What is wrong with our

resuscitation fluids?
CAPT Peter Rhee, MC, USN
MD, MPH, FACS, FCCM
Professor of Surgery / Molecular Cellular Biology
Director Navy Trauma Training Center Los Angels County + USC

Military
trauma care

Civilian
trauma care

WW I
Saline, colloid (gutta percha)

WW II
Edward P. Churchill
blood 1943

Korean conflict
Blood
Plasma

Vietnam
Crystalloids

resuscitation
Packed Red Cells
Its not Warm Whole Blood
Its cold and old and lousy
Its just cells

Crystalloids
Cheap
Water and lytes

Whole Blood:

Red cells
White cells
Coagulation factors
Water
Albumin
Signaling proteins
Sugars
Fats
Alcohol

Current Fluid Resuscitation

Hasnt changed since 1960s
Still using the lessons learned from Vietnam

Fluids are good

Vietnam conflict
Crystalloid
Shock Lung

Explanation
Shock Lung Syndrome ARDS
Shorter transport times
Better resuscitation methods
Aggressive use of fluids saved lives
Decreased renal failure
Better post op care
Better critical care

Historical Trends
KIA
Civil War
16.0%
Russo-Japanese 20.0%
WW I
19.6%
WW II
19.8%
Korea
19.5%
Vietnam
20.2%

DOW
13.0%
9.0%
8.1%
3.0%
2.4%
3.5%

1980s more fluid = better

Bishop, Shoemaker et al:
in critically ill patients on going ischemia is bad
Treated oxygen debt

Resuscitated before OR
Cut-downs

ATLS - emphasized IV access

Paramedics wanted to play
Two liters then blood
Many liters

mechanism
hemorrhage

cytokines

shock

ischemia

oxygen radicals

reperfusion

microcirculation

immune response - neutrophils

Inflammation

the good
Kills germs
Helps healing

the bad
endothelial
leakage

inflammation- the ugly

Acute lung injury (ALI)

Acute respiratory distress syndrome (ARDS)
Multiple organ dysfunction syndrome (MODS)
Systemic inflammatory response syndrome (SIRS)
Abdominal compartment syndrome (ACS)

Leukocytes
Rolling

Activation

L-selectin

Chemokines
cytokine

Firm
Adhesion

Transendothelial
migration

2-integrins
(CD18)
injury

L-selectin
P-selectin
E-selectin

chemokines

endothelium

ICAM-1
ICAM-2

PECAM-1
ICAM-1

Recombinant Humanized Monoclonal Anitibody Against

CD18 in Traumatic Hemorrhagic Shock: Results of a Phase
II clinical trail.
Rhee et al. J Trauma, 2000;49:611-620.

Why?
Why does a system
intended for fighting
pathogens and
healing turn against
its own tissues?

double
edge sword

Mean blood Pressure

140
120
mmHg

100
80

60
40
20
0
Baseline Hem 15 Shock
30

Shock End Res Res +

60
60

Group I - Shock + LR
Group III - Shock + Blood

Res +
120

Res +
180

Group II - No Shock + LR
Group IV - Shock + HTS

Lactated Ringers Resuscitation Causes Neutrophil Activation After

Hemorrhagic Shock.
Rhee et al, J Trauma, 1998, 44:313

350

Percent change / 10,000 cells

300

Neutrophil Activation
**
group I - LR + Hem
* = p < 0.05
group II - LR no Hem
group III - Shed Blood
group IV - 7.5% HTS

250

*
*

200

150

100

50

0
Baseline

H 15

S 30

S 60

End Res R+60

Time Periods

R+120

R+180

Neutrophil fluorescence, % change

Dextran and Hespan causes neutrophil activation after hemorrhagic shock

resuscitation in swine. Scultetus, Stanton, Anderson, Austin, Sun, Rhee. Shock, 13:52, 2000
900

* p< 0.05

800

Baseline
End Shock
End Res

700
600

500
400

300

200
100
0
am
h
S

m
He

a
Sh

Re

oo
l
B

d
De

a
x tr

n
H

e sp

an
5%

B
L
A

%
25

B
L
A

LR

Early Upregulation of ICAM-1 and

VCAM-1 Expression in Rats with
Hemorrhagic shock and Resuscitation.
Sun L, Ruff P, Austin B, Deb S, Martin, B, Burris D,
Rhee P, Shock 11:416-422,1999

E- and P-Selectin Expression Depends

on Resuscitation Fluid Used in
Hemorrhaged Rats.
Alam HB, Sun L, Ruff P, Austin B, Burris D, Rhee P,
J Surg Res 94:145-152,2000

esi
DN
a
A
La
dd
er

est
h

An

Re
s

Bl
oo
d

Re
s

no

m
He

no

He

em
LR

+H

LR

es
HT
SR

E selectin expression
Spleen

300 bp

E- and P-Selectin Expression Depends on Resuscitation Fluid Used in Hemorrhaged Rats.

