1. Hemorrhagic Shock John B. Holcomb, MD, FACS Commander, US Army Institute of Surgical Research Trauma Consultant for the Surgeon General Fort Sam Houston, Texas

2. 2 Fluid Resuscitation Following Injury: Rationale for the Use of Balanced Salt Solutions Rationale Early use of type-specific whole blood remains the primary treatment for shock due to blood loss Lactated Ringer’s (LR) is used to replace interstitial fluid and to support the intravascular volume until type-specific cross-matched blood is available LR is run at a very rapid rate—1000 to 2000 mL over 45 minutes—until whole blood is available Subsequent Steps Observe if the patient is a responder or nonresponder Base further whole blood transfusion on the patient’s response Seems very reasonable and sounds very similar to our recommendations Carrico CJ, et al. Crit Care Med. 1976;4:46-54.

3. 3 33 Discussion Platform >80% of combat-related deaths occur within 6 hours of wounding >80% of potentially preventable combat deaths are attributable to uncontrolled bleeding  Majority of deaths involve truncal (noncompressible) areas not conducive to tourniquets Management strategy includes novel pharmaceuticals, dressings, biological agents, tourniquets, and directed energy to stop internal bleeding that cannot be controlled by external compression methods Standard IV fluids can cause damage to the endothelium and coagulation system Hemorrhagic shock is a challenge to clinicians in both the civilian and combat casualty care setting

4. 4 44 A Definition of Hemorrhagic Shock A clinical syndrome resulting from: Decreased O 2 perfusion of vital organs Loss of blood volume Characterized by: Hypotension Tachycardia Pale, cold, and clammy skin Oliguria Decreased O 2 delivery or utilization

5. 5 55 Combat-Related Trauma In Operation Iraqi Freedom and Operation Enduring Freedom, >90% of casualties experience penetrating wounds  Largely from fragment dispersal of improvised explosive devises (IEDs) The Joint Theater Trauma Registry compared wounding patterns in these conflicts (Oct. 2001 to Jan. 2005) with available data from WWII, Korea, and Vietnam  Proportion of head and neck wounds higher  Proportion of thoracic wounds lower  Proportion sustained from explosions 78%, the highest seen in any large-scale conflict – Usually 50%-60% Owens BD, et al. J Trauma. 2008;64:295-299.

6. 6 66 Markers for Hemorrhagic Shock HCT <32% SBP <110 mm Hg HR> 105 bpm Acidosis: pH <7.25 BD <6 mmol/L INR> 1.5 Temp <34°C HCT=hematocrit; SBP=systolic blood pressure; HR=heart rate; BD=base deficit; INR=International Normalization Ratio. Tieu BH, et al. World J Surgery. 2007;31:1055-1064. McLaughlin D, et al. J Trauma. 2008;64(suppl):57-63.

7. 7 77 Classes of Hemorrhagic Shock Class I Hemorrhage (loss of <15%) Little tachycardia Usually no significant change in BP, pulse pressure, respiratory rate Class II Hemorrhage (loss of 15%-30%) HR >100 bpm, tachypnea, decreased pulse pressure Class III Hemorrhage (loss of 30%-40%) Marked tachycardia and tachypnea, decreased SBP, oliguria Class IV Hemorrhage (loss of >40%) Marked tachycardia and decreased SBP, narrowed pulse pressure, markedly decreased or no urinary output Immediately life-threatening Gutierrez G, et al. Crit Care. 2004;8:373-381.

8. 8 Adapted from Cosgriff N, et al. J Trauma. 1997;42:857-861; discussion 861-862. Major Torso Trauma Progressive Coagulopathy Core Hypothermia Metabolic Acidosis Active Hemorrhage Iatrogenic Factors Cellular Shock Tissue Injury Contact Activation Clotting Factor Deficiencies Massive Transfusion Pre-existing Diseases The “Bloody Vicious Cycle” Coagulopathy Develops Over Time—1997

9. 9 9 The Lethal Triad After 2003 Acidosis Hypothermia Coagulopathy Death Brohi K, et al. J Trauma. 2003;54:1127-1130. MacLeod J, et al. J Trauma. 2003;55:39-44.

