Damage Control

Resuscitation: Beyond

the MTP Dr Jonathan Tan

Senior Consultant,

Anaesthesiology, Intensive Care,

Tan Tock Seng Hospital, Singapore

Trauma shock and

Coagulopathy

Acute Coagulopathy of Trauma

Shock

Multifactorial aetiological Combination

Shock

Tissue injury related thrombin generation

Anticoagulant and Fibrinolysis activation

Hypothermia, Acidosis, Hemodilution, Factor

consumption.

Inflammation, SIRS, Coagulation. Crosstalk

Hess JR et al. J Trauma 2008,65:748-754 Nascimento et al. Critical Care 2010,14:202

Brohi K et al. J Trauma 2003;54:1127-1130

Brohi K et al. J Trauma 2008,64:1211-1217

Damage Control Resuscitation

Haemostatic Resuscitation;

Damage Control Resuscitation

Goal:

Minimize iatrogenic resuscitation injury

Prevent worsening shock & coagulopathy

Rapid correction of hypothermia, acidosis & direct correction of coagulopathy.

Obtain definitive haemostasis

Restore Physiology • HessJR, Holcomb JB et al.Transfusion 2006; 46:685-686

• Holcomb et al. J Trauma;2007;62:307-310

• Beekley AC et al. Crit Care Med 2008;36:S267-274

DCR Principles

Rapid recognition of at risk patient:- For MT, early coagulopathy of trauma.

“Permissive hypotention” before surgical hemostasis

Rapid definitive control of bleeding!

Treat Hypothermia, Acidosis, Hypocalcaemia. Resus!

Avoid excessive crystalloids and haemodilution

DCR Principles

Early transfusion of

PRBC:Plasma:Platelets in ? ratio!

Use of fresh whole blood? Fresh RBCs?

Adjuncts where appropriate: rFVIIa, anti-fibrinolytics, cryoprecipitate…

Frequent laboratory monitoring of coagulation status; use of point of care tests (Thromboelsatography).

MTP / Haemostatic

Resuscitation Protocol

Beyond just MORE blood…

MTP Key Components

Trigger: wastage vs too late!

Blood Packs: What? Ratio?

Adjuncts: +/- Pharmacologic

Monitoring: Targets?

Physiological Goals?

Treatment algorithm

Standardised

UK-DMS Protocol

Summary of UK-DMS experience in last 12 years: Afghanistan; Iraq

PROMMT: Findings

Pts did NOT receive constant ratio components during active resus

81% Hemorrhagic deaths within 1st 6hours.

Higher Plasma/Platelet:RBC ratios independently assosc with decreased 6hr mortality.

<1:2, 3-4Times more likely to die vs 1:1 or higher grp.

Only 72% rec Platelets by hour 3!

PROMMT: Findings

Survivors hour 6- 24: risk of death higher for low plasma ratios

>24hrs to 30days: Risk of death not assoc with component ratios

Survival bias still an issue

Supports 1:1:1 in MTP during resuscitation, DCS phase?

PROPPR: Findings

Less Exsanguination deaths

More Haemostasis achieved

More FFP but no increased Safety differences

Lower than predicted mortality in 1:1:2 group

1:1:1 ASAP on arrival then switch to guided therapy when haemorrhage control achieved

Crystaloid:RBC

Pts >10U RBC in 24hrs

C:RBC > 1.5:1: >70% risk MOF, 2x risk ARDS, ACS

So Far…

1:1:1 restore circulating vol and blood components

Limit Crystalloids

Warm!

Correct electrolytes: Ca, K

Adjuncts: Pharmacological

Haemorrhage control: stop 1:1:1; directed transfusions

Coagulation Monitoring

Thromboealstography (TEG®)

Rotational Thromboelastometry (ROTEM®)

Normal Values of TEG and ROTEM

TEG ROTEM

Clotting TIme R (Reaction Time)

4 – 8 min

CT (Clotting Time)

INTEM: 137 – 246 sec

EXTEM: 42 – 74 sec

Clot Kinetics K (Kinetics)

1 – 3 min

CFT (Clot Formation

Time)

INTEM: 40 -100 sec

EXTEM: 46 – 148 sec

Clot Strengthening α angle

47 – 74o

α angle

INTEM: 71 – 82o

EXTEM: 63 – 81o

Amplitude

Maximum Strength

53 – 73 mm INTEM: 52 – 72 mm

EXTEM: 49 – 71 mm

FIBTEM: 9 – 25 mm

ROTEM Tests

Test Name Test Description

In-TEM Mild Intrinsic Activation, High Sensitivity to Heparin, Screening Test

Ex-TEM Mild Extrinsic Activation, Lower Sensitivity to Heparin, Screening Test

Ap-TEM Inhibition of Fibrinolysis Detection to Hyper Fibrinolysis

Fib-TEM

Hep-TEM Reversal of Heparin Judgement of Coagulation without Heparin

Effect

A need for Point-of-Care evaluation of

Coagulation

• Where does the ROTEM/TEG fit into our MTP?

