Transfusion Strategies in a Trauma Patient

Disclosure Statement

• Cadence Pharmaceuticals- Research

Grant

Learning Objectives

• Enumerate various components of massive transfusion guidelines

• List the recent updates in transfusion strategies including 1;1;1 ratio of PRBC, FFP and Platelet

• Identify adjunct therapy that can be used to reduce bleeding and improve outcome

• Identify the benefits of a substantial bleeding protocol system.

Outline

• Introduction • Definitions of Massive Bleeding • Trauma Induced Coagulopathy • Damage Control Resuscitation • Massive Transfusion Protocols • Blood Component Ratios • Adjunct Therapy

Trauma is the leading cause of death for Americans between the ages of 1 and 44, and accounts for more years of lost life than cancer and heart disease combined

Centers for Disease Control and Prevention, National Center for Injury Prevention and Control. . 2007 Sauaia, A., et al., Epidemiology of trauma deaths: a reassessment. J Trauma, 1995. 38(2): p. 185-93.

What do we see at MHH?

• 6100 annual admissions • Average ISS- 18 (ISS

>16 mortality rate 10%) • (%) Blunt vs penetrating-

81 vs 19% • # ER to OR emergent

cases- 350-400, of which – 250-300 emergent

laparotomies – Remaining thoracotomies,

neck, extremity and preperitoneal packing)

Hemorrhage & Trauma

• Hemorrhage is responsible for 50% of deaths in the first 24 hours

• 2nd only to traumatic head head injury as leading of early trauma-related mortality

• In patients requiring one blood volume (10 pRBCs), fatality rates have been reported as high as 60%

• 25% of admitted trauma patients exhibit abnormal coagulation profiles

Sauaia, A., et al., Epidemiology of trauma deaths: a reassessment. J Trauma, 1995. 38(2): p. 185-93. Kauvar, D.S., R. Lefering, and C.E. Wade, Impact of hemorrhage on trauma outcome: an overview of epidemiology, clinical presentations, and therapeutic considerations. J Trauma, 2006. 60(6 Suppl): p. S3-11.

What does this mean?

Holcomb, J.B. and P.C. Spinella, Optimal use of blood in trauma patients. Biologicals, 2010. 38(1): p. 72-7.

• Immediate hemorrhagic mortality constitutes the largest group of potentially preventable deaths in the initial 24-hour period

Definitions of Massive Bleeding

Sorensen, B. and D. Fries, Emerging treatment strategies for trauma-induced coagulopathy. Br J Surg, 2012. 99 Suppl 1: p. 40-50. Martinowitz, U. and M. Michaelson, Guidelines for the use of recombinant activated factor VII (rFVIIa) in uncontrolled bleeding: a report by the Israeli Multidisciplinary rFVIIa Task Force. J Thromb Haemost, 2005. 3(4): p. 640-8.

• Massive blood loss is the total loss of a blood volume within 24 hours or an acute 50% reduction of the total blood volume within minutes of injury

Massive Transfusion

• Massive transfusion is generally accepted to be a transfusion of greater than 10 units of PRBCs or an equivalent patient’s blood volume in a 6-24 hour period.

Coagulopathy and Trauma

Consumption and Ongoing Blood Loss

Coagulation factors and platelets are consumed during the formation of clots

Acidosis

• Caused by tissue injury, hypoxia, hypo-perfusion and lactic acid production

• Effects hemostasis including platelet and coagulation protease dysfunction

• pH of 7.2 leads to a 50% loss of activity of the prothrombinase (FXa/Va) complex

• Thrombin production is reduced by half at a pH of 7.1 • Accelerated fibrinolysis

W.Z. Martini, J.B. Holcomb Acidosis and coagulopathy: the differential effects on fibrinogen synthesis and breakdown in pigs Ann Surg, 246 (2007), pp. 851–853 W.Z. Martini, D.L. Chinkes, A.E. Pusateri, J.B. Holcomb, Y.M. Yu, X.J. Zhang et al. Acute changes in fibrinogen metabolism and coagulation after hemorrhage in pigs Am J Physiol Endocrinol Metab, 289 (2005), pp. E930–E934

Hemodilution

M. Maegele, R. Lefering, N. Yucel, T. Tjardes, D. Rixen, T. Paffrath et al. Early coagulopathy in multiple injury: an analysis from the German Trauma Registry on 8724 patients Injury, 38 (2007), pp. 298–304

• Iatrogenic cause of traumatic coagulopathy

• Volume of fluid administered is proportional to the resultant coagulapthy

• Data shows that more than 40% of trauma patients develop a coagulopathy after >2 L of crystalloid and colloid administration, rising to >70% after >4 L.