10. 10 Trauma Shock COAGULOPATHY Genetics Hemorrhage Fibrinolysis Inflammation Acidemia Dilution Medications CoTS Resuscitation Blood loss Factor Consumption Hypothermia Other Diseases Data from International Group of Coagulation Investigators, 2008. The Cycle of Coagulopathy

11. 11 Acute Traumatic Coagulopathy in Combat Casualty Care Retrospective cohort study of 391 patients who received a transfusion Patient outcomes of Injury Severity Score (ISS) and mortality were assessed upon arrival to the ED – Physiologic associations of long bone fractures, central nervous system injuries, BD, and temperature The prevalence of acute coagulopathy in this cohort was 38% and increased with ISS Niles S, et al. J Trauma. 2008. In press. Brohi K, et al. J Trauma. 2003;54:1127-1130. MacLeod J, et al. J Trauma. 2003;55:39-44.

12. 12 0 10 20 30 40 50 60 INR <1.5INR 1.5-2.0 INR  2.0 Mortality (%) 12 Mortality by Level of Coagulopathy N=391 transfused casualties Niles S, et al. J Trauma. 2008. In press.

13. 13 Mortality by Coagulopathy and ISS 0 10 20 30 40 50 60 0-1415-24?25Total Injury Severity Score Mortality (%) Normal INR  1.5 P=.06 P=.13 P .001 Niles S, et al. J Trauma. 2008. In press.

14. 14 Clinical Perspective Trauma patients who are the most severely injured (≈10%) also represent the majority of in-hospital deaths Considerable attention has been directed toward damage control surgery and reversing the acidosis and hypothermia present on admission Less attention has been directed toward reversing coagulopathy related to blood loss and predicting those patients who will need aggressive transfusion strategies Holcomb JB, et al. J Trauma. 2007;62:307-310.

15. 15 3442 total patients 680 received 1+ units blood in first 24 hours 204 transferred from another facility 29 known younger than 18 years 81 security internees Total of 302 patients in study population  80 patients (26.5%) required massive transfusion (MT) A Predictive Model for Massive Transfusion in Combat Casualty Patients McLaughlin DF, et al. J Trauma. 2008;64(suppl):57-63.

16. 16 Variables in MT Equation Wald ValueCoefficient Standard Error Odds Ratio HR >10523.771.580.324.8 SBP <11014.961.260.333.5 pH < 7.2514.091.230.333.4 HCT <322.330.490.321.6 Adapted with permission from McLaughlin DF, et al. J Trauma. 2008;64(suppl):57-63. ©2008 Lippincott Williams & Wilkins http://lww.com.

17. 17 MT Scoring System SBP <110 HR >105 HCT<32 pH <7.25 ROC=.839 0 10 20 30 40 50 60 70 80 90 01234 Score % Probability of MT Adapted with permission from McLaughlin DF, et al. J Trauma. 2008;64(suppl):57-63. ©2008 Lippincott Williams & Wilkins http://lww.com. n= 168 n= 202 n= 151 n= 115 n= 62

18. 18 Comparison of 4 MT Prediction Studies AuthorVariablesROC Value McLaughlin et al.SBP, HR, pH, HCT0.839 Yücel et al. SBP, HR, BD, Hgb Male, +FAST, long bone/pelvic fracture 0.892 Moore et al.SBP, pH ISS >25 0.804 Schreiber et al Hgb ≤11 INR >1.5 Penetrating injury 0.804 Data from McLaughlin DF, et al. J Trauma. 2008;64:S57-S63; Yücel N, et al. J Trauma. 2006;60:1228-1236; discussion 1236-1237; Moore FA, et al. J Trauma. 2008;64:1010-1023; Schreiber MA, et al. J Am Coll Surg. 2007;205:541-545.

