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What is wrong with our resuscitation fluids?
CAPT Peter Rhee, MC, USNMD, MPH, FACS, FCCMProfessor of Surgery / Molecular Cellular BiologyDirector Navy Trauma Training Center Los Angels County + USC
Civilian trauma care
WW I Saline, colloid (gutta percha)
WW II Edward P. Churchill blood 1943
Korean conflict Blood Plasma
Vietnam Crystalloids
Military trauma care
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 goodFluids 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 DOW Civil War 16.0% 13.0% Russo-Japanese 20.0% 9.0% WW I 19.6% 8.1% WW II 19.8% 3.0% Korea 19.5% 2.4% Vietnam 20.2% 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 reperfusionshock ischemia
cytokines oxygen radicals microcirculation
immune response - neutrophils
Inflammation
the good the bad Kills germs Helps healing
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
Transendothelialmigration
Rolling Activation FirmAdhesion
L-selectin Chemokinescytokine
2-integrins(CD18)
injury
chemokinesL-selectinP-selectinE-selectin
ICAM-1ICAM-2 PECAM-1
ICAM-1
endothelium 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
020406080
100120140
Baseline Hem 15 Shock30
Shock60
End Res Res +60
Res +120
Res +180
m
m
H
g
Group I - Shock + LR Group II - No Shock + LRGroup III - Shock + Blood Group IV - Shock + HTS
*
Neutrophil Activation
Time PeriodsBaseline H 15 S 30 S 60 End Res R+60 R+120 R+180
P
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0
0
0
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0
50
100
150
200
250
300
350group I - LR + Hemgroup II - LR no Hemgroup III - Shed Bloodgroup IV - 7.5% HTS
* = p < 0.05*
**
*
*
*
Lactated Ringers Resuscitation Causes Neutrophil Activation After Hemorrhagic Shock.
Rhee et al, J Trauma, 1998, 44:313
Sham H
em
Sham R
esBlo
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xtran
Hespa
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5% AL
B
25% AL
B LR
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200
300
400
500
600
700
800
900Baseline End Shock End Res
*
* p< 0.05
*
*
*
*
Dextran and Hespan causes neutrophil activation after hemorrhagic shock resuscitation in swine. Scultetus, Stanton, Anderson, Austin, Sun, Rhee. Shock, 13:52, 2000
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
HTS
Res
LR +
He
LR no
He
Hem
no R
Bloo
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esthe
DNA
La
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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
m m es es sia dder
J Trauma, 1999, 46:582
0200400600800
100012001400160018002000
PBS
NS LR DEXTRAN 40HESPAN 6%5%
ALBUMIN25%
ALBUMIN3.5%
HTS7.5%
HTS
10%
25%
50%
75%
NEUTROPHIL FLUORESCENCE (ACTIVATION)
PERCENT CHANGE
FLUIDS
DILUTIONS
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
LungsLungs
MuraoMurao et al. et al. Effect of dose of hypertonic salineEffect of dose of hypertonic salineOn its potential to prevent lungOn its potential to prevent lungTissue damage in a mouse modelTissue damage in a mouse modelHemorrhagic shock. Hemorrhagic shock. Shock 2003: 20:29Shock 2003: 20:29
LungsLungs
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
LungsLungs
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
LungsLungs
LRLR
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
25%25% 5%5%
IntestineIntestine
Murao Y, et alHypertonic 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 leakVascular leak
Pascual JL, et alHypertonic 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
KidneyKidney
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
LiverLiver
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 Human neutrophilsneutrophils
Ortegon DP, Dixon PS, Crow KK et al The Effect of the Bovine Hemoglobin Oxygen Therapeutic HBOC-201 on Human Neutrophil Activation In VitroJ Trauma 2003; 55(4):755-761
MicrocirculationMicrocirculation
Hypertonic saline resuscitation attenuates neutrophil lung sequeHypertonic saline resuscitation attenuates neutrophil lung sequestration stration and transmigration by diminishing leukocyteand transmigration by diminishing leukocyte--endothelial interactions in a endothelial interactions in a
two hit model of hemorrhagic shock and infection.two hit model of hemorrhagic shock and infection.Pascal et al: Pascal et al: J TraumaJ Trauma. 54:121:2003. 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 shockIntravascular volume deficitIntravascular volume deficit
Inadequate tissue perfusionInadequate tissue perfusion
Replace = Intravascular volume deficitReplace = Intravascular volume deficit
HypotensionHypotension
AcidosisAcidosisDeathDeath
FluidsFluids
Where is the data?Where is the data?
to resuscitate or not to resuscitate
-Pre surgery fluids-hypotensive active hemorrhage
DuttonJ Trauma 52:1141
2002
-Pre-hospital-a consensus view.
