CHAPTER 4 - Shock

Annabel Barber G. Tom Shires III G. Tom Shires DEFINITION Shock is a pathophysiologic condition clinically recognized as a state of inadequate tissue perfusion. A constant internal en iron!ent "as first suggested #y the French physiologist $laude %ernard. In the !id&nineteenth century %ernard proposed that higher ani!als li ed in t"o ery different en iron!ents'a !ilieu int (rieur) in "hich the tissue ele!ents li e) and a !ilieu e*t (rieur) in "hich the #ody resides. +e stated that ,the sta#ility of the !ilieu int (rieur is the pri!ary condition for freedo! and independence of e*istence- the !echanis! "hich allo"s this is that "hich insures in the !ilieu int (rieur the !aintenance of all the conditions necessary to the life of the ele!ents.. %ernard "ent on to declare that ,the circulation of the #lood for!s a true organic en iron!ent) inter!ediary #et"een the e*ternal en iron!ent in "hich the indi idual as a "hole li es and the !olecules of the li ing cells "hich "ould other"ise not co!e into direct relationship "ith that e*ternal en iron!ent.. The notion that the constancy of the internal en iron!ent is protected #y !ultiple intrinsic !echanis!s) including renal) pul!onary) hepatic) and cell/ !e!#rane function) e ol ed o er the ne*t fifty years. 0alter $annon coined the ter! ,ho!eostasis). "hich led to the concept that an organis!1s fitness for sur i al is directly related to its capacity to !aintain ho!eostasis. Fro! this e ol ed the #iologic precept that the e*tracellular fluid) including circulation) is the true !ilieu of life #ecause it ena#les the cells of the #ody to function. In the first part of this century a ariety of theories addressed the cause of ascular collapse in in2ured patients. It "as assu!ed that this ascular collapse "as caused pri!arily #y to*ins. In a series of inno ati e e*peri!ents #eginning "ith %lalock) researchers deter!ined that al!ost all acute in2uries are associated "ith changes in fluid and electrolyte !eta#olis!. These studies sho"ed that the alterations "ere pri!arily the result of reductions in the effecti e circulating #lood olu!e and that this reduction !ay #e the result of loss of #lood as in he!orrhage) #ut also as a result of loss of ascular tone 3e.g.) in septic or neurogenic shock4) pu!p failure 3cardiac ta!ponade4 or !yocardial infarction) or loss of large olu!es of e*tracellular fluid) "hich occurs in patients "ith diarrhea) o!iting) or fistula drainage. %lalock1s studies sho"ed that fluid loss in in2ured tissues "as loss of e*tracellular fluid that "as una aila#le to the intra ascular space for !aintenance of circulation. The original concept of a ,third space. in "hich fluid "ould #e sequestered and thus una aila#le to the intra ascular space) e ol ed fro! those studies. During 0orld 0ar II plas!a #eca!e a fa ored resuscitati e solution in addition to "hole/#lood replace!ent. +o"e er) the principle that a li!ited a!ount of salt and "ater should #e gi en to the patient after surgical or other in2ury pre ailed through the 5orean 0ar) largely #ecause of the "ork of $oller and 6oyer in e*peri!ents done at the 7ni ersity of 6ichigan. %y the ti!e of the 8ietna! 0ar) the pro ision of olu!e resuscitation in e*cess of replace!ent of shed #lood #eca!e standard to !aintain adequate ho!eostasis. During 0orld 0ar II acute tu#ular necrosis had #een seen co!!only after hypo ole!ic shock) #ut "ith the li#eral use of fluid resuscitation

during the 8ietna! conflict) the incidence of acute tu#ular necrosis dra!atically decreased 3Ta#le 9/:4. The etiologic classification offered #y %lalock in :;<9 re!ains a useful outline for a !odern definition. %lalock suggested four categories- he!atogenic) neurogenic) asogenic) and cardiogenic. It no" is clear that shock is a syste!ic disorder that disrupts ital organ function as the e entual result of a ariety of causes. 0hereas he!orrhagic or trau!atic shock is characterized #y glo#al hypoperfusion) septic shock !ay #e associated "ith hyperdyna!ic circulation resulting in a !aldistri#ution of regional or intraorgan #lood flo". $onsequently) $erra1s description of shock as a ,disordered response of organis!s to an inappropriate #alance of su#strate supply and de!and at a cellular le el. !ay !ore accurately reflect the unifying functional a#nor!ality at the !eta#olic le el. $I=$7>ATO=? +O6EOSTASIS @reload The !a2ority of the #lood olu!e at rest is contained "ithin the enous syste!. The effect of the return of this enous #lood to the heart produces entricular end/diastolic "all tension) a !a2or deter!inant of cardiac output. Ara itational shifts in #lood olu!e distri#ution are rapidly co!pensated for #y acti e and passi e alterations in enous capacity. The thin/"alled syste!ic eins are highly co!pliant. As arteriolar inflo" increases) the enous pressure rises and enous capacitance passi ely increases. 0ith decreased arteriolar inflo") acti e contraction of the enous s!ooth !uscle cells and passi e elastic recoil co!#ine to increase return of #lood flo" to the heart) !aintaining adequate entricular filling and supporting cardiac output. In the nor!al heart) !ost changes in cardiac output are a reflection of alterations in preload. $hanges in position) intrathoracic pressure) intrapericardial pressure) and circulating #lood olu!e produce !a2or changes in cardiac output. Different enous #eds play different roles in regulating preload. 8eins in the skeletal !uscles sho" a !inor response to sy!pathetic sti!ulation and respond !ore to e*ternal factors) predo!inantly the #alance #et"een gra itational forces and the !uscle pu!p. Increases in sy!pathetic outflo" to the splanchnic ascular #ed produce a rapid and dra!atic reduction in the splanchnic #lood olu!e that nor!ally contains a#out BC percent of the total #lood olu!e. E*ercise and the response of central #aroreceptors during he!orrhage refle*i ely decrease the splanchnic capacitance after these sti!uli of sy!pathetic outflo". $utaneous noradrenergic ner es respond to hypothala!ic control and alter the enous tone of the skin to pro!ote ther!al regulation during resting heat stress) e*ercise de!ands) and the fe#rile response. The nor!al circulating #lood olu!e is !aintained "ithin narro" li!its #y #alancing salt and "ater intake "ith e*ternal losses #y the kidney1s a#ility to respond to alterations in he!odyna!ics and the hor!onal effects of renin) angiotensin) and antidiuretic hor!one. The su!!ation of these relati ely slo" responses) "hich !aintain adequate preload #y altering the circulating #lood olu!e) are o ershado"ed in the acute setting #y the changes in the enous tone) syste!ic ascular resistance) and intrathoracic pressure. In addition) the net effect of preload on the entricle also responds to the cardiac deter!inants of entricular function) including coordinated atrial contraction) "hich aug!ents entricular diastolic filling)

and tachycardia) "hich drops the effect of preload on the entricle #y co!pro!ising diastolic filling ti!e. 8entricular $ontraction The Frank/Starling cur e descri#es the arying force of entricular contraction as a function of its preload. The changes in force de elop!ent are e*plained #y the ultrastructural property of the !yocardiu!) "hich generates a force of contraction dependent on initial !uscle length. A ariety of disease states) including !yocardial in2ury) al e dysfunction) and cardiac hypertrophy) !ay alter the !echanical perfor!ance of the heart. E*peri!ental studies in #urn) septic) he!orrhagic) and trau!atic shock ha e docu!ented deteriorating intrinsic cardiac function during these in2ury states. 0hile the !echanis!s of these alterations in !yocardial perfor!ance are unclear) their effect on the e aluation and !anage!ent of glo#al perfusion in clinical shock !ay #e assessed #y S"an/Aanz catheterization that !easures preload indirectly as end/diastolic pressure) ther!odilution cardiac output) and esti!ations of calculated ascular resistance. Afterload Afterload is the force acting to resist !yocardial "ork during contraction. Arterial pressure is the !a2or co!ponent of afterload that influences the e2ection fraction. This ascular resistance is pri!arily deter!ined #y precapillary s!ooth !uscle sphincters in con2unction "ith other rheologic factors such as #lood iscosity. If afterload increases) stroke olu!e can #e !aintained in the presence of an increase in preload. 7nlike in nor!al heart function) in "hich stroke olu!e can #e !aintained in the face of increased ascular resistance #y increasing preload) the decreased effecti e circulating olu!e in shock states pre ents this co!pensatory !aintenance of cardiac output. This i!#alance of preload/after/load effects o er"hel!s the nor!al increase in inotropic state produced #y increased sy!pathetic ner e acti ity in the heart and #y increased circulating catechola!ines released #y the stress response. @AT+O@+?SIO>OA? OF +?@O8O>E6I$ S+O$5 +ypo ole!ic shock results fro! a decrease in the circulating or effecti e intra ascular olu!e. $onsequently) !ost of the signs of clinical shock are characteristic of peripheral hypoperfusion and increased adrenergic acti ity. ?oung) healthy patients in shock initially appear an*ious and e*hi#it restlessness. This #eha ior gi es "ay to apathy and lethargy after initiation of treat!ent. Frank co!a rarely results fro! #lood loss aloneD usually it is a sign of conco!itant direct #rain in2ury) or it is coincident "ith co!plete cardio ascular collapse. As intra ascular olu!e is lost) an increase in peripheral ascular resistance occurs to defend the #lood pressure in co!pensation for falling cardiac output. Differential increases in peripheral resistance in regional arteriolar #eds) particularly in the skin) gut) and kidney) further defends pressure at the cost of further decreasing organ flo". The pale) cool skin noted on e*a!ination and the #lanching of the #o"el "ith decreased pulses in the !esentery are gross signs seen at the #edside and at laparoto!y. A decrease in circulating #lood olu!e also results in tachycardia in response to decreased stroke olu!e fro! inadequate preload. The tachycardic response depends on the rate of #lood loss and the position of the patientD orthostatic testing !ay