19. 19 Component Therapy vs Warm Whole Blood Component Therapy: 1 U PRBC + 1 U Plt + 1 U FFP + 1 U cryo 680 COLD mL HCT 29% Plt 80K Coag 65% of initial concentration 1000 mg fibrinogen Warm Whole Blood: PRBC=packed red blood cells; Plt=platelet; FFP=fresh frozen plasma; cryo=cryoprecipitate. Armand R, et al. Transfus Med Rev. 2003:17:223-231. 500 mL WARM HCT: 38%-50% Plt: 150K-400K Coag: 100% 1000 mg fibrinogen

20. 20 0.4 0.45 0.5 020406080100120140160180200220240260280300 Time, min Plasma Factor Concentration (%) 20 A Mathematical Model for FFP Transfusion Strategies During Major Trauma Resuscitation With Ongoing Hemorrhage “A mathematical model for fresh frozen plasma transfusion strategies during major trauma resuscitation with ongoing hemorrhage”—Reprinted from, CJS December 2005; 48(6), Page(s) 470-478 by permission of the publisher. © 2005 Canadian Medical Association v/V=0.005 v/V=0.02 Rate of blood loss as a fraction of total blood volume per min v/V=0.005 v/V=0.0075 v/V=0.01 v/V=0.0125 v/V=0.015 v/V=0.0175 v/V=0.02 Factor concentration during resuscitation; transfusate PRBC 3 U: FFP 1 U: crystalloid 100 mL (factor concentration 0.5 at time 0). v/V = rate of blood loss as a fraction of total volume per minute.

21. 21 McClelland RN, et al. JAMA. 1967;199:830-834 Moore FD, et al. Ann Surg. 1967;166:300-301 Rhee P, et al. Crit Care Med. 2000;28:74-78 Brandstrup B, et al. Ann Surg. 2003;238:641-648 NHLBI ARDS NET Clinical Trials Network; Wiedemann HP, et al. N Engl J Med. 2006;354:2564-2575 Cotton BA, et al. Shock. 2006;26:115-121. The Cellular, Metabolic, and Systemic Consequences of Aggressive Fluid Resuscitation Strategies ( review, Cotton et al, 2006)

22. 22 Hypothesis: Normal resuscitation, compared with supranormal, requires less crystalloid volume, decreasing the incidence of intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS) 1999 to 2001 (n=85) versus 2001 to 2002 (n=71) Conclusion: Supranormal resuscitation, compared with normal resuscitation, was associated with more LR infusion, decreased intestinal perfusion (higher GAP CO2 ), and an increased incidence of IAH, ACS, multiple organ failure, and death Balogh Z, et al. Arch Surg. 2003;138:637-643. Supranormal Trauma Resuscitation Causes More Cases of Abdominal Compartment Syndrome

23. 23 Damage Control Resuscitation In the combat casualty care setting, clinicians treating coagulopathy often have:  Immediate access to PRBCs and thawed AB or A plasma  Rapid access to apheresis platelets, prepooled cryoprecipitate, fresh whole blood, and recombinant activated factor VIIa (rVIIa), as indicated Damage control resuscitation as a structured intervention begins immediately after rapid initial assessment in the ED and progresses through the OR into the ICU Holcomb JB, et al. J Trauma. 2007;62:307-310.

24. 24 Damage Control Resuscitation (cont) In the severely injured casualty, damage control resuscitation consists of 2 parts: Resuscitation limited to keep BP at ≈90 mm Hg, preventing renewed bleeding from recently clotted vessels Intravascular volume restoration accomplished by using thawed plasma as a primary resuscitation fluid in at least a 1:1 or 1:2 ratio with PRBCs  Minimizing crystalloid  rVIIa is occasionally used Holcomb JB, et al. J Trauma. 2007;62:301-310.

25. 25 Casualties Requiring Continued Resuscitation Blood bank notified to activate the massive transfusion protocol:  Individual coolers – 6 units of plasma – 6 units of PRBCs – 6 packs of platelets  The most severely injured also receive fresh warm whole blood as a resuscitative fluid  Crystalloid use is minimized and serves mainly as a drug carrier and to keep lines open  Multiple point-of-care lab checks – BD, Hgb, INR, Ca Lack of intraoperative coagulopathic bleeding has been remarkable Holcomb JB, et al. J Trauma. 2007;62:307-310. Kauver DS, et al. J Trauma. 2006; 61:181-184. Spinella PC, et al. Crit Care Med. 2007;35:2576-2581.