• How do we use the results?

• What are the limitations?

• How do we get the whole picture?

• Stat!

Algorithm?

• Screening: EXTEM + FIBTEM

• Fibrinolysis? Heparin?

• Other super anticoagulants?

• Platelet function??

Platelet Function!!??

Platelet Function Assessment

Bleeding Time

TEG + Platelet Mapping

Roche Multiplate

ROTEM….

Reagents detecting defect in platelet function wrt AA, ADP, Collagen, 2b-3a interactions…

Paucity of data and evidence

Big Blind spot that will kill our patients!

Platelet Function Assessment

For which patient?

Trauma

TBI

Antiplatelet drugs

Renal Failure

Coronary Artery disease; stenting

Ischaemic strokes

My ICU patient…

Everyone??!!??

DDAVP

1-deamino-8-D-arginine vasopressin

Enhances platelet adherence and platelet aggregate growth on endothelial surface

0.3ug/kg or 20U

Von Willebrand factor disease

Head Bleeds with antiplatelet effects

Prevents the development of hypothermia-induced impairment of primary haemostasis and significantly increases platelet aggregation during hypothermia and acidosis.

Ng KF et al: Low-dose desmopressin improves hypothermia-induced impairment of primary haemostasis in healthy volunteers. Anaesthesia 2011, 66:999-1005.468. Hanke AA, Dellweg C et al:Effects of desmopressin on platelet function under conditions of hypothermia and acidosis: an in vitro study using multiple electrode aggregometry*. Anaesthesia 2010, 65:688-691.

TEG/ROTEM/VHAs

Shown to save money and reduce unneccessary transfusions

May save lives

Use of VHAs endorsed by European and British Transfusion guidelines

Differentiate medical vs surgical bleeding. (Cardiac literature)

Used with Platelet Function Assay

TEG/ROTEM/VHAs

Will not identify “super” anticoagulants

As part of Haemostatic Resuscitation Protocol

After exsanguinating bleeding plugged

Localised, Specific, to the instituition and patient

It will NOT stop the bleeding!

Beyond Blood

Restore circulating vol 1:1:1, limit crystaloid

Warm

Check: Rotem, ABG, Temp

Correct… Ca, K, Lactate…

Directed coagulopathy and Hb correction

Quick reminder: tranexamic acid; rFVIIa

rFVIIa

Mode of Action

• Tissue Factor dependent pathway

• Tissue factor independent pathway:

Binds directly to activated platelets &

activates Xa on platelet surface. Initiates

thrombin burst.

• Rate and amount of thrombin generation

is paramount in clot stability and

resistance.

• ?Localized to site of injury without

systemic activation??

rFVIIa… Does it work?

Yes!

Haemophilia

Platelet Defects

Qn is…..

Does it work in Trauma??

rFVIIa… Evidence?

Kenet et al 1999, Lancet 354:1879

Numerous Case series; Registries; guidelines; own anecdotal success?

RCTs: Trauma, ICH

Boffard et al, J Trauma 2005: Reduction in RBCs transfused, ARDS, MODS in blunt trauma. Safety.

Phase 2. Safety. Efficacy.

Explosion of off label use in trauma.

rFVIIa in Trauma: Issues

Efficacy; Conditions for optimum effect

Timing

Safety

Dosing

Off label use implications

Cost

“Last-ditch” to Salvage to Optimum outcome improving??

Definitive RCT?.....

Was meant to be the ONE!!

J Trauma Sept 2010,Vol69,(3);489-500

150 Hospitals, 26 Countries

Aug 2005 – Sept 2008

Clinical management guidelines

Inclusion

18-70yr

< 4Hrs Injury to admission

Active Haemorrhage: Acidosis &/or

Hypotension; Ongoing volume loading

1st dose trial drug between 4U & 8U

RBC

Injury to 1st dose completed max

12hrs

Exclusion: futile, Time exclusions.

Intervention

3 doses of rFVIIa: 200ug/kg T0,

100ug/kg T1hr and T3hr.

Placebo

Randomized 1:1

Randomization: Random permuted

blocks

Results

Interim analysis: Blunt trauma mortality far lower. Power too low.

