Battlefield Medicine: Military Transfusion Practices

1. Battlefield Medicine:Military Transfusion Practices Matthew A Borgman, MD Major, US Army, Medical Corps Blood Banks Association of New York State 5 June 2009 Thanks for this opportunity to speak to you this morning. My intentions today are to give some introductory information on traumatic coagulopathy, describe the concept of hemostatic resuscitation, and give so data from the battlefield on this subjectThanks for this opportunity to speak to you this morning. My intentions today are to give some introductory information on traumatic coagulopathy, describe the concept of hemostatic resuscitation, and give so data from the battlefield on this subject

2. Acknowledgements Philip C Spinella, MD Conn. Children�s Medical Center US Army Institute of Surgical Research I�d like to acknowledge on of my mentors, Dr. Phil Spinella, who was originally going to give this presentationI�d like to acknowledge on of my mentors, Dr. Phil Spinella, who was originally going to give this presentation

3. Outline Introduction Damage Control Resuscitation Data from the Battlefield Plasma Platelets Fresh Whole Blood Conclusion This is the outline I will follow as I just alluded to. I will use one study each to discuss plasma, platelets, and fresh whole blood. I will also give some civilian supporting data before I conclude.This is the outline I will follow as I just alluded to. I will use one study each to discuss plasma, platelets, and fresh whole blood. I will also give some civilian supporting data before I conclude.

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

5. 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. Arrival SBP ~50 I�ll begin with a case report. This 24yo Iraqi special forces soldier arrived via helicopter to a CSH. He sustained multiple GSW to the flank and pelvis. As you can see, he was significantly hypotensive upon arrivalI�ll begin with a case report. This 24yo Iraqi special forces soldier arrived via helicopter to a CSH. He sustained multiple GSW to the flank and pelvis. As you can see, he was significantly hypotensive upon arrival

6. 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 Here�s a description of the injuries./procedures he received. As you can see, any one of them is a set-up for a massive transfusion. For you pathologists in the room, he�d likely be heading to your morgue.Here�s a description of the injuries./procedures he received. As you can see, any one of them is a set-up for a massive transfusion. For you pathologists in the room, he�d likely be heading to your morgue.

7. This is what the anesthesiologist faced. Blood went in, blood came out. Here�s the tally of the products he received:This is what the anesthesiologist faced. Blood went in, blood came out. Here�s the tally of the products he received:

8. You�ll notice the WB in the left hand corner stands for whole blood. When such a casualty arrives, the call (in the CSH) goes out for potential �walking donors� who are prescreened to donate. From donation, two hours later, after crossmatch and rapid screening for HIV, HTLV, Hep B/C, the blood is transfused. Notice the approximate ratio of the products transfused here. You�ll notice the WB in the left hand corner stands for whole blood. When such a casualty arrives, the call (in the CSH) goes out for potential �walking donors� who are prescreened to donate. From donation, two hours later, after crossmatch and rapid screening for HIV, HTLV, Hep B/C, the blood is transfused. Notice the approximate ratio of the products transfused here.

9. And here is that Iraqi soldier after that heroic effort. That is Dr. Al Beekley, the Army surgeon who treated him--he�s currently serving out in Tacoma, WA.And here is that Iraqi soldier after that heroic effort. That is Dr. Al Beekley, the Army surgeon who treated him--he�s currently serving out in Tacoma, WA.

10. Introduction: Battlefield Medicine How would you transfuse (resuscitate) this type of casualty? So I ask, how would you transfuse these types of casualties. If you were on the committee for a massive transfusion protocol, what info would you use to inform your decisions???So I ask, how would you transfuse these types of casualties. If you were on the committee for a massive transfusion protocol, what info would you use to inform your decisions???

11. 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 Hemorrhage remains the leading PREVENTABLE cause of death from trauma (head injury is the primary cause death). Resuscitating these casualities requires an understanding of WHY they are bleeding, and continue to bleed.Hemorrhage remains the leading PREVENTABLE cause of death from trauma (head injury is the primary cause death). Resuscitating these casualities requires an understanding of WHY they are bleeding, and continue to bleed.