26. 26 Adapted with permission from Borgman MA, et al. J Trauma. 2007;63:805-813. ©2007 Lippincott Williams & Wilkins http://lww.com. The Ratio of Blood Products Transfused Affects Mortality in Patients Receiving MTs at a Combat Support Hospital VariableOdds Ratio (95% CI)P value Plasma:RBC ratio8.6 (2.1–35).003 AIS head/neck score0.75 (0.61–0.94).013 AIS thorax score0.73 (0.57–0.92).009 SBP1.0 (0.98–1.01).457 Hemoglobin1.1 (0.91–1.2).501 BD0.89 (0.84–0.95)<.001 Odds Ratio Predicting Survival Using Multivariate Logistic Regression AIS=Abbreviated Injury Scale.

27. 27 Mortality by Plasma:RBC Ratio ( n=246 MTs [2003-2005 ]) Adapted with permission from Borgman MA, et al. J Trauma. 2007;63:805-813. ©2007 Lippincott Williams & Wilkins http://lww.com. P<.001 65 34 19 0 10 20 30 40 50 60 70 (Low) 1:8(Medium) 1:2.5(High) 1:1.4 Plasma:RBC Ratio Groups Mortality (%) Percentage mortality associated with low, medium, and high plasma to RBC ratios transfused at admission. Ratios are median ratios per group and include units of fresh whole blood counted both as plasma and RBCs.

28. 28 Comparison of the Primary Causes of Death in Each Plasma:RBC Ratio Group Time to Death Low = 2 hr Med = 4 hr High = 38 hr 0 10 20 30 40 50 60 70 80 90 100 Low n=20Medium n=18High n=31 1 0.5 1 2 1 11.5 6 4 2.5 7 Adapted with permission from Borgman MA, et al. J Trauma. 2007;63:805-813. ©2007 Lippincott Williams & Wilkins http://lww.com. 18.5 14

29. 29 UT Houston 4-Year Experience Variable Pre—1:2 (N = 97) Post—1:1 (N = 95)P value Age39±237±1.6.44 ISS29±128±1.2.53 ED INR1.8±0.21.62±0.08.41 Pre-ICU Cryst (L)9±17±0.4.07 Pre-ICU PRBC12±115±1.2.06 Pre-ICU FFP5±0.411±1.0<.0001 ICU Admit INR1.6±0.041.48±0.03.02 6 hr FFP:PRBC1: 2.41: 1.3.05 24 hr FFP:PRBC1:1.21: 1.0 Mortality30%15%<.05 Gonzalez E, et al. Paper presented at: 38th Annual Meeting of the Western Trauma Association; February 24-29, 2008; Squaw Creek, CA. No. 29.

30. 30 rVIIa+ to rVIIa- patients  24-hour mortality was 7/49 (14%) and 26/75 (35%), P=.01  30-day mortality was 15/49 (31%) and 38/75 (51%), P=.03 SBP was higher in the rVIIa+ group The use of rVIIa was associated with improved early and late survival after severe trauma and massive transfusion rVIIa was not associated with increased risk of thrombotic events Additional trials needed The Effect of rVIIa on Mortality in Combat-Related Casualties With Severe Trauma and MT Spinella PC, et al. J Trauma. 2008;64:286-294.

31. 31 Kaplan-Meier Curve of 24-Hour Mortality for rVIIa+ Patients vs rVIIa- Patients P =.004 by the log rank test. Adapted with permission from Spinella PC, et al. J Trauma. 2008;64:286-294. ©2008 Lippincott Williams & Wilkins http://lww.com. 0 20 40 60 80 100 0510152025 Hour of Death Cumulative Survival (%) P<.05 rVIIa No Yes 24-Hour Survival

32. 32 0 20 40 60 80 100 051015202530 Day of Death Cumulative Survival (%) 32 Kaplan-Meier Curve of 30-Day Mortality for rVIIa+ Patients vs rVIIa- Patients P =.002 by the log rank test. Adapted with permission from Spinella PC, et al. J Trauma. 2008;64:286-294. ©2008 Lippincott Williams & Wilkins http://lww.com. rVIIa No Yes 30-Day Survival P<.05

33. 33 Multicenter (16), Retrospective MT Study Increased Plasma and Platelet to RBC Ratios Improves Outcome in 466 Massively Transfused Civilian Trauma Patients Holcomb JB, Wade CE, Michalek JE, Chisholm GB, Schreiber MA, Gonzalez EA, Pomper G, Williams KL, Park MS, and The Trauma Outcomes Group. Conventional MT guidelines underrepresent the optimal plasma and platelet to RBC ratios. Survival in MT civilian patients is improved by increasing plasma and platelet ratios. Current survival after MT varies up to 80% at 16 major Level 1 Trauma centers. Prospective trials should aim for a 1:1 ratio of plasma and platelet to RBC ratios. Holcomb JB, et al. Abstract presented at: 128th Annual Meeting of the American Surgical Association; April 24-26, 2008; New York, NY. No. 6.

