Damage Control Resuscitation

1. Damage Control Resuscitation Mazen Kherallah, MD, FCCP Executive Director of Quality Assurance SEHA: Abu Dhabi Infectious Disease & Critical Care Medicine Consultant Sheikh Khalifa Medical City 1

2. Outline Introduction Damage Control Resuscitation Data from the Battlefield Plasma Platelets Fresh Whole Blood Conclusion

3. Definition of Massive Transfusion Replacement of a blood volume equivalent within 24hr >10 unit within 24 hr Transfusion > 4 units in 1 hr Replacement of 50% of blood volume in 3hrs A rate of loss >150ml/ hr

4. Hemorrhaging Trauma Patient: Case Report* 24 y/o Iraqi special forces soldier Multiple high-velocity GSW through-and-through flanks and pelvis. Arrived via helicopter. Unknown pre-hospital time. *courtesy of Dr. Al Beekley Arrival SBP ~50

5. Injuries Left lobe of liver laceration Through-and-through distal esophagus 6 gastrotomies Splenic rupture Proximal splenic artery injury Distal pancreas laceration Left kidney laceration Multiple small bowel enterotomies Evisceration of omentum through left flank Bladder injury Extra-peritoneal rectal injury Pelvic fracture Internal iliac artery and vein lacerations Left open tibia/fibula fracture

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7. Introduction: Battlefield Medicine How would you transfuse (resuscitate) this type of casualty?

8. Introduction: Trauma/Coagulopathy Hemorrhage is the leading preventable cause of death from trauma Resuscitating these casualties requires some understanding of why they are bleeding …and continue to bleed despite getting transfused

9. Hemostasis in Trauma Majority (90-95%) - Non-severe - Inflammation - Hypercoaguable - DVT / PE Minority (5-10%) - Severe Trauma - Consumption, Dilution - Hypocoaguable - Hemorrhagic Shock

10. Coagulopathy of Trauma “trauma triad” of hemorrhage, acidosis, hypothermia Dilutional coagulopathy Excessive use of crystalloid, RBCs Consumptive coagulopathy Hyperfibrinolysis 20% on admission with ISS>15 Acute coagulopathy of trauma

11. Complications of massive transfusion

12. The Lethal Triad Acidosis Hypothermia Coagulopathy Death Brohi , K, et al. J Trauma, 2003.

13. Coagulopathy of trauma Brohi , K, et al. J Trauma, 2003.

14. Thermal Coagulopathy The coagulation cascade is an enzymatic pathway that degrades with temperature and ceases at 92 F Hypothermia slows the enzymatic reactions of the coagulation cascade Hypothermia prevents the activation of platelets by traction on the glycoprotein 1b, IX, V complex by von Willebrand factor (VWF ) A temperature < 96°F or 35°C is associated with an increase in mortality.

15. Dilutional Coagulopathy Coagulopathy associated with trauma and massive transfusion – dilutional Plasma-poor RBCs dilutes coagulation factor concentrations Collins . Massive transfusion and current bloodbanking practices. In: Preservation of Red Blood Cells. National Academy of Sciences: Washington, DC; 1973:39-40 Loss of blood Critical requirements for fluid, volume, red cells, albumin Critical dilution for coagulation factors occur after loss of 1.2 blood volumes and for platelets at 2 blood volumes

16. Acidotic Coagulopathy Acidosis – interferes with the assembly of coagulation factor complexes Acidosis contributes more to coagulopathy more than hypothermia (not reversible)

17. Consumption Coagulopathy Consumption of coagulation factors and platelets – highly localized at site of injury Subendothelial smooth-muscle cells, Fibrobasts TF TF TF FVII Nanomolecule of TF present in every square meter of fibroblasts or smooth-muscle cell – all of FVII could be removed from the circulation by 3-30m 2 of endothelial disruption Schester, Glesen Taby, et al 1997 Dietzen, Page Tetzloff, 1997

18. Increased fibrinolysis Generation of thrombin at injury sites leads to its binding to thrombomodulin on normal endothelium with activation of protein C Reduced local thrombin concentrations lead to thin fibrin strands with high surface-to-volume ratios and prevent the activation of TAFI (thrombin-activated fibrinolysis inhibitor) Low vascular flow leads to release of tissue plasminogen activator (tPA) from intact endothelial cells

19. Acute Coagulopathy of Trauma Very early within 10 min of arrival Hypoperfusion and shock (oxygen debt) Anti-coagulation and hyperfibrinolysis Increased soluble thrombomodulin Increased activated protein C Decreased utilization of fibrinogen Decreased plasminogen activator inhibitor No coagulation factor deficiency or dysfunction at this early time. Brohi K. Acute Coagulopathy of Trauma. J Trauma. 2008:64(5);1211-1217

20. New Diagnostic criteria Avoids the “but he looked good” phenomenon Within the first five minutes in the ED Identify patients in trouble Identify patients with increased mortality Identify patients with increased probability of massive transfusion

21. Patients At Risk for Massive Transfusion: MT 23 Hypothermia < 96.5

22. Acidosis Base deficit (BD) ≥ 6 identifies patients that require early transfusion, increased ICU days and risk for ARDS and MOF BD of ≥ 6 is strongly associated with the need for massive transfusion and mortality in both civilian and military trauma. Patients have an elevated BD before their blood pressure drops to classic “hypotension” levels.