Hypothermia

S. Shafi, A.C. Elliott, L. Gentilello Is hypothermia simply a marker of shock and injury severity or an independent risk factor for mortality in trauma patients? Analysis of a large national trauma registry J Trauma, 59 (2005), pp. 1081–1085

• Common following traumatic injury caused by heat loss at the scene of injury and therapeutic treatments.

• Hypothermic patients (<35 °C) have significantly higher mortality than patients with the same severity of injury who remain NT.

• Coagulation protease activity is significantly affected below 33 °C

• Controlling for injury severity, it is an independent predictor of mortality

Trauma Induced Coagulopathy and Acute Coagulopathy of Trauma-Shock

• Trauma induced coagulopathy is an independent predictor of massive transfusion and death

• Coagulopathy increases mortality, transfusion requirements, multi organ failure, sepsis, and increased length of critical care stays

Brohi, K., et al., Acute traumatic coagulopathy. J Trauma, 2003. 54(6): p. 1127-30. MacLeod, J.B., et al., Early coagulopathy predicts mortality in trauma. J Trauma, 2003. 55(1): p. 39-44 Maegele, M., et al., Early coagulopathy in multiple injury: an analysis from the German Trauma Registry on 8724 patients. Injury, 2007. 38(3): p. 298-304.

Acute traumatic coagulopathy (ATC),

• Between 24-56% of critically injured patients are affected

• Pathophysiology is not fully understood, tissue trauma and systemic hypoperfusion appear to be the primary factors

Floccard, B., et al., Early coagulopathy in trauma patients: an on-scene and hospital admission study. Injury, 2012. 43(1): p. 26-32. Curry, N.S., et al., Transfusion strategies for traumatic coagulopathy. Blood Rev, 2012. 26(5): p. 223-32

Brohi and Cohen

• Theorized that ATC stems from overt activation of the protein C pathway.

• An acute phase coagulopathy and hyperfibrinolysis results in the inhibition of factors Va and VIIIa and reduces the pro-fibrinolytic effects of plasminogen activator inhibitor-1 (PAI-1)

Damage Control Resuscitation (DCR)

Duchesne, J.C., et al., Damage control resuscitation: the new face of damage control. J Trauma, 2010. 69(4): p. 976-90. Spinella, P.C. and J.B. Holcomb, Resuscitation and transfusion principles for traumatic hemorrhagic shock. Blood Rev, 2009. 23(6): p. 231-40.

• DCR attempts to minimize iatrogenic resuscitation injury and the effects of traumatic shock through the management principals of – Permissive hypotension – Hemostatic resuscitation – Damage control surgery

Permissive hypotension

• Targets a lower than normal blood pressure to promote thrombus formation until surgical hemostasis can be achieved

• Minimizes initial volume of fluid to reduce systolic blood pressure while decreasing dilutional coagulopathy and hypothermia associated with aggressive fluid resuscitation

Jansen, J.O., et al., Damage control resuscitation for patients with major trauma. BMJ, 2009. 338: p. b1778. Holcomb, J.B., et al., Damage control resuscitation: directly addressing the early coagulopathy of trauma. J Trauma, 2007. 62(2): p. 307-10

Permissive Hypotension

• Rat model suggested that a target MAP of 50–60 mmHg conferred survival benefit in animals with uncontrolled hemorrhagic shock max tolerance limit of 90 min

• Morrison 2011 RCT prelim data

– LMAP- pts received significantly fewer blood products, smaller volumes of fluids intra-operatively, were less likely to develop post-operative coagulopathy and had a significantly lower mortality (p = 0.03)

W.H. Bickell, M.J. Wall Jr., P.E. Pepe, R.R. Martin, V.F. Ginger, M.K. Allen et al. Immediate versus delayed fluid resuscitation for hypotensive patients with penetrating torso injuries New Engl J Med, 331 (1994), pp. 1105–1109 Morrison, C.A., et al., Hypotensive resuscitation strategy reduces transfusion requirements and severe postoperative coagulopathy in trauma patients with hemorrhagic shock: preliminary results of a randomized controlled trial. J Trauma, 2011. 70(3): p. 652-63

Damage control surgery (DCS)

Jansen, J.O., et al., Damage control resuscitation for patients with major trauma. BMJ, 2009. 338: p. b1778.

• Limits extensive procedures on unstable patients

• Goal of stabilization while minimizing contamination and hemorrhage

• Staged reoperation to restore anatomy and achieve definitive repair.

Hemostatic resuscitation

Holcomb, J.B. and P.C. Spinella, Optimal use of blood in trauma patients. Biologicals, 2010. 38(1): p. 72-7. Holcomb, J.B., et al., Damage control resuscitation: directly addressing the early coagulopathy of trauma. J Trauma, 2007. 62(2): p. 307-10.

