Inspiration for this talk from multiple sources, among them --Interview of Karim Brohi MD @ http://emcrit.org/podcasts/severe- trauma-karim-brohi/ http://emcrit.org/podcasts/severe- trauma-karim-brohi/ --Lecture by Karim Brohi MD on hypoT resus@ http://www.trauma.org/index.php/mai n/article/1424/ http://www.trauma.org/index.php/mai n/article/1424/ --Interview with Richard Dutton MD @ http://emcrit.org/podcasts/trauma- resuscitation-dutton/ http://emcrit.org/podcasts/trauma- resuscitation-dutton/ -- Conference lecture with Brian Cotton MD, Jay Johanning MD --Cath Hurn MD “There will be blood” http://podbay.fm/show/648203376/e/1 371743460?autostart=1 (also available at Social Media and Critical Care website scmm.org )
“Keeping things from getting too crazy or out of hand.” “Emergency control of situations that may cause the sinking of a ship”
permissive hypotension limiting crystalloids delivering higher ratios of plasma and platelets and/or clotting adjuncts as appropriate
Where did we get our resuscitation strategies from?? After World War II, Wiggers developed the classic ‘controlled’ hemorrhagic shock model, which documented that if severe shock was allowed to persist for several hours, an irreversible shock state occurred from which the animals could not be resuscitated. In the 1960s, Shires and associates used the ‘Wiggers Preparation’ to document that extracellular fluid deficits coexist with hemorrhagic shock and are best replenished with balanced salt solutions. This resulted in the standard 3:1 crystalloid-blood ratio of resuscitation LR resuscitation resulted in 0-10% mortality vs. 80% mortality with replaced blood only. (Wolfman, 63) Fink, M. Hayes,M. Soni, N. Classic papers in critical care. Ch. 12: “Fluids”. Springer-Verlag London Limited 2008.
“Resuscitation is limited to keep blood pressure at 90 mm Hg, preventing renewed bleeding from recently clotted vessels.” (Holcomb, 2007) Examples from vascular specialties, the military: Crawford ES. Ruptured abdominal aortic aneurysm. J Vasc Surg 1991;13:348-50 Holcomb JB. The 2004 Fitts Lecture: current perspective on combat casualty care. J Trauma 2005;59:990-1002 Aggressive volume resuscitation of patients with rAAAs before proximal aortic control predicted an increased perioperative risk of death, which was independent of systolic blood pressure… volume resuscitation should be delayed until surgical control of bleeding is achieved
Bickell, 1991: 16 swines treated with fluid or nothing Treatment group achieved higher MAPs. However, after 30- minutes 5 animals in the treatment group had died whereas all 8 animals in the control group had survived. They had significantly less blood loss as well. Others Nine trials compared hypotensive versus normotensive resuscitation (MAP >80). The relative risk of death with hypotensive resuscitation was 0.37. “The effect of hypotensive resuscitation was to reduce the risk of death in all the trials. This suggests that using a lower than normal blood pressure as a guide to fluid resuscitation consistently reduces the risk of death regardless of the severity of injury” Bickell, 1991: 16 swines treated with fluid or nothing Treatment group achieved higher MAPs. However, after 30- minutes 5 animals in the treatment group had died whereas all 8 animals in the control group had survived. They had significantly less blood loss as well. Others Nine trials compared hypotensive versus normotensive resuscitation (MAP >80). The relative risk of death with hypotensive resuscitation was 0.37. “The effect of hypotensive resuscitation was to reduce the risk of death in all the trials. This suggests that using a lower than normal blood pressure as a guide to fluid resuscitation consistently reduces the risk of death regardless of the severity of injury” Bickell WH, Wall MJ Jr, Pepe PE, et al. Immediate versus delayed fluid resuscitation for hypotensive patients with penetrating torsoinjuries. N Engl J Med. 1994;331:1105– 1109.
