1. Damage Control Resuscitation

2. acknowledgements
Inspiration for this talk from multiple sources, among them
--Interview of Karim Brohi
--Lecture by Karim Brohi MD on hypoT
--Interview with Richard Dutton
-- Conference lecture with Brian Cotton MD, Jay Johanning MD
--Cath Hurn MD “There will be blood” (also available at Social Media and Critical Care website scmm.org )

3. Definition “Keeping things from getting too crazy or out of hand.”
“Emergency control of situations that may cause the sinking of a ship”
As a tagline this was borrowed from maritime --used to describe a procedure first practiced by Dr. Stone in In “damage control”, rather than spending 6-8 hours in the OR to complete repair and closure, repair happens then in stages. The reasoning behind this was to prevent long OR times in a shocked patient, allow time for rewarming and resuscitation in the ICU. Goals of damage control are usually focused on: hemostasis, removal of GI contamination from bowel injury and resection or debridement of non-viable tissue. When necessary, the abdominal cavity is left in discontinuity. (as shown) This practice is now standard of care for the massively shocked trauma patient and is even used for general surgery as well.

4. Damage Control Resuscitation
permissive hypotension
limiting crystalloids
delivering higher ratios of plasma and platelets and/or clotting adjuncts as appropriate
Damage Control Resuscitation has gone by several terms and includes several concepts. There are 3 primary components:
permissive hypotension
limiting crystalloids
delivering higher ratios of plasma and platelets and/or clotting adjuncts as appropriate
All three of these are aimed at limiting/correcting coagulopathy and controlling hemorrhage.

5. What are we after in the trauma bay?
Picture perfect vital signs? We give fluid, high five each other because the patient has “stabilized”. But have we done our patients a service?
Without getting too academic today I want to introduce the concept of permissive hypotension and try to give you some support for its legitimacy, understanding that it (permissive hypotension) is not “standard of care” at present, nor is it applicable or appropriate for all patients. I’m interested in it as a strategy that we can start to use more often and maybe begin to incorporate into our culture of resuscitation at LGH. I invite you to check out the reference-list provided— we each chose the most read-able overview articles. And just give yourself a moment of pause to think before you high-five.
Think before you high-five

6. Less is more: Permissive Hypotension
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)
Bullet point one: if I asked any one of you what the ideal MAP goal for a patient is you would shout out something around 60/65. Because as we all know dipping much below this level starts to jeapordize perfusion to our “end-organs”. Also, it’s intuitive to want to fix a number that represents a pathological state. At the same time we recognize that treating hypovolemic shock is not the same as vasodilatory shock.
So what does the literature say in trauma? The literature supporting these goals in trauma patients comes from animal models of hemorrhagic shock performed by Dr. Wiggers at Case Western University by inducing animals and surgically bleeding them. He let them alone at this state with a MAP around 40 , for a few hours and then replaced the blood. What he found was that even when the blood volume was completely replaced, about 50% of the animals went on to die as the result of that sustained shock/acidosis and hypoperfusion.
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.
These theories seem to be confirmed by other studies showing mortality benefit from infusing crystalloids before the introduction of blood products.
The hypothesis was that the intracellular contraction in shock is not adequately addressed with blood products alone, which as colloidal solutions are more likely to stay extracellular. This model failed to account for the physiological reaction to shock with ongoing blood loss.
Fink, M. Hayes,M. Soni, N. Classic papers in critical care. Ch. 12: “Fluids”. Springer-Verlag London Limited 2008.

7. New Paradigm: Permissive Hypotension
“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:
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
This resuscitation-to-normal BP with crystalloids was/is pretty much standard [and is incorporated into ATLS guidelines], but leaders in the field are starting to think differently.
Accepted method in treatment of ruptured AAA patients . And in 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:

8. Evidentiary Basis: Animal studies
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 developed a model to study resuscitation in uncontrolled hemorrhage. A 5-mm aortotomy was inflicted in 16 anesthetized pigs, and the animals were separated into 2 groups. In the treatment group, resuscitation was started 6 minutes after aortotomy with aggressive infusion of crystalloid fluid
2003 Analysis of 44 studies of fluid resuscitation and 9 studies of hypotensive resuscitation…When hemorrhage is severe (injury to the aorta or rat tail removed), fluid resuscitation reduces the risk of death; but when hemorrhage is less severe (injury to vessels other that the aorta or solid organ), the risk of death is increased.
BUT REGARDLESS OF THE SEVERITY OF BLEEDING 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
Probably most important of these, Sondeen JL, Coppes VG, Holcomb JB. 2003
Sondeen demonstrated that after arterial injury and hemorrhage, followed by spontaneous clotting, if resuscitation commences and continues until the blood pressure reaches a systolic blood pressure of 94 ± 3 mm Hg, then newly formed clot is disrupted, bleeding resumes, blood pressure goes down, and the animal dies