• Describes a unified transfusion approach to severe hemorrhagic shock

• Begins immediately after the field assessment and is continued through the OR and into ICU

• Minimizes dilutional coagulopathy by replacing lost blood with plasma and platelet containing products

Does DCR work?

Cotton et al. published a large series investigating the efficacy of the 3 components of DCR in the civilian setting • Reduction in crystalloid and overall blood

product administration • Reduction in assoc. inflammatory mediators

of shock. • Associated with a 2.5-fold increased in 30 day

survival Cotton, B.A., et al., Damage control hematology: the impact of a trauma exsanguination protocol on survival and blood product utilization. J Trauma, 2008. 64(5): p. 1177-82; discussion 1182-3

Substantial Bleeding Protocols

(SBP) were developed to preemptively mitigate the lethal triad of acidosis, hypothermia, and coagulopathy through damage control resuscitation principles

Shaz, B.H., et al., Transfusion management of trauma patients. Anesth Analg, 2009. 108(6): p. 1760-8 chuster, K.M., et al., The status of massive transfusion protocols in United States trauma centers: massive transfusion or massive confusion? Transfusion, 2010. 50(7): p. 1545-51.

Purpose and Creation • A SBP

Addresses the organizational issues necessary to respond to massive blood loss in an immediate and sustained manner. It reduces provider variability, facilitates staff communication and compliance, and simplifies the administration of predefined ratios of blood components.

Nunez, T.C., et al., Creation, implementation, and maturation of a massive transfusion protocol for the exsanguinating trauma patient. J Trauma, 2010. 68(6): p. 1498-505 Cotton, B.A., et al., Damage control hematology: the impact of a trauma exsanguination protocol on survival and blood product utilization. J Trauma, 2008. 64(5): p. 1177-82; discussion 1182-3

Implementation of a SBP protocol

• Requires the multidisciplinary participation of specialist from emergency medicine, surgeons, anesthesiologists, critical care, transfusion medicine, nurses, pathology and blood bank personnel

• The logistical complexity of such an extensive

collaboration makes the implementation of MT programs inconsistent, even in Level I trauma centers

Cotton, B.A., et al., Damage control hematology: the impact of a trauma exsanguination protocol on survival and blood product utilization. J Trauma, 2008. 64(5): p. 1177-82; discussion 1182-3

Activation

Image: http://ljsilentg.com/wp-content/uploads/2013/02/Start-finish-line.jpeg

• Attending surgeon (at our institution) activates SBP based on available clinical data

• Basic data is sent to Blood Bank including trauma “code” name, est. age, gender and resuscitation location.

• Type and screen is sent from the ED to the BB to convert released components over to type-specific products as soon as possible

Activation of…

• SBP activates the release of a cooler with 6 units of universal donor plasma and 6 units of uncrossmatched PRBC.

• Rapid release of these products is possible by

keeping several units (4–6) of thawed universal donor (AB) plasma on hand at all times.

• Additionally, 1 units of apheresis platelets is released with the cooler

SBP Benefits

• 2005, Cotton et al. evaluated the implementation of a SBP. – Fixed component transfusion protocol reduced the

odds of mortality by 74%. – Decreased 30 day mortality (51% vs. 66%, p = 0.03) – Increased the percentage of unexpected survivors,

and reduced unexpected deaths (22% vs. 5% and 9% vs. 22%, respectively; p< 0.05)

Cotton, B.A., et al., Damage control hematology: the impact of a trauma exsanguination protocol on survival and blood product utilization. J Trauma, 2008. 64(5): p. 1177-82; discussion 1182-3

How is this benefit realized?

O'Keeffe, T., et al., A massive transfusion protocol to decrease blood component use and costs. Arch Surg, 2008. 143(7): p. 686-90;

discussion 690-1.

• SBP’s shorten the initial time for first product delivery and improves efficiency of delivery for future cycles of blood products

• Early transfusion of increased ratios of plasma and platelets – Riskin et al., found survivor benefit (reduction from

45% to 19% morality p = 0.02) with reduced time to first product in SBP patients, with comparable 24 hour ratios of FFP to PRBCs

– SBP reduced time to first documented transfusion for

cross-matched PRBCs, FFP, and platelets by 39%, 33%, and 42%, respectively

Riskin, D.J., et al., Massive transfusion protocols: the role of aggressive resuscitation versus product ratio in mortality reduction. J Am Coll Surg, 2009. 209(2): p. 198-205

Riskin, D.J., et al., Massive transfusion protocols: the role of aggressive resuscitation versus product ratio in mortality reduction. J Am Coll Surg, 2009. 209(2): p. 198-205. O'Keeffe, T., et al., A massive transfusion protocol to decrease blood component use and costs. Arch Surg, 2008. 143(7): p. 686-90; discussion 690-1.

