From the ED to the battlefield and back to the ED/bedside Resuscitation from Massive Hemorrhage & Development of the MTP: Perspective of an Obstetrical Anesthesiologist Alan I. Frankfurt, MD Partner, ATLAS Anesthesia Irving, Texas Department of Anesthesiology TH Dallas-Presbyterian Hospital -- Alan I. Frankfurt, MD

Learning Objectives Maryland Shock Trauma Somalia & Iraq/Afghanistan History lesson Incidence of MT DCR & “5 H’s” Coagulopathy and morbidity in hemorrhagic shock Lethal triad Evolution of the MTP: responding to an iatrogenic coagulopathy Maryland Shock Trauma Somalia & Iraq/Afghanistan 1:1:1 vs. 1:1:2-it’s a math thing PROMMTT PROPPRR Thoughts for your day to day practice in the ED. Alan I. Frankfurt, MD

HISTORY OF WARTIME PREHOSPITAL/ER SHOCK RESUSCITATION WW I/WW II Vietnam Korea OIF/OEF 50 years of Plasma, Albumin and Whole Blood Forward to the past( DCR): Early plasma ”WB” equivalent FWWB 40 years of Crystalloid/ Clear Fluids & WB: 3rd space resuscitation Fractionation of WB Alan I. Frankfurt, MD

Damage Control Resuscitation “5 H’s” Hemorrhage control OR timely fashion Definitive solution to bleeding is in the OR/IR Hypotensive resuscitation Systolic BP=80-90 torr “Tolerate” shock vs. Popping clots Hemostatic resuscitation Blood products early and often: Plasma Prevention of coagulopathy Dilution ACoTS Minimize crystalloid administration Homeostasis Hypothermia Acidosis Hypnosis: having our cake and eating it too DCA Vasoconstriction Vasorelaxed

Alan I. Frankfurt, MD Elements of hemostatic resuscitation, and level of evidence in support: R. Dutton; BJA 2012, Vol109 no. suppl 1 i39 Recommendations Evidence  Expedited anatomic control in OR Strong; widely accepted  Deliberate (permissive) hypotension Several prospective trials; widely accepted Early support of coagulation  Antifibrinolytic therapy One large prospective trial, several smaller studies; emerging standard  Early use of early plasma and platelets in massively bleeding patients 1:1:1 Controversial; variable application in clinical practice (PROMMTT); PROPPR trial  Vasodilation with anesthetic agents aka (DCA) Theory only. Minimal clinical data

Hypotensive Resuscitation A Historical Perspective Alan I. Frankfurt, MD

Hypotensive Resuscitation: A Balancing Act Alan I. Frankfurt, MD Hypotensive Resuscitation: A Balancing Act Permissive ischemia Tolerating short period of hypotension Vs. Popping a clot Minimize the risk of increased bleeding ----- Meeting Notes (9/18/14 10:45) ----- LCol. USA, MC North Africa and Italy Resuscitation Legion of Merit Alan I. Frankfurt, MD

Keep the SBP 80-90 torr until the bleeding is controlled. Blood Pressure at which Rebleeding Occurs after Resuscitation in Swine with Aortic Injury Jill L. Sondeen, PhD J of Trauma 54: (5) May Supp 2003 Reproducible blood pressure at which rebleeding occurred in test animals. Systolic 94 mmHG Diastolic 45 mmHG MAP 64 mmHG Similar to resuscitation pressures suggested by Drs. Cannon (WW1) and Beecher (WW2), respectively. Stern SA; Ann Emerg Med 1993 Feb; 22: 155 Burris D.; J Trauma 1999;46:216-223 Stern SA; Prehosp Emerg Care. 2002;6:81-91 Standard component of DCR Keep the SBP 80-90 torr until the bleeding is controlled. Alan I. Frankfurt, MD

73,000 foot view of Hemorrhage Resuscitation: Keeping the Resuscitation Fluids Administered to a Hemorrhaging Patient, Looking Like Blood Coming Out Early blood product administration (MTP) Early Plasma ? Cryoprecipitate & Platelets Minimize IV crystalloids Avoid coagulopathy Alan I. Frankfurt, MD

If not, what should we be following? Basics Alan I. Frankfurt, MD How much do young healthy trauma patients bleed before the patient demonstrates changes in routine vital signs (BP, P, RR, LOC). Do routine vital signs reflect EBL & occult shock? If not, what should we be following? What kills you when you “bleed to death”?