23. Coagulopathy and Trauma Derangements in coagulation occur rapidly after trauma By the time of arrival at the ED, 28% (2,994 of 10,790) of trauma patients had a detectable coagulopathy that was associated with poor outcome ( Brohi et al., 2003)

24. Limiting effects of coagulopathy Hypotensive resuscitation – reducing the therapeutic goal for mean blood pressure = less fluid, less blood Local modalities Fibrin glue Hemostatic bandages Argon lasers

25. Limiting effects of coagulopathy Antifibrinolytics Fresh whole blood Increase early availability of plasma using thawed but type-specific 5-day plasma Recombinant activated factor VIIA (rVIIa) or combinations of fibrinogen and prothrombin complex concentrates

26. Limiting effects of coagulopathy 7. Combination of all approaches with rapid identification of coagulopathic patients, prompt initiation of 1:1:1 resuscitation ratios with RBCs, prethawed universal donor AB plasma and pheresis patients, conversion to FWB, frequent use of rVIIa in conjunction with attention to avoiding hypothermia and treatment of acidosis.

27. Identify Patients in Trouble Acidosis: Base Deficit > - 6 Coagulopathy: INR > 1.5 Hypotension Systolic: B/P < 90 Hemoglobin: < 11 Temperature: < 96. 5 Pattern recognition Weak or absent radial pulse Abnormal mental status Severe Traumatic Injury

28. Outline Introduction Damage Control Resuscitation Data from the Battlefield Plasma Platelets Fresh Whole Blood Conclusion

29. Complications of massive transfusion Crystalloid:PRBCs 3:1 Ratio

30. How to Resuscitate these Patients Damage Control Resuscitation Hemostatic resuscitation Hypotensive resuscitation Bleeding Control Permissive hypotension: Minimize rebleed : avoid “popping the clot” First “patching up the holes,” and delaying definitive care Early surgical control of bleeding Prevent/treat: acidosis, hypothermia, hypocalcemia , coagulopathy

31. Hypotensive Resuscitation Time Honored technique developed by Military physicians during WWI and WWII Maximizing the resuscitation benefit to the mitochondria while minimizing rebleeding by avoiding “popping the clot” Supported by a significant body of scientific data. This approach preserves the resuscitation fluid within the vascular system Logistically sound by preventing needless waste of blood and fluids.

32. Standard Resuscitation Paradigm Crystalloid 3:1 Ratio Blood FFP Transient or no response 6-10 u PRBC Crystalloid

33. Hemostatic Resuscitation Damage control philosophy can be extended to hemostatic resuscitation R estoring normal coagulation M inimizing crystalloid Traditional resuscitation strategies dilute the already deficient coagulation factors and increase multiple organ failure The aggressive hemostatic resuscitation should be combined with equally aggressive control of bleeding

34. Hemostatic Resuscitation

35. Outline Introduction Damage Control Resuscitation Data from the Battlefield Plasma Platelets Fresh Whole Blood Conclusion

36. Data from the Battlefield Recent conflicts in Iraq and Afghanistan have provided means for the study large numbers of severely injured patients Military medicine has made an effort to be data driven Joint Theater Trauma Registry We’ll look at three studies: FFP:RBC ratio Platelet:RBC ratio Warm Fresh Whole Blood

37. FFP:RBC Ratio study 246 massively transfused patients at a Combat Support Hospital Divided into 3 FFP:RBC ratio groups <1:4, 1:2 - 1:4, >1:2 Compared baseline demographics and outcomes Performed multivariate regression analysis for overall mortality Borgman , MA, Spinella , PC, et al. “Ratio of blood products affects mortality in trauma,” J Trauma 2007:63(4); 805-813

38. Mortality Chi Square Low to Med: p=0.01 Med to High: p=0.02 Effect of FFP:RBC ratio on overall mortality n=31 n=56 n=165 FFP:RBC Ratio Borgman , MA, Spinella , PC, et al. “Ratio of blood products affects mortality in trauma,” J Trauma 2007:63(4); 805-813

