An Update on Fluid Resuscitation

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REVIEW Scandinavian Journal of Surgery 95: 136145, 2006

AN UPDATE ON FLUID RESUSCITATION

H. B. Alam

Massachusetts General Hospital, Harvard Medical School, Boston, MA, U.S.A.

ABSTRACT

Hemorrhagic shock is the leading cause of death in civilian and military trauma. Effec-tive hemorrhage control and better resuscitation strategies have the potential of savinglives. However, if not performed properly, resuscitation can actually exacerbate cellular

injury caused by hemorrhagic shock, and the type of uid used for resuscitation playsan important role in this injury pattern. It is logical to prevent this cellular injury throughwiser resuscitation strategies than attempting immunomodulation after the damage hasalready occurred. It is important to recognize that unlike numerous other variables, re-suscitation is completely under our control. We decide who, when and how should getresuscitated. This paper summarizes data from a number of studies to illustrate the dif-ferential effects of commonly used resuscitation uids on cellular injury, and how theserelate to clinical practice. In addition, some novel resuscitation strategies are describedthat may become clinically available in the near future.

Ke words: Resuscitation; shock; uids; blood; lasma; hertonic saline; cellular injur; hothermia;ene transcrition; aotosis; inammation; immune activation

Correspondence:Hasan B. Alam, M.D.Division of Trauma, Emerenc Surer, andSurgical Critical CareMassachusetts General Hospital165 Cambride Street, Suite 810Boston, MA 02114, U.S.A.Email: [email protected]

INTRODUCTION

Esanuination and central nervous sstem (CNS)injuries are the leadin causes of death in civilian(12) as well as militar trauma (3), and romt hem -orrhae control alon with adequate uid resuscita-tion are the ke comonents of earl trauma care.However, the otimal resuscitative strate remainscontroversial: te of uid, volume, rate, route ofadministration, and end oints of resuscitation. Thismanuscrit describes some of the benecial and ad-

verse effects of resuscitation uids on cellular re-sonses, and how the ma relate to our clinical rac-tice.

EVOLUTION OF FLUID USE IN TRAUMA

FLUID RESUSCITATION: EVOLVINg pARADIgM

It is now bein reconized that resuscitation uidsare not comletel innocuous, and the ma actuallotentiate the cellular injur caused b hemorrhaicshock. This concet of resuscitation injur hassteadil ained attention in recent ears. A reort bthe Institute of Medicine (1999) has described in de-tail the wide sectrum of adverse consequences thatcan follow resuscitative efforts (4). The concet of

lare volume crstalloid resuscitation was a roductof seminal work b Shires, Moer, Moss and othersdurin the 1960s (58), and it became common rac-tice durin the Vietnam conict. Their work sues-ted that infusion of lare-volume isotonic crstalloidsimroved survival, and resuscitation uids wereneeded not onl to relace the intravascular volumeloss, but also to relenish interstitial decits. There-fore, these investiators recommended uid relace-ment equal to three times the volume of blood loss(and as hih as 8:1 for severe shock). At that time theemhasis was on restoration of intravascular andinterstitial uid decits, without much imortance


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137An update on fuid resuscitation

attached to the ctotoic effects of crstalloid uids.Isotonic uids were used widel in Vietnam and itwas durin this eriod that the aearance of shocklun/Da Nan lun (later termed acute resiratordistress sndrome or ARDS) was rst described insoldiers that received massive crstalloid resuscita-tion. Toda, ARDS and Multile Oran Dsfunction

Sndrome are major causes of delaed mortalit intrauma atients. Clinicall, the role laed b resus-citation in the develoment of these comlications isdifcult to establish due to a remarkable aucit ofrosective randomized trials in this area. However,an ever-increasin basic science literature suortsthe new aradim that cellular injur is inuencednot onl b shock, but also b our resuscitation strat-eies. Toda, with the eas availabilit of advancedcellular research techniques, we can study the effectof resuscitation uids on the bioloical sstems inmuch reater detail. These ndins now have racti-cal imlications as well. While some of the modiedRiners solutions (ketone and ruvate based) re-main eerimental, lactated Riners is now com-

merciall available in the conventional racemic for-mulation or as a ure L-isomer solution, with mark-edly different properties. Although it is not clearlyknown whether the attenuation of cellular injurmarkers seen in the reclinical studies would trans-late into a measurable imrovement in clinical out-come in trauma atients, it remains an ecitin os-sibilit.