Clinical Signs Associated with Blood Loss: Alan I. Frankfurt, MD ACS ATLS Clinical Signs Associated with Blood Loss: Class EBL-estimated blood loss. %EBV Lost    Pulse Rate Blood Pressure  Mental Status Class I <750cc <15% <100  Normal  Slightly anxious Class II 750-1500cc 15-30% >100    Normal  Mildly anxious Class III Life threatening 1500(2000)cc 30-40% >120 Weak or intermittent Radial pulse Decrease Confused   Class IV Life Threatening >2000cc 40-50% >140 Absent radial pulse. Lethargic, Confused, Unconscious Loss of Effective Compensation Alan I. Frankfurt, MD

ATLS Clinical Signs Associated with Blood Loss Alan I. Frankfurt, MD ATLS Clinical Signs Associated with Blood Loss

Alan I. Frankfurt, MD Classification of Shock Using ED Admission Arterial Base Deficit Values Defined by JW Davis, MD et al. Admission Base Deficit Predicts Transfusion Requirements and Risk of Complications James W. Davis, MD; Jour of Trauma, Vol. 3, No. 5: 769

Alan I. Frankfurt, MD 2013 Questioning the validity of the ATLS classification in hypovolemic shock: the role of (venous) BD/Lactate

Mutschler et al. Critical Care 2013, 17:R42 Alan I. Frankfurt, MD Mutschler et al. Critical Care 2013, 17:R42

Mutschler et al. Critical Care 2013, 17:R42 Alan I. Frankfurt, MD Mutschler et al. Critical Care 2013, 17:R42

Alan I. Frankfurt, MD Mutschler et al. Critical Care 2013, 17:R42

Hemorrhagic death is the result of systemic vascular collapse Alan I. Frankfurt, MD

Systemic vascular collapse EBV~5000cc/70 kg person Venoconstriction Arterial constriction Vascular capacitance= X3 EBV Increasing blood loss Endothelial ischemia & Acidosis pH<7.2 Loss of vascular reactivity Catecholamines Systemic vasodilatation Vascular collapse Baseline vascular tone MAP Systemic vascular collapse 10% 20% 30% 40% 50-60%

Pathway to Vascular Collapse and Decompensated Shock Alan I. Frankfurt, MD Pathway to Vascular Collapse and Decompensated Shock Pathway to vascular collapse: Continuing hemorrhage Exhaustion of physiologic compensatory mechanisms LETHAL TRIAD: Acidosis, Hypothermia, Coagulopathy no cellular damage Compensated shock: Skin, skeletal muscle and bone Ischemia tolerant tissue: Vasoconstriction: Decompensated shock: cellular damage Ischemia intolerant tissue: Brain and heart Vasoconstriction

Lethal Triad of Trauma: Marker of Physiologic Exhaustion Alan I. Frankfurt, MD Coagulopathy INR Acidosis Hypothermia Best single live/die predictor in trauma & hemorrhage patients.

The Lethal Triad Lethal Triad Massive Hemorrhage Coagulopathy External bleeding Consumption of clotting factors Dilution IV fluids/MTP Fibrinolysis Dysfunction: H+/Temperature Acidosis(Lactate) Oxygen debt pH < 7.2 50% Factor dysfunction Vascular paralysis Lethal Triad Hypothermia Cold fluids Vasodilation Room temp Open abdomen Massive Hemorrhage Alan I. Frankfurt, MD

The Lethal Triad Drives Resuscitation Efforts Coagulopathy Floor Consumption Dilution Fibrinolysis Dysfunction Acidosis Oxygen debt pH <7.2 50% Factor dysfunction Vascular paralysis Lethal Triad Hypothermia Cold fluids Vasodilation Room temp Open abdomen Hemorrhage control (stop the bleeding) Operating room Interventional radiology Volume administration (fill the tank) Preload/Cardiac output/MAP CaO2 (oxygen carrying capacity) Hg x SpO2 x K pRBC Coagulation (make clots) MTP FFP Cryoprecipitate Platelets Antifibrinolytics Homeostasis (keep the patient warm) Normal physiologic environment Hypothermia Acidosis Calcium Damage Control Resuscitation Alan I. Frankfurt, MD

Damage Control Alan I. Frankfurt, MD

Damage Control Resuscitation Resuscitative measures that are taken to prevent physiologic exhaustion (lethal triad) and patient death. Alan I. Frankfurt, MD

