Managing the Coagulopathy of Trauma: Use of Transfusion Protocols and Prohemostatic Agents

Faculty Bryan A. Cotton, MD, MPH The University of Texas Health Science Center Houston, Texas Richard P. Dutton, MD, MBA University of Maryland School of Medicine R Adams Cowley Shock Trauma Center Baltimore, Maryland Martin A. Schreiber, MD, FACS Oregon Health & Science University Portland, Oregon

Hemorrhage Leading cause of death in first hour of arrival1 Responsible for more than 80% of OR deaths2 Accounts for nearly 50% of deaths in first 24 h2 1. Acosta JA, et al. J Am Coll Surg. 1998;186:528-533; 2. Kauvar DS, et al. J Trauma. 2006;60:S3-S11.

How Acute and How Lethal Is the Coagulopathy? 38% (+) coagulopathic on arrival; mortality (+) coagulopathic 24% (vs 4%)1 24% arrive (+) coagulopathic; these patients have higher mortality (46% vs 11%)2 MT patients, 70% coagulopathic on arrival; mortality in coagulopathic patients 67% (vs 42%) 3 MT=massive transfusion. 1. Niles SE, et al. J Trauma. 2008;64:1459-1465; 2. Brohi K, et al. J Trauma. 2003;54:1127-1130; 3. Cotton BA, et al. J Trauma. 2008;64:1177-1183.

What to Replace? PT: 0.87 BV lost Fibrinogen: 1.14 BV lost Platelets: 1.83 BV lost PT subhemostatic once patient has received only 3.6 U RBCs Preparedness is essential BV=blood volumes. Hirshberg A, et al. J Trauma. 2003;54:454-463.

Why Implement a Protocol? Many patients arrive with coagulopathy present An organized protocol to address exsanguinating hemorrhage in the most severely injured patients minimizes delays Delays in access to appropriate blood products Delays of sufficient quantities and ratios

Exsanguination Protocol Surgeon activates trauma exsanguination protocol (TEP) Blood bank prepares first round of products 10 U RBC 6 U plasma 2 apheresis platelets Blood bank begins preparation of next round of products 6 U RBC 4 U plasma Cotton BA, et al. J Trauma. 2008;64:1177-1183.

Exsanguination Protocol Unless specified, blood bank releases second box and ceases preparation of future boxes Surgeon notifies blood bank and stops TEP if Hemostasis achieved Case completed Patient expires Cotton BA, et al. J Trauma. 2008;64:1177-1183.

Damage Control Resuscitation Damage control hematology: the impact of a trauma exsanguination protocol on survival and blood product utilization (Cotton et al. Journal of Trauma, 2008) Three components Hematologic Limited crystalloid Permissive hypotension Cotton BA, et al. J Trauma. 2008;64:1177-1183.

Improved Survival 74% reduction in the odds of mortality Increase in unexpected survivors Decrease in unexpected deaths Less intraoperative crystalloid; fewer postoperative blood products Cotton BA, et al. J Trauma. 2008;64:1177-1183.

Higher Ratios Mortality reduction attributed to empiric delivery of higher, predefined ratios of plasma and platelets1 Higher fibrinogen (plasma):RBC ratio independently associated with improved survival2 Higher plasma and platelet ratios improved survival in MT patients1 1. Gunter OL Jr, et al. J Trauma. 2008;65:527-534; 2. Stinger HK, et al. J Trauma. 2008;64(2 suppl):S74-S85.

Predefined MT Protocols Predefined massive transfusion protocols are associated with a reduction in organ failure and postinjury complications (Cotton et al. Journal of Trauma, 2009) MT historically associated with higher rates of organ failure and postinjury complications Risk reduced with early delivery of blood products through predefined protocol MT=massive transfusion. Cotton BA, et al. J Trauma. 2009;66:41-49.

Predefined MT Protocols Implementation of protocol results in Reduction in MOF Fewer pulmonary issues Reduced incidence of open abdomens in compartment syndrome MOF=multiorgan failure. Cotton BA, et al. J Trauma. 2009;66:41-49.