Alam HB, Sun L, Ruff P, Austin B, Burris D, Rhee P, J Surg Res 94:145-152,2000

J Trauma, 1999, 46:582

NEUTROPHIL FLUORESCENCE (ACTIVATION)

PERCENT
CHANGE
2000
1800
1600
1400
1200
1000
800
600
400
200
0

75%
50%
25%
10%
PB

NS

FLUIDS

LR

DE

H
XT

AN

ES

40

5%
PA

6%

AL

25
%
BU

IN

AL

3.
5%
BU

M
IN

7.
5%
TS

DILUTIONS

TS

Human Neutrophil Activation and Increased Adhesion by Various

Resuscitation Fluids. Rhee, et al, Critical Care Medicine, 2000, 28:74-78

Effects of Lactated Ringer's Solution on Human Leukocytes.

Koustova, Stanton, Gushchin, Stegalkina, Alam, Rhee. Journal of Trauma. 52:872-878;2002

Cytokine Expression Profiling in

Human Leukocytes after Exposure to
Hypertonic and Isotonic Fluids.
Gushchin V., Stegalkina S., Alam H.B.,
Kirkpatrick J.R., Rhee P.M., Koustova E. Journal
of Trauma. 2002:52:867-871.

52:867-871;2002

Summary
Human whole blood assay:
neutrophil activation and adhesion

Swine hemorrhagic shock model:

neutrophil activation and adhesion,
serum cytokine response,
concentrating on serum and changes over time.

Rat hemorrhagic shock model:

ICAM-1, VCAM-1 (inducible and constitutive in the lung
and spleen)

E-Selectin, P-selectin (inducible and constitutive in lung

and spleen)

apoptosis (gut, liver)

BAX staining (lung)

SUMMARY

Crystalloids causes inflammation

Colloids (artificial) causes inflammation
Albumin no inflammation
Shed blood great stuff
Hypertonic saline - immunosuppressive

Lungs

Murao et al.
Effect of dose of hypertonic saline
On its potential to prevent lung
Tissue damage in a mouse model
Hemorrhagic shock.
Shock 2003: 20:29

Lungs

Shi HP, Deitch EA, Xu DZ, Lu Q, Hauser CJ. Hypertonic Saline Improves
Intestinal Mucosa Barrier Function and Lung Injury After Trauma-Hemorrhagic
Shock Shock 2002; 17(6):496-501

Lungs

Powers KA, Woo J, Khadaroo RG, et al. Hypertonic resuscitation

of hemorrhagic shock upregulates the anti-inflammatory
response by alveolar macrophages. Surgery 2003;134:312-8

Lungs

LR

25%

5%

Powers KA, Kapus A, Khadaroo RG et al.

Twenty-five percent albumin prevents lung injury following shock/resuscitation
Crit Care Med 2003; 31(9):2355-2363

Intestine

Murao Y, et al
Hypertonic Saline Resuscitation Reduces Apoptosis and Tissue Damage of
the Small Intestine in a Mouse Model of Hemorrhagic Shock
Shock 2003; 20(1):23-28

Vascular leak

Pascual JL, et al
Hypertonic Saline Resuscitation of Hemorrhagic Shock Diminishes Neutrophil
Rolling and Adherence to Endothelium and Reduces In Vivo Vascular Leakage
Ann Surgery 2002; 236(5):634-642

Kidney

nen A, Et al.
Effects of whole blood, crystalloid, and colloid resuscitation of
hemorrhagic shock on renal damage in rats: an ultrastructural study.
J Ped Surg, 38(11):2003;1642

Liver

Shah KJ, Chiu WC, Scalea TM, et al.

Detrimental Effects of Rapid Fluid Resuscitation on Hepatocellular Function and Survival
After Hemorrhagic Shock. Shock 2002; 18(3):242-247

Human neutrophils

Ortegon DP, Dixon PS, Crow KK et al

The Effect of the Bovine Hemoglobin Oxygen Therapeutic HBOC-201
on Human Neutrophil Activation In Vitro
J Trauma 2003; 55(4):755-761

Microcirculation

Hypertonic saline resuscitation attenuates neutrophil lung sequestration

and transmigration by diminishing leukocyte-endothelial interactions in a
two hit model of hemorrhagic shock and infection.
Pascal et al: J Trauma. 54:121:2003

Pascual, et al Hypertonic Saline Resuscitation Attenuates Neutrophil Lung

Sequestration and Transmigration by Diminishing Leukocyte-Endothelial
Interactions in a Two-Hit Model of Hemorrhagic Shock and Infection J Trauma.
2003;54:121132.