un!ask cardio ascular insta#ility "ith tachycardia and hypotension in a patient "ho appears sta#le "hen e*a!ined in the supine position. Significant orthostasis reflects a <C percent reduction in circulating #lood olu!e in young patients. $o!pensatory =esponses The follo"ing co!pensatory responses occur during shock3:4 >oss of circulating intra ascular olu!e results in increased ascular tone) "hich ele ates peripheral ascular resistance) resulting in a redistri#ution of #lood flo" a!ong the organ syste!s of the #ody. %lood flo" to those organs that are ,autoregulated) . such as the heart and the #rain) is !aintained at the e*pense of cutaneous) splanchnic) and renal circulatory #eds) "hich depend on sy!pathetic tone for #lood flo". 3B4 Decreases in intra ascular olu!e sti!ulate increased sy!pathetic acti ity) "hich di!inishes agal inhi#ition of the rate and the force of cardiac contraction. Areater !yocardial contractility and enhanced enous return) "hich help to i!pro e stroke olu!e) acco!pany the tachycardia present during shock. $ardiac output is increased #y these responses) as is !yocardial o*ygen consu!ption. %lood pressure is !aintained #y increases in total peripheral resistance and cardiac output. 3<4 >oss of circulating intra ascular olu!e leads to decreased capillary hydrostatic pressure. Transcapillary influ* of e*tra ascular e*tracellular fluid then occurs fro! the interstitial space as a result of this alteration in Starling forces. This !o#ilization of the interstitial fluid pool into the intra ascular space has t"o !a2or effectscirculating intra ascular olu!e is increased) and #lood iscosity is decreased secondary to dilution. 394 In addition to the increased syste!ic o*ygen/carrying capacity produced #y he!odilution) tissue e*traction of o*ygen is enhanced in he!orrhagic shock #y the presence of acidosis and ele ated le els of erythrocyte B)</diphosphoglycerate 3B)</ D@A4. Decreased deli ery of cellular su#strates leads to increased anaero#ic !eta#olis! of glucose and accu!ulation of lactic acid. The resultant tissue acidosis produces a right"ard shift in the o*yhe!oglo#in dissociation cur e) decreasing the affinity of he!oglo#in for o*ygen) there#y !aking !ore o*ygen a aila#le to the tissues. +ypo*ia also sti!ulates respiratory centers) leading to hyper entilation and respiratory alkalosis and a su#sequent increased rate of erythrocyte synthesis of B)</ D@A. This produces a further) !ore prolonged right"ard shift of the o*yhe!oglo#in dissociation cur e 3Fig. 9/ :4. 3E4 Arteriolar constriction and loss of circulating olu!e di!inish renal #lood flo". %oth afferent and efferent arterioles are then sti!ulated) "ith resultant cortico!edullary shunting of the re!aining flo" in an atte!pt to !aintain an effecti e glo!erular filtration rate. 7rine output su#sequently decreases as "ater and sodiu! are retained. $learance of urea and acids) as "ell as #uffering capacity) are di!inished) leading to a loss of control of acid/#ase #alance. 3F4 $hanges in #lood olu!e in association "ith afferent sensory i!pulses lead to !arked release of epinephrine and norepinephrine early in the course of he!orrhagic shock. The increased secretion of these catechola!ines #y the adrenal glands is an

acute) short/li ed response) usually li!ited to the day of in2ury unless co!plications occur. Epinephrine and norepinephrine produce asoconstriction and tachycardia) resulting in increased cardiac output and #lood pressure. Alycogenolysis) lipolysis) and skeletal !uscle #reakdo"n are sti!ulated) and insulin release is inhi#ited) pro!oting glucose !o#ilization) protein cata#olis!) and negati e nitrogen #alance. Epinephrine incites insulin resistance in skeletal !uscle) and perhaps in other tissues) thus fa oring glucose utilization #y insulin/independent tissues such as the heart and the #rain. The acute catechola!ine response also results in retention of sodiu! and "ater in the pro*i!al tu#ule of the nephron. 3G4 @ituitary adrenocorticotropic hor!one 3A$T+4 release is sti!ulated in he!orrhagic shock #y decreased #lood olu!e) decreased arterial pressure) pain) hypo*e!ia) and hypother!ia. After se ere he!orrhage) circulating cortisol pro ides no feed#ack inhi#ition on A$T+ release) #ut feed#ack is restored once #lood olu!e has #een ree*panded. $ortisol potentiates the actions of epinephrine and glucagon on glucose !eta#olis! and insulin resistance and further sti!ulates !o#ilization of a!ino acids fro! skeletal !uscle. Increased cortisol secretion also results in renal sodiu! and "ater retention. 3H4 7nlike the counterregulatory hor!ones) insulin secretion is di!inished in shock. This relati e hypoinsuline!ia aug!ents the !o#ilization of glucose) a!ino acids) and fat stores sti!ulated #y epinephrine) glucagon) cortisol) and gro"th hor!one. 3;4 Arginine asopressin 3A8@4) also kno"n as antidiuretic hor!one 3AD+4) is secreted in response to increased seru! os!olarity and hypo ole!ia 3Fig. 9/B4. It appears) ho"e er) that hypo ole!ia is the !ore potent sti!ulus) producing a picture si!ilar to the syndro!e of inappropriate antidiuretic hor!one secretion in response to he!orrhage and shock. Arginine asopressin increases "ater per!ea#ility and passi e sodiu! transport in the distal tu#ule of the nephron) allo"ing increased "ater resorption. Arginine asopressin is also a potent splanchnic asoconstrictor. Acti ation of the renin/angiotensin syste! occurs in shock in response to increased sy!pathetic sti!ulation of the 2u*taglo!erular cells ia a #eta/adrenergic !echanis!) decreased renal perfusion pressure) and co!positional changes in tu#ular fluid. =enin) released fro! the 2u*taglo!erular apparatus) results in increased production of angiotensin I) "hich is rapidly con erted to angiotensin II in the lung. Angiotensin II is a po"erful arterial and arteriolar asoconstrictor and sti!ulates renal prostaglandin production as "ell as the release of aldosterone and A$T+. Increased aldosterone secretion during shock occurs in response to increased circulating le els of angiotensin II and A$T+. Aldosterone increases sodiu! resorption in the distal nephron in e*change for potassiu! and hydrogen ions and represents the principal !echanis! #y "hich the kidney !ay e*crete the accu!ulated #y/products of anaero#ic !eta#olis! and cellular da!age. @rostaglandins) particularly @AE B) and kallikreins) produced in the kidney) function locally to dilate renal essels and increase renal #lood flo". Thro!#o*ane A Bresults in splanchnic and cutaneous asoconstriction and !ay pro!ote cardio ascular dysfunction. @latelet/acti ating factor) produced #y sti!ulated !acrophages) results in coronary asoconstriction and cardiac depression and increases platelet aggregation. The leukotrienes) produced #y acti ated !ast cells) also are potent asoconstrictors and appear to pro!ote !uscle cata#olis! and a!ino acid release.