MLR Analysis for 30-Day Survival P value 95% CI ED protocol activation 2.79 .042 1.039-7.497 Plasma:RBC ratio of 2:3 12.28 <.001 3.860-39.069 Platelet:RBC ratio of 1:5 3.72 .009 1.392-9.975 Trauma Attending activation 0.895 .922 0.960-8.337 ED type and screen sent 0.195 .130 0.023-1.621 Age in years 0.98 .354 0.957-1.015 Male gender 0.75 .599 0.264-2.157 Injury Severity Score 0.96 .190 0.941-1.357

Recombinant Factor VIIa (rVIIa) rVIIa: Adjuvant for treatment of coagulopathy in patients with severe torso hemorrhage rVIIa: Binds tissue factor at site of endothelial injury, triggering local coagulation process rVIIa: Reduces incidence/severity of coagulopathy in severely injured patients with ongoing transfusions Martinowitz U, et al. J Trauma. 2001;51:431-438; Rizoli SB, et al. Crit Care. 2006;10:1-11; Stein DM, et al. J Trauma. 2008;64:620-627.

Recombinant Factor VIIa (rVIIa) Several OIF/OEF studies showed improved outcomes1,2 Phase II trauma study of rVIIa demonstrated a reduction in RBC use, trend toward less MOF3 Potentially limited with acidosis and thrombocytopenia4,5 Reports of thromboembolic adverse events6 1. Perkins JG, et al. J Trauma. 2007;62:1095-1099; 2. Spinella PC, et al. J Trauma. 2008;64:286-294; 3. Boffard KD, et al. J Trauma. 2005;59:8-15; 4. Martini WZ, et al. Ann Surg. 2007;246:831-835; 5. Stein DM, et al. J Trauma. 2005;59:609-615; 6. O’Connell KA, et al. JAMA. 2006;295:293-298.

Recent Studies: rVIIa Stein et al. Injury (2008) Objective: Examine safety and efficacy of rVIIa for reversing mild to moderate coagulopathy Retrospective review, 2004-2006 Results: Decreased utilization of PRBCs and FFP; lower vol fluid administration; rapid reversal of coagulopathy Stein DM, et al. Injury. 2008;39:1054-1061.

Recent Studies: rVIIa Horton et al. Am Surg (2008) Objective: Examine frequency and patterns of rVIIa use since Jan 2005 Survey of 156 US trauma centers, level I and II Horton JD, et al. Am Surg. 2008;74:413-417.

Prothrombin Complex Concentrate (PCC) PCC: Clotting factors (II, VII, IX, and X) that can be used to reverse coagulopathy PCC: Effects are fast and long acting PCC: Use in trauma patients appears safe and beneficial in critically injured population Associated with thrombogenicity Kalina M, et al. Am Surg. 2008;74:858-861; Köhler M. Thromb Res. 1999;95(4 suppl):S13-S17; Riess HB, et al. Thromb Res. 2007;121:9-16.

Recent Studies: PCC Dickneite et al. Br J Anaesth (2009) Objective: Compare effects of PCC and FFP on hemorrhage after injury and impact of both agents on coagulation function in vivo Porcine trauma model: 47 castrated male pigs Results: PCC, not FFP, reversed hemodilution effects Dickneite G, et al. Br J Anaesth. 2009.

Recent Studies: PCC Riess et al. Thromb Res (2007) Objective: Examine efficacy of PCC for reversing anticoagulant effects 60 patients with bleeding complications or undergoing invasive procedures Result: Rapid and safe reversal of anticoagulation with PCC Riess HB, et al. Thromb Res. 2007;121:9-16.

Question-and-Answer Session

Bryan A. Cotton, MD, MPH Associate Professor of Surgery The University of Texas Health Science Center and Center for Translational Injury Research Houston, Texas

What are your thoughts concerning recombinant factor VIIa data, including studies indicating that the agent may reduce transfusion requirement but have no effect on ultimate outcome?

Availability of recombinant factor VIIa when unable to get surgical control Medivac helicopters Fluid replacement to avoid hemodilution Smaller-volume trauma centers No in-house trauma surgeon Delivered with the second box of product

Timing of use Protracted wait = poor outcome Have agent ready early enough but not too early

Martin A. Schreiber, MD, FACS Oregon Health & Science University Portland, Oregon

From your perspective, how has recombinant factor VIIa evolved as an off-label drug to treat the coagulopathy of trauma?

Evolution of rVIIa use Previously misused based on improper patient care Crystalloid and blood products Used as rescue drug to counter cycle of coagulopathy Current recognition of coagulopathy on admission Need for resuscitation with high ratios of plasma to platelets Replacement Therapy Fell behind Still evolving

Richard P. Dutton, MD, MBA Professor of Anesthesiology University of Maryland School of Medicine Attending Anesthesiologist R Adams Cowley Shock Trauma Center Baltimore, Maryland

Which of the treatment strategies that are just beginning to be recognized for the coagulopathy of trauma do you believe will be routinely performed 5 years from now?

Better testing of coagulation early Individual factor therapy Combinations of factor therapy Fibrinolytic mechanism Use of deep anesthesia

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