between using LR and NS LR MAY exacerbate hyperkalemia Hypertonic Saline is no better TAKE HOME – USE NS (Sparingly) Kaafarani et al. Scandinavian Journal of Surgery 103:81-88, 2014

Why not Resuscitate with Colloid? Theoretically may stay intravascular?

SAFE TRIAL No difference in mortality, ventilator days, renal failure, or LOS Subgroup analysis – worse mortality in TBI patients

Colloid Take Home Point Resuscitation is EXPENSIVE MAY be harmful in patients with TBI, BURN, Trauma Start with NS – then use PRODUCT if you have to X

HYPOTENSIVE RESUSCITATION

Still Bleeding? – Don’t aim for “NORMAL BP” Permissive Hypotension – especially in those with no brain or spinal cord injury until surgical control of bleeding Maintain cerebral perfusion – SBP 80’s acceptable until bleeding stopped “Hypotensive resuscitation is a safe strategy for use in the trauma population and results in a significant reduction in blood product transfusions and overall IV fluid administration … maintaining a target minimum MAP of 50 mm Hg, rather than 65 mm Hg, significantly decreases postoperative coagulopathy and lowers the risk of early postoperative death and coagulopathy.” Kobayashi et al. Surg Clin N. Am 92 (2012) Morrison et al. J Trauma Mar;70(3):652-63

N Engl J Med 1994; 331: October 27, 1994 Landmark NEJM article Compared immediate versus delayed fluid resuscitation before operative intervention

Delayed group compared to traditional resuscitation Delayed group received no more than 100cc fluid prior to OR Delayed group had better survival, fever complications, shorter LOS N Engl J Med 1994; 331: October 27, 1994

Target BP before Hemorrhage Control Accept MAP of 50 Decrease dilutional coagulopathy Avoid hypothetical “pop the clot” Restrict inflammatory cascade Kaafarani et al. Scandinavian Journal of Surgery 103:81-88, 2014

1:1:1

1:1 PRBC: FFP Transfusion Borne out of military rationale Walking blood banks with Fresh Whole Blood High FFP:RBC ratio (1:1) is independently associated with ◦Improved survival to hospital discharge ◦Improved overall mortality J Trauma 2007; 63:805 –813

1:1 Transfusion works for civilians too!

1:1 Platelets: PRBC is also important

Take home point Re: 1:1:1 Improves 30 day survival Reduces incidence of pneumonia, pulmonary failure, abdominal compartment syndrome LOWER 24 hour transfusion requirement Johnsson et al. Scand J Trauma, Resus, Emergency Med. 2012

Hemostatic adjuncts

Hemostatic Adjuncts Factor VIIa Prothrombin Complex Tranexamic Acid

Factor VIIa CONTROL TRIAL – looked at Use of Factor VIIa in the management of refractory trauma hemorrhage Pro-thrombotic Agent TRIAL did not show a significant mortality benefit Factor VII also has a variety of thromboembolic complications – increased significantly over controls Johnsson et al. Scand J Trauma, Resus, Emergency Med. 2012

Factor VIIa Alarcon. UPMC Trauma Rounds Winter X

Prothrombin Complex (PCC) Cocktail of 3 or 4 factors Can be used to correct INR rapidly in trauma Less thrombotic complications than Factor VIIa Annals of Pharmacotherapy, July / August, Volume 45

Administration of PCC to patients with massive bleeding Found to reliably lower INR with a single dose No thrombotic complication May warrant a RCT

Smaller studies Promising results to reverse Coumadin related coagulopathy Unanswered as to whether should be used with MTP Matsushima et al. American J Surgery (2015)

Use of PCC for Damage Control Resuscitation ? Low volume product which does not result in hemo-dilution

Tranexamic Acid Not a pro-coagulant Prevents fibrinolyisis

Patients randomized to receive TXA or Placebo 3 hours from injury TXA found to reduce mortality from bleeding significantly (4.9% vs 5.7%). The Lancet. Volume 376. July 3, 2010

TXA in the USA Given more liberally in Europe “… in most centers, [TXA] is given following individual practitioner decisions rather … protocol” Dutton, Anesthesia 2015, 70 (Suppl 1),

TXA take home point Tranexamic Acid is an antifibrinolytic Administration in cases of massive hemorrhage within the first 3 hours can have an effect on mortality

Massive transfusion protocols

“The Massive Transfusion Protocol (MTP) facilitates the replacement of massive blood loss with appropriate blood products in a timely fashion.” J Trauma. 2006;60:S91–S96. Other Authors.