3:C4 The response of the e*tracellular fluid to acute he!orrhagic shock has #een de!onstrated e*peri!entally in ani!al !odels. 7sing different isotopes to !easure si!ultaneously the total/#ody red #lood cell !ass) plas!a olu!e) and interstitial fluid olu!e) researchers can deter!ine the distri#ution of these co!ponents of the e*tracellular fluid after shock. A :C percent #lood loss in splenecto!ized dogs produces no e idence of clinical shock. =ed #lood cell and plas!a loss in this !odel "ere deter!ined to #e equal to the olu!e of shed #lood) "ith no e idence of additional e*tracellular fluid loss. +o"e er) a BE percent #lood loss in the sa!e !odel results in hypotension and an :H to BF percent reduction of functional e*tracellular fluid olu!e in addition to the !easured losses of red #lood cells and plas!a. Further losses of e*tracellular fluid olu!e in addition to red #lood cells and plas!a can #e de!onstrated "hen the !agnitude of he!orrhage is increased to <E) 9E) or e en EC percent of circulating #lood olu!e. 0ith less se ere shock !odels) there re!ains a reduction in the early equili#rating e*tracellular fluid a aila#le for intra ascular influ*) "hile total anato!ic e*tracellular fluid !ay #e nor!al. As there is no !easured e*ternal loss of this functional e*tracellular fluid olu!e in any of these !odels) it is presu!ed that these changes represent an internal redistri#ution of the e*tracellular fluid in response to he!orrhagic shock 3Fig. 9/<4. It has #een de!onstrated that #lood reinfusion after he!orrhagic shock restores the !easured deficit in red #lood cell !ass and plas!a olu!e) #ut not the deficit in e*tracellular fluid olu!e. +o"e er) the addition of a #alanced salt solution or e*tracellular fluid ,!i!ic) . such as lactated =inger1s solution) to the shed #lood infusion results in return of e*tracellular fluid olu!es to control le els. 6ortality in a !odel of ,irre ersi#le . shock "as reduced fro! HC percent in ani!als gi en only #lood to <C percent #y restoration of the functional e*tracellular fluid olu!e "ith #alanced salt solutions in addition to return of shed #lood. This loss of functional e*tracellular fluid olu!e during shock is partially e*plained #y the transcapillary influ* of interstitial fluid into the intra ascular space in response to decreased capillary hydrostatic pressures. +o"e er) the !agnitude of intra ascular refilling is inadequate to e*plain the total reduction of e*tracellular fluid o#ser ed. The isotonic !o e!ent of interstitial "ater and sodiu! into the cellular !ass represents the !ost likely !echanis! for the additional reduction of e*tracellular fluid olu!e) and isotonic !o e!ent of "ater and sodiu! into !uscle cells has #een de!onstrated during he!orrhagic shock 3Fig. 9/94. 3::4 A se!iper!ea#le cell !e!#rane functions through acti e transport !echanis!s to !aintain the ionic differences #et"een intracellular and e*tracellular fluid. A negati e cellular !e!#rane potential difference ensues and is i!portant for cell ho!eostasis and control of olu!es and concentrations in the fluid co!part!ents. This transcellular !e!#rane potential difference !ay #e !easured serially in i o using >ing/Aerard ultra!icroelectrodes. In !uscle and li er tissue this !e!#rane potential difference ser es as a relia#le indicator of cellular dysfunction during he!orrhagic shock. During profound acute he!orrhagic shock) the transcellular !e!#rane potential difference in skeletal !uscle falls fro! /;C to /FC !8. This fall in potential difference is specific to the state of shock and independent of acid/#ase status. Alterations in !e!#rane potential difference in pri!ate !odels of acute he!orrhagic shock are re ersi#le) "ith reco ery of the nor!al difference after adequate fluid resuscitation) including replace!ent of losses fro! the e*tracellular fluid co!part!ent 3Fig. 9/E4. 6uscle #iopsies o#tained conco!itantly "ith !easure!ents of transcellular !e!#rane potential allo" !easure!ents of

intracellular "ater and electrolytes. These studies de!onstrate the correlation of altered !e!#rane potential difference and cellular s"elling) !arked #y increased intracellular "ater) an influ* of e*tracellular sodiu! and chloride) and an efflu* of intracellular potassiu!. There appears to #e little change in intracellular sodiu! acti ity) indicating that the e*tra sodiu! that diffuses into the cell during !e!#rane dysfunction is #ound to fi*ed charges or co!part!entalized into the organelles. Decreased production of AT@ in association "ith anaero#ic !eta#olis! results in a di!inished a#ility to control sodiu! flu* and has #een proposed as a cause of cellular dysfunction during he!orrhagic shock. +o"e er) le els of high/energy phosphate co!pounds are !aintained in li er and skeletal !uscle early in he!orrhagic shock at a ti!e "hen alterations in !e!#rane potential difference ha e already occurred. $ellular !e!#rane dysfunction is not pre ented #y ad!inistration of such high/ energy phosphates as AT@/6g$l B. The fall in concentration of intracellular AT@ appears to #e the effect of cellular dysfunction and not its pri!ary cause. Other possi#le e*planations for cellular dysfunction during he!orrhagic shock are decreased acti ity of the sodiu!/potassiu! pu!p responsi#le for !aintenance of !e!#rane potential difference independent of AT@ content) or changes in !e!#rane per!ea#ility. These effects !ight occur through the actions of infla!!atory !ediators generated in response to in2ury and he!orrhage. Tu!or necrosis factor/ alpha 3TNF/ a4) a cytokine produced #y acti ated !acrophages) is i!plicated in the !ediation of alterations in skeletal !uscle !e!#rane dysfunction and the he!odyna!ic consequences of sepsis and !ay play a si!ilar role in he!orrhagic shock. Other factors) such as platelet/acti ating factor) leukotrienes) thro!#o*ane A B) and co!ple!ent acti ation) ha e also #een i!plicated. 3:B4 Nitric o*ide is a potent regulator of #asal #lood essel tone. It is a u#iquitous free radical produced as a result of t"o for!s 'constituti e and induci#le 'of nitric o*ide synthase. The induci#le for! 3iNOS4 is up/ regulated #y endoto*in and proinfla!!atory cytokines) such as interleukin/ : 3I>/:4 and tu!or necrosis factor 3TNF4 in !acrophages) 5upffer cells) ascular s!ooth !uscle) and endotheliu!. It is likely that nitric o*ide plays ital regulatory roles in the cardio ascular) pul!onary) gastrointestinal) i!!une) and central ner ous syste!s. @ul!onary Derange!ents in Shock Acco!panying successful fluid resuscitation is the e!ergence of pul!onary dysfunction in : to B percent of the sur i ors of shock. This occurs in so!e patients "ithout lung in2ury per se. Originally referred to as shock lung) adult respiratory distress syndro!e "as first descri#ed in :;FG. This disorder) no" referred to as acute respiratory distress syndro!e 3A=DS4) is characterized #y hypo*ia 3despite o*ygen therapy4) decreased pul!onary co!pliance) diffuse or patchy infiltrates on chest */ ray) and noncardiac pul!onary ede!a. Etiology The pul!onary syste! e*hi#its a stereotypic response to insult. That is) a ariety of in2uries can trigger a final co!!on path"ay) resulting in the sy!pto! co!ple* kno"n as A=DS. These include direct pul!onary in2ury) such as that seen in aspiration) inhalation in2ury) pul!onary contusion) and near dro"ning) and see!ingly unrelated disorders) such as !ultiple transfusions and trau!a such as fractures. $o!!on to all these disorders is the initiation of infla!!atory !ediators. These result in increases in !icro ascular per!ea#ility and su#sequent proteinaceous fluid

deposition in the al eolar epithelial and pul!onary capillary endothelial interface. =esulting fro! this disruption are a#nor!al entilation and perfusion relationships and su#sequent hypo*ia 3Fig. 9/F4. The pheno!enon of noncardiac ede!a occurs as a result of derange!ents of lung !icro ascular per!ea#ility. 7nder nor!al conditions) a s!all a!ount of fluid !o es out of the pul!onary capillaries and is cleared fro! the interstitiu! #y pul!onary ly!phatics 3Fig. 9/G4. Flu* is go erned #y Starling forces descri#ed #y the equationI J 5f3@! / @t4 / s3@! / @t4 "here- I J transcapillary e*change 5f J filtration coefficient of "ater @! J capillary hydrostatic pressure @t J tissue interstitial pressure s J os!otic reflection coefficient @! J capillary colloid os!otic pressure @t J tissue interstitial colloid os!otic pressure In the pathologic state) the al eolar&capillary interface is disrupted and the resultant fluid o er"hel!s pul!onary ly!phatic clearance. These a#nor!alities ha e #een docu!ented to occur prior to) or "ithout) associated chest/*/ray a#nor!alities. Diuretics and fluid restriction ha e no i!pact on this pathophysiology and are not useful. >ike"ise) colloid ad!inistration has not #een sho"n to effecti ely decrease e*tra ascular lung "ater) #ecause the nor!al #arrier is disrupted and is per!ea#le to large !olecules such as al#u!in. @ul!onary failure associated "ith sepsis has #een studied e*tensi ely) and it is likely that si!ilar !echanis!s are operati e in other conditions resulting in A=DS. Endoto*in or lipopolysaccharides 3>@S4 ha e a direct effect on pul!onary endothelial cells) increasing cellular per!ea#ility. This has #een o#ser ed in in/ itro and in/ i o !odels. Other acti e !ediators include co!ple!ent) eicosanoids) platelet/acti ating factor) leukotrienes) and thro!#o*ane AB. Diagnosis The diagnosis of A=DS #egins "ith clinical suspicion and is #ased on docu!entation of hypo*ia) a#nor!al chest */ray) and a !easured decreased lung co!pliance. 6ultiple scales for grading the se erity of lung in2ury are in use) !ost of "hich include percentage of a#nor!al lung seen on */ray and the a!ount of positi e end/ e*piratory pressure 3@EE@4 required to !aintain adequate o*ygenation. These scales ha e #een criticized #ecause of the su#2ecti e nature of grading of */rays and practice ariations in the use of @EE@. Therapy for A=DS