34. 34 Thawed Plasma FFP that is kept for up to 5 days at 4°C Present upon arrival in the ED  Used as a primary resuscitative fluid This approach not only addresses the metabolic abnormality of shock, but initiates reversal of the early coagulopathy of trauma Multiple centers are now using this product  Decreases waste by 60% to 70% Malone DL, et al. J Trauma. 2006;60(suppl):91-96. Armand R, et al.Transfus Med Rev. 2003;17:223-231.

35. 35 Risks of FFP and Platelets Reports of transfusion-related acute lung injury (TRALI) from the UK hemovigilance Serious Hazards of Transfusion scheme suggest a risk from FFP in the region of 1 in 60,000 units  This may now be the most common cause of death from transfusion, and is the most frequent serious complication of FFP In 100% of the TRALI cases arising from FFP, a female donor was identified as the source of the HLA/HNA antibodies Must be alive to have some of these complications MacLennan S, et al. J Trauma. 2006;60(suppl):46-50.

36. 36 Combat Case—IED, May 2006

37. 37 Combat Case—IED, May 2006 (cont)

38. 38 Combat Case Fragment wound in back 30 min evac to CSH Arrives pH=6.9 BD=25 Temp=35ºC INR=2 HCT=10 SBP=60 mm Hg HR=140 bpm Upon arrival arrested in the ED Clam shell/clamp aorta/to OR Lines and DCR started in the ED

39. 39 Radiographic Findings

40. 40 Combat Case

41. 41 The Surgical Field

42. 42 Fragment

43. 43 The Surgical Team

44. 44 Outcome 30 FFP, 32 RBC, 10 cryo, 20 platelets, rVIIa, 5 liters of LR Bleeding stopped with packing No coagulopathic bleeding Abdomen closed day 3 Recovered and discharged to local hospital in 14 days

45. 45 Prior Coordination and Cooperation Cannot be done in isolation and made up at 0200 ED staff Anesthesia Surgery/Trauma ICU Transfusion/blood bank Nursing Very small numbers  3% of all civilian trauma admissions  15% to 70% mortality

46. 46 Multiple Papers Presented and Submitted on This Topic Military experience 252 patients + AAST 07 Denver paper 140 (1:1) - AAST 07 Vanderbilt paper 139 + AAST 07 Tulane paper 135 + EAST 08 Vanderbilt paper 69 + German Trauma Society 409 + WTA Glue grant 405 + WTA Houston 192 + ASA 08 abstract 467 + 8 papers + (2068) and 1 “negative” (140) ≈20 abstracts submitted to AAST-08 on this subject AAST=American Association for the Surgery of Trauma; EAST=Eastern Association for the Surgery of Trauma; WTA=Western Trauma Association.

47. 47 Summary Uncontrolled hemorrhage is a major problem  MT used in 3% of all civilian trauma admissions  Very high mortality Predictive models are here  Rapid Dx of MT patients who are in shock and coagulopathic Must start plasma and platelets much earlier

48. 48 Summary (cont) Use physiology (not tradition) to drive diagnosis and interventions Don’t make the presenting problems worse with repeated iatrogenic injury Accept known risks and benefits

49. 49 Changing early resuscitation practices for the severely injured from crystalloid- based to primarily blood products Over the past 12 months, lyophilized plasma transfused into injured pigs—it is equivalent to fresh whole blood and FFP MGH, OHSU, USAISR Back to the Future? MGH=Massachusetts General Hospital; OHSU=Oregon Health Sciences University; USAISR=US Army Institute of Surgical Research.

50. 50 The Trauma Team