FOU, Alm.del - 2023-24 - Bilag 73: Henvendelse af 16/1-24 samt materiale fra foretræde 22/2-24 vedrørende mobil blodbank, fra Eldon Biologicals A/S

Forsvarsudvalget 2023-24
FOU Alm.del Bilag 73
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Whole Blood at Point of Injury:

new treatment paradigm for NATO

U.S. Army Institute of Surgical Research

COL Andrew P. Cap, MS, MD, PhD, FACP

Chief, Coagulation and Blood Research Program, USAISR

Associate Professor of Medicine, Uniformed Services University

Co-Chair, NATO Blood Panel

FOU, Alm.del - 2023-24 - Bilag 73: Henvendelse af 16/1-24 samt materiale fra foretræde 22/2-24 vedrørende mobil blodbank, fra Eldon Biologicals A/S

Disclaimer:

The opinions or assertions contained herein are the

private views of the author and are not to be

construed as official or as reflecting the views of the

Department of the Army or the Department of

Defense.

Disclosures:

I have no relevant conflicts of interest.

I am an active duty officer in the U.S. Army.

FOU, Alm.del - 2023-24 - Bilag 73: Henvendelse af 16/1-24 samt materiale fra foretræde 22/2-24 vedrørende mobil blodbank, fra Eldon Biologicals A/S

Outline:

1. Overview of combat trauma epidemiology: cause of death

and time to death

2. Pathophysiology of hemorrhagic shock and

Blood Failure

3. State-of-the-art combat casualty care: Remote Damage

Control Resuscitation (RDCR)

4. Implications for NATO

5. Conclusions

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US Military Death Distribution

(2001-2011)

Potentially Survivable Deaths -

976

(24.5%)

4,596 Combat Deaths

Died of Wounds

(≥ Role II)

580 deaths

Killed in Action

(Role I)

4,016 deaths

- 3,040 nonsurvivable

976 potentially survivable

Eastridge. J Trauma Acute Care Surg. 2012

BLEEDING IS THE PROBLEM

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Time to Death: KIA/DOW

“Golden Hour” is too late to start DCR…

Number of KIA and DOW Deaths by Time Increment (AFG)

N=457

KIA

120

DOW

100

Must start resuscitation pre-hospital:

Remote DCR (RDCR)!

Shackelford, et al.

JTS 2016.

>30

>60

>90

>2 hours >4 hours >6 hours >8 hours

>10

>12

>24

>1 week

minutes minutes minutes minutes minutes

to 4

to 6

to 8

to 10 hours to hours to hours to or more

or less

to 30

to 60

to 90

to 2

hours

hours 12 hours 24 hours 1 week

minutes minutes minutes hours

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Pre-hospital blood transfusion



Large reduction in risk of death

Which curve do you

want to be on?

I’ll take lower

probability of death!

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Timing is everything Transfusion must start

15min from MEDEVAC rescue (36min from POI)

Best results:

transfusion within

15min of MEDEVAC

(36min of POI)

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Start transfusion here if not sooner!

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Trauma + Hemorrhagic Shock:

Blood Failure

HEMORRHAGIC SHOCK:

Low cardiac output



Poor tissue perfusion



Oxygen debt



Requires aggressive,

Acidosis



immediate intervention

Fibrinolysis/

Coagulopathy/

Platelet dysfunction



More bleeding



DEATH… IN MINUTES

Need to restore functionality of WB!

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Blood + Endothelium =

Blood as an Organ

• Embryonic mesoderm



hemogenic endothelium



HSC



blood: 3d

week embryo

• Blood = RBCs, WBCs,

Platelets, Plasma,

and…

Endothelium (10

cells)

• Microcirculation

estimated to cover an

area of up to 7000 m

• Largest organ system,

highest turnover rate.

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Loss of Blood + Damaged

Endothelium



Blood Failure

Must replace the full functionality of blood. Give WHOLE BLOOD.

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Remote

No R2 or

R3 within

1 hour?

Move DCR

out of

hospital to

keep

patient

alive!

RDCR

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+ Damage Control

Damage Control:

First, only do the things

essential to keeping the ship

afloat.

Plug holes & stop

bleeding.

Rotondo MF, Schwab CW, et al.

J Trauma.

1993;35(3):375-82.

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+ Resuscitation

Emergency treatment to restore:

Circulating blood volume

Aid oxygen delivery

Replace hemostatic potential

Treat

Blood

Failure…

by giving

what the

patient is

losing:

BLOOD!

