ICS SOA 2015

1. Blood and plasma:
Learning from the pre-hospital setting
Major David N Naumann RAMC
Clinical Research Fellow
University of Birmingham
Tuesday 8th
December 2015
Dr Nick Crombie
Chief Investigator
RePHILL
@DrNickCrombie
@MidwinterMJ
@dave_surg

2. Introduction
Clinical context
– Haemorrhagic shock
– Pre-hospital evacuation
and
resuscitation
Clinical context
– Haemorrhagic shock
– Pre-hospital evacuation
and
resuscitation

3. Introduction
Clinical context
– Haemorrhagic shock
– Pre-hospital evacuation
and
resuscitation
Clinical context
– Haemorrhagic shock
– Pre-hospital evacuation
and
resuscitation
Intended audience
Trauma/emergency and
ICU practitioners
Intended audience
Trauma/emergency and
ICU practitioners

4. Scope:
Pre-hospital blood products
1. Why pre-hospital?
2. The evidence so far
3. The future…
1. Why pre-hospital?
2. The evidence so far
3. The future…

5. Timeline
Vietnam war (60s-70s) Kiel F. Development of
a blood program in
Vietnam. Mil Med.1966;
131:1469-82
Whole blood, red cells

6. Timeline
Vietnam war (60s-70s)
Civilian practice 1985
Kiel F. Development of
a blood program in
Vietnam. Mil Med.1966;
131:1469-82
Dalton AM. Use of blood
transfusions by helicopter
emergency medical services:
is it safe? Injury.1993; 24:
509-10
Whole blood, red cells
O-
red cells

7. Timeline
Vietnam war (60s-70s)
Civilian practice 1985
Modern battlefield from 2008
Kiel F. Development of
a blood program in
Vietnam. Mil Med.1966;
131:1469-82
Dalton AM. Use of blood
transfusions by helicopter
emergency medical services:
is it safe? Injury.1993; 24:
509-10
Calderbank P et al.
Emerg Med J. 2011; 28:
882-3.
Malsby RF. Mil
Med.2013; 178:785-91.
Whole blood, red cells
O-
red cells
Whole blood, plasma, O-
red cells

8. Why pre-hospital?
• In-hospital blood products superior to crystalloid
for haemorrhagic shock

9. Why pre-hospital?
• In-hospital blood products superior to crystalloid
for haemorrhagic shock
• Crystalloid restriction & liberal blood product
usage in trauma1,2
1. Dawes R, Thomas GO. Battlefield resuscitation. Curr Opin Crit Care. 2009;15:527-35
2. NICE Guidelines for trauma; 2015 (in draft)

10. Why pre-hospital?
• In-hospital blood products superior to crystalloid
for haemorrhagic shock
• Crystalloid restriction & liberal blood product
usage in trauma1,2
• Military experience of en-route care3
1. Dawes R, Thomas GO. Battlefield resuscitation. Curr Opin Crit Care. 2009;15:527-35
2. NICE Guidelines for trauma; 2015 (in draft)
3. Morrison JJ et al. En-route care capability from point of injury impacts mortality after severe wartime injury. Ann Surg.
2013;257:330-4.

11. Why pre-hospital?
• In-hospital blood products superior to crystalloid
for haemorrhagic shock
• Crystalloid restriction & liberal blood product
usage in trauma1,2
• Military experience of en-route care3
• Makessense biologically
1. Dawes R, Thomas GO. Battlefield resuscitation. Curr Opin Crit Care. 2009;15:527-35
2. NICE Guidelines for trauma; 2015 (in draft)
3. Morrison JJ et al. En-route care capability from point of injury impacts mortality after severe wartime injury. Ann Surg.
2013;257:330-4.

12. Why pre-hospital?
Reduce
hyperfibrinolysis?
Plasma repairs
endothelial glycocalyx?
Attenuate
coagulopathy?

13. Remember the risks too
Transfusion is not without risk:
•ARDS1
•Multi-organ failure2
•Mortality3-5
1. Chaiwat O et al. Anesthesiology. 2009;110:351-60
2. Johnson JL et al. Arch Surg. 2010;145:973-7
3. Malone DL et al. J Trauma. 2003;54:898-905
4. Dunne JR et al. Surg Infect. 2004;5:395-404
5. Robinson WP et al. J Trauma. 2005;58:437-45

14. Also:
• Logistics, shelf life
• Costs and equality
• Wastage

15. Carrying pre-hospital blood products
• London HEMS
• South Wales
• Kent Surrey Sussex
• HM Forces
• Others…

16. Statement… controversial?
If pre-hospital blood products
improve patient outcomes, they
should be available* for everyone
in the UK
*Enduring funding, logistics, capability, availability, traceability, clinical governance

17. Statement… controversial?
If pre-hospital blood products
improve patient outcomes, they
should be available* for everyone
in the UK
Must be EVIDENCE based
*Enduring funding, logistics, capability, availability, traceability, clinical governance