12. Hemostasis in Trauma The vast majority of trauma patients that arrive to the ED are in a relatively hypercoagulable state due to activation of the coagulation system from trauma. The minority of patients, and these are the ones at risk of death from hemorrhage, are hypocoagulable for multiple reasons.The vast majority of trauma patients that arrive to the ED are in a relatively hypercoagulable state due to activation of the coagulation system from trauma. The minority of patients, and these are the ones at risk of death from hemorrhage, are hypocoagulable for multiple reasons.

13. Coagulopathy of Trauma Historic �trauma triad� of hemorrhage, acidosis, hypothermia Platelet/factor dysfunction with low pH and temp Dilutional coagulopathy Excessive use of crystalloid, RBCs Consumptive coagulopathy Hyperfibrinolysis 20% on admission with ISS>15 Acute coagulopathy of trauma Classically, the trauma triad or blood vicious cycle describes the continued hemorrhage that occurs and is aggravated by acidosis and hypothermia. As you know, the function of platelets and coagulation factor proteases decline with decrease temperature and pH. The coagulopathy is also dilutional, as patients are resuscitated initially with crystalloids or red blood cell units. There is a consumptive coagulopathy as well, as factors, platelets, fibrinogen are used up due to widespread activation. Additionally, a phenomenon known as the acute coagulopathy of trauma has also been described.Classically, the trauma triad or blood vicious cycle describes the continued hemorrhage that occurs and is aggravated by acidosis and hypothermia. As you know, the function of platelets and coagulation factor proteases decline with decrease temperature and pH. The coagulopathy is also dilutional, as patients are resuscitated initially with crystalloids or red blood cell units. There is a consumptive coagulopathy as well, as factors, platelets, fibrinogen are used up due to widespread activation. Additionally, a phenomenon known as the acute coagulopathy of trauma has also been described.

14. 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. Dr. Karim Brohi has found in his lab that this occurs very early, and is directly due to tissue hypoperfusion and ischemia. Via the protein C pathway, there is decreased utilization of fibrinogen and plasminogen activator inhibitor. As this occurs early, it is before there is any deficiency of factors. Dr. Karim Brohi has found in his lab that this occurs very early, and is directly due to tissue hypoperfusion and ischemia. Via the protein C pathway, there is decreased utilization of fibrinogen and plasminogen activator inhibitor. As this occurs early, it is before there is any deficiency of factors.

15. Outline Introduction Damage Control Resuscitation Data from the Battlefield Plasma Platelets Fresh Whole Blood Conclusion Next I will discuss damage control resuscitation.Next I will discuss damage control resuscitation.

16. Damage Control Resuscitation The battleship premise of first �patching up the holes,� and delaying definitive care Early surgical control of bleeding Prevent/treat: acidosis, hypothermia, hypocalcemia, coagulopathy, shock Consider permissive hypotension Prevents �popping the clot� Contra-indicated in traumatic brain injury The concept of damage control originated in the navy: when a ship was hit, the priority was to patch up the holes, delaying definitive repairs until you�re assured the ship won�t sink. Here, the concept is to establish early surgical control of bleeding, prevent and/or treat acidosis, hypothermia, hypocalcemia, coagulopathy and shock. One can also consider permissive hypotension, an older concept which prevents popping the clot or re-bleeding.The concept of damage control originated in the navy: when a ship was hit, the priority was to patch up the holes, delaying definitive repairs until you�re assured the ship won�t sink. Here, the concept is to establish early surgical control of bleeding, prevent and/or treat acidosis, hypothermia, hypocalcemia, coagulopathy and shock. One can also consider permissive hypotension, an older concept which prevents popping the clot or re-bleeding.