IS TRAUMA AN IMMUNE DISEASE?

Eerts in the eld now tend to aree that serioustraumatic and thermal injuries lead to immune ds-function and subsequent cellular damae (910). Ac-

cordin to this concet, trauma atients who survivethe earl ost-injur eriod, enter a hase of Ss-temic Inammator Resonse Sndrome (SIRS),which in some atients leads to raid onset of Mul-tile Oran Dsfunction Sndrome (MODS), with ahih mortalit rate. However, majorit of seriouslinjured atients survive the initial SIRS resonse(without develoin earl MODS), and manifest aComensator Anti-inammator Resonse Sn-drome (CARS) with suressed immunit and hihchances of develoin an infection. The resultant in-fection can then lead to late MODS and death. Anumber of aroaches have been tried to correct thisost-traumatic immune dsfunction, with marinalresults (1113). However, a more loical aroach

would be to revent the onset of immune dsfunc-tion, rather than tr to control multile interconnec-ted cascades once the have been activated.

DOES EARLy FLUID RESUSCITATION IMpROVESURVIVAL?

Althouh it is widel believed that earl aressiveuid resuscitation is benecial, clinical and basic sci-ence literature fails to provide conclusive supportingevidence (1419). While analzin the data, it is im-ortant to differentiate between the victims of bluntand enetratin trauma. As almost 20% of blunt trau-

ma atients can have associated traumatic brain in-jur, and uid resuscitation to revent hotensionand secondar brain injur ma be a loical aroachin this group. However, this is not true in the settingof enetratin trauma. As a matter of fact, the basicrationale for administerin intravenous uids in a-tients with onoin bleedin has been challened

reeatedl for almost a centur (20). Theoreticall,uid resuscitation in the absence of (or rior to) hem-orrhae control can eacerbate bleedin due to thedisrution of earl soft thrombus, coauloath, andhemodilution (2124). A sstematic review of 52 ani-mal trials concluded that uid resuscitation aearedto decrease the risk of death in models of severe hem-orrhae (RR= 0.48), but increased the risk of death inthose with less severe hemorrhae (RR=1.86) (25).Furthermore, hotensive resuscitation, whenevertested, reduced the risk of death (RR = 0.37). The roofof this concet in humans was ublished in the NewEnland Journal of Medicine in 1994 (26). In thatstud, hotensive atients with enetratin injurto the torso were randomized to routine uid resus-

citation, or resuscitation was delaed until bleedinhad been suricall controlled. The results of thisstud demonstrated a survival advantae in the de-laed resuscitation rou (70% versus 62%, =0.04).This stud has enerated a viorous debate, and itsndins have been etensivel scrutinized for faults.Desite all the controvers, the most imressive nd-in remains the fact that delain uid resuscitationdid not increase the mortalit in these atients. Theissue of timin and volume of uid resuscitation in

bleedin atients has also been addressed b TheCochrane Database of Sstematic Reviews (27). Onlsi randomized clinical trails met the inclusion crite-ria, and a careful review failed to provide any evi-

dence in suort of (or aainst) early or large volumeintravenous uid administration in uncontrolledhemorrhae. Based uon all this information, it isreasonable to conclude that uid resuscitation is nota substitute for earl hemorrhae control. Low vol-ume, careful resuscitation is reasonable, eseciallwhen trin to et a din atient to denitive care.However, earl aressive uid resuscitation, in theabsence to hemorrhae control, cannot be justied.