Damage Control Resuscitation “5 H’s” Homeostasis Hypothermia Acidosis Ionized calcium Labs INR/TEG ABG Base deficit Lactate CBC/Chem 7/platelets Fibrinogen Hypnosis: having our cake and eating it too DCA Hypotension Vasoconstriction/Hypovole mia Vasodilatation/Euvolemia Hemorrhage control OR timely fashion Hypotensive resuscitation Systolic BP=80 torr Ischemia vs. Popping a clot Hemostatic resuscitation Early plasma administration Fibrinogen/EG Minimize crystalloid administration MTP 1:1:1:(1) ratio riaSTAP TXA rF7 RBC Hct 35-40% Platelets >100,000

Massive Transfusion Protocols Alan I. Frankfurt, MD

MTP initiation: Bleeding and in hypovolemic shock Massive Transfusion Protocol Version 1.0 Composition and Implementation Alan I. Frankfurt, MD Shipment # pRBCs Plasma Platelets 1 5 2 1 apheresis 3 4 Role of : rF7a vs. TXA MTP initiation: Bleeding and in hypovolemic shock Not sure what is bleeding. How long it will take to stop the bleeding. What it is going to take to stop the bleeding. When you’re bleeding too fast to wait for the labs.

Is there a role for rF7 in massive hemorrhage? Massive Transfusion Protocol Version 2.0 (Modify based upon severity of blood loss & institutional capabilities) Early plasma Day 1-3 Plasma ratio vs. Plasma deficit Last in, first out: <14 days old Fibrinogen vWB F8 F13 Fibronectin Europe vs. USA Lyophilized fibrinogen Anti- fibrinolytic Fibrinogen is the first factor to reach critically low levels during massive bleeding Is there a role for rF7 in massive hemorrhage?

Advanced Trauma Life Support (ATLS) Alan I. Frankfurt, MD Advanced Trauma Life Support (ATLS) Hemorrhaging patient 2 large bore PIV Evidence of shock: Pulse > 100/min SBP < 100 torr 2000 cc crystalloid fluids to normalize BP Shock persist 1.Continue IV crystalloids and 2.pRBC Frequent labs (guide FFP and platelet administration) Transient responders > 100cc/min blood loss

Advanced Trauma Life Support (ATLS) Hemorrhage resuscitation circa1980 Crystalloid infusion: Dilution clotting factors Does not carry oxygen Hypothermia Worsening of bleeding pRBC administration: Signs of shock Playing catch up with coagulation FFP/Cryoprecipitate Driven by PT/PTT lab test 20” lab result turn around 20 minutes to dethaw Continued crystalloid fluid administration and pRBC Platelets Iatrogenic driven coagulopathy

Bloody Vicious Cycle of Biblical Proportion Alan I. Frankfurt, MD Bloody Vicious Cycle of Biblical Proportion Hemorrhage Resuscitation with IV fluids Hemodilution Hypothermia Acidosis Coagulopathy

Breaking the Bloody Vicious Cycle Damage Control Resuscitation“5 H’s” Hemorrhage control OR timely fashion Definitive hemorrhage control Hypotensive resuscitation Systolic BP=80-90 torr “Tolerate” shock vs. Popping clots Hemostatic resuscitation Blood products early and often: Plasma Prevention of coagulopathy Minimize crystalloid administration Homeostasis Hypothermia Acidosis Year 2000 (limited trauma centers) DCS DCR: “WB equivalent” Early plasma

Is There a Role for Whole Blood in Civilian Hemorrhage Resuscitation? Keeping Fluids Going Into our Patients Looking Like Blood Coming Out During a Hemorrhage Resuscitation Is There a Role for Whole Blood in Civilian Hemorrhage Resuscitation?

