1. UNCLASSIFIEDwww.milblood.milASBPO Transfusion Practices with Combat Wounded Francis (Frank) M. Chiricosta, LTC, MC Transfusion Medicine Consultant, US Army

2. UNCLASSIFIEDwww.milblood.milASBPO Overview Massive Transfusion / Coagulopathy Resuscitation change in practices Traditional Guidelines / Practices Use of plasma Use of Fresh Whole Blood Factor VIIa Age of blood

3. UNCLASSIFIEDwww.milblood.milASBPO Hemorrhagic Mortality While bleeding is the #2 cause of mortality, hemorrhage is the #1 reversible cause for mortality Bleeding to death is an acute problem Almost all mortality from hemorrhage occurs within 1 st 24 hours Early control of hemorrhage can save lives Data adapted from: Acosta, et al. J Am Coll Surg 1998 & Sauaia, et al. J Trauma 1995 Slide courtesy JG Perkins

4. UNCLASSIFIEDwww.milblood.milASBPO Massive transfusion One body volume in 24 hours “Dilutional” coagulopathy –depleted coagulation factors –thrombocytopenia –hypoperfusion –confounding conditions: DIC, sepsis

5. Pathophysiology of Trauma With decreased blood pressure –Base deficit increased –Lactate Increased –Hematocrit Modestly Decreased –Heart Rate Increased Adapted from: Collins JA, Simmons RL, James PM, Bredenberg CE, Anderson RW, Heisterkamp CA 3rd.The acid-base status of seriously wounded combat casualties. I. Before treatment. Ann Surg. 1970 Apr;171(4):595-608. Base Deficit mEq/L 0 2 4 6 8 10 Lactate mg/100 mL 20 40 60 80 100 Hematocrit % 20 40 Heart Rate (BPM) 70 90 110 130 150 N=450 combat casualties in the Vietnam War on Admission Slide courtesy JG Perkins

6. Pathophysiology of Trauma Coagulopathy Acidosis Hypothermia

7. UNCLASSIFIEDwww.milblood.milASBPO Traditional resucitation Replace lost volume first with crystalloid May be able to restore normal BP Blood transfusion comes later Potential complications of aggressive fluid resuscitation –“Pop the clot” –Hemodilution –Coagulopathy –Hypothermia –Acidosis

8. UNCLASSIFIEDwww.milblood.milASBPO Damage Control Resucitation Do not replace volume quickly Hypovolemia / hypotension is tolerated Stop bleeding Correct abnormal physiology later “... inaccessible or uncontrolled sources of blood loss should not be treated with intravenous fluids until the time of surgical control.” --Cannon WB, FaserJ, CollewEM: The preventive treatment of wound shock. JAMA, 47:618, 1918 1918! Not a totally new idea

9. UNCLASSIFIEDwww.milblood.milASBPO Coagulopathy of Trauma Hemodilution due to resucitation… and Coagulopathy that is due to the trauma itself Evidence that coagulopathy starts before fluid resuscitation; not a dilutional coagulopathy Molecular mechanism: thrombomodulin, protein C (Brohi, K)

10. UNCLASSIFIEDwww.milblood.milASBPO Massive Transfusion, Transfusion considerations assessment: clinical and lab together –microvascular bleeding –PT/PTT > 1.5 nl, plt < 50 – 100 –Warm patient one 6-pk platelets roughly same coag. factors as U FFP Plt, CRYO, FFP short/difficult supply Fresh whole blood

11. UNCLASSIFIEDwww.milblood.milASBPO Massive Transfusion, Problematic transfusion management –Transfused plasma is foreign to recipient; has anti-A, -B; A substance, B substance –ABO incompatible plasma (e.g. type O rbc/WB/Plt to type A patient) may be associated with adverse outcome (Blumberg, N)

12. UNCLASSIFIEDwww.milblood.milASBPO Massive Transfusion, complications Citrate toxicity –Hypocalcemia, prolonged QT –With normal liver, not generally a problem –Rapid infusion centrally can be a problem –Alkalosis with metabolism Hyperkalemia? –Usually the opposite: with metabolic derangement, K + goes low –Theoretic problem in renal failure