AggRESSIVE OR SUpRA-NORMAL RESUSCITATION

This concet ained momentum based uon the workof Shoemaker and associates, who suested that anoen debt builds u durin shock which must be

reaid b erformin aressive resuscitation in theintensive care settin (28). To rea this tissue oendebt, cardiac oututs were ushed into sura-nor-mal rane (29) with volume loadin, blood transfu-sion, and inotroic drus. This was continued untilcardiac output reached a plateau, or when the tissueoen consumtion became indeendent of oendeliver. However, numerous subsequent studieshave failed to show an imrovement in outcome withthis aroach (3035). Aressive uid resuscitationon the other hand has been imlicated in numerousost-resuscitation comlications such as AbdominalComartment Sndrome (3638). Therefore, desite


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138 H. B. Alam

its theoretical appeal this approach is no longer wid-ely practiced.

IMpACT OF RESUSCITATION FLUIDS ONCELLULAR FUNCTIONS

There is now accumulatin evidence that most cel-lular functions are inuenced b infusion of resusci-tation uids. There are a number of ke variables thatovern the resonse, such as; 1) uid comosition,2) uid tonicit, 3) duration of eosure, 4) te ofcells that are eosed, 5) resence or absence of infec -tion/inammation, 6) resence or absence of secondhit, 7) timin of uid administration. Althouh cel-lular responses during the post-resuscitation periodinvolve almost all cell tes throuh multile inter-connected cascades, for ease of resentation ndinsfrom selected studies have been summarized undersome broad cateories:

A) EFFECTS OF RESUSCITATION STRATEgIES ONNEUTROpHIL ExCITATION AND IMMUNE ACTIVATIONIN VIVO

Neutrohil mediated tissue injur has been identiedas a ke mechanism of ost-resuscitation oran dam-ae (39). In a swine model of hemorrhaic shock, ithas been shown that resuscitation with racemic lac-tated Riners solution (DL-LR, equal amounts of Dand L isomers of lactate) or mere infusion of DL-LR(without hemorrhae) caused an increase in neutro-hil oidative burst (40). In a similar model, neutro-hil ecitation was inuenced b the dose and rate ofDL-LR administration, and resuscitation with arti-cial colloids (Detran and Hesan) had an even more

ronounced effect on neutrohil ecitation (41). Onthe other hand, no sinicant neutrohil ecitationwas seen in animals that were resuscitated with h -ertonic saline, or fresh whole blood.

B) IMpACT OF RESUSCITATION FLUIDS ON HUMANWHITE BLOOD CELLS (Ex-VIVO)

Similar to the animal data, eosure of human bloodto isotonic crstalloids and articial colloids has beenshown to cause an increase in oidative burst, and theeression of adhesion molecules on the neutrohilsin a dose deendent fashion (42). Interestinl, in thisstud natural colloids (albumin) did not ecite theneutrohils, and eosure to hertonic saline (HTS)

actuall suressed neutrohil functions. This su-pressive effect of hypertonic saline on neutrophilfunctions ma be throuh the modulation of che-moattractant recetor sinalin athwas (43). WhenHTS is combined with detran, the suressive ro-erties of HTS overcome the stimulator roerties ofdetran (44). Resonse of cells to lactated Riners(LR) solution deends uon its comosition. Whileconventional LR containin racemic lactate (D andL-isomer) is ro-inammator, substitution of race-mic lactate with L-isomer of lactate, or ketone bodies(b-hdrobutrate), can attenuate neutrohil activa-tion and alter the eression of leukocte enes

known to be involved in inammation, cell mira-tion, and aotosis (45). Usin customized cDNA ar-rays, we have shown that isotonic and hypertonicuids do not differ in their effect on the ctokineenes in human leukoctes (46), but hertonicitdecreases the eression of immune activation associ-ated enes (47). Furthermore, the comosition and

tonicit of the resuscitation uids can also have adramatic inuence on the life san of circulatin cells(48).

