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

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

• 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.           4
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.   5
Why Implement a Protocol?

• Many patients arrive with coagulopathy
• An organized protocol to address
  exsanguinating hemorrhage in the most
  severely injured patients minimizes delays
     Delays in access to appropriate blood
     Delays of sufficient quantities and ratios

 Exsanguination Protocol

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

 • Unless specified, blood bank releases
   second box and ceases preparation of future
 • 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.   10
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.          12
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.      13
MLR Analysis for 30-Day Survival

                               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

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.      15
  J Trauma. 2008;64:620-627.
Recombinant Factor VIIa (rVIIa)

 • Several OIF/OEF studies showed improved
 • Phase II trauma study of rVIIa demonstrated a
   reduction in RBC use, trend toward less MOF3
 • Potentially limited with acidosis and
 • 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.                    16
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.   19
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

Dickneite G, et al. Br J Anaesth. 2009.           20
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.   21
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
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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