13. UNCLASSIFIEDwww.milblood.milASBPO Massive Transfusion, complications Hypothermia (use of blood warmer) –PT/PTT elevation –Platelet dysfunction Dilutional coagulopathy Old blood is bad blood? Transfusion reactions –More error prone –Less likely to recognize

14. UNCLASSIFIEDwww.milblood.milASBPO Packed Red Blood Cells purpose of the transfusion To increase oxygen carrying capacity in an anemic patient when it is needed Need is based on clinical assessment of risk of complications of low oxygen delivery (e.g.. when cardiac oxygen demand increases to increase cardiac output)

15. UNCLASSIFIEDwww.milblood.milASBPO Traditional Guidelines

16. UNCLASSIFIEDwww.milblood.milASBPO Existing Guidelines Red cell transfusion –Purpose: oxygen carrying –loss of 30%+ of blood volume –normovolemic, P>100, SBP<100, ssx Diluent: normal saline only Assessment: clinical; H/H may not be valid Golden Hour

17. UNCLASSIFIEDwww.milblood.milASBPO Red Cell Indications clinical studies Hébert, et al. 1999 –randomized, controlled clinical trial, 838 critically ill patients liberal group: Hb tx. trigger 10g/dl restrictive group: trigger 7 g/dl –findings: overall 30-day mortality similar (p=0.11) lower rates for restrictive group for less acutely ill and age<55 (p=0.02, 0.03) in-hospital mortality rate lower in restrictive group (p=0.05)

18. UNCLASSIFIEDwww.milblood.milASBPO Red Cell Indications clinical studies Hébert, et al. 1999 –findings: liberal group had significantly higher rates for: –MI (p=0.02) –pulmonary edema (p<0.01) no significant difference in other complications trend toward lower 30-day mortality in restrictive group decreased blood exposure in restrictive group

19. UNCLASSIFIEDwww.milblood.milASBPO Red Cell Indications clinical studies Carson, 1998 –almost 9000 patients 60 years and older getting hip fracture repair –at pre-transfusion Hb (“trigger”) of 8 to 10 g/dl, no difference in 30- and 90-day mortality between transfused and not transfused Weiskopf, 1998 –experiment in isovolemic hemodilution in 23 healthy adults –Hb as low as 5g/dl tolerated at rest

20. UNCLASSIFIEDwww.milblood.milASBPO Treating Bleeding Related to Coagulation Abnormalities Platelets, FFP, and CRYO General rule: If bleeding greater than expected and is of a microvascular nature and lab values meet threshold (or not available in time or dysfunction of hemostasis is known or suspected)

21. UNCLASSIFIEDwww.milblood.milASBPO Microvascular Bleeding surgical: wetness/oozing from all or most exposed tissue, no visible vessel to mechanically stop non-surgical: –ecchymosis at sites other than surgical wound –oozing around catheters; from mucosal surfaces

22. UNCLASSIFIEDwww.milblood.milASBPO Platelets Indications, Guidelines and Practice Parameters American Society of Anesthesiology –Prophylactic transfusion is rarely indicated if thrombocytopenia is due to increased destruction –With surgery, usually not indicated >100,000 usually indicated <50,000 between 50 and 100,000: base on risk of bleeding –With microvascular bleeding, same guidelines as for surgery known platelet dysfunction –Procedures associated with insignificant blood loss may be done <50,000

23. UNCLASSIFIEDwww.milblood.milASBPO Fresh Frozen Plasma Indications, Guidelines and Practice Parameters American Society of Anesthesiology, 1996 –urgent reversal of warfarin effect –correction of known factor deficiency –for correction of microvascular bleeding in the presence of elevated (>1.5 x nl.) PT or PTT –for correction of microvascular bleeding in a patient who has received >1 blood volume

24. UNCLASSIFIEDwww.milblood.milASBPO Fresh Frozen Plasma Indications, Guidelines and Practice Parameters College of American Pathologists, 1994 –with active bleeding or procedure and PT* 1.5 x midpoint of normal (18s) or PTT* 1.5 x top of normal (51s) –in massive transfusion with microvascular bleeding and coagulation abnormality *fibrinogen must be normal, >100mg/dl; patient not on heparin