C) DIFFERENTIAL EFFECTS OF RESUSCITATION FLUIDSON MARKERS OF CELLULAR INJURy IN VARIOUS ORgANS

Once activated, neutrohils bind to comlimentaradhesion molecules (selectins, beta2 interins) on theendothelium before transmiration into the tissues.It has been demonstrated that these adhesion mole-cules are up regulated following resuscitation withracemic LR in a rodent model of hemorrhaic shock(4950). Furthermore, in these studies LR resuscita-tion was associated with histologic evidence of acute

lun injur, whereas none of these adverse ndinswere noted following resuscitation with fresh whole

blood. We know that injured cells undero death viatwo distinct mechanisms: aotosis and necrosis.Aotosis, while more controlled, requires ener. Inthe absence of ener the cells ma undero deathvia the poorly controlled process of necrosis. Al-thouh balanced aotosis is essential for homeosta-sis and in the recover from certain disease rocesses(5154), a marked increase in aotosis can be amarker of cellular injur and oran dsfunction (5556). Usin aotosis as a marker of cellular injur, ithas been shown that resuscitation with racemic LRresults in increased aotosis in intestinal mucosa,

smooth muscle, liver (57), and lun (58) in rodents.pulmonar and heatic aotosis is markedl re-duced if lactate in the solution is substituted with b-hdrobutrate (ketone Riners) or sodium ru-vate (ruvate Riners) (5961). Desiner uidscontainin other formulations of ruvate (e.. ethlruvate) are also suerior to conventional solutions(62). In a recent stud Shires (63) has conrmed thatuids differ dramaticall in their caacit to inducetissue aotosis, and that modied Riners solutions(ketone and bicarbonate Riners) cause sinicantlless aotosis comared to the racemic LR. Thesendins noted in small animal models (rodents), havealso been validated in a clinicall relevant model ofhemorrhae in swine, where resuscitation with con-

ventional LR solution increased aototic cell deathin liver and lun (64). This was easil revented bsimle elimination of D-lactate from the Riners so-lution. We now know that the modied Riners so-lutions eert their rotective effects throuh ost-translational modications of ke reulator roteins(65), and b selective acetlation of histones (withsubsequent alterations in ene transcrition) (66). Theimact of resuscitation strateies can also be seen inwell rotected sites such as the brain, where thehsioloic state of the central nervous sstem cellscan be altered b chanin the comosition of resus-citation uids (across the blood brain barrier) (67).


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Furthermore, resuscitation inuences not onl thereulation and functions of cells but also the inte-rit of the surroundin etra-cellular matri (68).

D) EFFECT ON gENE REgULATION: INTEgRATEDAppROACH TO DATA ANALySIS

Similar to the circulatin cells, reulation of ene e-ression in the tissues is also inuenced b resuscita-tion strateies. We have discovered that ~7% of enesin rats are altered following shock and resuscitation.In each oran studied, the ene eression rolewas deendent uon the uid used for resuscitation(69). Althouh transcritional rolin is now a well-established technique, its alication to sstematicstudin of various bioloical henomena is still lim-ited due to roblems with hih-volume data analsisand interpretation. Interpretation of these large data-sets in the contet of accumulated knowlede on hu-man functional networks could ield bioloicallmeaninful information. Usin this interated a-roach to data analsis, a comrehensive database

has now been ublished, which further conrms thatcellular mechanisms at the level of ene reulationare rofoundl inuenced b shock, and b the choiceof resuscitation strate (70).

HypERTONIC SALINE

The use of HTS for resuscitation from hemorrhaewas rst described in 1980, when Velasco et al. (71),and DeFelie et al. (72), reorted in searate studiesthat herosmotic sodium chloride raidl eandslasma volume after major blood loss. Because of itsabilit to mobilize interstitial uids into the vascular

sace, 250 ml of 7.5% saline can achieve results com-arable to resuscitation with 23 liters of 0.9% saline.Since the oriinal reorts, HTS has been used in avariet of circumstances and thousands of aershave appeared in the literature, including eight dou-

ble-blinded randomized trials evaluatin HTS or HTSwith detran (HSD) for rehosital or emerenc de-artment treatment of traumatic hotension. Im-proved rates of survival after discharge were repor-ted with HSD in seven of eiht trials, althouh statis-ticall sinicant imrovement in overall survivalwas seen in onl one trial. A meta-analsis for theevaluation of HSD as the initial treatment for ho-volemic shock reviewed the oriinal records from sitrials (and 604 subjects) (73). Overall dischare sur-