GreavesJ R Coll Surg Edinb. 47:451
2002
-Pre-hospital-hypotensive blunt trauma patients.
DulaPreHosp Emerg Care. 6:417
2002
-Pre hospital-bleeding trauma patients
KwanCochrane Data. SystRev. (1):CD002245
2001
-Pre-hospital-serious trauma patients
TurnerHealth Tech Ass 4:31
2000
-Pre-surgery fluids-hypotensive penetrating torso injuries
BickellNEJM 331:1105
1994
-Pre-hospital fluids-trauma patients
KaweskiJ Trauma 990:1215
1990
-Paramedic system-open intra abdominal vascular trauma
Aprahamian J Trauma. 23:687-90
1983
to resuscitate or not to resuscitate
-Pre surgery fluids-hypotensive active hemorrhage
DuttonJ Trauma 52:1141
2002
-Pre-hospital-a consensus view.
GreavesJ R Coll Surg Edinb. 47:451
2002
-Pre-hospital-hypotensive blunt trauma patients.
DulaPreHosp Emerg Care. 6:417
2002
-Pre hospital-bleeding trauma patients
KwanCochrane Data. SystRev. (1):CD002245
2001
-Pre-hospital-serious trauma patients
TurnerHealth Tech Ass 4:31
2000
-Pre-surgery fluids-hypotensive penetrating torso injuries
BickellNEJM 331:1105
1994
-Pre-hospital fluids-trauma patients
KaweskiJ Trauma 990:1215
1990
-Paramedic system-open intra abdominal vascular trauma
Aprahamian J Trauma. 23:687-90
1983
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-Case report-Extremity compartment synd
BlockJ Trauma 39:787
1995
-Abdominal Compartment syndrome
Balogh J Trauma 54:848
2003
-Case report- cardiac tamponade
HashimJ Trauma 53:1183
2002
-Elective colonic resection-randomised controlled trial.
LoboLancet;359:1812
2002
Institute of Medicine
Committee on Fluid Resuscitation for Combat CasualtiesInstitute of Medicine, National Academy PressWashington, DC 1999.
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
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-LactatedRingers
L-LactatedRingers
Component mM mM mM3-D-beta- hydroxybutyrate 28 --- --- DL-lactate --- 28 --- L-Lactate --- --- 28 Sodium 130 130 130 Potassium 4 4 4 Calcium 1.5 1.5 1.5 Chloride 109 109 109 pH 7.5 7.5 7.5 Osmolarity 275 275 275
sham NR L-L
RDL
-LR KR PR
L
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s
w
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R
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(
%
)
0
20
40
60
80
100
120
*
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? How much? just the right amountjust the right amount
Combat casualty
!Obtain access but withhold fluids !Encourage oral fluids
!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
!Control bleeding with pressure to bleeding site / consider tourniquet!Transport to higher level of care
Vital signs and mental status
AbnormalNormal
Searching for the Optimal Resuscitation Method: Recommendations Searching for the Optimal Resuscitation Method: Recommendations for the for the Initial Fluid Resuscitation in Combat Casualties.Initial Fluid Resuscitation in Combat Casualties. Rhee, Koustova, Alam. Rhee, Koustova, Alam. J J TraumaTrauma, 2003,54:S52, 2003,54:S52--6262
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. Good B. Bad C. Ugly D. Depends E. 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
What is wrong with our resuscitation fluids?Military trauma careresuscitationCurrent Fluid ResuscitationExplanationHistorical Trends1980s more fluid = bettermechanismthe goodinflammation- the ugly Why?Early Upregulation of ICAM-1 and VCAM-1 Expression in Rats with Hemorrhagic shock and Resuscitation. Sun L, Ruff P, Austin B,SummarySUMMARYFluids researchHemorrhagic shockto resuscitate or not to resuscitateto resuscitate or not to resuscitateOther outcomesInstitute of MedicineRecommendationsComponents of Ketone and Lactated Ringers Solutions.Ethyl PyruvateFuture fluid developmentsFluids vs No fluidsconclusionLactate RingersConclusionsW C Feilds