The therapeutic goal is to !aintain tissue o*ygenation. Supple!ental o*ygen is supplied to !aintain @aO B of FE !!+g or !ore. +e!oglo#in concentration should #e !aintained at :B gKd> or higher) "ith #uffering of p+ to allo" opti!al o*ygen transport. A pul!onary artery catheter is desira#le to !onitor central olu!es and !i*ed enous saturations. Fluid o erload or underresuscitation can ad ersely effect the patient "ith A=DS. Standard pul!onary !anage!ent includes the use of a olu!e entilator in the !andatory !ode "ith tidal olu!e and rate set to allo" adequate car#on dio*ide e*change. This usually can #e acco!plished "ith rates of :C to :B #reaths per !inute and tidal olu!es of :C to :B !>Kkg dry "eight. @EE@ is initiated at E c!+BO to appro*i!ate glottic pressure. Sedation and paralysis !ay #e necessary. @EE@ is used in order to !aintain o*ygenation at nonto*ic 3EC percent or less4 le els of o*ygen. In !anaging the patient "ith A=DS) the entilator is set at :CCL o*ygen and the opti!al le el of @EE@ is identified. This le el is found #y increasing @EE@ #y incre!ents of B.E c!+BO) allo"ing at least <C !in for equili#ration and !easuring arterial and !i*ed enous #lood gases) pul!onary capillary "edge pressure) and cardiac output. @EE@ is increased to as !uch as BC c!+BO) and opti!al settings 3highest o*ygenation "ithout co!pro!ise of cardiac output4 are identified. @EE@ is then set at this le el and o*ygen decreased incre!entally to !aintain a @aO B of FE !!+g) "ith a goal of ECL inspired o*ygen or less. @EE@ can then #e decreased) if o*ygenation is !aintained) #y incre!ents of B.E c!+BO e ery :B h. The potential risks of @EE@ are e*acer#ated #y hypo ole!ia. 8olu!e loading to assure adequate filling pressures #efore @EE@ is applied is #eneficial in interpreting changes in "edge pressure and cardiac output that !ay occur after use of @EE@. Increased intrathoracic pressure and decreased enous return can cause depression of cardiac output. >o"ering of @EE@ is necessary if cardiac output #eco!es co!pro!ised. 0edge pressure !easure!ents !ay #e corrected in the patient "ith nonco!pliant lungs #y su#tracting one/fourth of the applied @EE@ fro! the !easured "edge pressure. @neu!othora* can occur at high pressures 3MBC c!+BO4 and can #e catastrophic. @eak air"ay pressures should #e carefully !onitored. @atients "ith chronic o#structi e lung disease characterized #y pree*isting increases in functional residual capacity !ay not #enefit fro! @EE@ therapy. Trials of early application of @EE@ in patients at high risk for A=DS failed to sho" any #enefit in o erall !ortality or co!plications. The course of A=DS has #een relati ely unaffected in trials of anti/infla!!atory drugs such as i#uprofen and sepsis trials using anticytokine therapy 3interleukin/: receptor antagonist) !onoclonal anti#odies to TNF4. T+E=A@? FO= S+O$5 +ypo ole!ic Shock Initial care of the in2ured patient should follo" the guidelines fro! the ad anced trau!a life support procedures of the A!erican $ollege of Surgeons $o!!ittee on Trau!a. In a patient "ho has undergone trau!a) !ore than one causati e factor !ay #e operating. Once the diagnosis of shock has #een !ade and supporti e therapy #egun) a diligent search can #e !ade for the causati e factor or factors. Deficits of total #ody "ater and electrolytes usually is su#tle) and correction requires specific

therapy "ith crystalloid solutions. =eductions in the e*tracellular fluid olu!e 3plas!a and interstitial fluids4 as a result of #urns) peritonitis) and so!e for!s of crush in2ury are !ore easily recognized. Specific therapy should #e started "ith electrolyte solutionsD occasionally plas!a or so!e source of protein is required as "ell. E*ternal #lood loss should #e corrected i!!ediately "ith appropriate fluid therapy. Fluid =esuscitation $o!position of =esuscitation Fluids >actated =inger1s Solution >actated =inger1s solution is the !ost "idely a aila#le and !ost frequently used #alanced salt solution 3crystalloid4 for fluid resuscitation during shock. It is safe and ine*pensi e) and it equili#rates rapidly throughout the e*tracellular co!part!ent) restoring the e*tracellular fluid deficit associated "ith #lood loss. $oncern that the lactate content of =inger1s solution !ight aggra ate the lactic acidosis coe*isting "ith he!orrhagic shock is un"arranted. Studies in ani!al !odels and hu!an #eings de!onstrate that the use of lactated =inger1s solution in addition to #lood replace!ent results in !ore rapid return of seru! lactate and p+ to nor!al le els than does replace!ent "ith #lood alone. >actate is rapidly con erted to #icar#onate in the li er. %ecause of the rapid equili#ration of #alanced salt solutions into the e*tracellular space) larger olu!es !ay #e required for adequate resuscitation) resulting in decreased intra ascular oncotic pressure. Although there has #een no docu!ented increase in !or#idity or !ortality secondary to the appropriate use of #alanced salt solutions) it has #een speculated that loss of large olu!es of #alanced salt solution into the interstitial space during resuscitation !ay su#sequently contri#ute to postresuscitation organ dysfunction) particularly pul!onary ede!a and respiratory failure. These potentially deleterious effects of #alanced salt solution appear to #e offset #y the acti e ly!phatic circulation) "hich #uffers against fluid o erload and helps to !aintain nor!al oncotic gradients #et"een the intra ascular and interstitial spaces. $olloid Solutions The use of colloidal su#stances that tend to re!ain intra ascular continues to #e ad ocated #y so!e) in lieu of #alanced salt solution) for resuscitation. Ad!inistration of fluid preparations containing colloidal su#stances such as al#u!in raise the intra ascular colloidal pressure) leading to intra ascular influ* of interstitial fluid. %ecause colloids re!ain #riefly in the intra ascular space) a lo"er total olu!e of resuscitati e fluid is required to attain he!odyna!ic sta#ility than "hen crystalloid solutions are usedD it has #een theorized this ser es to pre ent postresuscitation fluid o erload. +o"e er) colloid solutions are !ore e*pensi e) !ay #ind and decrease the ionized fraction of seru! calciu!) decrease circulating le els of i!!unoglo#ulins) decrease the i!!une reaction to tetanus to*oid) and decrease endogenous production of al#u!in. 6ore i!portant) use of colloid/ containing solutions as resuscitati e therapy during he!orrhagic shock further co!pro!ises the e*tracellular fluid olu!e deficit rather than restoring it. This "as confir!ed in a study #y Areenhalgh and colleagues in "hich seru! al#u!in le els "ere !aintained #y e*ogenous ad!inistration of al#u!in in pediatric #urn patients. No differences "ere de!onstrated in ter!s of resuscitation) !aintenance fluid require!ents) su#sequent co!plications) length of stay) or !ortality.