17. Hemostatic Resuscitation To prevent or treat coagulopathy of trauma 1:1:1 ratio of Plasma: RBC: PLT Thawed Plasma use Limit excessive use of RBCs & crystalloids Use RBCs of decreased storage age Consider early use of Fibrinogen (Cryo) and rFVIIa Warm Fresh Whole Blood � when available A part of Damage Control Resuscitation is the hemostatic resuscitation, the focus of which is to prevent or treat the coagulopathy of trauma. Here, utilizing a ratio of 1:1:1 of plasma:platelets:RBC. The Military uses thawed AB- Plasma so it�s readily available. Additionally, limiting the excessive use of RBCs and crystalloids to prevent dilutional coagulopathy Using RBCs of decreased storage age if possible Consider the early use of cryoprecipitate and factor VIIa And use warm fresh whole blood if feasible. A part of Damage Control Resuscitation is the hemostatic resuscitation, the focus of which is to prevent or treat the coagulopathy of trauma. Here, utilizing a ratio of 1:1:1 of plasma:platelets:RBC. The Military uses thawed AB- Plasma so it�s readily available. Additionally, limiting the excessive use of RBCs and crystalloids to prevent dilutional coagulopathy Using RBCs of decreased storage age if possible Consider the early use of cryoprecipitate and factor VIIa And use warm fresh whole blood if feasible.

18. Outline Introduction Damage Control Resuscitation Data from the Battlefield Plasma Platelets Fresh Whole Blood Conclusion Now some data from the battlefield�Now some data from the battlefield�

19. 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 The recent conflicts in Iraq and Afghanistan have provided means for the study of large numbers of severely injured casualties. The military has made an effort to make improvements that are data driven. The Joint Theater Trauma Registry has been an indispensable resource for studying this data. We�ll limit our discussion to three military studies: on the FFP:RBC ratio, PLT:RBC ratio, and Warm Fresh Whole BloodThe recent conflicts in Iraq and Afghanistan have provided means for the study of large numbers of severely injured casualties. The military has made an effort to make improvements that are data driven. The Joint Theater Trauma Registry has been an indispensable resource for studying this data. We�ll limit our discussion to three military studies: on the FFP:RBC ratio, PLT:RBC ratio, and Warm Fresh Whole Blood

20. FFP:RBC Ratio study 246 massively transfused patients at a CSH 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 In this first study, which was the first to begin this debate of plasma ratios in trauma resuscitation, we looked at 246 massively transfused patients at a CSH. MT is defined as receiving =10 units of RBC or whole blood in a 24 hour period. We divided the patients into three groups based on the FFP:RBC ratio groups noted, and then compared their baseline demographics and outcomes. We then performed a multivariate logistic regression analysis for overall mortality.In this first study, which was the first to begin this debate of plasma ratios in trauma resuscitation, we looked at 246 massively transfused patients at a CSH. MT is defined as receiving =10 units of RBC or whole blood in a 24 hour period. We divided the patients into three groups based on the FFP:RBC ratio groups noted, and then compared their baseline demographics and outcomes. We then performed a multivariate logistic regression analysis for overall mortality.

21. This chart represents the mortality in the 3 ratio groups. The red column are those who received less than 1 unit of plasma for every 4 units of blood. The green are those who received at least 1 unit of plasma for every 2 units of blood, and the yellow are those in between. As you can see, there is a dramatic decrease in mortality: 655, 34%, to 20%. This chart represents the mortality in the 3 ratio groups. The red column are those who received less than 1 unit of plasma for every 4 units of blood. The green are those who received at least 1 unit of plasma for every 2 units of blood, and the yellow are those in between. As you can see, there is a dramatic decrease in mortality: 655, 34%, to 20%.

22. The 3 groups were equal in the injury severity scores, and the percentage of those who were severely injured The 3 groups were equal in the injury severity scores, and the percentage of those who were severely injured

23. They were also equal in baseline numbers, with the exception of hemoglobin, as the low plasma group were slightly more anemicThey were also equal in baseline numbers, with the exception of hemoglobin, as the low plasma group were slightly more anemic

24. Cause of death by ratio group When you look at the cause of death in each group, you find that the low plasma group died much more often from hemorrhage (95% vs. 39% in the higher plasma group). This first group also died much quicker. Death from MOF or sepsis was increased in the group on the right, which you would expect in such a population--as patients survived hemorrhage, they became at risk of these other things. When you look at the cause of death in each group, you find that the low plasma group died much more often from hemorrhage (95% vs. 39% in the higher plasma group). This first group also died much quicker. Death from MOF or sepsis was increased in the group on the right, which you would expect in such a population--as patients survived hemorrhage, they became at risk of these other things.