vival rates were better with HSD resuscitation ascomared to conventional resuscitation. HSD resus-citation was articularl effective for the sub-rouof atients that had sustained head injur with a dis-chare survival rate of 38%, as comared to a rate of27% for the control rou receivin saline. In theclinical literature, there has been a remarkable ab-sence of deleterious effects with HTS administrationin more than 1,000 trauma and surical atients. Noincrease in the incidence of hernatremic seizure,increased bleedin or blood transfusion requirement,coauloathies, renal failure, cardiac arrhthmias, orcentral ontine melinolsis has been attributed to

hertonic resuscitation in trauma atients. Theseclinical trials had used HTS as a volume eander,

but a more advantaeous effect of HTS administra-tion ma be the attenuation of immune mediated cel-lular injur. A number of reclinical studies havedemonstrated that HTS has the otential to modulatethe ost-trauma immune resonse, with an overall

attenuation of immune mediated cellular injur (7475). The salutar roerties of hertonic saline arerimaril eerted throuh its effects on neutrohil-endothelial interactions. For eamle, in addition todecreasin neutrohil ecitation (4042), HTS resus-citation decreases inammation (76), neutrohil-en-dothelial bindin (77), lun damae (78), and bowelinjur (79). A number of eleant studies have furtherelucidated the subcellular athwas that are inu-enced b eosure to hertonic saline (8083). Therecentl established Resuscitation Outcome Consor-tium (ROC) (84), funded b the National Institutes ofHealth and the US Deartment of Defense is read tostart two multicenter trials of hertonic resuscita-tion in two oulations of trauma atients to be con-

ducted simultaneousl. Stud 1 would determine theimact of hertonic resuscitation on survival for

blunt or enetratin trauma atients in hovolemicshock, whereas Stud 2 would evaluate its imact onlon term (6 month) neuroloic outcome after severetraumatic brain injur. Both studies will be three arm,randomized, blinded intervention trials comarinhertonic saline/detran (7.5% saline/6% detran70, HSD), hertonic saline alone (7.5% saline, HTS),and normal saline (NS) as the initial resuscitationuid administered to these atients in the rehositalsettin. In addition to the rimar endoints, com-rehensive data about the immunoloic consequen-ces of hertonic resuscitation would also be col-

lected. Hopefully, these studies would provide theconclusive evidence that is needed to et FDA a-roval for the routine use of HTS in the treatment oftrauma atients.

CONSENSUS CONFERENCES

Control of hemorrhae and judicious resuscitationare critical elements of earl battleeld care. How-ever, the otimal strate for both of these oals ishighly controversial due to a general lack of categoryI/II clinical evidence. In addition to clinical benets,the militar must also take into account the loisticalasects of the aroach (weiht, volume, storae re-

quirements etc). The Ofce of Naval Research (ONR)and the US Arm Medical Research and MaterialCommand (MRMC) have suorted the basic re-search in this eld for man ears. primaril as a re-sult of leadershi and fundin b the ONR, threesinicant consensus conferences were held wheredata on uid resuscitation was analzed b eerts,and recommendations made to imrove clinical rac-tice and to uide future research. The rst meetinwas under the supervision of the Institute of Medi-cine (IOM) in 1998. The IOM reort concluded thatthe current resuscitation strategies were inadequate,otentiall harmful, and needed radical chanes. It


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identied numerous areas of future research, and rec-ommended that combat casualties should be resusci-tated with 250 mL bolus of 7.5% saline (4). Unfortu-natel the US Food and Dru Administration (FDA)has not et aroved this uid for clinical use. In thefollow-u meetin (June 2001, Uniformed ServicesUniversit) a number of clinical recommendations

were made includin: who should (and should not)be resuscitated, end oint of resuscitation, as well asthe otimal uid (85). As the choice was deliberatellimited to FDA aroved aents (available in the US),Hetastarch (hdro ethl starch, 500cc) was nar-rowl recommended as the uid of choice for use inthe battleeld. In the third meetin (October 2001,Toronto, Canada) the scoe was widened to includeuids that were available in other NATO countries(even if not available in the United States) (86). Atthis meetin a combination uid (7.5% saline and 6%detran-hertonic saline detran) was recommen-ded as the initial uid of choice (87). At all of thesemeetins eerts areed that aressive resuscitationis deleterious, an ideal uid is et not available,

and that low volume resuscitation (hertonic, col-loid, or combination) is the most suitable choice formilitar needs. proceedins of the last two meetinshave been ublished as a secial sulement of the

Journal of Trauma (Ma 2003), includin the recom-mendations for the initial uid resuscitation of com-

bat casualties (88).