Nu!erous e*peri!ental and clinical studies ha e e*a!ined the issue of the superiority of crystalloid o er colloid resuscitation. 6oss and associates de!onstrated that adequate resuscitation of pri!ates fro! potentially lethal he!orrhage "ith #alanced salt solution or #alanced salt solution plus EL al#u!in resulted in restoration of circulation para!eters and perfusion to nor!al. Although the olu!e of #alanced salt solution required "as three ti!es greater than that of the colloid solution) no !easura#le differences "ere o#ser ed #et"een the t"o groups in pul!onary co!pliance or postresuscitation lung "ater content. In another study pri!ates "ere su#2ected to plas!apheresis sufficient to decrease the seru! oncotic pressure significantly) si!ilar to the situation occurring after crystalloid resuscitation. Narins and co"orkers de!onstrated that e*tra ascular lung "ater) pul!onary co!pliance) o*ygenation) and shunt fraction did not change. This "as true "hen pul!onary capillary "edge pressure "as not ele ated. +olcroft and colleagues also reported that pul!onary ede!a after resuscitation for he!orrhagic shock "ith #alanced salt solution could #e produced only #y sustained ele ations of pul!onary artery pressure. Auyton and >indsey found that lo"ering intra ascular colloid oncotic pressure alone does not result in pul!onary ede!a in dogs) #ut does lo"er the le el of left atrial pressure necessary to produce pul!onary dysfunction. In a !odel si!ilar to that of Narins) De!ling and associates further de!onstrated a !arked increase in pul!onary ly!ph flo" "ithout de elop!ent of pul!onary ede!a) apparently co!pensating for the altered oncotic pressure gradient. In a clinical study) +oro itz and Shires reported an incidence of pul!onary dysfunction in B.: percent of ;GH patients undergoing operati e procedures after se ere trau!a) despite recei ing large olu!es of crystalloid. $arey reported no e idence of acute pul!onary ede!a in EF in2ured patients in 8ietna!) despite an a erage resuscitation olu!e of :B > of #alanced salt solution. As it is "ell esta#lished that sta#ilization of he!odyna!ic para!eters after he!orrhagic shock requires a greater olu!e of crystalloid than colloid solution) !eaningful prospecti e clinical trials co!paring crystalloid and colloid require resuscitation to equal end points and not to equal olu!es. 7sing these guidelines) 8irgilio and colleagues found no differences in pul!onary function or shunt fraction a!ong B; patients undergoing aortic surgery rando!ized to #alanced salt solution or colloid solution resuscitation. In addition) Shires III and co"orkers found no differences in e*tra ascular lung "ater either i!!ediately after operation or B9 to 9H h later in :; aortic surgery patients rando!ized to #alanced salt solution or colloid resuscitation) despite a !arkedly lo"er intra ascular oncotic pressure in the #alanced salt solution group 3Fig. 9/H4. >o"e and associates found no differences in sur i al rates) incidence of pul!onary failure) or postoperati e pul!onary dysfunction in sta#le and unsta#le trau!a patients undergoing laparoto!y "ho recei ed #alanced salt solution or colloid solution resuscitation. >ucas found that the use of colloid not only prolonged the resuscitation phase #ut also delayed postresuscitation diuresis) perhaps through failure of restoration of the interstitial olu!e deficit. Further) the incidence of postresuscitation hypertension "as higher in patients gi en al#u!in) suggesting that renal function !ay #est #e protected during resuscitation fro! shock #y rapid replace!ent of the intra ascular and total e*tracellular fluid deficits. A !eta/analysis of colloid ersus

crystalloid fluid resuscitation that included !any of the studies cited here concluded that crystalloid is superior to colloid for resuscitation after trau!a in hu!an #eings) "ith a :B percent reduction in !ortality after crystalloid infusion. There is therefore no clinical e idence that appropriate resuscitation "ith #alanced salt solution is associated "ith any har!ful effects on pul!onary function "hen guided #y he!odyna!ic para!eters. No protecti e effect of colloid solutions on postresuscitation pul!onary function can #e de!onstrated) e en though colloid solutions do produce transiently greater intra ascular e*pansion per unit olu!e gi en than do crystalloid solutions. As the olu!e e*pansion "ith colloid occurs to so!e e*tent #y further co!pro!ise of the e*tracellular fluid olu!e) renal function during shock !ay #est #e preser ed #y crystalloid resuscitation. +ypertonic Saline $linical and e*peri!ental studies ha e de!onstrated that a s!all olu!e of hypertonic saline can #e an effecti e initial resuscitati e solution. +ypertonic saline resuscitation results in a lo"er "ater load than equi alent resuscitation "ith #alanced salt solutions. +o"e er) patients resuscitated "ith hypertonic saline solution require close !onitoring of electrolytes to pre ent hypernatre!ia and hyperos!olar co!a. =ecent studies in patients ha e sho"n that "hile #lood pressure !ay #e ele ated !ore rapidly in the first fe" !inutes after shock and resuscitation) no changes in sur i al rates occurred. In ie" of the need for electrolyte !onitoring and lack of the definition of the olu!es appropriate for infusion) long/ter! #enefits ha e not #een esta#lished. In ani!al studies sho"ing deterioration of cellular function there "as a higher !ortality B9 h after hypertonic salineKde*tran resuscitation. +etastarch +ydro*yethyl starch 3hetastarch4 is an artificial colloid deri ed fro! a!ylopectin) "ith colloidal properties si!ilar to those of al#u!in. It is less e*pensi e than al#u!in) and) #ecause of its larger !olecular "eight and need for enzy!atic degradation) it has a longer plas!a half/life than al#u!in. As "ith any colloidal solution) hetastarch restores intra ascular olu!e at the further e*pense of the already co!pro!ised interstitial space "hen used in resuscitation during shock. =esuscitation "ith hetastarch also !ay #e difficult to control) #ecause the slo" equili#ration of these large !olecules can lead to rapid fluctuations in central enous pressure. 6ild and transient coagulopathies ha e #een noted in patients resuscitated "ith hetastarch) and a role in depression of the reticuloendothelial syste! has #een postulated. De*tran De*tran) in 9C kD and GC kD solutions) has also #een used as a plas!a e*pander. Although de*tran has a shorter half/life than hetastarch) it also appro*i!ates the colloidal acti ity of al#u!in "hen gi en #y intra enous infusion. $linical studies ha e de!onstrated no differences in rates of organ dysfunction or !ortality "hen resuscitation "ith de*tran is co!pared to that "ith #alanced salt solutions. +o"e er) de*tran use is associated "ith a greater risk of anaphyla*is than is hetastarch or al#u!in and has produced coagulation defects and i!!unoglo#ulin depression. %lood Su#stitutes @eriodic shortages of #lood products and the infectious risks associated "ith transfusions ha e fueled the search for an efficacious artificial #lood su#stitute. Early

studies using free he!oglo#in o#tained fro! outdated #lood resulted in allergic reactions) renal failure) coagulopathies) and i!!une dysfunction secondary to reaction to retained erythrocyte stro!al ele!ents. The su#sequent purification of stro!a/free he!oglo#in 3SF+4 has eli!inated these side effects) #ut pro#le!s "ith the use of SF+ for resuscitation re!ain. SF+ has an a#nor!ally high affinity for o*ygen) has a short plas!a half/life) and is a aila#le only fro! hu!an sources. Although #inding "ith other !olecules or incorporation into liposo!es !ay reduce o*ygen affinity and i!pro e plas!a retention ti!e) SF+ "ill pro#a#ly not #eco!e a practical su#stitute for #lood until an artificial or ani!al donor source #eco!es a aila#le. %o ine SF+ appears to #e one useful approach for treating he!orrhage 3Fig. 9/;4. @erfluoroche!ical co!pounds ha e uniquely enhanced a#ilities to dissol e gases) particularly o*ygen and $OB) #ut require e!ulsification to #e "ater solu#le. @erfluorodecalin 3Fluorosol/DA4 also contains electrolytes) #icar#onate) and starch to o#tain os!otic and p+ #alance "ith plas!a. The o*ygen/carrying capacity of this e!ulsion is lo"er than that of he!oglo#in) and thus its use requires higher inspired o*ygen concentrations 3Fig. 9/:C4. Fluorosol/DA has #een e*tensi ely used in Oapan and in clinical trials has pro ed an effecti e su#stitute for he!oglo#in. @otential ad erse effects include acute pul!onary ede!a) acti ation of co!ple!ent and the coagulation cascade) acute respiratory failure) and depression of the reticuloendothelial syste!. It is e*pensi e and requires special storage to pre ent gelatinization. 8olu!es Appropriate for =esuscitation 6odels of ,controlled he!orrhage. in ol e instru!entation of ani!als and "ithdra"ing #lood to arious end points to si!ulate shock. 6any of these e*peri!ents ha e #een criticized for their failure to reproduce clinical circu!stances. In !odels of uncontrolled he!orrhage) ascular in2uries are created to allo" free he!orrhage. A ,hy#rid !odel. of controlled and uncontrolled he!orrhage "as created #y Stern and associates. @igs "ere su#2ected to controlled he!orrhage #y rapidly "ithdra"ing #lood fro! a fe!oral catheter to a significant le el of shock 3<C !!+g4 o er <C !in) re!o ing an a erage of 9C !>Kkg. Su#sequently) uncontrolled he!orrhage "as induced #y creating a tear in the aorta. =esuscitation olu!es of EE.H !>Kkg and ;C !>Kkg of saline "ere used in a short period of ti!e) after "hich shed #lood "as reinfused. These "ere the olu!es necessary to atte!pt to achie e a preselected !ean arterial pressure 36A@4. The high olu!es used in these e*peri!ents are roughly equi alent to F.<> in a GC kg hu!an #eing. Despite aggressi e fluid and #lood ad!inistration) the goal 6A@ "as ne er achie ed in the Stern study. It !ight #e argued that the t"o insults induced in this s"ine !odel are too se ere) that the !odel is not clinically rele ant) and that the olu!es used for resuscitation "ere e*cessi e. Nonetheless) fluid resuscitation using arying a!ounts of olu!e is associated "ith a lo"er !ortality than "hen no resuscitation is ad!inistered 3Fig. 9/::4. In the Stern study) the sur i al rate fell precipitously in ani!als recei ing a large olu!e in a short a!ount of ti!e in an atte!pt to restore a 6A@ of HC !!+g. Although significantly increased #lood loss also "as seen in the large/ olu!e 3;C !>Kkg4 resuscitation group in the Stern study) the !echanis! of death "as not studied. In the Soucy study) uncontrolled he!orrhage treated "ith a !oderate olu!e 39C !>Kkg4 of isotonic saline solution "as associated "ith increased sur i al ti!es and decreased !ortality.