Civilian Use of Whole Blood is Limited Alan I. Frankfurt, MD Civilian Use of Whole Blood is Limited Military: (Fresh Warm) Whole Blood Warm: 20-24 C* Fresh if < 24 hours old Walking blood bank Pre-tested Civilian: Whole Blood Cold: 1-4C* Formal testing for transmissible disease. 72 hours Licensed for 21 days Difficult to obtain from blood centers Fractionation of WB Efficient use of blood product Financial ≠

Is the MTP (1:1:1) the Modern Day Whole Blood Equivalent: Crystalloid fluid Poor volume expander Carries no oxygen, coagulation factors What if we administer the fractionated parts of WB as a 1:1(:1) ratio? Volume Oxygen delivery Coagulation factors

Origin of the (Civilian) MTP 1:1:1 transfusion ratio Alan I. Frankfurt, MD John Hess, MD; Richard Dutton, MD: From ISR to Maryland STU 2000 Transfusion Vol. 44, Issue 6 pp. 809-813, June 2004 Blood transfusion rates in the care of acute trauma John J. Como, Richard Dutton, Thomas M. Scalea, Bennette B. Edelman, John R. Hess Transfus Med Rev. 2003; 17: 223-31 Treating coagulopathy in trauma patients Armand R., Hess JR

Origin of the MTP 1:1:1 Ratio Maryland Shock Trauma, Baltimore Md. Alan I. Frankfurt, MD Origin of the MTP 1:1:1 Ratio Maryland Shock Trauma, Baltimore Md. Early plasma administration Dr. Como et al.(Transfusion 2004); “Blood transfusion rates in the care of acute trauma” 8% (479/5645 trauma admissions 2000) received RBC transfusion 3% > 10U RBC/24 hours 90% ultimately received plasma 5645 trauma admissions to Shock Trauma Center in 2000 5219 units of RBC 5226 units of FFP RBC ED FFP ICU Lack of immediate availability of plasma 1:1 ratio

Birth of the Massive Transfusion Protocol (MTP) Alan I. Frankfurt, MD Birth of the Massive Transfusion Protocol (MTP) Question: “Are we using FFP in the ICU to rescue an iatrogenic (ATLS) induced coagulopathy from the ED/OR resuscitation?” “What if we gave the FFP at the same time as the pRBC in patients with massive hemorrhage?” (personal communication, Richard Dutton, MD) Drs. Dutton, Hess & Holcomb 1:1 RBC/FFP in ED Baltimore, Md. 2000 Bagdad, Iraq 2005

1 unit pRBC: 1 unit FFP: = 1 unit (apheresis) platelets Is the Massive Transfusion Protocol 1:1:1 ratio the WB equivalent? (Kinda) 1 unit pRBC: 1 unit FFP: = 1 unit (apheresis) platelets 1 unit “whole blood” equivalent?

MTP 1:1:1 “Hemotherapy induced hemodilution” Alan I. Frankfurt, MD MTP 1:1:1 “Hemotherapy induced hemodilution” Temp Hct Platelets Coagulation Factor % Fibrinogen Amount of anticoagulant and additives Whole Blood 500cc WFWB 37* C 38- 50% 150,000 to 400,000 100% 1500 mg 63cc Component Therapy 680cc 1 unit: PRBC, FFP, Platelet -30-0*C 29% 88,000 65% 950 mg 205cc

MTP 1:1:1 “Hemotherapy induced hemodilution” Alan I. Frankfurt, MD MTP 1:1:1 “Hemotherapy induced hemodilution” Temp Hct Platelets Coagulation Factor % Fibrinogen Amount of anticoagulant and additives Whole Blood 500cc WFWB 37* C 38- 50% 150,000 to 400,000 100% 1500 mg 63cc Component Therapy 680cc 1U: PRBC, FFP, Platelet -30-0*C 29% (10%) 26% 88,000 (30%) 55,000 65% 750 mg 205cc

MTP 1:1:2 “Hemotherapy induced hemodilution” Alan I. Frankfurt, MD MTP 1:1:2 “Hemotherapy induced hemodilution” Temp Hct Platelets Coagulation Factor % Fibrinogen Amount of anticoagulant and additives Whole Blood 500cc WFWB 37* C 38- 50% 150,000 to 400,000 100% 1500 mg 63cc Component Therapy 680cc 2PRBC, 1FFP, 1Platelet -30-0*C 29% 88,000 65% 750 mg 205cc 40% 55,000 52% Storage related losses Any crystalloid administered will further dilute all 3 blood components. 36% 37,000 52% 1:1:2 1:1:1 26% 55,000 65%

PROPPR Trial: JAMA 2015, 313(5): 471-482 Study Question In patients with severe trauma and predicted to require massive transfusion, does the use of a transfusion protocol using a 1:1:1 ratio of plasma to platelets to red blood cells (RBCs) compared to 1:1:2 improve mortality? Alan I. Frankfurt, MD