39. Mortality % n=31 n=56 n=165 Variable Low ratio FFP:RBC 1:8 (0:22 – 1:4) Medium ratio FFP:RBC 1:2.6 (1:3.9 – 1:2.1) High ratio FFP:RBC 1:1.4 (1:2 – 1:0.6) p value ISS 18 (16-25) 18 (14-25) 18 (16-25) 0.83 %ISS >25 23 20 22 0.94 FFP:RBC ratio Data: median (IQR) Borgman , MA, Spinella , PC, et al. “Ratio of blood products affects mortality in trauma,” J Trauma 2007:63(4); 805-813

40. Mortality % n=31 n=56 n=165 Variables upon admission Low ratio FFP:RBC 1:8 (0:22 – 1:4) Medium ratio FFP:RBC 1:2.6 (1:3.9 – 1:2.1) High ratio FFP:RBC 1:1.4 (1:2 – 1:0.59) P-value INR 1.78 (1.00-2.86) 1.54 (1.30-2.10) 1.54 (1.30-2.19)   0.86 Hgb 9.4 (7.1-10.9) 10.8(8.5-12.6) 10.9(9-13.1) 0.01 Plt level 225 (132-275) 177 (128-241) 216 (150-277) 0.79 Base Deficit 13 (4-14) 8 (3-14) 8 (4-13) 0.39 Temp 97 (94.9-97.6) 96.5 (94.2-98.0) 96.0 (94.0-97.5) 0.14 HR 122 (97-149) 117 (103-133) 112 (92-129)   0.08 Data: median (IQR)

41. Cause of death by ratio group 95% 70% 39% Mortality % Borgman , MA, Spinella , PC, et al. “Ratio of blood products affects mortality in trauma,” J Trauma 2007:63(4); 805-813

42. Multivariate for Survival

43. Limitations of 1:1 study Retrospective Regression analysis may not include all confounders Survivorship bias, in that those that died early died before they could receive plasma. 24 hour totals of FFP and RBC “catch-up” bias: where the survivors, who survive to 24 hours get transfused plasma later in the day to correct their coagulopathy and our numbers are simply a reflection of this.

44. Applying Hemostatic Resuscitation Must identify who is at risk EARLY Death from hemorrhage typically occurs in the first 6 hours Applying hemostatic resuscitation liberally places patients at unnecessary risk for multiorgan failure, respiratory compromise, and thromboembolic events Several predictive scores TASH score ABC score

45. TASH: Trauma-associated Severe Hemorrhage Score Systolic blood pressure (<100 mm Hg=4 pts , <120 mm Hg=1 pt ) Hemoglobin (<7 g/dL=8 pts , <9 g/dL=6 pts , <10 g/dL=4 pts , <11 g/dL=3 pts , and <12 g/dL=2 pts ) Intra-abdominal fluid (3 pts ) Complex long bone and/or pelvic fractures (AIS 3/4=3 pts and AIS 5=6 pts ) Heart rate (>120=2 pts ) Base excess (<-10 mmol /L=4 pts , <-6 mmol /L=3 pts , and <-2 mmol /L=1 pt ), Gender (male=1 pt ).

46. Mortality based on TASH score % MT <10 10-15 16-25 26-39 40-54 >54 TASH score 0-8 9-10 11-12 13-14 15-16 >16 High ratio (n) 432 167 182 144 134 288 Low ratio (n) 492 152 144 102 77 160 p value * n.s. n.s. n.s. n.s. 0.009 0.025 Borgman, MA Unpublished data TASH: Trauma-associated Severe Hemorrhage Score

47. Potential Plasma Mechanisms Activates human endothelial cell kinase pathways Protective for endothelial cell injury Restores endothelial glycocalyx Needed for cell integrity and function Decreased pulmonary and lymphatic endothelial cell permeability Increased Syndecan-1 expression Endothelial cell glycocalyx membrane protein involved in cell function and integrity JB Holcomb. Presented at 2009 Shock Society Conference

48. Plasma Composition Electrolytes (mmol/L) average unit of FFP ~ 300cc Na 165 (48mmol/unit) K 3.3 (1.0mmol/unit) Glucose 20 Calcium 1.8 Citrate 20 Lactate 3 pH 7.2-7.4 (LR 6.5, NS 5.0) Phosphate 3.63

49. Thawed Plasma Thawed plasma should be used as a primary resuscitative fluid. This product should be present upon arrival of the casualty in the ED This approach not only addresses the metabolic abnormality of shock, but initiates reversal of the coagulopathy present.