9. Meanwhile, in humans 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
The earliest, and often-sited trial was performed by Bickel et al in It was a randomized control trial of 598 penetrating trauma to the abdomen with SBP <90 (including SBP not palpable), wherein the control group got fluids as they do in current practice and LR was given to penetrating trauma pts as soon as they were in the ambulance. The experimental group was given KVO (imagine being on those EMS crews where you have a patient who’s obviously bleeding and you’re starting a KVO gtt!). (Not sure how they got this one past the IRB, honestly. Average SBP was 60)They referred to this group as the “delayed resuscitation” group. Fluids and blood were then initiated at time of operation for SBP goal 100. OUTCOME: All in all, patients in the immediate group received about 1L prior to operation and the same intraop. As expected they had a HIGHER MAP on presentation, lower hct, higher PT/PTT. The overall rate of survival was significantly higher in the delayed-resuscitation group than in the immediate-resuscitation group (70 percent vs. 62 percent, P = Immediate also had a trend (p=.11) toward more blood loss intraop and trend (p=.08) toward more post-op complications.
From this, authors concluded that DELAY OF FLUID RESUSCITATION UNTIL OPERATIVE INTERVENTION is likely beneficial. (Most importantly, it emphasized early operative hemostasis.)
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

10. Others 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.
In 2002 Dr Dutton and others studied “hypotensive” resuscitation in particular. This time blunt injury patients were included. No difference was found. The sample size was quite small and the ISS scores were not equal…suggests the need for a larger trial.
-A newer study (RCT) whose results on the first 90 patients are published before print. Hypotensive group seems to be doing better but we’ll still have a while to wait for the outcomes.
Morrison CA et al., Hypotensive resuscitation …l. Trauma Mar;70(3):
Dutton RP, MacKenzie CF, Scalea TM. Hypotensive resuscitation during active haemorrhage: impact on in-hospital mortality. J Trauma. 2002;52:

11. Theory
“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
As you can see, there is some intriguing evidence in favor of much more restricted fluid resuscitation than we currently employ.

12. Practice Points
Delay aggressive fluid resuscitation until operative control is achievable. SBP >70 and MAP >55 appear safe*.
An SBP of 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.
Based on the Bickle study there is pretty good evidence to support this first bullet point for penetrating trauma patients and one can probably using reason apply this to blunt trauma “moderate hypotension for less than 30 minutes can be tolerated by trauma patients without progression to end-organ failure” and may prevent clot-breakup/coagulopathy.
In answer to the second question: Probably, and It depends. Obviously its complicated when you have different goals between studies. As usual, more studies are needed before this is something that’s protocolized—for now the use of this strategy will remain dependent on the patient, provider and circumstances. What about the CT scan? Answer: hypotensive patients shouldn’t be IN the CT scan.
* Except in the above populations

13. Hypotensive Resuscitation (Dr. Jay Johanning)
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.”

14. “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

15. Blood Product Ratios and Limiting the Use of Crystalloids.
II. Written in Blood
Blood Product Ratios and Limiting the Use of Crystalloids.

16. 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)

17. 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.

18. 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

19. 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
Dutton, R.P., (2005). Damage Control Anesthesia, International Trauma Care,

20. 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), )
Current trends

21. Literature Review- Blood Product Ratios

22. 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), )
RESULTS:
For the low ratio group the plasma to RBC median ratio was 1:8 (interquartile range, 0:12-1:5), for the medium ratio group, 1:2.5 (interquartile range, 1:3.0-1:2.3), and for the high ratio group, 1:1.4 (interquartile range, 1:1.7-1:1.2) (p < 0.001). Median Injury Severity Score (ISS) was 18 for all groups (interquartile range, 14-25). For low, medium, and high plasma to RBC ratios, overall mortality rates were 65%, 34%, and 19%, (p < 0.001); and hemorrhage mortality rates were 92.5%, 78%, and 37%, respectively, (p < 0.001). Upon logistic regression, plasma to RBC ratio was independently associated with survival (odds ratio 8.6, 95% confidence interval ).