25. UNCLASSIFIEDwww.milblood.milASBPO Fresh Frozen Plasma Inappropriate Use Volume expander, Source of albumin, When heparin is cause of lab abnormality, When a specific therapy is available (VIII, IX, ATIII, Vitamin K, DDAVP) On a routine schedule with red cell transfusion (prophylactically in massive transfusion) British JH 2004

26. UNCLASSIFIEDwww.milblood.milASBPO Evidence against Routine Schedule of Plamsa in Massive Transfusion Mannucci et al. Vox Sang 42(3):113-23 (1982) “Standard schemas involving the administration of platelet concentrates and/or fresh-frozen plasma without evaluation of hemostasis … failed to decrease the requirements for … packed red cells. Therefore, indiscriminate administration in the massively transfused postoperative patient of blood components based on preestablished schemes appears to be unjustified.”

27. UNCLASSIFIEDwww.milblood.milASBPO Current Practice with Plasma More aggressive? earlier Agrees with traditional guidelines: –Apply aggressive strategy for patients that present with coagulopathy –Is treating bleeding assoc with abnl lab Apparent conflict with guidelines (ratio, routine schedule), but not if there is evidence of coagulopathy

28. UNCLASSIFIEDwww.milblood.milASBPO Evidence Supporting use of 1:1 Ratio RBC:plasma Borgman, MA. J Trauma 2007 Retrospective study Stratified patients by ratio of plasma:rbc Improved outcome with higher plasma proportion

29. UNCLASSIFIEDwww.milblood.milASBPO Recent Evidence, Plasma Mortality % RBC:FFP ratio (Borgman, MA. J Trauma 2007) Slide courtesy JG Perkins

30. UNCLASSIFIEDwww.milblood.milASBPO Evidence Supporting use of Apheresis Platelets Retrospective study pts at Ibn Sina Received 10 or more rbcs/FWB Compare groups: –Did not get platelets or FWB –Received platelets and not FWB –Received FWB Findings:

31. Time Period: January 2004 – December 2006 Study Profile - Retrospective CSH = Combat Support Hospital, RBC = red blood cell, FWB = fresh whole blood, aPLT = apheresis platelets, MT = massive transfusion 8,618 Trauma Patients Arrived at CSH 2,024 (23%) Received Blood Transfusions 12 MT occurred during hospital course, not on admission 89 treated at forward surgical teams/hospitals prior to transfer to CSH 434 charts reviewed for analysis 708 (8.2%) Received ≥ 10 u Blood (RBC + FWB) in 24 hours 285 Platelets – either as FWB or aPLT149 No FWB or aPLT 23 Both FWB and aPLT78 FWB184 aPLT

32. UNCLASSIFIEDwww.milblood.milASBPO 48 Hour and 30 Day Survival by Platelet versus No Platelet Groups Log Rank p=0.003 P<0.001 p=0.04

33. UNCLASSIFIEDwww.milblood.milASBPO 48 Hour and 30 Day Survival by Fresh Whole Blood versus Apheresis Platelet Subgroups p=0.72 p=0.87 Log Rank p=0.96

34. UNCLASSIFIEDwww.milblood.milASBPO

35. UNCLASSIFIEDwww.milblood.milASBPO Factor VII Use rFVIIa (NovoSeven) –Hemophiliac with anti-VIII (approved for) –Coumadin reversal –Stroke –Massive transfusion

36. UNCLASSIFIEDwww.milblood.milASBPO Factor VII Use and Outcome in OIF 1 of 2 Jan04 – Oct05, records for 61 of 117 patients who rec’d FVIIa Groups: –Early (FVIIa before 8 units blood) –Late (after 8 units) Groups similar for severity of injuries - Perkins, JG. J Trauma, 2007 May;62(5):1095-9

37. UNCLASSIFIEDwww.milblood.milASBPO Factor VII Use and Outcome in OIF 2 of 2 Early group rec’d fewer units of blood (20.6 vs. 25.7, p=0.048) and pRBC (16.7 vs. 21.7, p=0.049) Similar outcomes –Mortality (33.3% vs. 34.2%, p=NS) –ARDS (5.9 vs. 6.8%, p=NS) –Infection (5.9% vs. 9.1%, p=NS) –Thrombotic events (0% vs. 2.3%, p=NS)