Fluids research
Sidney Ringers
Concerning the influence exerted by each of
the constituents of the blood in the contraction
of the ventricle, J Physiology, 1882;(3) 378

Physiology
Immunology

Hemorrhagic shock
Intravascular volume deficit

Inadequate tissue perfusion

Replace = Intravascular volume deficit

Fluids
Hypotension

Death
Acidosis
Where is the data?

to resuscitate or not to resuscitate

1983
1990

Aprahamian
J Trauma. 23:687-90

Kaweski
J Trauma 990:1215

1994

Bickell

2000

Turner

2001
2002
2002
2002

NEJM 331:1105
Health Tech Ass 4:31

Kwan
Cochrane Data. Syst
Rev. (1):CD002245

Dula
PreHosp Emerg Care.
6:417

Greaves
J R Coll Surg Edinb.
47:451

Dutton
J Trauma 52:1141

-Paramedic system
-open intra abdominal vascular trauma
-Pre-hospital fluids
-trauma patients
-Pre-surgery fluids
-hypotensive penetrating torso injuries
-Pre-hospital
-serious trauma patients
-Pre hospital
-bleeding trauma patients
-Pre-hospital
-hypotensive blunt trauma patients.
-Pre-hospital
-a consensus view.
-Pre surgery fluids
-hypotensive active hemorrhage

to resuscitate or not to resuscitate

1983
1990

Aprahamian
J Trauma. 23:687-90

Kaweski
J Trauma 990:1215

1994

Bickell

2000

Turner

2001
2002
2002
2002

NEJM 331:1105
Health Tech Ass 4:31

Kwan
Cochrane Data. Syst
Rev. (1):CD002245

Dula
PreHosp Emerg Care.
6:417

Greaves
J R Coll Surg Edinb.
47:451

Dutton
J Trauma 52:1141

-Paramedic system
-open intra abdominal vascular trauma
-Pre-hospital fluids
-trauma patients
-Pre-surgery fluids
-hypotensive penetrating torso injuries
-Pre-hospital
-serious trauma patients
-Pre hospital
-bleeding trauma patients
-Pre-hospital
-hypotensive blunt trauma patients.
-Pre-hospital
-a consensus view.
-Pre surgery fluids
-hypotensive active hemorrhage

 Excess mortality associated with the use

of a rapid infusion system at a level I
trauma center.
Hambly P.R. DuttonR.P. Resuscitation 1996;31:127

Other outcomes
1995

Block
J Trauma 39:787

2002

Lobo
Lancet;359:1812

2002

Hashim
J Trauma 53:1183

2003

Balogh
J Trauma 54:848

-Case report
-Extremity compartment synd
-Elective colonic resection
-randomised controlled trial.
-Case report
- cardiac tamponade
-Abdominal Compartment
syndrome

Institute of Medicine

David Longnecker (Chair)

Univ Penn Health System

William G Baxt
Univ Penn Health System

Joseph C Fratantoni
Biologics, C.L. McIntosh &
Associates

Jureta W. Horton
U Tex SWMS

John P. Kampine
MC Wisconsin

Harvey G. Klein
NIH

Committee on Fluid Resuscitation for Combat

Casualties
Institute of Medicine, National Academy Press
Washington, DC 1999.

Joseph E. Rall
NIH

George F Sheldon
UNC

Blane C. White
Wayne State USM

Recommendations
Initial fluid - 250cc bolus of 7.5%
hypertonic saline vial rapid-infusion
system
Research to modify LR
eliminate -D-lactate, reduce total -L-lactate
add ketones, add free radical scavengers
and antioxidants

Components of Ketone and

Lactated Ringers Solutions.
Ketone Ringers DL-Lactated
Ringers
Component
3-D-beta- hydroxybutyrate

DL-lactate
L-Lactate
Sodium
Potassium
Calcium
Chloride
pH
Osmolarity

mM

28
----130
4
1.5
109
7.5
275

L-Lactated
Ringers

mM

mM

--28
--130
4
1.5
109
7.5
275

----28
130
4
1.5
109
7.5
275

Lungs with PARP cleavage (%)

120

100

80

60

40

20

m
a
sh

NR

R
R
L
L
L
DL

KR

PR

Ethyl Pyruvate

Ringers ethyl pyruvate solution: a novel resuscitation fluid

for the treatment of hemorrhagic shock and sepsis. Fink
MP. J Trauma 54:S141, 2003

Future fluid developments

Ketone ringers
(Ketone Rheengers)
Hypertonic saline
with or without
colloids
Freeze dried plasma
Hypertonic
hyperoncotic FDP
FDP with HBOCs

Fluids vs No fluids
Prehospital = no data
Before surgical control = no data
After hemorrhage control = wise

How much?

just the right amount

Combat casualty
!Control bleeding with pressure to
bleeding site / consider tourniquet
!Transport to higher level of care

Vital signs and mental status

Normal
!Obtain access but
withhold fluids
!Encourage oral fluids

Abnormal
!Obtain IV access and administer fluids
(7.5% hypertonic saline up to 500 cc)
!If more fluids needed, switch to isotonic
or colloid fluids or whatever

Searching for the Optimal Resuscitation Method: Recommendations for the

Initial Fluid Resuscitation in Combat Casualties. Rhee, Koustova, Alam. J
Trauma, 2003,54:S52-62

conclusion
Different fluid effects the immunological
system differently
Resuscitation fluids may contribute to
resuscitation injury
Need better resuscitation fluids to
minimize resuscitation injury
It would be more prudent to prevent
resuscitation injury than to attempt
immuno-modulation

Lactate Ringers

A.
B.
C.
D.
E.

Good
Bad
Ugly
Depends
All of the above

Conclusions

W C Feilds
always carry a small flask of whiskey in
case of snake bites,... and always carry a
small snake