23. 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), )
Groups were similar in terms of severity, adjuncts products
Patient’s receive PRBCs before FFP
Non-survivors did not die due to a low FFP:PRBC ratio, they got a lower ratio because they died.

24. 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.
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) DOI: /CCM.0b013e31829a6ecb

25. 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.
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.
On the whole:
The current published literature, though limited by a number of the factors mentioned above, suggests that there may be a benefit in mortality for transfusion of higher volumes of plasma (perhaps with the greatest benefit with a transfusion ratio somewhere in the 1:1.5-2 plasma : RBC range).

26. 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, ) 26

27. Literature Review- Limiting Crystalloids

28. 365 Civilian patients: Multi-Institutional analysis of MTPs (prospective comparative study therapeutic, )
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), )

29. 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)
In other words, when cells are edematous they cease to function well.

30. Complications Associated with Aggressive Crystalloid Resuscitation
-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.
-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
(Cotton et al., (2006). The cellular, metabolic, and systemic consequences of aggressive fluid resuscitation strategies. Shock, 26(2), )

31. 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.
Current recommendations

33. “Greatness, is a lot of small things done well.” - Eric Thomas

34. “Just enough education to perform”

35. Reversal of Coagulopathy & Thromboelastograpy Directed Therapy

36. Objectives 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

37. Clotting Cascade Damaged surface Trauma Fibrin clot XII XIIa XI XIa
IX IXa
Trauma
VIIa
VII
Tissue factor
VIIIa X Xa X
UFH Va
LMWH
Prothrombin
II (Thrombin)
Xa inhibitors
Fibrinogen
Fibrin
VKA DTI
XIIIa
Fibrin clot

38. FDA Indications FDA Supported Indications
Reduce the risk of systemic embolism in patients
with non-valvular AFib
Apixaban Dabigatran Rivaroxaban
DVT prophylaxis in knee/hip replacement
Rivaroxaban
Treatment of DVT/PE and extended Tx
Non-FDA Approved Indications
Treatment of DVT/PE
Apixaban
Dabigatran
Acute Coronary Syndromes*
* Investigational

39. Pharmacokinetic Comparison
Warfarin
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
Dosing Interval
Daily
BID
Half life (t1/2) hr 40
12-17
4-9 12
Onset
Slow
Rapid
Peak Effect
5-7dys
1-2hrs
2-4hrs
3hrs
Monitoring
Yes No
Drug
Interactions
High
Drugs/food
Moderate
P-gp
3A4, P-gp
Low
Reversal
Renal Dose
Bleeding ++ +
+/-
Warfarin, Dabigatran, Rivaroxaban, Apixaban. LexiComp. Hudson, OH

40. Hemorrhage Risk Factors
Demographics
Age (>75y/o)
Low Body Mass (<50kg)
Comorbidities
Renal Insufficiency
Liver Disease
Prior hemorrhage
Stroke Hx
Peptic Ulcer Disease
Concomitant Meds
Intensity of anticoagulation
P2Y12 inhibitor (clopidogrel, prasugrel, ticagrelor)
Aspirin
others
Ageno. Chest 2012; 141: e44s-e88s.

41. Bleeding and Reversal Warfarin Vitamin K Fresh Frozen Plasma
PO or IV
Fresh Frozen Plasma
Recombinant Factor VII
Prothrombin Complex Concentrates (PCC)

42. Then
Ansell. CHEST. 2008;133;

43. Serious or life- threatening bleeding
Now
INR
Bleeding
Therapeutic Options
> 3.0 – 10 No
bleeding
Hold warfarin until INR returns to normal range
>10
No bleeding
Hold warfarin and give vitamin K mg PO*
Any INR
Serious 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
* Low dose reduces INRs 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.
Holbrook. CHEST. e152-e184

44. CHEST and ICH Guidelines
Holbrook. CHEST. e152-e184, AHA/ASA ICH Guidelines. Stroke 2010;41:

45. Bleeding and Reversal DTI Xa Inhibitors( Xarelto) No direct antidote
Prothrombin Complex Concentrates (PCC)
Recombinant Factor VII
Fresh Frozen Plasma
Dabigatran is dialyzable
Xa Inhibitors( Xarelto)
Under development (Andexanet alfa, Portola Pharmaceuticals)