• Stanford University Medical Center protocol reduced time to first documented transfusion for cross-matched PRBCs, FFP, and platelets by 39%, 33%, and 42%, respectively

• Likewise, at Parkland Hospital

in Dallas, a delivery time of less than 10 minutes was achieved for the first cooler and subsequent cycles intervals were reduced from 42 to 18 minutes

• The benefit of MT protocol has been attributed to early transfusion of increased ratios of plasma and platelets

• Evidence suggests that outcomes are closely linked to a

reduced time between components, with ratios at 6 hours being more predictive of improved outcomes than ratios at 24 hours

Cotton, B.A., et al., Damage control hematology: the impact of a trauma exsanguination protocol on survival and blood product utilization. J Trauma, 2008. 64(5): p. 1177-82; discussion 1182-3 Gonzalez, E.A., et al., Fresh frozen plasma should be given earlier to patients requiring massive transfusion. J Trauma, 2007. 62(1): p. 112-9. 62. Sisak, K., et al., Massive transfusion in trauma: blood product ratios should be measured at 6 hours. ANZ J Surg, 2012. 82(3): p. 161-7

While the importance of timing in multi-component transfusion is clear, the optimum ratios of components are less defined….

Blood Component Ratios

• WWI beginning of Vietnam, whole blood (WB) preferred product for resuscitation of hemorrhage

• Advances in component separation

1960-70s led to blood centers providing components (RBC, plasma, platelets) and removed whole blood from supply

Cannon WB et al, JAMA 1918 Kauvar DS et al. J Trauma 2006 and Strandenes G et al. Transfusion 2013 Spinella, P.C. and J.B. Holcomb, Resuscitation and transfusion principles for traumatic hemorrhagic shock. Blood Rev, 2009. 23(6): p. 231-40.

Blood Component Ratios

• One of the central tenets of hemostatic resuscitation is the delivery of fresh frozen plasma (FFP), platelets and red blood cells (RBC) in a ratio approaching 1:1:1

Dilution and storage loss reduce the effectiveness of component blood product therapy compared with fresh whole blood.

Dutton R P Br. J. Anaesth. 2012;109:i39-i46

© The Author [2012]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com

What is the best ratio?

• Murad et al. pooled analysis of four studies and showed that FFP:RBC ratios of greater than 1:3 are associated with a significant reduction in mortality (OR 0.38; 95% CI 0.24–0.60)

• Teixeira et al. and Zink et al. also found increase FFP: PRBC ratios were an independent predictor of survival

• Gunter et al. showed that 30 day mortality was

significantly decreased (41% versus 62%) with higher ratios of FFP and PLT to PRBC

Survivor Bias

• “In trauma resuscitation research, the conundrum of reverse causation is whether treatment caused patients to survive longer or patients received treatment only because they survived long enough.”

• The most important source of bias comes from the impact of survival

because patients who survive are more likely to receive FFP than patients who die, creating an artifactual association of survival with higher P:E ratios.

• Ho et al. examined 26 studies investigating blood product ratios and survivor bias.

– Fifteen of the 26 reviewed studies were determined to

be survivor bias unlikely – 10 of these 15 studies support improved survival

outcome with higher FFP:RBC ratios

Ho, A.M., et al., Prevalence of survivor bias in observational studies on fresh frozen plasma:erythrocyte ratios in trauma requiring massive transfusion. Anesthesiology, 2012. 116(3): p. 716-28.

PROMMTT study

• 10 center observation trial highlighted the variable nature of infusion, the importance of time, and improved outcomes with higher product ratios (n = 905, the analysis group).

• Primary outcome of interest was in-hospital mortality with a primary independent variables single plasma:RBC and platelet:RBC transfusion ratios

Holcomb, J.B., et al., The Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) Study: Comparative Effectiveness of a Time-Varying Treatment With Competing Risks. Arch Surg, 2012: p. 1-10.

PROMMTT • In the first 6 hours, patients with ratios less than 1:2

were 3 to 4 times more likely to die than patients with ratios of 1:1 or higher.

• In pts receiving at least 3 units protective association between higher transfusion ratios and in-hospital mortality appears strongest within 6 hours and diminishes over time

• Mortality shifts from exsanguination to head injury, respiratory distress, organ failure, and infection after the first 24 hours. Holcomb, J.B., et al., The Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) Study: Comparative Effectiveness of a Time-Varying Treatment With Competing Risks. Arch Surg, 2012: p. 1-10.

So where are we now?

• Two studies are currently underway to address the questions of time to transfusion and optimal ratio of product delivery.

• A European trial, the Activation of Coagulation and Inflammation in Trauma (ACIT), aims to characterize temporal effects of coagulation and inflammation

• The Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) study designed to definitely evaluate the benefit of blood product ratios on outcome.