$urrent studies in unanesthetized ani!als i!ply that early resuscitation of he!orrhagic shock "ith a !oderate olu!e of isotonic solution is superior to delayed resuscitation "ith isotonic or hypertonic solutions. 8olu!e replace!ent appears to result in a centrally !ediated refle* rela*ation of peripheral ascular #eds and increased perfusion "ith little or no associated increase in !ean arterial pressure. The e*istence of this postulated ,shock set/point. of autoregulated lo" #lood pressure could account for the poor results in the studies outlined a#o e in "hich the resuscitati e goal "as to achie e a predeter!ined ,nor!al. #lood pressure. Ti!ing of =esuscitation In the first part of the t"entieth century) $annon stated) ,+e!orrhage in the case of shock !ay not ha e occurred to a !arked degree #ecause #lood pressure has #een lo" and flo" too scant to o erco!e the o#stacle offered #y a clot.. $annon also stated) ho"e er) ,The lo" #lood pressure of shock has #een !et #y the in2ection of nor!al or hypertonic salt.. E*perience gained in the treat!ent of soldiers during the 5orean and 8ietna! "ars esta#lished that early resuscitation "as associated "ith a lo"er incidence of renal failure and "ith increased sur i al 3see Ta#le 9/:4. $urrent clinical protocols for resuscitation fro! he!orrhagic shock are #ased on nu!erous studies in the #asic and clinical sciences. The practice of early ad!inistration of fluids to icti!s of he!orrhagic shock has #een the do!inant !ethod of treat!ent for t"enty years) #ut this !ethod has #een challenged. Ani!al studies of ,delayed resuscitation. in rats after uncontrolled he!orrhage i!plied that there "as no #eneficial effect of olu!e resuscitation. In a s"ine !odel) %ruttig and colleagues sho"ed that early resuscitation "as associated "ith higher !ortality "hen co!pared to ani!als "ith ,delayed resuscitation). "hich "as no resuscitation. This ,early resuscitation. necessitated gi ing the entire resuscitation olu!e in F !in) #eginning 9 !in after the aortic tear. This resulted in little clot for!ation) pro#a#ly #ecause of e*tre!ely rapid dilution of clotting factors) and it resulted in three ti!es the #leeding olu!e co!pared to controls "ithout fluids. The %ruttig study is at ariance "ith that of Aross and associates) in "hich delayed resuscitation for uncontrolled he!orrhage "as associated "ith increased !ortality "hen co!pared to ani!als that "ere not resuscitated. A droperidol/keta!ine 3D54 !i*ture "as used for anesthesia #y !any in estigators. To e*a!ine the !echanis! responsi#le for these increases in !ortality associated "ith resuscitation) %ilysky2 and co"orkers de!onstrated that D5 anesthesia "as associated "ith increases in #lood loss and !ortality. The poor outco!es "ere thought to #e fro! the asodilatory effects of the anesthetic drugs. In the sa!e study) pento#ar#ital "as found not to cause asodilatation "as not associated "ith e*cessi e #lood loss. This effect of anesthesia "as confir!ed in a study of rats o#ser ed after recei ing pento#ar#ital anesthesia. D5 anesthesia "as associated "ith ongoing he!orrhage and increased !ortality) #ut in contrast to se eral pre ious studies) all ani!als resuscitated in the Shires study fared #etter) regardless of the anesthetic used 3Fig. 9/:B4.

T"o large clinical trials "ere perfor!ed to test the ,scoop and run. philosophy) delaying resuscitation until the patient reached the hospital. In #oth studies) delayed resuscitation "as not associated "ith decreased sur i al. The groups "ith delayed resuscitation did not progress !ore fa ora#ly than the groups "ith early resuscitation. Additionally) these studies "ere perfor!ed in selected patients in an ur#an setting "ith relati ely short prehospital ti!eD therefore) the ,delay. "as only appro*i!ately <C !in. 6odern ur#an e!ergency !edical ser ices usually can #e relied on to pro ide transport to a >e el I or II trau!a center "ithin <C !in. It should #e noted that in #oth clinical trials fluids "ere not "ithheld. The 5a"eski study "as a retrospecti e re ie" of data o#tained fro! trau!a patients. @atients "ho "ere less se erely in2ured recei ed less fluid. In the 6atto* study) the ,delayed resuscitation. group recei ed GG: P :BBH !> of fluid preoperati ely and "ere gi en co!para#le a!ounts of crystalloid and #lood in the operating roo!. In neither study did patients "ho "ere gi en fluid ha e a "orse outco!e. %ickell and colleagues reported a rando!ized clinical trial on the effect of presurgical infusion of isotonic fluids in penetrating trau!a to the torso. The study has se eral !ethodological pro#le!s) including the inclusion of resuscitated patients "ith the nonresuscitated patients prior to statistical analysis) precluding alidation of results. In analyzing the data "ith appropriate statistical !ethods) no differences can #e found in #lood pressure at ad!ission) incidence of co!plications) length of hospitalization) or sur i al. Ad2u ant Therapy 8asopressors The clinical state of he!orrhagic shock is defined #y the presence of inadequate tissue perfusion resulting fro! hypo ole!ia. Treat!ent "ith asopressors during shock !ay ele ate #lood pressure) #ut at the e*pense of further increased peripheral resistance and di!inished tissue perfusion. 8asopressor therapy also !ay "orsen the plas!a olu!e deficit associated "ith he!orrhage) and the use of such agents in place of adequate fluid resuscitation is inad isa#le. Adenosine Triphosphate 3AT@4 The de!onstration of decreased high/energy phosphate le els #y so!e in estigators during he!orrhagic shock) as "ell as a decreased rate of con ersion fro! adenosine diphosphate 3AD@4 to AT@) led to an interest in AT@ replace!ent as an ad2u ant therapy for he!orrhagic shock. In e*peri!ental !odels) AT@/6g$lB has #een found to i!pro e sur i al rates in potentially lethal shock "hen co!#ined "ith adequate fluid resuscitation. +o"e er) #ecause AT@ is rapidly degraded in plas!a and tissue and cannot cross intact cellular !e!#ranes #ecause of its charge) it is unlikely that the i!pro ed sur i al is a result of restoration of cellular AT@ content. The i!pro e!ents !ay #e fro! the re ersal of hypoperfusion secondary to local asodilatory effects) degradation and pro ision of phosphate precursors that !ay cross the cell !e!#rane) or #lockade of cellular uptake of calciu!. Infusion of AT@/ 6g$lB !ay result in !arked he!odyna!ic insta#ility in the hypo ole!ic patient) "hich li!its its usefulness in the clinical treat!ent of he!orrhagic shock. @ositioning 6ost first/aid courses teach that the patient in shock should #e placed in the head/ do"n position. It is true that so!e for!s of shock) particularly neurogenic shock) respond to the head/do"n position) #ut the effect of posture on the cere#ral circulation