46. Agents Generic Name Brand Name Approved Uses PCC - 4 Factor
Kcentra (Octaplex, Beriplex)
Reversal of acute major bleeding due to warfarin
Activated PCC - 4 Factor
(anti -inhibitor coagulant complex)
Feiba
Hemophilia A and B
PCC – 3 Factor
Profilnine® SD
Hemophilia B with factor IX
deficiency
Recombinant Factor VIIa
NovoSeven® RT
Patients with factor VII deficiency or with hemophilia A or B
Kcentra Package Insert. CSL. April;2013.
Feiba. Medical letter. Baxter. 2;2011. Profilnine SD. Factor Levels. Grifols. 03/12. NovoSeven. LexiComp. Hudson, OH

47. Factor Content Kcentra 4 18 11 16 23 19 14 Feiba NF 4 18 12 21 19 15
16 23 19 14
Feiba NF 4 18 12 15
Profilnine SD 3
40 Trace
37 23
rFVIIa
N/A
100
Kcentra Package Insert. CSL. April;2013.
Feiba. Medical letter. Baxter. 2;2011. Profilnine SD. Factor Levels. Grifols. 03/12. NovoSeven. LexiComp. Hudson, OH

48. Non inverse relationship between plasma factor VII levels and INR.
Imberti et al(Blood Transf Apr.’11,9(2) ).
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 % of factor VII is needed for adequate hemostasis.

49. Pro & Con Table Agent C o s t A v a i l V o l u m e Infus Time
Admix Time O
n s
e t
Effectiv eness
Infect Risk
Thrombo sis Risk
FFP + Lg
120 min - ++
Kcentra $$ Sm
20 min
FEIBA
$$$
15 min
Profilnine $
NovoSeven
Push
+++
Kcentra. LexiComp. Hudson, OH
Feiba. LexiComp. Hudson, OH Profilnine SD. LexiComp. Hudson, OH NovoSeven. LexiComp. Hudson, OH Cupp. Pharmacist’s Letter Oct

50. Prothrombin Complex Concentrate (PCC)
Rebound Drug Effects
Anticoagulation Reversal Pharmacokinetics
Agent
Onset
Duration
Rebound of Anticoagulant
Protamine
5 min
Irreversible
Likely with SBQ dosing from postponed drug delivery
Vitamin K
4-12hrs
Days for
INR
Dose dependent
Fresh Frozen Plasma (FFP)
1-4hrs
6hrs
4-6hrs
Prothrombin Complex Concentrate (PCC)
10-
15min
12-24hrs
≈12hrs
rFactor VII
10min
6-12hrs

51. Full Anticoagulation Reversal for Life Threatening Hemorrhage
Oral Drug Generic Brand Reversal Strategy
Vit K Antagonist
Warfarin Coumadin PCC - 4 factor + Vitamin K 10mg IV
Rivaroxaban Apixaban Edoxaban
Xarelto Eliquis
Factor Xa Inhibitor
PCC - 4 factor
DTI
Dabigatran
Pradaxa
PCC - 4 factor
Immediately after IV UFH bolus: 1mg protamine per 100
units heparin
30-60min post UFH: 0.5mg protamine per 100 units heparin
UFH
Heparin
N/A
≤8hrs since dose: 1mg of protamine per 1 mg of enoxaparin
8-12hrs since dose: 0.5mg of protamine per 1 mg of enoxaparin
Enoxaparin
Lovenox
LMWH
≤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
Dalteparin
Fragmin
Factor Xa Inhibitor
Fondaparinux
Arixtra
PCC - 4 Factor

52. Dosing 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 INR
Dose of 4F-PCC (Units of Factor IX)
Maximum Dose (Units of Factor IX)
2 to <4
25 units/kg
2500 units
4-6
35 units/kg
3500 units
>6
50 units/kg
5000 units

53. Thromboelastogarphy( teg)

54. Thromboelastogarphy( teg)
Developed by H. Hartert in Germany in 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 ;86(2S):88S

55. Thromboelastography Functional assay Factor Deficiencies
Global evaluation of(from initiation of protein coagulation through lysis)clot.
Factor Deficiencies
Fibrinogen Function
Platelet Function
Clot Strength
Lysis
Standard coagulation tests, termed the plasma clotting assays, include the prothrombin time (PT) and activated partial thromboplastin time (aPTT), provide general measures of the extrinsic and intrinsic clotting pathway integrity, respectively. These tests are performed on platelet-poor plasma and are unable to assess the true rate of clot formation, overall strength of the clot and the degree of clot lysis (fibrinolysis) as TEG can. (4)

56. Coagulopathy of Trauma
Pro-thrombotic State
DVT / PE
(Majority)
Hemorrhagic State
Bleeding
Ongoing hypotension
Integral to limiting hemorrhage and subsequent survival is one’s ability to form a fibrin clot at the site of injury. However, the same hemostatic process required to limit hemorrhage can also be life threatening when venothromboembolic (VTE) complications occur. Hence, a delicate balance exists between pro-coagulant and anticoagulant activities in vivo. It is important to be able to accurately evaluate the hemostatic status after injury so we adequately restore clotting factors in a bleeding patient or assess the efficacy of pharmacologic therapy in prothrombotic patients.
Coagulopathy of trauma is dynamic.