Bickell et al, 1994. Prospective controlled trial. N= 598 Control= standard practice Experimental= NO IV Fluid. Fluids and blood were then initiated at time of operation for SBP goal 100 OUTCOMES Control group got 1L additional fluid, had a higher MAP at presentation Survival rate was significantly higher (p=.04) in the delayed- resuscitation group. Control group also had a trend (p=.11) toward more blood loss intraop and trend (p=.08) toward more post-op complications Bickell WH, Wall MJ Jr, Pepe PE, et al. Immediate versus delayed resuscitation for hypotensive patients with penetrating torso injuries. N Engl J Med 1994;331:1105-9
Dutton RP, et al. 2002 RCT. N= 55 Randomized to SBP goal 70 or 100. No difference in mortality. (injury severity scores higher in low- BP group…possible benefit?) Morrison et al, 2011. Number so far= 90 Allocated to MAP goal >50 or >65. The lower MAP goal group shows less blood products, less IV fluid, less perioperative mortality, trend toward less 30-day mortality. However the complete f/up article is still not in print. Dutton RP, MacKenzie CF, Scalea TM. Hypotensive resuscitation during active haemorrhage: impact on in-hospital mortality. J Trauma. 2002;52: 1141-1146. Morrison CA et al., Hypotensive resuscitation …l. Trauma. 2011 Mar;70(3):652-63.Trauma. Morrison CA et al., Hypotensive resuscitation …l. Trauma. 2011 Mar;70(3):652-63.Trauma.
“Lower blood pressure enhances regional vasoconstriction and facilitates clot formation and stabilization. Controlled volume administration reduces the development of hypothermia and limits dilution of red cell mass, platelets, and clotting factors. Weighed against this is the potential for worsening hypoperfusion, with a risk for increased acidosis and organ system injury.” Dutton, 2007
Delay aggressive fluid resuscitation until operative control is achievable. SBP >70 and MAP >55 appear safe*. An SBP of 91-97 has been identified as the pressure at which clots blow in animal models Still under investigation: Should hypotensive resuscitation extend beyond the trauma bay/ambulance into the OR? (probably) it depends on the individual patient and the need to balance the potential for worsening hypoperfusion to end- organs. Example elderly, traumatic brain injured patients, patients with cardiac/valvular disease. * Except in the above populations
Goals of Fluid Resuscitation Therapy Improved state of consciousness (if no TBI) Palpable radial pulse corresponds roughly to systolic blood pressure of 80 mm Hg Avoid over-resuscitation of shock from torso wounds. Too much fluid volume may make internal hemorrhage worse by “Popping the Clot.”
“There are things that you think you will never need to know, things you may need to know only one time in your life, but you can save a life because you have that knowledge.” - Eric Thomas
II. Written in Blood Blood Product Ratios and Limiting the Use of Crystalloids.
Historical Practice Data from the 1950s and 60s noted altered sodium, water distribution and retention following trauma with surgical management. Treatment surrounded management of intravenous fluids to balance input and output. (Cotton et al., 2006) The 1970s brought forward the thought of a “Golden Hour,” a concept emphasizing rapid diagnosis, surgery and resuscitation. Resulting in prolonged “fix everything now” surgeries. (Dutton, 2005) Chief publications in the 1980s stressed the importance of “supranormal resuscitation,” and the infusion of large amounts of fluid regardless of objective measurements. The late 1980s marked a major movement toward abbreviated laparotomy, with a definitive surgery only after correction of acidosis, coagulopathy and hypothermia. Coinciding with these advances, Intra-abdominal compartment syndrome (ACS) became attributed to major interstitial swelling secondary to “supranormal resuscitation.” This led to the present day management of trauma with Damage Control Laparotomy and the minimization of crystalloids with increased use of blood products. (Cotton et al., 2006)
Damage Control Laparotomy Phase 1 consists of transport to the OR in order to control hemorrhage and prevent contamination and further injury. The abdomen or site of injury is packed and left open with wound vac in place. Phase 2 starts in the OR with extended focus in the ICU where the patient can be physiologically stabilized, resuscitated and warmed in order to correct both acidosis and coagulopathy. Phase 3 is a staged definitive surgery to reconstruct the abdomen and close.
Concentration on Phase 2-Resuscitation Beginning in the Trauma Bay or OR, Resuscitation can happen concurrently with surgery. The Anesthesia and MTP response team is focused on correcting the lethal triad: Acidosis, Hypothermia and Coagulopathy This is done by administration of fluids, PRBC, FFP, platelets, Vitamin K, tranexamic acid, buffers, electrolytes and other interventions
Damage Control Anesthesia Recommendations During Surgery SBP 90 mm Hg Urine Output present PaCO2 < 50 pH> 7.25 Lactate Stable INR < 1.6 Plt > 50,000 Hct > 25% Deep Anesthesia Stabilization in ICU – SBP >100 – Urine Output > 0.5ml/kg/hr – PaCO2 < 40 – pH >7.35 – Lactate WNL – INR < 2 – Plt > 50,000 – Hct >20 – Lactate WNL Dutton, R.P., (2005). Damage Control Anesthesia, International Trauma Care, 197-201.