Massive Transfusion Protocols Standardize replacement of platelets and clotting factors in optimum ration to PRBC Increase speed and efficiency of transfusion

Arch Surg. 2008; 143(7): J Trauma. 2009;66:

Early activation Direct notification of the blood bank Achievement of pre-defined ratios PI process All help to improve outcome and survival

MTP here at VCU “ACTIVATE MTP” PLACE THE ORDER IN CERNER Send 2 samples to the blood bank Transfuse “Emergency Release Uncrossmatched Blood” if you have to With each release it needs to be ordered again

MTP at VCU Protocol 1 Keep Ahead Order 4 RBC Keep Ahead Order 4 FFP Release 8 RBC Release 6 FFP Protocol 2 Order 1 dose Platelets Order 1 dose Cryo Release 8 RBC Release 8 FFP Release 1 dose Platelets – (250 – 300cc) Release 1 dose Cryo Optional Order Activated Factor VII Protocol 3 Release 4 RBC Release 4 Plasma Order 1 dose Platelets Release 1 dose Platelets – (250 – 300cc) Protocol 4 Order 1 dose Platelets Order 1 dose Cryo Release 4 RBC Release 4 FFP Release 1 dose Platelets Release 1 dose Cryo Protocol 5 Release 4 RBC Release 4 FFP Order 1 dose Platelets Release 1 dose Platelets – (250 – 300cc) Protocol 6 Release 4 RBC Release 4 FFP Order 1 dose Platelets Release 1 dose Platelets – (250 – 300cc) Protocol 7 Order 1 dose Platelets Order 1 dose Cryo Release 4RBC Release 4 FFP Release 1 dose Platelets Release 1 dose Cryo Protocol 8 Release 4 RBC Release 4 FFP Order 1 dose Platelets Release 1 dose Platelets – (250 – 300cc) Protocol 9 (Alert: MTP: Trauma has been completed. Refer back to normal Blood Product ordering pathway)

Termination of MTP Nursing unit will notify TM to slow rate of preparation and delivery of blood products when bleeding slows to a specified rate. When the protocol is cancelled, nursing unit will notify TM. Keep Ahead orders for blood/ blood products can still be utilized for 24 hours from time of entry

LABORATORY TESTING

Intraoperative Targets Hemoglobin > 7 INR <2 Platelet Count > 50 K Fibrinogen > 100 Guide Clot Strength with TEG Kaafarani et al. Scandinavian Journal of Surgery 103:81-88, 2014

Laboratory Guidance PT / INR, PTT are warmed to 37C before analysis This can normalize results and under diagnose coagulopathy Tests can take 30 minutes to an hour

TEG Provide clinically relevant information on clot strength A Quantitative method of giving clot strength over time Are run at patient temperatures Takes 5 minutes Can be used to run “ongoing resuscitation” Johnsson et al. Scand J Trauma, Resus, Emergency Med. 2012

TEG Johnsson et al. Scand J Trauma, Resus, Emergency Med. 2012

How about pressors to avoid fluid? J Crit Care (2010) 25, 173 J Trauma (2011) 71: J Trauma (2008) 64: 9-14

Late Resuscitation in ICU Hemostasis achieved in the OR “A la carte resuscitation” Volume Resuscitation Guided in ICU by ◦Clearance of Lactate ◦Volume Status Assessment (LTTE) Generally Tolerate Hgb > 7

In CONCLUSION Hemostatic Resuscitation Expedite hemorrhage control Limit crystalloid resuscitation to prevent dilutional coagulopathy USE BLOOD EARLY Transfuse PRBC:FFP:Plts in a 1:1:1 fashion Factor VII – bad TXA, PCC may have roles within a MTP MTP is a good thing TEG assays