38. UNCLASSIFIEDwww.milblood.milASBPO Conclusions Regarding Blood Therapy in Massive Transfusion For select patients with coagulopathy (7-8%) Use of either FWB or aPLT is associated with improved survival at 48 hrs and 30 days FWB and aPLT appear equivalent with regards to survival FFP:RBC ratios 1:2 to 1:1 are associated with improved survival at 48 hours, though this survival benefit is not apparent at 30 days. FVIIa use might reduce red cell with no appreciable excess adverse outcome

39. UNCLASSIFIEDwww.milblood.milASBPO Is Old Blood Bad Blood? “Age:” duration of storage Storage lesion –Decreased pH –Increased K+ –Decreased 2,3-DPG –Decreased deformability Clinical outcomes worse? (or not)

40. UNCLASSIFIEDwww.milblood.milASBPO Age of Blood: the Evidence Retrospective Inconsistent definition of age Different preservatives, modifications Inconsistent findings Uniform or near uniform findings/conclusions: –Number of units is associated with worse outcome –Findings are insufficient to recommend routine use of “young” units

41. UNCLASSIFIEDwww.milblood.milASBPO Age of Blood: the Evidence Basran Anesth Analg 2006;103:15–20 Retrospective, 321 re-do CABG pts Measures of age: mean; oldest unit Findings: correlates with longer LOS, mortality Conclusions: should be studied with RCT before informing practice

42. UNCLASSIFIEDwww.milblood.milASBPO Age of Blood: the Evidence Vamvakas Transfusion 1999;39:701-710 Retrospective, 269 cardiac surgery pts Measures of age: mean; Findings: age correlates with pneumonia, not with wound infection Conclusions: should be studied with RCT before guiding transfusion policy

43. UNCLASSIFIEDwww.milblood.milASBPO Age of Blood: the Evidence Vamvakas Transfusion 2000;40:101-109 Retrospective, 268 cardiac surgery pts Measures of age: mean; oldest; 2 oldest Findings: age does not correlate with LOS, time on ventilator Conclusions: future studies of transfusion should consider age

44. UNCLASSIFIEDwww.milblood.milASBPO Age of Blood: the Evidence Keller J Trauma 2002;53:1023–1025 Retrospective registry 18 hospitals, 86 trauma pts who rec’d 1-4 units Measures of age: mean; oldest; 2 oldest; number >7d; >14d; >21d; >28d Findings: only number of units >14d correlated with total LOS, not with ICU stay or vent Conclusions: further study needed

45. UNCLASSIFIEDwww.milblood.milASBPO Age of Blood: the Evidence Leal-Noval Anesthesiology 2003;98:815-22 Prospective cohort, 585 cardiac surgery pts Measures of age: mean; oldest; youngest Findings: –age does not correlate with LOS, time on ventilator, MI –Oldest unit and youngest unit correlates with pneumonia Conclusions: age does not increase morbity except maybe pneumonia (number of units)

46. UNCLASSIFIEDwww.milblood.milASBPO Age of Blood: the Evidence Van de Watering Transfusion 2006;46:1712-1718 Retrospective, 2732 cardiac surgery pts Measures of age: mean; oldest; youngest; comparisons for patients with all units 18d Findings: age correlates with number; no correlation with outcome Conclusions: there is no justification for limitation of storage time

47. UNCLASSIFIEDwww.milblood.milASBPO Age of Blood: the Evidence Walsh Crit Care Med 2004; 32(2):364 –371 Randomized ControlledTrial, 22 critical pts Comparison: ≤5d vs ≥20d Findings: age has no adverse effect on gastric function or measures of global oxygenation Conclusions: no support for the use of fresh red cells in critically ill patients

48. UNCLASSIFIEDwww.milblood.milASBPO Summary Current resucitation emphasizes early control of bleeding, later correction of injury Aggressive plasma transfusion is probably best practice for coagulopathic bleeding patient Component therapy better than FWB FWB as good when component therapy not available rFVII may be helpful in reducing red cell use We will do our patients more good (or at least less harm) by reducing number of units compared with reducing age of units