18. The obvious question:
“Do pre-hospital blood
products improve
outcomes for patients?”

19. So what is the
evidence so far?

20. Includes: all studies of pre-hospital blood
products that report patient outcomes

21. All published studies (n=28)
Military (n = 9)
Case Series
Barkana 1999
Malsby 2013
Glassberg 2013
O’Reilly 2014
Chen 2014
Powell-Dunford 2014
Civilian (n = 19)
Case Series
Dalton 1993
Berns & Zietlow 1998
Prause 1999
Badjie 2012
Higgins 2012
Chew 2013
Mena-Munoz 2013
Sherren 2013
Weaver 2013
Bodnar 2014
Sunde 2015
Cohort Studies
O’Reilly 2014
Smith 2014
Gross 2014
Cohort studies
Price 1999
Sumida 2000
Kim 2012
Badjie 2013
Wolf 2014
Brown 2015(a)
Brown 2015(b)
Case-control
Wheeler 2013

22. Trauma
Military (n = 9)
Case Series
Barkana 1999
Malsby 2013
Glassberg 2013
O’Reilly 2014
Chen 2014
Powell-Dunford 2014
Civilian (n = 12)
Case Series
Dalton 1993
Prause 1999
Sherren 2013
Weaver 2013
Bodnar 2014
Cohort Studies
O’Reilly 2014
Smith 2014
Gross 2014
Cohort studies
Price 1999
Sumida 2000
Kim 2012
Wolf 2014
Brown 2015(a)
Brown 2015(b)
Case-control
Wheeler 2013

23. Mixed Trauma and non-trauma
Military (n = 0) Civilian (n = 7)
Case Series
Berns & Zietlow 1998
Badjie 2012
Higgins 2012
Chew 2013
Mena-Munoz 2013
Sunde 2015
Cohort studies
Badjie 2013

24. Retrospective
Military (n = 9)
Case Series
Barkana 1999
Malsby 2013
Glassberg 2013
O’Reilly 2014
Chen 2014
Powell-Dunford 2014
Civilian (n = 18)
Case Series
Dalton 1993
Berns & Zietlow 1998
Prause 1999
Badjie 2012
Higgins 2012
Chew 2013
Mena-Munoz 2013
Sherren 2013
Bodnar 2014
Sunde 2015
Cohort Studies
O’Reilly 2014
Smith 2014
Gross 2014
Cohort studies
Price 1999
Sumida 2000
Kim 2012
Badjie 2013
Wolf 2014
Brown 2015(a)
Brown 2015(b)
Case-control
Wheeler 2013

25. Prospective
Military (n = 0) Civilian (n = 1)
Case Series
Weaver 2013

26. Quality of evidence1
: Very Low
Military (n = 9)
Case Series
Barkana 1999
Malsby 2013
Glassberg 2013
O’Reilly 2014
Chen 2014
Powell-Dunford 2014
Civilian (n = 17)
Case Series
Dalton 1993
Berns & Zietlow 1998
Prause 1999
Badjie 2012
Higgins 2012
Chew 2013
Mena-Munoz 2013
Sherren 2013
Weaver 2013
Bodnar 2014
Sunde 2015
Cohort Studies
O’Reilly 2014
Smith 2014
Gross 2014
Cohort studies
Price 1999
Sumida 2000
Kim 2012
Badjie 2013
Wolf 2014
Case-control
Wheeler 2013
1. GRADE method: Kerwin AJ et al. J Trauma Acute Care Surg.
2012;73:S283-7.

27. Quality of evidence1
: Low
Military (n = 0) Civilian (n = 2)
Cohort studies
Brown 2015(a)
Brown 2015(b)
1. GRADE method: Kerwin AJ et al. J Trauma Acute Care Surg.
2012;73:S283-7.

28. Non randomised data
Military (n = 9)
Case Series
Barkana 1999
Malsby 2013
Glassberg 2013
O’Reilly 2014
Chen 2014
Powell-Dunford 2014
Civilian (n = 19)
Case Series
Dalton 1993
Berns & Zietlow 1998
Prause 1999
Badjie 2012
Higgins 2012
Chew 2013
Mena-Munoz 2013
Sherren 2013
Weaver 2013
Bodnar 2014
Sunde 2015
Cohort Studies
O’Reilly 2014
Smith 2014
Gross 2014
Cohort studies
Price 1999
Sumida 2000
Kim 2012
Badjie 2013
Wolf 2014
Brown 2015(a)
Brown 2015(b)
Case-control
Wheeler 2013

29. Randomised data(!)
Military (n = 0) Civilian (n = 0)

30. Randomised data
Military (n = 0) Civilian (n = 0)
No RCTs!
(yet)

31. Outcomes
• Long term mortality (up to 30 days)
• Early mortality (<24 hours)
• In-hospital transfusion requirement
• Vital signs
• Biochemical/haematological indices