Importance of PROPPR

• Provide valid, clinical trial framework for in-hospital trauma

• Address survival bias, primary critique of prior

retrospective studies • Understand mechanisms of trauma induced coagulation

(TIC) and inflammation – will be 1st to characterize natural history of coagulopathy and inflammation.

46

PROPPR Study

• Randomized, 2-group, controlled Phase III trial with Vanguard stage

• 2 groups – 1) 1:1:1 plasma:platelets:RBC ratio 2) 1:1:2 plasma:platelets:RBC ratio • Total enrollment: 680 subjects

47

PROPPR

• Houston enrolled one patient every 3 days. • In the first 24 hours, following patients in the hospital

for up to 30 days, and getting 30 day vital status, 2000 data points were collected on each patient

• Average # of transfusion during initial resuscitation is 12 units RBCs randomized to 1:1:1 or 1:1:2 with 18-26 units of total blood products transfused during the initial resuscitation.

Adjunct Therapy

Tranexamic acid (TXA)

• CRASH-2 study, examined the effect of (TXA) on mortality and transfusion requirements in 20,000 adult patients with traumatic injury and hemorrhagic shock

• Mortality and mortality from bleeding were improved

following TXA administration (RR = 0.91; 95% CI 0.85–0.97) and (RR = 0.85; 95% CI 0.76–0.96), respectively

• Benefit of TXA was observed only when administration

within the first 3 h of injury

Shakur, H., et al., Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet, 2010. 376(9734): p. 23-32. 6Roberts, I., et al., The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet, 2011. 377(9771): p. 1096-101, 1101 e1-2.

MATTERs trial

Morrison, J.J., et al., Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) Study. Arch Surg, 2012. 147(2): p. 113-9.

• Similar benefit was present in the combat injured.

• Despite being more severely

injured, the TXA group had lower unadjusted mortality than the no-TXA group (17.4% vs 23.9%, respectively; P=.03),

• Independently associated with survival (odds ratio=7.228; 95% CI, 3.016-17.322) and less coagulopathy (P=.003)

rFVIIa

• Two RCTs have shown a reduction in transfused pRBC following rFVIIa administration in blunt trauma although an improvement in mortality was not observed

• Systematic reviews of rFVIIa do not support rFVIIa as standard treatment for traumatic bleeding and should be considered in the management of refractory life-threatening hemorrhage, primarily in blunt trauma, when all conventional measures to control bleeding have failed

Prothrombin Complex Concentrates

• PCC pooled human plasma and contain 4 vitamin K dependent factors II, VII, IX, and X – 3 factor combo without F VII most commonly available

in the US • Effective alternative to FFP and rFVIIa for rapid

reversal of Coumadin therapy • Off label uses include coagulopathy due to

hepatic failure and traumatic hemorrhage • Primary complication is thrombosis

Ann Pharmacother. 2011 Jul;45(7-8):990-9. doi: 10.1345/aph.1Q096. Epub 2011 Jul 5. Prothrombin complex concentrate for critical bleeding.

Patanwala AE, Acquisto NM, Erstad BL.

PCC in Trauma

• Animal models have shown an emerging role for PCC in traumatic hemorrhage. – 4-factor PCC reversed PT, improved thrombin generation,

shortened time to hemostasis, and reduced volume of blood loss compared to FFP

– In trauma patients with intracranial hemorrhage and elevated INR who were receiving oral VKAs, the use of a 4-factor PCC protocol resulted in improved times to normalization of INR, reversal of coagulopathy, and decreased time to operative intervention vs. FFP alone

• Advantages low volume vs FFP and avoids the necessity of thawing product, citrate toxicity, TRALI, and ABO group specificity

Fibrinogen concentrate

• Schochl et al. described use of fibrinogen concentrates and decreased the need for pRBC transfusion (29% vs. 3% in FFP control (P< 0.001) and platelet concentrate utilization (91% of vs. 56% in FFP control)

• Multi organ failure was significantly decreased in patients exclusively treated with coagulation factor concentrates

• Benefit of fibrinogen concentrate on mortality have been mixed

Schochl, H., et al., Transfusion in trauma: thromboelastometry-guided coagulation factor concentrate-based therapy versus standard fresh frozen plasma-based therapy. Crit Care, 2011. 15(2): p. R83. Nienaber, U., et al., The impact of fresh frozen plasma vs coagulation factor concentrates on morbidity and mortality in trauma-associated haemorrhage and massive transfusion. Injury, 2011. 42(7): p. 697-701.

What are other programs doing for SBP?

• Young et al. surveyed the University Health System

Consortium, an alliance of 107 academic medical centers with 232 affiliated hospitals to evaluate use of SBP

• 25 Responders to survey

Young, P.P., B.A. Cotton, and L.T. Goodnough, Massive transfusion protocols for patients with substantial hemorrhage. Transfus Med Rev, 2011. 25(4): p. 293-303.