"hen confronted "ith true hypo ole!ia has not #een defined. The patient "ith !ultiple trau!a often has in2uries in the a#do!en and chest) so that the routine use of the Trendelen#urg) or head/do"n) position !ay interfere "ith respiratory e*change far !ore than "hen the patient is left supine. The #eneficial effect of the head/do"n position pro#a#ly is the result of transient autotransfusion of pooled #lood in the capacity or enous side of the peripheral circulation. This #eneficial effect can #e o#tained easily #y ele ating #oth legs "hile !aintaining the head) trunk) and ar!s in the supine position. This is the preferred position for the treat!ent of hypo ole!ic shock. 6AST Aar!ent There has #een enthusias! for the in/the/field application of !ilitary antishock trousers) the 6AST gar!ent. 0hen applied to the e*tre!ities "ith !odest pressures) the gar!ent functions "ell as a splint and !ay control so!e enous #leeding. 0hen applied at high pressures) the resultant increase in total peripheral resistance !ay ele ate the syste!ic pressure "hile decreasing cardiac output and peripheral perfusion. Additionally) inflation of the a#do!inal #olster !ay co!press the inferior ena ca a) i!pairing enous return to the heart #y further increasing the enous resistance. Se eral reports of reperfusion in2ury "ith co!part!ent syndro!es in unin2ured li!#s ha e appeared. The 6AST de ice !ay #e of alue "hen used strictly as a te!porizing de ice or occasionally as specific treat!ent of #leeding pel ic fractures. Its use !ust not delay the i!!ediate repletion of intra ascular and e*tra ascular olu!e #y fluid therapy or interfere "ith rapid transport of the in2ured patient. @ul!onary Support In the past) !ost "riting on the treat!ent of hypo ole!ic shock stated that #reathing high o*ygen concentrations pro#a#ly is of little alue during a period of hypotension. These conclusions "ere #ased on the notion that the principal defects are in olu!e flo" to tissues and decreased cardiac output. The o*ygen saturation in the !a2ority of patients "ith unco!plicated hypo ole!ic shock generally is nor!al) and the s!all increase in dissol ed o*ygen in the #lood contri#uted #y raising the @O B a#o e this le el is insignificant) particularly "ith a !arkedly decreased cardiac output. This concept continues to #e alid in ter!s of i!pro e!ent of the shock state or tissue o*ygenation. Ne ertheless) in the s!all #ut significant group of patients in hypo ole!ic shock in "ho! the o*ygen saturation is not nor!al) the initial use of increased o*ygen concentrations !ay #e e*tre!ely i!portant) #ecause the fall in cardiac output acco!panying he!orrhagic shock has #een sho"n to co!pound e*isting defects in o*ygenation. This can occur in patients "ith pree*isting defects) such as chronic o#structi e lung disease. 6ore frequently) pro#le!s in o*ygenation arise directly fro! the patient1s in2uries and !ay include a coe*isting pneu!othora*) pul!onary contusion) aspiration of gastric contents or #lood) or air"ay o#struction. Although o*ygen is not routinely ad!inistered to patients in shock) if any dou#t e*ists as to the possi#ility of one of these circu!stances or the adequacy of o*ygenation of arterial #lood) the initial ad!inistration of o*ygen until the in2uries to the patient ha e #een diligently assessed is certainly 2ustified. If o*ygen is ad!inistered to patients under these circu!stances) it should #e deli ered through a loose/fitting face !ask designed for this purpose. If a controlled air"ay is indicated for other reasons) an endotracheal tu#e is ideal. The use of nasal catheters) particularly those passed into the nasopharyn*) is a oided #ecause of potential co!plications of pharyngeal

lacerations and gastric distention. Aastric rupture has #een recorded secondary to a nasal catheter1s #eing inad ertently placed in the esophagus. Anti#iotics Anti#iotics "ere used in the treat!ent of hypo ole!ic shock for !any years and "ere thought to e*ert a protecti e !echanis! against the ra ages of hypo ole!ia. Su#sequent data failed to support this hypothesis. The use of anti#iotics in patients "ho ha e open or potentially conta!inated "ounds continues to #e sound practice "hen co!#ined "ith good surgical de#ride!ent and care. The use of "ide/spectru! anti#iotics is ad isa#le as a pre enti e !easure in the se erely in2ured patient. $efo*itin B g I.8. has pro ed to #e a safe and effecti e single agent in !ultiorgan a#do!inal in2uries. Analgesics Treat!ent of pain in the patient "ith hypo ole!ic shock is rarely a pro#le!. +o"e er) if the causati e in2ury produces se ere pain) e.g.) fracture) peritonitis) or in2ury to the chest "all) control of pain #eco!es !andatory. 0hen the patient is !o ed to an e!ergency facility "here physicians and care are a aila#le) si!ple supporti e !easures 3ad!inistration of intra enous fluids) passing of catheters4 "ill gi e reassurance. The need for analgesics is greatly reduced) #ecause the need to allay fear and an*iety is decreased. If the patient continues to ha e se ere pain) the o#ser ations !ade #y %eecher in 0orld 0ar II are critical. 6any #attle casualties recei ed !orphine or other narcotic agents #y su#cutaneous ad!inistration soon after "ounding. %ecause these analgesics did not enter the circulation i!!ediately) the pain continued and the patient ulti!ately recei ed se eral doses that "ere poorly a#sor#ed. Once effecti e therapy "as #egun for shock) the doses pre iously ad!inistered "ere a#sor#ed) and profound sedation resulted. As a result) the reco!!endation "as !ade that s!all doses of narcotics #e gi en intra enously for the !anage!ent of pain in the patient "ith shock. Steroids Adrenocorticoid depletion "as regarded as a contri#utory factor in shock after it "as learned that the presence of hypo ole!ic shock could deplete the adrenal corte* of adrenocortical steroids. Su#sequent studies ha e sho"n that adrenocortical steroid production is sti!ulated !a*i!ally #y the presence of hypo ole!ic shock. Steroid depletion "ith hypo ole!ic shock !ay occur in the elderly patient or in patients "ith specific adrenocortical diseases) such as incipient Addison1s disease) postadrenalecto!y patients) or patients "ho ha e had adrenal suppression "ith e*ogenous adrenocortical steroids. In these specific instances) the intra enous ad!inistration of hydrocortisone is desira#le. In the trau!a patient "ith hypo ole!ic shock) ad!inistration of adrenocorticoids is not indicated. 6onitoring $ontinuous #edside !onitoring of circulatory efficacy) including assess!ent of the heart rate) arterial #lood pressure) urinary output) and peripheral perfusion) re!ains the cornerstone for resuscitation. Adequate resuscitation is indicated "hen adequate cere#ral function and urinary output are restored. In the patient "ith !ultiple in2uries) central enous pressure 3$8@4 !onitoring is useful. Although left entricular o erload can occur "hile right entricular function and $8@ re!ain nor!al) this is not often the case in the a#sence of !yocardial in2ury. $hanges o er ti!e in the $8@

"ith fluid infusion do indicate the a#ility of the !yocardiu! to pu!p the olu!e presented to it. A nor!al/to/depressed $8@ that does not rise "ith rapid ad!inistration of crystalloid fluid usually indicates continuing hypo ole!ia. The presence of an ele ated $8@ or its rapid rise in response to fluid ad!inistration is indicati e of i!pair!ent of the pu!ping !echanis!. Although this usually represents pri!ary !yocardial deficiency and should #e treated as outlined in the follo"ing section on cardiogenic shock) any !echanical o#struction to enous return "ith cardiac ta!ponade or !ediastinal co!pression #y intrapleural air or #lood !ust #e i!!ediately attended to in the in2ured patient. The use of a #alloon/ tipped S"an/ Aanz catheter allo"s !easure!ent of pul!onary artery and pul!onary "edge pressures as "ell as ther!odilution cardiac output deter!inations. The early use of the S"an/Aanz catheter rarely is necessary in the initial e!ergency depart!ent treat!ent for he!orrhagic shock. +e!orrhagic shock !ay #eco!e refractory to the therapies descri#ed a#o e and #eco!e irre ersi#le. $o!plete ascular collapse "ith hypotension unresponsi e to olu!e or drug inter ention e entually leads to lethal central ner ous syste! and cardiac dysfunction. Irre ersi#ility is difficult to define #ut has #een related to the duration and olu!e of he!orrhage) the age and pree*isting cardio ascular fitness of the patient) and the coe*istence of !assi e trau!a "ith !ultiple direct organ derange!ent. %efore the physician concludes that refractory shock has occurred) the !ultiple causes of failure to respond to therapy should #e resol ed. These include continuing unsuspected #lood loss into the chest or a#do!en) inadequate olu!e replace!ent) inadequate clotting) !ultisyste! trau!a "ith occult thoracic in2uries) including cardiac ta!ponade and he!opneu!othora*) and acute !yocardial insufficiency fro! direct in2ury or secondary to prolonged coronary hypoperfusion. $ardiogenic Shock $ardiogenic shock occurs "hen the heart is una#le to generate sufficient cardiac output to !aintain adequate tissue perfusion. 7nlike hypo ole!ic shock) cardiogenic shock is !anifested #y hypotension in the face of adequate intra ascular olu!e. $ardiogenic shock that is unresponsi e is associated "ith significant !ortality and !or#idity) particularly in con2unction "ith !yocardial infarction and the secondary end/organ in2uries of pul!onary ede!a) oliguric renal failure) and co!a. @athophysiology 6yocardial failure !ay result fro! a ariety of diseases) including al ular heart disease) cardio!yopathy) and direct !yocardial contusion. Acute !yocardial infarction is the !ost frequent cause of cardiogenic shock) "hich is often fatal "hen 9C percent of the left entricular !ass has #een lost. @apillary !uscle dysfunction) ische!ic entricular septal defects) !assi e left entricular infarction) and arrhyth!ias are co!plications of acute !yocardial infarction that !ay lead to cardiogenic shock. The initial co!pensatory response to di!inished !yocardial contraction is tachycardia) in an atte!pt to !aintain cardiac output) despite a decreased left entricular e2ection fraction) at the e*pense of increasing !yocardial o*ygen consu!ption. As cardiac inde* falls #elo" B >K!inK!Bhypotension produces refle* sy!pathetic asoconstriction. This atte!pt to !aintain central pressure #y increasing peripheral ascular resistance leads to decreasing organ perfusion. An increase in