CHANgES IN CLINICAL RESEARCH AND pRACTICEOF RESUSCITATION.

The consensus conferences described here sstemati-call evaluated all the available data and made stronrecommendations that have catalzed a noticeablearadim shift. For eamle, the US Arm and Navhave authorized the use of low volume resuscitationfor combat casualt care and other NATO forces havedeveloed similar rotocols. The larin absence ofood clinical evidence has romted collaboration

between the National Institutes of Health and the USDeartment of Defense to establish a consortium ofclinical centers for conducting resuscitation research.Hoefull, this consortium will rovide the much-needed clinical data to validate and conrm theromisin basic science ndins. The resuscitationstrateies that are bein utilized b the US militarin Iraq and Afhanistan alread reect the chanintrends. Resuscitation in the combat zones is more se-lective (uids iven onl when needed), is low vol-

ume, and aims for ractical endoints (e.. alabeulse). Colloid uids (e.. Hesan and Hetand) arereplacing conventional crystalloids for early resusci-tation thus minimizin the loistical burden. Also,earl hemorrhae control is bein rioritized overaressive uid resuscitation. It is too earl to deter-mine the direct imact of these new hemorrhae con-trol and resuscitation strateies on combat casualtoutcomes. However, it is ver encourain to notethat for the rst time since the Crimean war, the killedin action (KIA) rate has markedl droed below thehistoric 20% to around 1014% (8990).

NOVEL RESUSCITATION STRATEgIES

1. pHARMACOLOgICAL RESUSCITATION

While resuscitation restores tissue erfusion, it doesnot have an secic anti-inammator or ro-sur-vival roerties. In an attemt to imrove the out-

come, investiators have added various rotectiveaents to the resuscitation reimen with ood results(9194). An even more ecitin aroach would be toimrove survival throuh secic harmacoloicalagents without an uid resuscitation, such as directmaniulation of gene transcription (epigenetic code)to create a pro-survival phenotype. A brief descrition ofthe underlin mechanisms ma hel to clarif thisconcet. The ke reulator site of ene transcrition(and subsequent downstream athwas) is located atthe level of chromatin, a 1:1 comle of DNA androteins, redominantl comosed of histone ro-teins. Various reulator sinals can affect ene tran-scrition b inuencin the activit of histones, mostnotabl throuh acetlation. The two enzmes that

govern the process of acetylation are histone acetyltransferase (HAT) (95), and histone deacetlase(HDAC) (9697). Modulation of the histone code isone of the most ustream cellular events, which si-multaneousl reulates a subset of enes that are co-ordinatel eressed to roduce secic downstreameffects. We have reviousl shown that hemorrhaicshock is associated with an imbalance in HAT/HDACratio, an altered acetylation pattern of histones, anda decrease in ene transcrition otential (66). In thateeriment, resuscitation reversed the shock-inducedsuression of ene transcrition in a uid secicfashion, i.e. each resuscitation uid had a distinctiveattern of histone acetlation (histone code). Inter-

estinl, brief administration of HDAC inhibitors inthis model, durin 45 minutes of resuscitation, waseven more effective in reversin the shock-inducedimbalance, and increasin acetlation of histones. Thefollowu eeriments have now established that di-rectl taretin the histones with HDAC inhibitors(HDACI), such as valroic acid (VpA, 300 m/k)and suberolanilide hdroamic acid (SAHA), canraidl correct shock induced alterations, and im-rove survival in reclinical models of hemorrhae(98). Imressivel, this survival advantae wasachieved without administration of an resuscitationuids. The effect of hemorrhae and resuscitation onhistone acetlation is almost identical in rodents andswine (99), and theoreticall administration of

HDACI should imrove survival in lare animalmodels in a similar fashion (under investiation).This raises the ossibilit that cell survival, and ulti -matel oranism survival, can be imroved throuhdirect modulation of ene transcrition in the settinof lethal hemorrhae. This ecitin aroach is cur-rentl bein tested and rened under the DefenseAdvanced Research prorams Aenc (DARpA)Survivin Blood Loss roram.