PROPPR Trial: Results 24 hour/30 day all cause mortality Alan I. Frankfurt, MD PROPPR Trial: Results 24 hour/30 day all cause mortality No difference between 1:1:1 vs 1:1:2 Reduced mortality in 1:1:1 group from exsanguination in the first 24 hours. The Kaplan-Meier survival curves for a 3 hour endpoint: Statistically significant mortality difference between the two groups. This was not one of the allowed primary outcomes. Our current definitions of massive transfusion are outdated. Critical Administration Threshold (CTA): 3 units/hour

Cryoprecipitate 1:1:1:1(?) Alan I. Frankfurt, MD

ROTEM Radically Alters Transfusion in Combat Casualty Resuscitation Andrew P. Cap1, Philip C. Spinella1,3, Nichole K. Ingalls5, Christopher E. White1,2, Alejandra G. Mora1, Heather F. Pidcoke1, Nicolas Prat1, Lorne H. Blackbourne1, Joseph J. DuBose4 1United States Army Institute of Surgical Research, Fort Sam Houston, TX 78234-6315, 2San Antonio Military Medical Center, Fort Sam Houston, TX 78234 3 Washington University in St. Louis, St. Louis, MO 63108, 4 Baltimore CSTARS, R. Adams Cowley Shock Trauma Center / University of Maryland School of Medicine, Baltimore, MD 21201, 5 Nellis Air Force Base, NV 89191 MTP RATIO DRIVEN RESUSCITATION ROTEM DRIVEN RESUSCITATION x5 *There were 16 and 15 transfused patients respectively in each period that did not receive RBC.

ROTEM Radically Alters Transfusion in Combat Casualty Resuscitation Andrew P. Cap1, Philip C. Spinella1,3, Nichole K. Ingalls5, Christopher E. White1,2, Alejandra G. Mora1, Heather F. Pidcoke1, Nicolas Prat1, Lorne H. Blackbourne1, Joseph J. DuBose4 1United States Army Institute of Surgical Research, Fort Sam Houston, TX 78234-6315, 2San Antonio Military Medical Center, Fort Sam Houston, TX 78234 3 Washington University in St. Louis, St. Louis, MO 63108, 4 Baltimore CSTARS, R. Adams Cowley Shock Trauma Center / University of Maryland School of Medicine, Baltimore, MD 21201, 5 Nellis Air Force Base, NV 89191 Conclusions 1. DCR utilizing a 1:1:1 ratio driven MTP may underestimate the need for cryoprecipitate and platelets 2. ROTEM driven resuscitation more closely approximated a 1:1:1:1 transfusion ratio. *There were 16 and 15 transfused patients respectively in each period that did not receive RBC.

How Much Difference Does Additional Cryoprecipitate and Platelets Make? 2003 Iraq 2012 Afghanistan Mortality: >20% No platelets and cryoprecipitate available in theater Mortality: <10% Greater cryoprecipitate and platelets availability. ISS scores higher in casualties in 2012 than those in 2003. Evolving MTP 1:1:1:1

Putting it all together Alan I. Frankfurt, MD Putting it all together Massive Transfusion Protocol THR Dallas

MTP & Uncontrolled Hemorrhage Alan I. Frankfurt, MD MTP & Uncontrolled Hemorrhage PYXIS/L&D resuscitation BLOOD BANK resuscitation TXA 1-2 grams IV slowly 1 gram IVPB over 8 hours riaSTAP 2-4 grams IV O negative pRBC (+/- Liquid Plasma) iSTAT Hgb; ABG/VBG; ionized Ca Lactate Round 1 MTP O negative pRBC AB negative FFP (+/- cryoprecipitate) (+/- platelets) Round 2 MTP Type specific pRBC Type specific FFP ( +/- platelets)

Uijttewall WS et al., Am J Physiol Rethinking the Acceptable Hematocrit and Platelet marginalization during massive hemorrhage Higher Hct increased platelet interaction with the endothelium. Platelet concentrations along the endothelium remains almost x7 that of the average blood concentration. Uijttewall WS et al., Am J Physiol 1993, 264: H1239-H1244

Maintain a Hct 35%: Shear stress & platelet margination Alan I. Frankfurt, MD Maintain a Hct 35%: Shear stress & platelet margination 35% 21% Hardy JF et. Can J Anaesthe 2006, 53: S40-S58