25. Multivariate for Survival As you can see, the Plasma:RBC ratio was associated with an 8.6 odds of survival per our multivariate regression analysis. As you can see, the Plasma:RBC ratio was associated with an 8.6 odds of survival per our multivariate regression analysis.

26. Limitations of 1:1 study Retrospective Regression analysis may not include all confounders Survivorship bias 24 hour totals of FFP and RBC �catch-up� bias There are of course many limitations to this, and other such retrospective studies. Our regression may not include all the variables, or enough missing variables. There could have been a survivorship bias, in that those that died early died before they could receive plasma. And a 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.There are of course many limitations to this, and other such retrospective studies. Our regression may not include all the variables, or enough missing variables. There could have been a survivorship bias, in that those that died early died before they could receive plasma. And a 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.

27. 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 Let me take this opportunity to say that hemostatic resuscitation must be applied appropriately and early. As I just noted, death from hemorrhage occurs early. However, applying hemostatic resuscitation too liberally places patients at unnecessary risk for MOF, respiratory compromise, or thromboembolic events. To help with this, several predictive scores have been calculated to predict those at risk for a massive transfusion.Let me take this opportunity to say that hemostatic resuscitation must be applied appropriately and early. As I just noted, death from hemorrhage occurs early. However, applying hemostatic resuscitation too liberally places patients at unnecessary risk for MOF, respiratory compromise, or thromboembolic events. To help with this, several predictive scores have been calculated to predict those at risk for a massive transfusion.

28. Mortality based on TASH score To briefly digress to some civilian data I have been working with, this is data from about 2000 patients in the German Trauma Registry. We excluded patients who died within the ED and calculated FFP:RBC ratios based transfusions in the ED and OR, before arrival to the ICU. The mean total time was less than 3 hours. This significantly reduces both survivor and catch-up bias. On this graph the Y axis represents mortality, as you move to the right on the X axis are patient groups with increasing risk of receiving a massive transfusion. The yellow line are those who received at least 1:2 units of FFP:RBC. You will notice that there is no real difference in mortality for those who are not at risk, but when you get to a score of 15, or 40% risk of massive transfusion, there is a significant increase in mortality for those that were in the low plasma group. I will also say that those who received more plasma on this side of the graph had increased incidence of MOF, and decreased vent-free days, further emphasizing the point that hemostatic resuscitation needs to be employed appropriately. To briefly digress to some civilian data I have been working with, this is data from about 2000 patients in the German Trauma Registry. We excluded patients who died within the ED and calculated FFP:RBC ratios based transfusions in the ED and OR, before arrival to the ICU. The mean total time was less than 3 hours. This significantly reduces both survivor and catch-up bias. On this graph the Y axis represents mortality, as you move to the right on the X axis are patient groups with increasing risk of receiving a massive transfusion. The yellow line are those who received at least 1:2 units of FFP:RBC. You will notice that there is no real difference in mortality for those who are not at risk, but when you get to a score of 15, or 40% risk of massive transfusion, there is a significant increase in mortality for those that were in the low plasma group. I will also say that those who received more plasma on this side of the graph had increased incidence of MOF, and decreased vent-free days, further emphasizing the point that hemostatic resuscitation needs to be employed appropriately.

29. 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 This is a study evaluating apheresed platelets and survival in combat casualties. Note that these are apharesed units, not platelet concentrates.This is a study evaluating apheresed platelets and survival in combat casualties. Note that these are apharesed units, not platelet concentrates.

30. Mortality at 30 daysCox 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 To account various admission factors, they conducted a cox hazard multivariate regression. Note that both the plasma ratio and the aPLT ratio were associated with mortality at 30 days. There was also an association with mortality with the age of RBC units, though this was difficult to tease out since patients received units of various ages. To account various admission factors, they conducted a cox hazard multivariate regression. Note that both the plasma ratio and the aPLT ratio were associated with mortality at 30 days. There was also an association with mortality with the age of RBC units, though this was difficult to tease out since patients received units of various ages.