Survey results…

• 70% used a 1:1 ratio of pRBC/plasma for the initial resuscitation cycle, with some institutions altering ratios from cycle to cycle.

• Thawed plasma was available in only 60% of the responding hospitals for at least a portion of the first cycle, potentially delaying early administration.

• The routine use of cryoprecipitate and rVIIa as an adjunct therapy occurred in 36% and 15 % of protocols, respectively

Damage control resuscitation principles.

• Early transfusion of red blood cells:plasma:platelets in a 1:1:1 unit ratio

• Use of thawed plasma and fresh whole blood when available

• Appropriate use of coagulation factor products (rFVIIa) and fibrinogen containing products (fibrinogen concentrates, cryoprecipitate)

• Use of fresh RBCs (storage age of <14 days) • When available thromboelastography to direct blood

product and the hemostatic adjunct (anti-fibrinolytics and coagulation factor) administration

Rapid recognition of high risk for trauma-induced coagulopathy (massive transfusion prediction)

Permissive hypotension

Rapid definitive/surgical control of bleeding

Prevention/treatment of hypothermia, acidosis, and hypocalcemia Avoidance of hemodilution by minimizing use of crystalloids

Damage control resuscitation principles.

Conclusions/Summary

• While prospective randomized data are not currently available to guide many of these current practices, it must be recognized that the preponderance of data suggests that a balanced approach to plasma, platelets and RBCs, implemented early will improve outcome.

• 2000 • 1. Centers for Disease Control and Prevention, National Center for Injury Prevention and Control. . 2007 [cited

2012 6/21/2012]. • 2. Sauaia, A., et al., Epidemiology of trauma deaths: a reassessment. J Trauma, 1995. 38(2): p. 185-93. • 3. Acosta, J.A., et al., Lethal injuries and time to death in a level I trauma center. J Am Coll Surg, 1998. 186(5): p.

528-33. • 4. Kauvar, D.S., R. Lefering, and C.E. Wade, Impact of hemorrhage on trauma outcome: an overview of

epidemiology, clinical presentations, and therapeutic considerations. J Trauma, 2006. 60(6 Suppl): p. S3-11. • 5. Brohi, K., et al., Acute traumatic coagulopathy. J Trauma, 2003. 54(6): p. 1127-30. • 6. MacLeod, J.B., et al., Early coagulopathy predicts mortality in trauma. J Trauma, 2003. 55(1): p. 39-44. • 7. Wudel, J.H., et al., Massive transfusion: outcome in blunt trauma patients. J Trauma, 1991. 31(1): p. 1-7. • 8. Grounds, R.M., et al., Use of recombinant activated factor VII (Novoseven) in trauma and surgery: analysis of

outcomes reported to an international registry. J Intensive Care Med, 2006. 21(1): p. 27-39. • 9. Holcomb, J.B. and P.C. Spinella, Optimal use of blood in trauma patients. Biologicals, 2010. 38(1): p. 72-7. • 10. Cotton, B.A., et al., Damage control hematology: the impact of a trauma exsanguination protocol on survival and

blood product utilization. J Trauma, 2008. 64(5): p. 1177-82; discussion 1182-3. • 11. Hess, J.R., et al., Giving plasma at a 1:1 ratio with red cells in resuscitation: who might benefit? Transfusion,

2008. 48(8): p. 1763-5. • 12. Holcomb, J.B., et al., Increased plasma and platelet to red blood cell ratios improves outcome in 466 massively

transfused civilian trauma patients. Ann Surg, 2008. 248(3): p. 447-58. • 13. Shaz, B.H., et al., Increased number of coagulation products in relationship to red blood cell products transfused

improves mortality in trauma patients. Transfusion, 2010. 50(2): p. 493-500. • 14. Spinella, P.C., et al., Effect of plasma and red blood cell transfusions on survival in patients with combat related

traumatic injuries. J Trauma, 2008. 64(2 Suppl): p. S69-77; discussion S77-8. • 15. Zink, K.A., 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(5): p. 565-70; discussion 570. • 16. Sorensen, B. and D. Fries, Emerging treatment strategies for trauma-induced coagulopathy. Br J Surg, 2012. 99

Suppl 1: p. 40-50. • 17. Martinowitz, U. and M. Michaelson, Guidelines for the use of recombinant activated factor VII (rFVIIa) in

uncontrolled bleeding: a report by the Israeli Multidisciplinary rFVIIa Task Force. J Thromb Haemost, 2005. 3(4): p. 640-8. • 18. Curry, N. and P.W. Davis, What's new in resuscitation strategies for the patient with multiple trauma? Injury,

2012. 43(7): p. 1021-8. • 19. Maegele, M., et al., Early coagulopathy in multiple injury: an analysis from the German Trauma Registry on 8724

patients. Injury, 2007. 38(3): p. 298-304. • 20. Brohi, K., M.J. Cohen, and R.A. Davenport, Acute coagulopathy of trauma: mechanism, identification and effect.

