Managing the Coagulopathy of Trauma: Use of Transfusion Protocols and

Prohemostatic Agents

Faculty

2

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

3

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

4

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.

MT=massive transfusion.

What to Replace?

5

• 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

Hirshberg A, et al. J Trauma. 2003;54:454-463.

BV=blood volumes.

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

6

Exsanguination Protocol

Cotton BA, et al. J Trauma. 2008;64:1177-1183.7

• 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 2 apheresis platelets

8

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

9

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

10Cotton 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

111. 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

12

Predefined massive transfusion protocols areassociated 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

13

• 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.

OR 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

MLR Analysis for 30-Day Survival

14

Recombinant Factor VIIa (rVIIa)

15

• 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)

16

• 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

17

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

18

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)

19

• 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

20

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

21

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.

22

Question-and-Answer Session

23

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?

24

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

25

Timing of use

• Protracted wait = poor outcome

• Have agent ready early enough but not too early

26

27

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?

28

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 evolving29

30

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?

31

• Better testing of coagulation early

• Individual factor therapy

• Combinations of factor therapy

• Fibrinolytic mechanism

• Use of deep anesthesia

32

Thank you for participating in this CE activity.

To receive credit for this activity, please complete the posttest and evaluation by clicking the “posttest” tab located above and following the instructions.

To download the reference list or supplemental slides for this program, please click the appropriate link on the home page of this activity.

www.bloodcmecenter.org

33