Current trends Extensive discussion is present in scholarly research regarding the ratio of PRBCS to FFP in order to ensure the best possible outcome for our patients. Furthermore there is increased awareness of the theoretical benefits of limiting use of crystalloids (NS and LR). (Cotton et al., (2006). The cellular, metabolic, and systemic consequences of aggressive fluid resuscitation strategies. Shock, 26(2), 115-121.)
246 Military patients: US Army Combat Support Hospital (retrospective chart review, 2007) RESULTS: For the low ratio group the plasma to RBC median ratio was 1:8 mortality rate was 65%, For the medium ratio group, 1:2.5 mortality rate was 34% For the high ratio group, 1:1.4 mortality rate was 19% (Borgman, M.A., (2007). The ratio of blood products transfused affects mortality in patients receiving massive transfusions at a combat support hospital. Journal of Trauma, 63(4), 805-813.)
150 Civilian patients: University of Alabama. (2005-2007) RESULTS: HRR= 40% mortality LRR= 58% mortality However, “survival bias was introduced as the patients in the low-ratio group died early which effectively fixed them at a low FFP-PRBC ration for the remained of the resuscitation period (p. 361).” (Snyder, C.W. et al., (2009). The Relationship of Blood Product Ratio to Mortality:Survival Benefit of Survival Bias?. Journal of Trauma, 66(2), 358-364.)
Clinical review: Fresh frozen plasma in massive bleedings - more questions than answers Bartolomeu et al. Critical Care 2010, 14:202 Hallet, J., Lauzier, F., Mailloux, O., Trottier, V., Archambault, P., Zarychanski, R., & Turgeon, A. (2013) The Use of Higher Platelet: RBC Transfusion Ratio in the Acute Phase of Trauma Resuscitation: A Systematic Review. Critical Care Medicine. 41(12). 2800-2811. DOI: 10.1097/CCM.0b013e31829a6ecb Hallet, J., Lauzier, F., Mailloux, O., Initial studies have reported significant reductions in mortality, but are uncontrolled and methodologically flawed, particularly by survivorship bias. Presently, clinical decisions should be based in assessing the pros and cons of both strategies while considering local resources and individual clinical context.
The Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) Study: Comparative Effectiveness of a Time-varying Treatment with Competing Risks John B. Holcomb, et al. JAMA Surg. Feb 2013; 148(2): 127–136. John B. HolcombJAMA Surg. Feb 2013; 148(2): 127–136. PROMMTT was a prospective, multicenter observational cohort study (10 centers) Conclusions In the first 6 hours, patients with ratios < 1:2 were 3–4 times more likely to die than patients with ratios ≥1:1. ‘ After 24 hours, plasma and platelet ratios were unassociated with mortality, when competing risks from non-hemorrhagic causes prevailed.
Theoretical basis of improved results with High Ratio Infusion “FFP is hypothesized to include a mechanism at the cellular level in combination of the replacement of coagulation factors... FFP repairs and normalizes the vascular endothelium by restoring tight junctions, building the glycocalyx, and inhibiting inflammation and edema.” (Pati, M.N. et al., 2010). Protective effects of fresh frozen plasma on vascular endothelial permeability, coagulation, and resuscitation after hemorrhagic shock are time dependent and dimnish between days 0 and 5 after thaw. Journal of Trauma. 69, 55-62.)
365 Civilian patients: Multi-Institutional analysis of MTPs (prospective comparative study therapeutic, 2007-2010) RESULTS Patients who received less blood product received more crystalloid over 24-hour period. A direct relationship was seen between increased crystalloid use and VAP, bacteremia and sepsis. Of the “MTP patients (10 or more units) an increased fourfold morbidity was seen in patients with a 24 hour crystalloid volume in excess of 5 L.” (Duchesne, J.C. et al., (2013). Diluting the benefits of hemostatic resuscitation: A multi-institutional analysis. Trauma Acute Care Surgery, 75(1), 76-82.)