Curr Opin 2010. 69(4): p. 976-90.

• Crit Care, 2007. 13(6): p. 680-5. • 21. Brohi, K., et al., Acute traumatic coagulopathy: initiated by hypoperfusion: modulated through the protein C

pathway? Ann Surg, 2007. 245(5): p. 812-8. • 22. Floccard, B., et al., Early coagulopathy in trauma patients: an on-scene and hospital admission study. Injury,

2012. 43(1): p. 26-32. • 23. Ganter, M.T.a.P., Jean–François, New insights into acute coagulopathy in trauma patients. Best Practice &amp;

Research Clinical Anaesthesiology, 2010. 24(1): p. 15-24. • 24. Jansen, J.O., et al., Damage control resuscitation for patients with major trauma. BMJ, 2009. 338: p. b1778. • 25. Duchesne, J.C., et al., Damage control resuscitation: the new face of damage control. J Trauma, • 26. Spinella, P.C. and J.B. Holcomb, Resuscitation and transfusion principles for traumatic hemorrhagic shock.

Blood Rev, 2009. 23(6): p. 231-40 • 27. WB, C., The preventive treatment of wound shock. JAMA. 1918; 70:618. JAMA, 1918. 70: p. 618. • 28. Cirocchi, R., et al., Damage control surgery for abdominal trauma. Cochrane Database Syst Rev, 2010(1): p.

CD007438. • 29. Holcomb, J.B., et al., Damage control resuscitation: directly addressing the early coagulopathy of trauma. J

Trauma, 2007. 62(2): p. 307-10. • 30. Cotton, B.A., et al., Damage control resuscitation is associated with a reduction in resuscitation volumes and

improvement in survival in 390 damage control laparotomy patients. Ann Surg, 2011. 254(4): p. 598-605. • 31. Shaz, B.H., et al., Transfusion management of trauma patients. Anesth Analg, 2009. 108(6): p. 1760-8. • 32. Borgman, M.A., et al., The ratio of blood products transfused affects mortality in patients receiving massive

transfusions at a combat support hospital. J Trauma, 2007. 63(4): p. 805-13. • 33. Morse, B.C., et al., Outcomes after massive transfusion in nontrauma patients in the era of damage control

resuscitation. Am Surg, 2012. 78(6): p. 679-84. • 34. Stinger, H.K., et al., The ratio of fibrinogen to red cells transfused affects survival in casualties receiving massive

transfusions at an army combat support hospital. J Trauma, 2008. 64(2 Suppl): p. S79-85; discussion S85. • 35. Nunez, T.C., et al., Creation, implementation, and maturation of a massive transfusion protocol for the

exsanguinating trauma patient. J Trauma, 2010. 68(6): p. 1498-505. • 36. Dente, C.J., et al., Improvements in early mortality and coagulopathy are sustained better in patients with blunt

trauma after institution of a massive transfusion protocol in a civilian level I trauma center. J Trauma, 2009. 66(6): p. 1616-24.

• 37. Stawicki, S.P., et al., The concept of damage control: extending the paradigm to emergency general surgery. Injury, 2008. 39(1): p. 93-101.

• 38. Duchesne, J.C., et al., Review of current blood transfusions strategies in a mature level I trauma center: were we wrong for the last 60 years? J Trauma, 2008. 65(2): p. 272-6; discussion 276-8.

• 39. Malone, D.L., J.R. Hess, and A. Fingerhut, Massive transfusion practices around the globe and a suggestion for a common massive transfusion protocol. J Trauma, 2006. 60(6 Suppl): p. S91-6.

• 40. O'Keeffe, T., et al., A massive transfusion protocol to decrease blood component use and costs. Arch Surg, 2008. 143(7): p. 686-90; discussion 690-1.

• 41. Riskin, D.J., et al., Massive transfusion protocols: the role of aggressive resuscitation versus product ratio in mortality reduction. J Am Coll Surg, 2009. 209(2): p. 198-205.