32. Outcomes
Long term mortality
No benefit with pre-hospital blood products
(OR 1.29, 95% CI: 0.84–1.96)
– Heterogenous data (I2
63%)
– Most studies do not compare like-for-like injury
severity

33. Outcomes
Early mortality
PHBP protective PHBP harmful

34. Outcomes
In-hospital transfusion (n = 6 studies)
•No statistically significant reduction in in-hospital
blood product administration
•Pre-hospital blood recipients received more blood
products in hospital

35. Outcomes
Vital signs (n = 4 studies)
•Pre-hospital blood recipients had greater correction
of Shock Index
– (but had worse parameters in first place)
– Lack of pre- and post- transfusion vital signs

36. Outcomes
Coagulopathy (n = 3 trauma studies)
•Pre-hospital blood recipients less likely to get
trauma-induced coagulopathy?
– Results variable and dependent on injury burden

37. Outcomes
Acidosis (n = 2 studies)
•Pre-hospital blood associated with greater acidosis
– But different transport timings ?longer period of bleeding

38. Outcomes
Adverse events (n = 7 studies)
•3 out of 759 patients had suspected transfusion
reaction

39. A few specific
examples

40. Pre-hospital blood products absolute reduction in mortality of 11%

41. BUT:
Historic control
Pre-hospital blood-recipients:
•Shorter transport times
•More frequent pre-hospital airway support,
•More tranexamic acid
•Greater in-hospital transfusion ratios (FFP:PRBC 1:1 vs. 0.46:1).

42. And…
Penn-Barwell JG et al. Improved survival
in UK combat casualties from Iraq and
Afghanistan: 2003-2012. J Trauma Acute
Care Surg. 2015;78:1014-20.

43. Blunt trauma: 50 pre-hospital blood vs. 1365 control
– Improved survival
– Blood recipients more often transfers
– Blood recipients managed more aggressively (more
crystalloid and platelets)

44. All trauma: 240 pre-hospital blood vs. 480 control
–Pre-hospital blood: reduced 24h mortality
–But no statistically significant difference in 30-day mortality

45. Summary of evidence so far:
• 28 studies (21 trauma)
– Retrospective (except for one)
– Very low quality of evidence (except for two)
– None are randomised
– Heterogenous

46. Pre-hospital blood product RCTs
Name Full Intervention Control Country N Stage
PUPTH Prehospital Use of
Plasma in Traumatic
Hemorrhage
Thawed FFP Standard care
(0.9% NS)
USA
(Virginia)
210 Recruiting
(NCT02303964
)
PAMPer Pre-hospital Air Medical
Plasma
Thawed FFP Standard care USA
(Pittsburgh)
600 Recruiting
(NCT01818427
)
COMBAT Control Of Major
Bleeding After Trauma
Thawed FFP Standard care
(0.9% NS)
USA
(Denver)
150 Recruiting
(NCT01838863
)
RePHILL Resuscitation with Pre-
HospItaL bLood
products
1:1 PRBC and
LyoPlas
Standard care
(0.9% NS)
UK
(Birmingham)
490 Set-up

47. RePHILL
A Multi-Centre Randomised Controlled Trial of Pre-
Hospital Blood Product Administration versus Standard
Care for Traumatic Haemorrhage.
@RePHILL_trial
SBP<90 or
no radial pulse
Traumatic injury
Pre-hospital medical team

48. RePHILL
A Multi-Centre Randomised Controlled Trial of Pre-
Hospital Blood Product Administration versus Standard
Care for Traumatic Haemorrhage.
@RePHILL_trial
SBP<90 or
no radial pulse
Traumatic injury
Pre-hospital medical team

49. RePHILL
A Multi-Centre Randomised Controlled Trial of Pre-
Hospital Blood Product Administration versus Standard
Care for Traumatic Haemorrhage.
Primary endpoint (composite):
•All cause mortality
•Failure to achieve 2h Lactate
clearance ≥20%
@RePHILL_trial
SBP<90 or
no radial pulse
Traumatic injury
Pre-hospital medical team

50. RePHILL
A Multi-Centre Randomised Controlled Trial of Pre-
Hospital Blood Product Administration versus Standard
Care for Traumatic Haemorrhage.
Other endpoints:
•ROTEM
•Platelet function (multiplate)
•Pre-hospital details
•Vital signs
•Venous lactate concentration
•Total blood product receipt
•ARDS and other complications
•Transfusion-related complications
•SOFA scores
@RePHILL_trial

51. Key messages
• Pre-hospital blood products are yet to be shown to
be of any clinical benefit
• Major logistical and financial implications
• Randomized (clinical) data required

52. Key messages
• Pre-hospital blood products are yet to be shown to
be of any clinical benefit
• Major logistical and financial implications
• Randomized (clinical) data required
• What do I do now?
• Follow best practice according to local guidelines
• Be skeptical
• Watch closely for results of RCTs!

53. @dave_surg
@RePHILL_trial
@DrNickCrombie
@MidwinterMJ