Theoretical basis of improved results with decreased Crystalloid use. “Cellular volume seems to drive many of the basic metabolic changes responsible for protein synthesis, cell turnover, and overall cellular performance. The cellular membranes…do not tolerate significant gradients in hydrostatic pressure.” (Cotton et al., (2006). The cellular, metabolic, and systemic consequences of aggressive fluid resuscitation strategies. Shock, 26(2), 116)
Complications Associated with Aggressive Crystalloid Resuscitation -Cellular acidification -Inflammation -Altered glucose production and metabolism -Insulin disturbances -Disruption of cardiac myocyte action potential -Decreased cardiac output -Cardiac arrhythmias and ventricular dysfunction -Pulmonary Edema and ARDS -Increase gut permeability/ bacterial translocation -Ileus -Anastomic dehiscence -Decreased tissue healing -Abdominal Compartment Syndrome -Dilution of coagulation factors -Decreased blood viscosity -Disordered neurotransmitter metabolism -Disturbances in the release of catecholamines, glutamate, and acetylcholine. (Cotton et al., (2006). The cellular, metabolic, and systemic consequences of aggressive fluid resuscitation strategies. Shock, 26(2), 115-121.)
Current recommendations “Effective and aggressive incorporation of high ratio resuscitation is essential to correct the combination of metabolic acidosis, hypothermia, and acute coagulopathy of trauma shock associated with severe tissue injury and tissue hypoperfusion.” (Duchesne et al., 2013) Limit excessive crystalloid resuscitation in the acute phase of trauma/hemorrhage ATLS Guidelines Initial infusion of 1-2 L of crystalloid followed by PRBC if there is no response, when hemorrhagic shock is suspected.
After this presentation the audience will be able to: – Discuss pharmacology of novel oral agents – Describe risk factors for hemorrhage – Describe agents used to stop hemorrhaging – Develop an algorithm for life threatening hemorrhages
Now Holbrook. CHEST. e152-e184 * Low dose reduces INRs 6.0-10 to < 4.0 in 1.4 days after PO or 24 hrs after IV. High dose IV vit K begins reducing INR within 2 hrs with a correction to normal generally by 24 hrs. INRBleedingTherapeutic Options > 3.0 – 10No bleeding Hold warfarin until INR returns to normal range >10>10No bleeding Hold warfarin and give vitamin K 2.5 - 5mg PO * Any INRSerious or life- threatening bleeding Hold warfarin and administer PCC and supplement with vitamin K 5-10mg IV * infusion and repeat as necessary Alternatively, FFP or recombinant VIIa may be supplemented with vitamin K 5-10 mg IV infusion may be used instead of PCC
CHEST and ICH Guidelines Holbrook. CHEST. e152-e184, AHA/ASA ICH Guidelines. Stroke 2010;41:2108-2129.
DTI –No direct antidote –Prothrombin Complex Concentrates (PCC) –Recombinant Factor VII –Fresh Frozen Plasma –Dabigatran is dialyzable Xa Inhibitors( Xarelto) –No direct antidote Under development (Andexanet alfa, Portola Pharmaceuticals) –Prothrombin Complex Concentrates (PCC) –Recombinant Factor VII –Fresh Frozen Plasma
Kcentra Package Insert. CSL. April;2013. Feiba. Medical letter. Baxter. 2;2011. Profilnine SD. Factor Levels. Grifols. 03/12. NovoSeven. LexiComp. Hudson, OH. 2013. Generic NameBrand NameApproved Uses PCC - 4 FactorKcentra (Octaplex, Beriplex) Reversal of acute major bleeding due to warfarin Activated PCC - 4 Factor (anti -inhibitor coagulant complex) FeibaHemophilia A and B PCC – 3 FactorProfilnine® SDHemophilia B with factor IX deficiency Recombinant Factor VIIaNovoSeven® RTPatients with factor VII deficiency or with hemophilia A or B
Imberti et al(Blood Transf Apr.’11,9(2)117- 119). - Non inverse relationship between plasma factor VII levels and INR. - Noted that with INR < 4.5, usually sufficient levels of factor VII to allow 3 factor PCC to be effective. - When higher, levels are usually too low(<10%) and 4 factor PCC is more effective. - Unlike other clotting factors, only 10- 15% of factor VII is needed for adequate hemostasis.