50. Apheresis Platelets Evaluated 462 casualties in Iraq who received a massive transfusion Three groups based on aPLT:RBC ratio >1:16, 1:8-16, <1:8 Evaluated 24hr, 30 day survival Perkins, JG, Cap, AP, Spinella , PC, et al. “Evaluation of the impact of Apheresis Platelets.” J Trauma. 2009; 66: S77-S85

51. Mortality at 30 days Cox Hazard Regression Variable Hazard Ratio p Value ISS 1.06 <0.001 INR 1.16 0.03 Plasma Ratio 0.98 0.01 aPLT ratio 0.91 <0.001 Base deficit 1.04 0.07 Stored RBC units 1.03 0.08 Perkins, JG, Cap, AP, Spinella , PC, et al. “Evaluation of the impact of Apheresis Platelets.” J Trauma. 2009; 66: S77-S85

52. Survival to 24hrs and 30 days Perkins, JG, Cap, AP, Spinella , PC, et al. “Evaluation of the impact of Apheresis Platelets.” J Trauma. 2009; 66: S77-S85

53. Warm Fresh Whole Blood Spinella, PC, Perkins, JG, et al “Association of Warm Fresh Whole Blood with Survival” J Trauma. 2009; 66;S69-S76 Retrospective, 354 pts transfused ≥ 1U of RBCs Compared patients transfused Fresh Whole Blood + (PRBC, FFP) Stored components (PRBC, FFP, aPLTs) Groups compared equal in: Age, severity of injury Admission vital signs and labs, RBC amount Average patient was in hemorrhagic shock Base deficit of 6 and INR of 1.4

54. Variable WFWB (n=100) CT (n=254) P value Total RBC (U) 16 (11-22) 16 (10-22) 0.44 Anticoagulant / Additives (L) 2.1 (1.5 – 3.1) 3.3 (2.1 – 4.6) <0.001 Results

55. Kaplan Meier Curve of 30 day survival WFWB group CT group Log rank test, p= 0.002 Warm Fresh Whole Blood Component Therapy

56. Variables OR (95.% C.I.) P value WFWB group* 15.4 (2.3 – 106) 0.005 Plasma:RBC ratio 10.3 (2.3 - 45.) 0.002 ISS 0.94 (0.91 - 0.97) 0.001 GCS eyes (normal) 3.91 (1.5 - 10.4) 0.006 Base deficit 0.88 (0.82 – 0.95) < 0.001 Multi-variate Logistic Regression for 30 day survival – Patient study groups * Reference group were CT patients AUC (95% CI) = 0.9 (0.85-0.95)

57. Variables OR (95.0% C.I.) p value WFWB (U) 2.15 (1.21-3.8) 0.016 Plasma (U) 1.09 (1.02-1.18) 0.019 RBC (U) 0.91 (0.85-0.97) 0.003 Base Deficit 0.91 (0.84-0.97) 0.002 GCS eyes (normal) 3.8 (1.4-10.2) 0.009 ISS 0.94 (0.91-0.98) 0.001 Multi-variate Logistic Regression for 30 day survival – individual blood product amounts AUC (95% CI) = 0.9 (0.86 – 0.95)

58. Variable WFWB (n=100) CT (n=254) p value Pulmonary Embolism 7 (7%) 11 (4%) 0.3 Myocardial Infarction 1 (1%) 0 (0%) 0.28 Cerebral Stroke 0 (0%) 5 (2%) 0.33 ARDS 7 (7%) 7 (3%) 0.08 Deep Vein Thrombosis 15 (15%) 21 (8%) 0.06 Renal Failure 8 (8%) 7 (3%) 0.04 Comparison of adverse events between study groups

59. Discussion Potential mechanisms for WFWB association with improved survival Improved function of RBCs, plasma, platelets in WFWB Thoroughly documented - Increased storage time for all blood products leads to decreased function 1-4 WFWB use minimizes use of old RBCs Old RBCs: hyperinflammatory, immunomodulatory, impair vasoregulation, poor O2 delivery Increased anti-coagulants and preservatives in stored components 1 Spinella PC, Crit Care Med, 2007 2 Napolitano LM, Crit Care Clinics, 2004 3 Lavee J, J Thor Cardiov Surg , 1989 4 Mohr R, J Thor Cardiov Surg , 1988

60. Discussion WFWB patients - Increased incidence of Renal failure ARDS, DVT – approached significance Since survival increased in WFWB group May be result of these patients living long enough to develop these complications Univariate analysis only and not adjusted with multivariate analysis

61. Component Therapy vs Fresh Whole Blood PRBC Hct 55% 335 mL Plt 5.5x10 10 50 mL FFP 80% 275 mL So Component Therapy Gives You 1U PRBC + 1U PLT + 1U FFP + 10 pk Cryo = 660 COLD mL Hct 29% Plt 87K Coag activity 65% 750 mg fibrinogen 500 mL Warm Hct: 38-50% Plt: 150-400K Coags: 100% Armand & Hess, Transfusion Med. Rev., 2003 1500 mg Fibrinogen