31. Survival to 24hrs and 30 days Notice the Kaplan Meier curves to 24 hours and 30 days, the main benefit coming early. Notice the Kaplan Meier curves to 24 hours and 30 days, the main benefit coming early.

32. Warm Fresh Whole Blood 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 The whole blood study evaluated 354 patients who received any transfusion. Those who received whole blood (which they calculated to be at least 30% of the total transfused volume), compared to those who only received component therapy. Both groups were equal in demographics, injury severity, and degree of shock.The whole blood study evaluated 354 patients who received any transfusion. Those who received whole blood (which they calculated to be at least 30% of the total transfused volume), compared to those who only received component therapy. Both groups were equal in demographics, injury severity, and degree of shock.

33. They found that though they received the same amount of blood, the component therapy group received much more anticoagulant in additivesThey found that though they received the same amount of blood, the component therapy group received much more anticoagulant in additives

34. Here is the Kaplan Meier curve for survivalHere is the Kaplan Meier curve for survival

35. When they performed the regression analysis, being in the whole blood group had the strongest odds of survival at 30 days, followed by plasma:RBC ratioWhen they performed the regression analysis, being in the whole blood group had the strongest odds of survival at 30 days, followed by plasma:RBC ratio

36. Both the amount of whole blood and plasma transfused also incurred increased odds of survivalBoth the amount of whole blood and plasma transfused also incurred increased odds of survival

38. 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 So why was there improved survival with WFWB? Is it improved function? So why was there improved survival with WFWB? Is it improved function?

40. 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

41. Limitations Retrospective Hypothesis generating not hypothesis testing WFWB group had mix of WFWB, RBC, plasma Not available in database Crystalloid and colloid amounts AIS scores Cause of death

42. Military vs. Civilian data There are significant differences in military trauma More often blast and penetrating trauma vs. blunt trauma However, civilian studies have generally corroborated military findings Two studies: (of 7 civilian) German Trauma Registry US Multicenter Study

43. German Trauma Study 713 patients transfused >10 units Divided into 3 RBC:FFP ratio groups: <0.9, 0.9 � 1.1, >1.1 Excluded deaths in the ED Minimizes survivorship bias Counted transfusions in ED and OR (not ICU) Average 4 hours Minimizes catch-up bias

44. German Trauma StudyRBC:FFP ratio mortality

45. US multicenter review 16 centers, 467 patients Excluded deaths within 30 min 4 groups based on 1:2 ratio cut-off of plasma or plt to RBCs: 24hr survival High plasma, high platelets 87% High plasma, low platelets 86% Low plasma, high platelets 83% Low plasma, low platelets 58%

46. Survival to 30 days

47. Massive Transfusion Protocol Implemented �trauma exsanguination protocol� Before/after cohort study 10 pRBC + 6 FFP + 2 PLT Then 6 pRBC + 4 FFP + 2 PLT Mortality 65.8% to 51.1% Showed decreased RBC and FFP and PLT utilization

48. Decreased utilization of blood products

49. Current Army Policy Transfuse to a ratio of 1:1:1 of FFP:RBC:PLT for those patients presenting with severe life threatening trauma/hemorrhage at risk for massive transfusion Use of fresh whole blood is authorized for patients with life-threatening injuries (at discretion of MD)

50. Conclusions Early FFP and Plt should be part of a massive transfusion protocols Fresh Whole Blood may have civilian application (mass casualties, massive transfusion) Prospective trials are needed to study blood product ratios and fresh whole blood http://www.usaisr.amedd.army.mil/cpgs.html

51. Questions Email: maborgman@gmail.com MT Patients: 3% of admissions Mortality of 30-60% TRALI occurs in 1-5/10,000 ptsMT Patients: 3% of admissions Mortality of 30-60% TRALI occurs in 1-5/10,000 pts

56. 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

57. Fresh Whole Blood 2831 FWB donor units 3 (0.11% +HCV) 2 +HTLV 0 (HBV, HIV) Baghdad Combat Support Hospital Biokit (Madrid, Spain) 408 screened 2 positive HCV (units discarded)