• data points on each patient

• 42. Gonzalez, E.A., et al., Fresh frozen plasma should be given earlier to patients requiring massive transfusion. J Trauma, 2007. 62(1): p. 112-9. • 43. Sisak, K., et al., Massive transfusion in trauma: blood product ratios should be measured at 6 hours. ANZ J Surg, 2012. 82(3): p. 161-7. • 44. Hirshberg, A., et al., Minimizing dilutional coagulopathy in exsanguinating hemorrhage: a computer simulation. J Trauma, 2003. 54(3): p. 454-63. • 45. Ho, A.M., M.K. Karmakar, and P.W. Dion, Are we giving enough coagulation factors during major trauma resuscitation? Am J Surg, 2005. 190(3): p. 479-84. • 46. Kashuk, J.L., et al., Postinjury life threatening coagulopathy: is 1:1 fresh frozen plasma:packed red blood cells the answer? J Trauma, 2008. 65(2): p. 261-70;

discussion 270-1. • 47. Murad, M.H., et al., The effect of plasma transfusion on morbidity and mortality: a systematic review and meta-analysis. Transfusion, 2010. 50(6): p. 1370-83. • 48. Teixeira, P.G., et al., Impact of plasma transfusion in massively transfused trauma patients. J Trauma, 2009. 66(3): p. 693-7. • 49. Gunter, O.L., Jr., et al., Optimizing outcomes in damage control resuscitation: identifying blood product ratios associated with improved survival. J Trauma, 2008. 65(3):

p. 527-34. • 50. Curry, N.S., et al., Transfusion strategies for traumatic coagulopathy. Blood Rev, 2012. 26(5): p. 223-32. • 51. Johansson, P.I. and J. Stensballe, Hemostatic resuscitation for massive bleeding: the paradigm of plasma and platelets--a review of the current literature. Transfusion,

2010. 50(3): p. 701-10. • 52. Zehtabchi, S. and D.K. Nishijima, Impact of transfusion of fresh-frozen plasma and packed red blood cells in a 1:1 ratio on survival of emergency department patients

with severe trauma. Acad Emerg Med, 2009. 16(5): p. 371-8. • 53. Stansbury, L.G., et al., Controversy in trauma resuscitation: do ratios of plasma to red blood cells matter? Transfus Med Rev, 2009. 23(4): p. 255-65. • 54. de Biasi, A.R., et al., Blood product use in trauma resuscitation: plasma deficit versus plasma ratio as predictors of mortality in trauma (CME). Transfusion, 2011. 51(9):

p. 1925-32. • 55. Magnotti, L.J., et al., Improved survival after hemostatic resuscitation: does the emperor have no clothes? J Trauma, 2011. 70(1): p. 97-102. • 56. Snyder, C.W., et al., The relationship of blood product ratio to mortality: survival benefit or survival bias? J Trauma, 2009. 66(2): p. 358-62; discussion 362-4. • 57. Ho, A.M., et al., Prevalence of survivor bias in observational studies on fresh frozen plasma:erythrocyte ratios in trauma requiring massive transfusion. Anesthesiology,

2012. 116(3): p. 716-28. • 58. Holcomb, J.B., et al., The Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) Study: Comparative Effectiveness of a Time-Varying

Treatment With Competing Risks. Arch Surg, 2012: p. 1-10. • 59. Shakur, H., et al., Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a

randomised, placebo-controlled trial. Lancet, 2010. 376(9734): p. 23-32. • 60. Roberts, I., et al., The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled

trial. Lancet, 2011. 377(9771): p. 1096-101, 1101 e1-2. • 61. Morrison, J.J., et al., Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) Study. Arch Surg, 2012. 147(2): p. 113-9. • 62. Boffard, K.D., et al., Recombinant factor VIIa as adjunctive therapy for bleeding control in severely injured trauma patients: two parallel randomized, placebo-controlled,

double-blind clinical trials. J Trauma, 2005. 59(1): p. 8-15; discussion 15-8. • 63. Hauser, C.J., et 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(3): p. 489-500. • 64. Stanworth, S.J., et al., Recombinant factor VIIa for the prevention and treatment of bleeding in patients without haemophilia. Cochrane Database Syst Rev, 2007(2): p.

CD005011. • 65. Schochl, H., et al., Goal-directed coagulation management of major trauma patients using thromboelastometry (ROTEM)-guided administration of fibrinogen

concentrate and prothrombin complex concentrate. Crit Care, 2010. 14(2): p. R55. • 66. Schochl, H., et al., Transfusion in trauma: thromboelastometry-guided coagulation factor concentrate-based therapy versus standard fresh frozen plasma-based

therapy. Crit Care, 2011. 15(2): p. R83. • 67. Nienaber, U., et al., The impact of fresh frozen plasma vs coagulation factor concentrates on morbidity and mortality in trauma-associated haemorrhage and massive

transfusion. Injury, 2011. 42(7): p. 697-701. • 68. Young, P.P., B.A. Cotton, and L.T. Goodnough, Massive transfusion protocols for patients with substantial hemorrhage. Transfus Med Rev, 2011. 25(4): p. 293-303. • 69. Holcomb, J.B., et al., Admission rapid thrombelastography can replace conventional coagulation tests in the emergency department: experience with 1974 consecutive

trauma patients. Ann Surg, 2012. 256(3): p. 476-86. •