HCT & Platelet count: Synergistic Effect on Clotting Hct level Platelet count Percentage platelet interaction with subendothelium Hct =40% 200,000 19.3 +/- 7.8 100,000 7.5 +/- 2.8 50,000 2.5 +/- 0.8 Hct=20% 3.3 +/- 4.0 2.8 +/- 0.7 0.6 +/- 0.2 Transfusion 1994, Vol. 34, No.6

Plasma Alan I. Frankfurt, MD

Plasma RBC Platelets Thawed FFP/FP <24 hrs Alan I. Frankfurt, MD Plasma Frozen: “FFP” < 8 hrs; “FP” < 24 hrs Thawed FFP/FP <24 hrs Thawed plasma 24 hrs-5 days Never Frozen: “Liquid Plasma” Thawed shelf life: 5 days RBC Platelets Shelf life: 26 days

Plasma deficit vs. Plasma ratio pRBC:FFP Vs. Plasma deficit: (Total RBC)-(Total FFP)

BLOOD PRODUCT USE IN TRAUMA RESUSCITATION: Plasma deficit versus plasma ratio as predictors of mortality in trauma Andreas R. de Biasis, Lynn G. Stansbury, Richard P. Dutton, Debra M. Stein, Thomas Ml Scalea, and John R. Hess Plasma deficit (Total RBC)-(Total FFP)<2 Mortality was related to plasma deficit, not plasma ratio 0-3 hours post injury Early plasma availabililty Gold:Red:Gold:Red….. Simultaneous administration of plasma along with pRBC Thawed plasma/Liquid (never frozen) plasma in ED/L&D Lyophilized plasma Unavailable in USA ? Lyophilized fibrinogen

Future Developments Lyophilized FFP Alan I. Frankfurt, MD Future Developments Lyophilized FFP Logistic requirements: Storage No refrigeration required Room temperature Easily transported Quickly reconstituted Rapid volume expansion Rapid 1:1 pRBC/FFP ration obtained Contains all clotting factors Shelf life 2 years Clotting factor ABO considerations No blood typing required French military medicine 1994 FDA: compassionate approval for the US military Special forces

Plasma & the Endothelium (The other 50% of making a strong clot) Alan I. Frankfurt, MD

Role of the Endothelia Glycocalyx and Resuscitation Fluids Choice Alan I. Frankfurt, MD Role of the Endothelia Glycocalyx and Resuscitation Fluids Choice Extremely fragile Composition Glycoproteins Proteoglycans Key determinants of membrane permeability in various vascular organ systems. 0.2-1.0 mm thickness 1000 cc plasma embedded in the EG.

Alan I. Frankfurt, MD

Plasma: 1000 different proteins Plasma: 1000 different proteins Coagulation factors Immunoglobulin Albumin Coagulation Procoagulant Anticoagulants Overall health of the endothelium Resuscitation/Repair of the EG Hemorrhagic shock

Early Plasma vs Crystalloid Effects of Resuscitation Fluids on the Integrity of the Endothelial Glycocalyx: Alan I. Frankfurt, MD Iatrogenic Injury

Review: Transfusion Protocol Version 2.0 We are here

Platelets Alan I. Frankfurt, MD

Platelets Platelet Storage: “One size does not fit all” Decisions that shaped the policy on PLT storage temperature

Platelet Aggregation 2 hours 22*C FIRM, BUT REVERSIBLE ADHESION IRREVERSIBLE Scanning electron micrograph of discoid, dormant platelets Activated, aggregating platelets illustrating fibrin strands Flowing disc-shaped platelet Rolling ball-shaped Hemisphere-shaped Spreading Platelet Aggregation 2 hours 22*C Adapted from: Kuwahara M et al. Arterioscler Thromb Vasc Biol 2002; 22: 329–34.

Platelet Storage: Effects of temperature 5 day life span 1-2 hours to “activate” 4*C 48 hour life span Immediately “activated” Refrigeration of platelets abandoned in 1970’s. Logistics vs. Patient requirements

Historical perspective on platelet storage 2 patient populations with different platelet requirements Patient population: Trauma, OB(PPH, Abruption, Accreta) Requirement: Immediate bleeding problem Immediate clot formation & hemostasis (activated platelets) 4*C platelets Immediately primed Survival time: hours Patients receiving chemotherapy prophylaxis against future bleeding Long circulation time (platelet survival) 22*C platelets 1-2 hours for priming Survival time: days

Fibrinogen & Clot strength The 80% Solution Non pregnant state: 200-400 mg% Pregnant state: 400-700(1000) mg%

Fibrinogen (F1) is the Weak Link in the Clotting System Alan I. Frankfurt, MD Hemorrhage Rapid depletion of F1 (fibrinogen) Clot formation Fibrin precursor Platelet interaction Activation Binding Aggregation

What is the Optimal Fibrinogen Threshold for Optimal Clot Formation?