Trial stopped early due to high likelihood of futility.

Total 573 enrolled

481 blunt, 92 penetrating

Baseline demographics statistically same. (ISS, pH, Hb, Vitals, lactate, GCS)

Blunt Trauma Gp

30 day mortality 11.0% Rx v 10.7%

Durable morbidity rates no diff.

Trend towards decreased MOF in rFVIIa gp 45% v 53% p=0.06

Significant reduction in blood pdts used.

RBC 6.9 vs 8.1, FFP 4.7 vs 6.9 at 24hrs

48hrs total allogenic blood transfused 19 vs 23.5

No diff: Platelet, Cryo use.

Blunt Trauma Gp: Safety

Total number of Significant Adverse

Events same

Thrombotic events: 16.1% (rFVIIa) vs

13.2% placebo. p=0.38

SAFE…. ?

Penetrating gp

Mortality rFVIIa grp 18.2% vs 13.2%

p=0.4.

No diff in secondary endpoints

FFP use reduced in rFVIIa gp. 3.8U v

5.7U p=0.04

No diff in SAE, with venous thrombosis

higher in placebo grp. p=0.04

Post hoc analysis combining both grps

less ARDS in rFVIIa grp (8 vs 22

events) p=0.022

CONTROL Trial: Discussion

rFVIIa: Proven haemostatic agent

Modest reduction in RBC use. Is reduction of 1-1.5U of blood transfused clinically significant??

Safety: Combination of 2 RCTs in trauma, total of 837pts: No increased thrombotic risk. ?Young pt population?

Benefits: Reduction in ARDS? Both trials show benefit??

Discussion

Compliant Use of patient management protocols: improved “standard care”?

See appendix of study for details: DCS, Resus targets,colloid use guidelines, Ventilation strategy…

Safety of rFVIIa in RCTs

NEJM Nov 4, 2010. 363;(19). 1791-1800

35 RCTs (9 in healthy volunteers) spanning 12 years, heterogenous disease states. CONTROL trial NOT included.

4119 patients, 349 healthy volunteers

Arterial Thromembolic events 5.5% rFVIIa, 3.2% placebo. P=0.003

Venous events no diff.

Factors for increased risk: Neuro-events, Age (esp >65), higher rFVIIa doses, concomitant haemostatic agent used

• ANZHR 386 trauma pts, 45 with triad

• Triad: INR>1.5, pH<7.2,Core temp<35

• Use of rFVIIa assoc with survival in 31%

of patients

• Use in pH<6.91 appears futile

Cannot recommend as 1st line agent

Use as part of a haemostatic protocol; bundle of measures

TTSH rFVIIa guidelines

Used as part of MTP

pH>7.2; Temp>34; iCa >0.9

90-100ug/kg; 2nd dose at hour 2

Off label use implications & Cost: inform family; fill forms

“Last-ditch” to Salvage to Optimum outcome improving??

THINK of it!

Tranexamic Acid

Tranexamic Acid

Antifibrinolytic agent

Lysine analogue; Competitive inhibition

Plasma T1/2 120min

Prevents Plasmin activation

Dose? Cardiac surgery? Trauma?: Large

variation.

Cave! Dose accumulation with Renal failure.

274 hospitals, 40 countries, 20211pts

With OR at Risk of significant bleeding

Within 8 hours of injury

Clinical inclusion criteria only

1g over 10min, 1g over 8 hours

CRASH2

Significant reduction in all cause mortality and that due to bleeding.

However, no significant reduction in blood transfusions in treatment arm.

Tranexamic Acid

Issues…

8 Hours from injury: Prehospital influences?

Lack of precision of inclusion criteria?

Fibrinolytic assays?

Safety: Vascular occlusions? Seizures?

Dosing

ISS not presented for groups

Blood component ratios in both groups?

Issues…

No difference in transfusion: was benefit due to other properties of Tranexamic acid or reduced Plasmin proinflammatory effects?

How??

Wait for it………

Lancet Mar 26, 2011:377:1096-101.

Death due to bleeding 35%

Discussion

Used in dose and manner prescribed:

Reduced all cause mortality, esp death due to bleeding.

Give it early! < 3 hours post injury

?? Given > 3 hours, increased risk of death.

Editorial comment re availability of coagulant blood pdts and benefit of tranexamic acid, esp in pre hospital care.

Whole blood Viscoelastic Hemostatic Assays?....

Conclusion

Stopping the Bleeding: Interventionalist’s job

Making the blood clot: YOUR job.