Anticoagulation Reversal Pharmacokinetics AgentOnsetDurationRebound of Anticoagulant Protamine5 minIrreversible Likely with SBQ dosing from postponed drug delivery Vitamin K4-12hrsDays for INR Dose dependent Fresh Frozen Plasma (FFP) 1-4hrs6hrs4-6hrs Prothrombin Complex Concentrate (PCC) 10- 15min 12-24hrs≈12hrs rFactor VII10min4-6hrs6-12hrs
Full Anticoagulation Reversal for Life Threatening Hemorrhage Oral DrugGenericBrandReversal Strategy Vit K Antagonist WarfarinCoumadinPCC - 4 factor + Vitamin K 10mg IV Factor Xa Inhibitor Rivaroxaban Apixaban Edoxaban Xarelto Eliquis PCC - 4 factor DTIDTIDabigatranPradaxaPCC - 4 factor UFHHeparinN/A Immediately after IV UFH bolus: 1mg protamine per 100 units heparin 30-60min post UFH: 0.5mg protamine per 100 units heparin LMWH EnoxaparinLovenox ≤8hrs since dose: 1mg of protamine per 1 mg of enoxaparin 8-12hrs since dose: 0.5mg of protamine per 1 mg of enoxaparin DalteparinFragmin ≤8hrs since dose: 1 mg of protamine per 100 anti-Xa units 8-12hrs since dose: 0.5 mg of protamine per 100 anti-Xa units Factor Xa Inhibitor FondaparinuxArixtraPCC - 4 Factor
As literature comes forth, focus on the outcome! –Laboratory reversal versus hematoma reduction! The goal is to stop the bleed, not the surrogate marker lab value that may lag behind. Pre-Treatment INRDose of 4F-PCC (Units of Factor IX) Maximum Dose (Units of Factor IX) 2 to <425 units/kg2500 units 4-635 units/kg3500 units >650 units/kg5000 units
Developed by H. Hartert in Germany in 1948 as a research tool. First clinical application in liver transplantation by Kang 25 years later. Historically, widest use in CPB and liver transplantation. More recently, with advent of damage control and hemostatic resuscitation, increased use for directed blood therapy. TEG predicts blood product usage in trauma patients. J Trauma. 1997;42(4):716-22 TEG accurately measures coagulopathy in trauma patients. Anesth Analg. 1998;86(2S):88S
Functional assay Global evaluation of(from initiation of protein coagulation through lysis)clot. Factor Deficiencies Fibrinogen Function Platelet Function Clot Strength Lysis
Pro-thrombotic State DVT / PE (Majority) Hemorrhagic State Bleeding Ongoing hypotension Coagulopathy of trauma is dynamic.
CONTACT TISSUE COMMON PATHWAY THROMBIN / FIBRINOGEN
Hemostasis profile: R time AngleMA LY Fibrin strands clot kinetics strength/elasticity dissolution LY
R (reaction) time Coagulation factors K (clotting) time Interaction of factors, fibrin & platelets Alpha angle Fibrin & platelets Maximal Amplitude (MA) Platelet function Lysis 30/60 (LY30/60) Fibrinolysis
Probable cause: fibrinogen deficiency Common treatment: Cryoprecipitate, FFP, or prothrombin complex Patient status: bleeding
Gsw to pelvis and right LE Rectal, Small Bowel, Sacral, & Open Femur Fx Arrived in Class IV Shock
Intra-op after 11 PRBC, 2 Plt, 4 Cryo, 6 FFP, 3 WB, & 1 Factor VIIa Post-op after 19 PRBC, 2 Plt, 4 Cryo, 6 FFP, 6 WB, & 1 Factor VIIa
Sigmoid Colon, Small Bowel, and Abdominal Wall Injury 2 PRBC given intra-op
Post-op TEG shows early fibrinolysis TEG after Amicar infusion
Clinical Randomisation of an Antifibrinolytic in Significant Hemorrhage
Guideline for Blood Product Use Abnormal TEG Prolonged R time Transfuse 4 units FFP Decrease Maximum Amplitude Transfuse platelets Prolonged K time or Decrease a-Angle Transfuse 4 units FFP then 4 units Cryoprecipitate Consider rVIIa if abnml after above Increase LY30 Amicar or Tranexamic Acid
Hemorrhage is the enemy (early) Hypercoagulability is the enemy (late) Diagnosis: time consuming and confusing TEG is extremely useful “Whole blood coagulation measurement” Fast One test Easily repeatable It’s what you want-clot measurement