FOU, Alm.del - 2023-24 - Bilag 73: Henvendelse af 16/1-24 samt materiale fra foretræde 22/2-24 vedrørende mobil blodbank, fra Eldon Biologicals A/S

= RDCR (today)

The essentials:

•

Hemorrhage control

•

Resuscitation

•

TXA

•

WHOLE BLOOD

•

Plasma (FDP) as a bridge to WB

•

Avoid clear fluids

ROLO!

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DCR = Hemostatic Resuscitation



Blood must be able to deliver oxygen & form clots!

•

Minimize crystalloid,

DO NOT USE HEXTEND

•

RBC:FFP:PLT:cryo = “1:1:1:1” or better:

WHOLE BLOOD

•

Treat loss of RBC, fibrinogen, platelet function, etc.

•

Tranexamic acid for fibrinolysis

THIS, not that!

Need all parts of

blood to replace

lost organ function

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Start with plasma until you can get WB or DCR

with components (1:1:1)

Plasma given pre-

hospital as a bridge

to full DCR reduces

mortality by 1/3 (23%

vs. 33%)!

Proof of concept for

FDP as a bridge to

WB in RDCR...

Note: outcomes even

better with

plasma+RBC

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NATO COMEDS/MHCWG:

Focus on Pre-Hospital Care

•

Must reduce mortality pre-hospital (R2 or R3 too late)

•

Pre-Hospital Care Improvement Initiative (PHCII) – key

events:

–

March 2016: Landstuhl workshop sponsored by

MILMEDCOE

–

June 2016: 45

COMEDS plenary, Dublin: FRA volunteers to

lead PHCII

–

September 2016: 22

MHCWG meeting in Landstuhl

–

June 2017: Budapest MILMEDCOE workshop

–

March 2018: Brussels MHCWG review of PHCII progress

–

April 2018: TIDESPRINT/Genoa: NATO Futures adopts BFF

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Output of MILMEDCOE 2016

Landstuhl workshop: BFF

•

TCCC as basis of pre-hospital care

–

Imperative to extend training throughout the force

•

10-1-2 (current NATO standard) should be refined

–

Need to push hemorrhage control to self/buddy aide level

–

1 hour to resuscitation – miss opportunity to

prevent early

hemorrhage deaths

–

2 hours to surgery is too late (unless blood provided far forward)

•

New goals:

0-30-60 – with Blood Far Forward (BFF)

–

Immediate self/buddy hemorrhage control

–

30 minutes to resuscitation with blood

–

60 minutes to surgery ideally (perhaps 2 hrs with BFF)

•

BFF key to reducing battlefield mortality

•

Pediatric trauma care not doctrinal but needs to be

–

ethical imperative in view of injuries to non-combatant children

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Output of MILMEDCOE 2017

Budapest workshop: BFF is key!

•

TCCC

as basis of pre-hospital care

•

Early hemorrhage deaths can be avoided by:

–

Training all personnel in

hemorrhage control

(tourniquets,

hemostatic dressings) for self/buddy aid

–

Transfusing blood

at point-of-injury (POI) and

en route

surgical care (and give TXA)

•

Must begin implementation of BFF!

TXA

Low Titer O

Whole Blood

(LTOWB)

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All blood products start as WB

WB collection kit

RBC

FFP

aPLT

Whole Blood

Donor

We separate WB into components

by centrifugation to treat isolated

blood deficiencies like anemia. In

bleeding, we need ALL the

components (WB)!

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Why give WB?

It’s simple!

Don’t make things worse (clear fluids)!

Give the patient what he or she is losing!

Keep it simple (one product)!

Can be “universal” (O Low Titer anti-A&B

in plasma, RBCs compatible with all)

• New AABB standard

• No need to match blood types in

emergency

LTOWB: get it in QUICKLY, because people DIE quickly!

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WB is more concentrated

1:1:1 Component Therapy:

6 x RBC (AS-5)

6 x FFP

1 x aPLT

6 x 120 ml = 720ml

6 x 50 ml = 300ml

1 x 35 ml = 35ml

Whole Blood x 6 Units:

6 x 63ml = 378ml

Total =1055ml

Total: 378ml

3 times the volume of anticoagulant & additives in

reconstituted whole blood from components (1:1:1)

compared to whole blood!

Spinella PC, J Trauma. 2009;66:S69-76

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WB contains platelets:

the

critical

effectors of hemostasis.

