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

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m

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Group I - Shock + LR Group II - No Shock + LRGroup III - Shock + Blood Group IV - Shock + HTS

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Neutrophil Activation

Time PeriodsBaseline H 15 S 30 S 60 End Res R+60 R+120 R+180

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* = p < 0.05*

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Lactated Ringers Resuscitation Causes Neutrophil Activation After Hemorrhagic Shock.

Rhee et al, J Trauma, 1998, 44:313

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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

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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

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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