2. EMERgENCy pRESERVATION AND RESUSCITATION (EpR)

profound shock from blood loss does not resond


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well to conventional methods of resuscitation (100).Even when the underlin cause can be treated andcirculation restored, cerebral ischemia lastin 5 min-utes or loner invariabl results in severe brain dam-ae. Often the underlin injuries are rearable butthe atient dies of irreversible shock or severe braindamae. In this settin, strateies to maintain cere-

bral and cardiac viabilit lon enouh to ain controlof hemorrhae and restore intravascular volumecould be life-savin. This requires an entirel newaroach to the roblem, with emhasis on raidtotal bod reservation, reair of injuries durinmetabolic arrest, and controlled resuscitation: Emer-enc preservation and Resuscitation (EpR). Cur-rentl, hothermia is the most effective method forreservin cellular viabilit durin roloned eri-ods of ischemia. No clinical studies have been con-ducted to test the theraeutic benets of hothermiain trauma atients. However, well-desined reclini-cal studies clearl suort this concet. In esanui-nating cardiac arrest, rapid induction of deep/pro-found hothermia (75% lon term survival (111). More im-portantly, it was shown in that study that hypother-mia could be used successfull even after 60 minutesof normothermic shock, and that the survivin ani-mals were not onl neuroloicall intact but also hadnormal conitive functions. Subsequent studies de-termined that to achieve the best outcome rofound

hothermia must be induced raidl (2C/minutes)and reversed at a slower rate (0.5C/minutes) (112113). Induction of hothermia has been shown topreserve various cell types in the central nervous sys-tem, in addition to rovidin some immunoloicaladvantaes (114115). The otimal deth of hother-mia is 10C, and decreasin the temerature to ultra-rofound levels (5C) ma actuall worsen the sur-vival (116). Hothermia can be induced usin smallortable equiment (suitable for austere settins)(117). This is associated with ecellent total bodreservation which ma have sinicant imlica-tions not onl for treatment of traumatic injuries but

also for reservin orans for translant (118). Thereis some earl data from small animal models to su-est that reversible metabolic arrest (and tissue res-ervation) can also be achieved with inhaled aentssuch as hdroen sulde (119). It ma sound futuris-tic, but the eertise to reserve the viabilit of keorans, durin reair of otherwise lethal injuries is

now available. Discussions are currentl underwato desin a feasibilit clinical trial to obtain transla-tional data that ma justif a wider alication of thisaroach in trauma ractice.

CONCLUSIONS

An ideal uid for the resuscitation of trauma victimsshould be safe, efcacious, chea, eas to store andtransort (eseciall imortant for the militar), havethe caacit to carr oen and nutrients to the cells,and should rotect the cells from resuscitation injur.Unfortunatel, such a uid is not available toda. Be-cause of the emerin data on uid ctotoicit, we

should consider resuscitation uids as drus, withwell dened indications and contraindications, safedosaes, and side effects. patients resonse to trau-ma is inuenced b a number of variables (co-morbidroblems, severit of injuries, deree of shock, delain denitive care etc). However, as comared to mostof the other variables that cannot be altered, resusci-tative strate is entirel under our control. We choosethe nature of the uids, their rate of administration,timin, and the end oints of resuscitation. We alsoma decide not to resuscitate in selected atients.