1. Primary hemostatic plug: PLT + VWF

adhesion on exposed collagen

2. PLT surface (& microparticle) phosphatidyl

serine + FVa



catalytic surface for

thrombin generation (cell-based model of

coagulation)

3. PLT aggregation



organization of fibrin

into bundles, clot retraction (mechanical

hemostasis)

4. PLT secretion



PLT recruitment, PAI-

1/A2AP (anti-fibrinolysis), sCD40L (immune

activation), serotonin (vasoconstriction)

5. Maintenance of vascular endothelial

integrity via CLEC-2, GPVI receptors

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Need a platelet product that really works!

Which platelets would you want if you were bleeding?

•

Current standard of care 5day 22C-stored platelets make weak clots

•

4C storage (cold) maintains clot strength



WB has cold platelets!

1000

400

Clot strength (Pa)

Stress (Pa)

100

200

Strain

Strain %

100

1000

Fresh 5 d RT 5 d 4C 10 d 4C 14 d 4C

Nair

BJH

2017

in press

Compared to Fresh; n=4,

< 0.05

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4C-stored WB Hemostatic Function Over Time:

drop in PLT aggregation but preserved clotting

Cold

Pidcoke

Transfusion

2013

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WB vs. Components:

More concentrated, simpler

WB 4°C

Hgb

HCT

PLT

Fibrinogen,

Factors

12-13

35-37

138-165

Normal @

baseline, FVIII ≥

50% d7

Nearly normal

d21

≥ 50% baseline

d7-10 at 4C

8 bags, one

storage mode

(8 U, 4000 ml)

Components (1:1:1)

90-120

All 62% dilution @

baseline, plus loss

FVIII

Reduced vs. WB

TEG clot

strength

PLT

aggregation

Practical

aspects (4L)

Nearly complete

loss d5 in 22C-PLT

13 bags, three

storage modes

(6:6:1, 4150 ml)

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Whole Blood Recent Combat Data

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Fresh Whole Blood is Better than CT

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WB options: walking BB (fresh but

untested) vs. stored

WFWB (WBB)

Best hemostasis

(100%)

CPD WB 4°C

< WFWB w/

decrease in PLT

function after d14

At least equivalent

to components* @

1:1:1

CPDA-1 WB 4°C

< WFWB w/

decrease in PLT

function after d14

At least equivalent

to components* @

1:1:1

*Assuming RT-PLT

Highest

infectious risk

Use as WFWB

w/in 8 hrs or

refrigerate

Need pre-titered

O donors to get

universal;

OTW

type-specific

Low infectious risk

(standard)

21d shelf life

Low infectious risk

(standard)

35d shelf life

LTOWB or type-

specific

LTOWB or type-

specific

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Priorities for Action

•

NATO standards for:

–

WB Production, Storage/Shipping

–

WB Use

•

EU Regulatory relief to allow “trained

personnel” to collect/transfuse WB in pre-

hospital setting

•

NATO “RDCR” Clinical Practice Guideline (CPG)

on pre-hospital blood use (consistent with

JTS/TCCC)

•

NATO-wide adoption of

FDP

(↑production)

•

NATO standards for all blood interoperability,

traceability

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NATO Policy Needs

•

NATO standard setting critical:

–

Think of WB and BFF as a:

“common (human) fuel policy”

Low Titer O

Whole Blood

(LTOWB)

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Give BLOOD for (R)DCR

LTOWB is the simplest way to deliver the functionality

of lost patient blood.

The freshest WB is the most functional.

BUT: most available data on improved outcomes with

pre-hospital transfusion based on COMPONENTS!

ANY mix of WB or components is better than clear

fluid.

4°C

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History of Pre-Hospital Shock

Resuscitation

Whole Blood is King!

WW I

WW II

Korea

Vietnam

Components are cool!

OIF/OEF

60 years of Blood

Back to

30 years of Clear Fluids the



future???

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Golden Hour is too late…

NEED BLOOD at POI

Number of KIA and DOW Deaths by Time Increment

N=457

KIA

120

DOW

100

JTS 2016.

>30

>60

>90

>2 hours >4 hours >6 hours >8 hours

>10

>12

>24

>1 week

minutes minutes minutes minutes minutes

to 4

to 6

to 8

to 10 hours to hours to hours to or more

or less

to 30

to 60

to 90

to 2

hours

hours 12 hours 24 hours 1 week

minutes minutes minutes hours

FOU, Alm.del - 2023-24 - Bilag 73: Henvendelse af 16/1-24 samt materiale fra foretræde 22/2-24 vedrørende mobil blodbank, fra Eldon Biologicals A/S

LTOWB

Cold

Platelets

TXA

Questions?

FDP