Plasma Fibrinogen levels & Optimal Hemostasis 150-300 mg/dl Linear increase in clot strength with increasing F1 levels. 625 mg/dl Clot strength equal to whole blood Pregnancy level > 28 weeks 1000 mg/dl Clot strength equal to x3 whole blood Clot strength vs. Hypercoagulability Nielsin V, Levy J: Fibrinogen and Bleeding: Old Molecule-New Ideas Anesth Analg 2007; 105: 902-3

Sources of Fibrinogen: Volume considerations & Preparation time. Allogenic blood products Thawing Typing (ABO if possible) Infection Fresh frozen plasma (FFP) Cryoprecipitate Fibrinogen concentrate riaSTAP 1 grams of riaSTAP/bottle 50cc sterile water US “off label” Acquired hypofibrinogenemia Europe Eliminated cryoprecipitate International Journal of Obstetric Anesthesia (2010) 19, 218-234

Fibrinogen Concentrate RiaSTAP Human donor Pooled plasma product Lyophilized Viral inactivation Predictable mg content/vial 1000 mg/vial No thawing required Pyxis storage ? Thrombogenic potential

Tranexamic Acid (TXA) Lysine analogue antifibrinolytics Resuscitation in a drawer (pyxis)

Alan I. Frankfurt, MD Plasminogen Plasmin

Mode of Action of Lysine Analogue Tranexamic Acid (TXA) Mannucci PM, Levi M. N Engl J Med 2007;356:2301-2311 TXA Figure 1. Mode of Action of Lysine Analogues (Aminocaproic Acid and Tranexamic Acid). Activation of plasminogen by endogenous plasminogen activators results in plasmin, which causes degradation of fibrin. Binding of plasminogen to fibrin makes this process more efficient and occurs through lysine residues in fibrin that bind to lysine-binding sites on plasminogen (Panel A). In the presence of lysine analogues, these lysine-binding sites are occupied, resulting in an inhibition of fibrin binding to plasminogen and impairment of endogenous fibrinolysis (Panel B).

Alan I. Frankfurt, MD CRASH-2 Study

Resuscitation in a drawer Alan I. Frankfurt, MD Resuscitation in a drawer Factor 1 (fibrinogen) riaSTAP TXA rF7a Combat gauze Calcium Factors: 2, 7, 9, 10 PCC (prothrombin concentrate complex) Vitamin K dependent factors Factor 8/vWB Endothelium Lyophilized plasma Platelets Factor 5 Entegrion Lyophilized platelets Located in the ED/L&D unit pyxis Future

Citrate Intoxication & “ionized "Calcium Alan I. Frankfurt, MD Citrate Intoxication & “ionized "Calcium Citrate intoxication 90% citrate FFP & Platelets Calcium & Magnesium Rate of transfusion, not total blood products Measured calcium vs. Ionized calcium Total calcium is normal even when ionized calcium of critically low Total calcium measures both calcium bound to citrate and free, ionized calcium

Summary Alan I. Frankfurt, MD

Maintain or re-establishing a survivable physiologic state Damage control: Maintain or re-establishing a survivable physiologic state Damage Control Surgery Hemostasis (definitive) If you need to be in the OR, get there quickly Damage Control Resuscitation Hypotension (permissive) Avoid popping clots Hemostatic resuscitation Clotting factors early and often: MTP Plasma deficit Pharmacologic Homeostasis Keep the patient warm Damage Control Anesthesia Hypnosis Get them anesthetized Alan I. Frankfurt, MD

Damage Control Resuscitation Goals Fibrinogen >250-400 mg% FFP Cryoprecipitate risSTAP: fibrinogen concentrate Hct 35-40% Platelet interaction Platelet concentration >100,000 Plasma Plasma deficit < 2 Early plasma administration Endothelial glycocalyx Coagulation factors Anticoagulants pH Base deficit & Lactate Temperature Active warming measures Ionized calcium 4 will get you 4 Hypotension unresponsive to volume

Alan I. Frankfurt, M.D. F7040@aol.com Questions?? Alan I. Frankfurt, M.D. F7040@aol.com