Based on the work done in our laborator andothers, the effects of various resuscitation uids oncellular functions can be summarized as follows:

ISOTONIC CRySTALLOIDS

Sinicant immune activation and induction of cel-lular injur are seen with these uids, eseciall ra-cemic lactated Riners solution. We know that a verlare number of trauma atients receive LR and dowell clinically. However, the patients that developlate comlications of increased inammator re-sponse are usually the ones that also have undergonesevere hemorrhaic shock and massive uid resusci-tation. Thus, LR ma be safe in small doses that the

bod can obviousl tolerate, but not in larer amountsiven over short eriods followin hemorrhaicshock and trauma. Modications of LR, such as elim-

ination of D-lactate can decrease these adverse ef-fects, and comlete substitution of lactate with othermonocarbotaes (e.. ketone bodies or ruvate)seems to be benecial.

HypERTONIC CRySTALLOIDS

As comared to LR, hertonic saline causes su-ression of neutrohil oidative burst activit, de-creases neutrophil-endothelial adhesions, and attenu-ates immune mediated cellular injur. Because of itsloistic advantaes and immunoloic benets, HTSwith or without a colloid seems to be the ideal uid


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toda for militar alication. However, a manufac-turer will have to obtain FDA aroval for its use asa volume eander in the USA. Althouh addition ofdetran to HTS tends to rolon the volume ean-sion resonse, we feel that it miht be easier to obtainFDA aroval for a simle solution (HTS) than acombination solution (HTS and detran). Studies

scheduled to be erformed under the NIH sonsoredResuscitation Outcome Consortium are eected toprovide the conclusive evidence.

ARTIFICIAL COLLOIDS

Detran and Hesan cause sinicant neutrohil ac-tivation. However, combination of detran with h-ertonic saline blunts this resonse. When iven incombination, colloids also rolon the hemodnamicresponse of hypertonic saline resuscitation.

pLASMA

It has the most favorable effect on neutrohil activa-

tion as well as numerous markers of cellular injur.plasma is also a ver effective volume eander.However, it has all the well reconized roblems thatare associated with storage, transport, and infusionof blood roducts. Autoloous freeze dried lasma isa romisin alternative that can be reconstituted in aheroncotic, hertonic fashion when needed. Thisis currently a focus of active investigations under theDeartment of Defense funded research rorams.

FRESH WHOLE BLOOD

It is b far the best and most effective uid for resus-citation of hemorrhaic shock in animal models.

Fresh whole blood is however not clinicall available.Even if available, loistics of storae and transortmake it an unrealistic otion. One ecetion is theuse of walkin blood bank b the militar, wherefresh whole blood is used in emerenc situation.There is currentl tremendous interest in investiat-in whether earl use of whole blood (or comonentscombined to create whole blood) would benet theseverel traumatized (120).

ARTIFICIAL BLOOD

All the products tested to date have failed to live upto eectations. However, the rationale behind thedeveloment of safe and effective oen carrin

resuscitation product is valid, and the results of anonoin multi-institutional hase III trial testin ahuman hemolobin based solution are eected comeout in the near future.

pHARMACOLOgIC RESUSCITATION

Administerin secic aents to rotect aainst isch-emia-reerfusion injur, or theraies that can inducea ro-survival henote (throuh u reulation ofselected enes) are ver attractive concets. These arelikel to be the net frontier in resuscitation research.In the future, severel traumatized atients are likel

to receive desiner uids sulemented with acocktail of aents secicall chosen to aument theintrinsic survival pathways.

EMERgENCy pRESERVATION AND RESUSCITATION

Viabilit of ke orans can be maintained durin 23

hours of arrest b earl alication of total bodemerenc reservation strateies. After reair ofotherwise lethal injuries, resuscitation can be er-formed in a controlled fashion. There is raidl ac-cumulatin reclinical data to suort this concet.Currentl, induction of rofound hothermia is themost effective method to achieve this oal.

ACKNOWLEDgMENTS

I would like to thank all the co-investigators, visitingresearchers, surgical residents, research assistants,medical students and administrative staff who havemade it ossible to do this work over the ears. I

would eseciall like to thank peter Rhee, MD, MpH(Catain, US Nav) for his ioneerin work in thiseld and for his mentorshi. Also acknowleded isthe enerous fundin rovided b the Deartment ofDefense (Ofce of Naval Research and DARpA), andthe National Institutes of Health for some of the re-search work described in this manuscrit.

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Received: July 31, 2006

An Update on Fluid Resuscitation

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