57. CONTACT TISSUE COMMON PATHWAY THROMBIN / FIBRINOGEN
The hypercoagulable state resulting from tissue injury has been attributed mainly to extrinsic (TF)-dependent thrombin generation. The contact pathway (TF-independent) can also lead to thrombin generation in vitro but the physiologic significance of this pathway in vivo has been less well understood. (20-21)
In cardiac patients, contact pathway enzyme, FXIa, was significantly higher in those with acute coronary syndrome (ACS) than in those with stable angina pectoris (SAP) pointing to its role in vascular thrombosis. Hence both the intrinsic and extrinsic pathways may both have a role in maintaining hemostasis after injury.
THROMBIN / FIBRINOGEN

58. Hemostasis profile: R time  Angle MA LY
Selected parameters will be discussed here.
R time – time to first fibrin strand formation; this is the point at which all other plasma clotting assays (e.g., PT/aPTT) stop measuring. Its value will increase with coagulation factor deficiency or its value will decrease when the coagulation factors involved in thrombin generation is increased as when FVIIa is administered.
α-angle measures the angle between the tangent line drawn from the curve to the split point and the tracing's horizontal line, in degrees. It is reflective of kinetic interaction of fibrin/fibrinogen with platelets.
Maximum Amplitude – Reflects ultimate clot strength due to fibrin/fibrinogen interaction with GPIIb/IIIa receptor on functioning platelets.
Lysis 30 – Rate of amplitude reduction (clot break down) and is an indication of clot stability
Hemostasis profile:
R time  Angle MA LY
Fibrin strands clot kinetics strength/elasticity dissolution

59. TEG Components R (reaction) time K (clotting) time Alpha angle
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
Developed by H. Hartert in Germany in 1948 as a research tool
First used clinically in liver transplantation by Kang in Pennsylvania more than 25 years later
Widest use in cardiopulmonary bypass (CPB) and liver transplantation
Other uses: Trauma / Obstetrics / Surgery / ICU / Hypercoagulable states etc.
2 studies only
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
Utility under investigation at Balad LTC Donald Jenkins and Maj Steve Abbate

60. Graphic Result

62. Patient status: bleeding
Platelet Abnormality
Patient status: bleeding
Probable causes:
Factor deficiency
Low platelet count
Low platelet function
In this tracing, bleeding is probably due to a combination of factors. The long R value suggests a coagulation factor deficiency, while the low MA suggests low platelet count and/or platelet dysfunction.
The TEG decision tree, used as a guide for bringing the hemostatic system back into balance, suggests that the R should be reduced first, then the MA.

63. JW’S TEG PROFILE

64. Fibrinogen Deficiency
Patient status: bleeding
Probable cause: fibrinogen deficiency
Common treatment: Cryoprecipitate, FFP, or prothrombin complex
Common treatments for fibrinogen deficiency include cryoprecipitate, FFP, and prothrombin complex. The choice of treatment is determined by product availability and protocols at each institution.

65. TEG DIRECTED THERAPY- pt. 1
Gsw to pelvis and right LE
Rectal, Small Bowel, Sacral, & Open Femur Fx
Arrived in Class IV
Shock

66. Same Patient
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

67. GSW to Left Flank- pt. 2
Sigmoid Colon, Small Bowel, and Abdominal Wall Injury
2 PRBC given intra-op

68. GSW to Left Flank- pt. 2 Post-op TEG shows early fibrinolysis
TEG after Amicar infusion

69. Clinical Randomisation of an Antifibrinolytic in Significant Hemorrhage

70. Guideline for Blood Product Use
Abnormal TEG
Prolonged R time
Prolonged K time or Decrease a-Angle
Transfuse 4 units FFP
Transfuse 4 units FFP
then 4 units Cryoprecipitate
Consider rVIIa if abnml after above
Decrease Maximum Amplitude
Increase LY30
Transfuse platelets
Amicar or Tranexamic Acid

71. 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

72. QUESTIONS???