afterload further i!pairs left entricular function and increases !yocardial "ork. The co!#ination of increased !yocardial o*ygen de!and) hypotension) and shortened diastole a!plifies the !is!atch #et"een coronary arterial o*ygen deli ery and !yocardial o*ygen de!and) e*tending the zone of infarction in the patient "ho does not recei e pro!pt inter ention. Treat!ent Although the goal of !edical !anage!ent of cardiogenic shock has #een to enhance entricular perfor!ance and i!pro e glo#al perfusion) the traditional !anage!ent "ith fluids and inotropic drugs continues to yield a !ortality of HC to ;C percent. The techniques that !a*i!ize entricular perfor!ance parado*ically increase !yocardial o*ygen de!and at a ti!e "hen therapy) to li!it infarct size and sal age re ersi#ly ische!ic !yocardiu!) should include !ini!izing !yocardial de!and and atte!pting to pro ide early reperfusion. Initial therapy includes opti!izing entricular preload #y !anipulating filling pressure) decreasing afterload in the patient "ith adequate systolic pressure) correcting arrhyth!ias) and i!pro ing contractility to sustain ital organ perfusion. 6onitoring and 8olu!e 6anage!ent Supple!ental o*ygen) pain relief and sedation) and continuous electrocardiographic !onitoring should #e initiated early. A Foley catheter is inserted for !onitoring urine output. $utaneous o*i!etry and auto!ated arterial #lood pressure cuff !easure!ents can #e used in place of an intraarterial catheter for continuous arterial pressure !onitoring and #lood gas deter!inations. @lace!ent of a S"an/Aanz catheter for !easure!ent of cardiac output and pul!onary artery "edge pressure is crucial to therapeutic decision/!aking in these critically ill patients. $ardiogenic shock "ith lo" cardiac output and arterial hypotension can occur in so!e patients "ith nor!al to slightly ele ated pul!onary artery "edge pressures. A s!all increase in left entricular filling pressure #y olu!e infusion !ay !a*i!ize cardiac output ia the Frank/Starling !echanis!. It should #e e!phasized that although he!odyna!ic !easure!ents suggest !yocardial insufficiency) !echanical o#struction) such as cardiac ta!ponade in the in2ured patient or pul!onary e!#olis! in the postoperati e patient) !ay #e present. Although these diagnoses are !ade largely on clinical grounds in the e!ergency setting) olu!e infusion usually is of so!e #enefit "hile echocardiography) pericardiocentesis) or thoracentesis are perfor!ed quickly. $onstant igilance is required during olu!e challenge in this settingD increased filling pressures !ay lead to further !yocardial ische!ia and acute pul!onary ede!a. If any pul!onary co!plications e ol e) early intu#ation and !echanical entilation "ill decrease the !yocardial o*ygen de!and as a consequence of the increased "ork of #reathing and correct arterial hypo*e!ia that !ay further i!pair cardiac perfor!ance. Inotropic Agents The #eta:/adrenergic receptors of the !yocardiu! respond to e*ogenous sy!patho!i!etic drugs #y increasing contractility and i!pro ing cardiac output. These effects are o#tained at the cost of increasing !yocardial o*ygen de!and in the setting of already/co!pro!ised !yocardial perfusion) #ut intra enous infusion of dopa!ine !ay pro!ptly re erse life/ threatening hypotension and restore !ean arterial pressure to a#out HC !!+g. The dopa!inergic effects of splanchnic) coronary) and renal asodilatation at lo" 3B to E !gKkgK!in4 doses are aug!ented #y

adrenergic/!ediated increases in contractility and heart rate as dosages rise to E to H !gKkgK!in. At higher doses) alpha/adrenergic receptor effects predo!inate) and central arterial pressure can increase "hile coronary artery constriction further decreases coronary #lood flo". Dopa!ine also causes a aria#le increase in heart rate and can precipitate other arrhyth!ias) "hich underscores the need to titrate the lo"est accepta#le dose. Do#uta!ine) a synthetic catechola!ine "ith predo!inantly inotropic effect) appears to #e less arrhyth!ogenic and !ay redistri#ute cardiac output to the coronary circulation. Studies appear to fa or do#uta!ine o er dopa!ine for treating cardiogenic shock after cardiopul!onary #ypass or !yocardial infarction. Digitalis re!ains a contro ersial drug in acute pu!p failure. Although ery useful in the treat!ent of supra entricular arrhyth!ias) digitalis increases !yocardial o*ygen consu!ption and adds ery little he!odyna!ic #enefit relati e to therapy "ith sy!patho!i!etic agents. 8asodilator Agents So!e patients "ith lo" cardiac output and high filling pressures ha e near/ nor!al arterial #lood pressure in the setting of profoundly decreased perfusion #y clinical assess!ent. In these circu!stances) systolic entricular "all stress is high) and reducing afterload should increase cardiac output and decrease !yocardial "ork. An agent such as sodiu! nitroprusside should #e used "ith e*tre!e caution in hypotensi e patients #ecause redistri#ution of an already depressed cardiac output a"ay fro! the coronary and cere#ral circulation can occur) and any decrease in syste!ic diastolic pressure "ould further depress coronary perfusion pressures. 6echanical Support As the role of early reperfusion strategies e ol es 3including thro!#olysis) percutaneous translu!inal coronary angioplasty) and e!ergency #ypass4) !echanical therapy can te!porarily support the failing !yocardiu! until these !odalities are initiated or so!e !yocardial reco ery occurs. Despite significant associated !or#idity) successful !echanical cardiac support "ill !aintain organ perfusion "hile decreasing !yocardial o*ygen de!and #y unloading the left entricle and reducing !yocardial "ork. The intraaortic #alloon pulsation de ice has #een used !ost "idely. It can #e inserted at the #edside and fulfills the criteria of ele ating diastolic #lood pressure) "hich increases pul!onary perfusion) "hile decreasing !yocardial "ork) #y increasing cardiac output distal to the entricle. It is unclear "hether this de ice i!pro es long/ter! sur i al) #ut it clearly supports the failing !yocardiu! "hile reco ery or other inter entions proceed. Those patients "ith surgically correcta#le pro#le!s after acute !yocardial infarction appear to respond #etter than patients "ho "ere not operati e candidates after te!porary !echanical support. >eft heart #ypass #y left atriu!&to&fe!oral artery circulatory #ypass and te!porary i!plantation of left entricular assist de ices !ay #e e en !ore effecti e in assu!ing cardiac "ork. These techniques usually ha e #een li!ited to patients "ith cardiogenic shock after cardiac surgery) #ecause operati e place!ent is required. The role of these techniques !ay #roaden if ongoing studies support i!pro ed sur i al rates fro! early re ascularization #y thro!#olytic therapy) coronary angioplasty) and e!ergency surgery. Arrhyth!ias

=apid entricular rates can depress cardiac output to shock le els. 8entricular end/ diastolic pressure decreases as a result of shortened filling ti!e) and entricular rela*ation is inco!plete #y the end of the a##re iated diastolic period. $ardiac output falls #ecause stroke olu!e cannot #e co!pensated for #y the rapid heart rate. Digo*in is the drug of choice for atrial fi#rillation or atrial flutter) #ut electrical cardio ersion should #e pro!ptly undertaken for tachycardia that produces hypotension and hypoperfusion. =esistant sinus tachycardia) "hile "ell tolerated #y the nor!al heart) !ay produce a lo" flo" state in the diseased heart. 8erapa!il has #een useful in treating tachyarrhyth!ias of atrial origin) and propranolol slo"s sinus tachycardia. %eta #lockade can further decrease cardiac output in this setting) and a careful search for the cause of the sinus tachycardia) including fe er) hypo ole!ia) and drug effect) should #e undertaken. I!!ediate nonsynchronized direct/current electrical shock is !andatory treat!ent for entricular fi#rillation or entricular flutter that has caused cardiogenic shock "ith loss of consciousness. 8entricular fi#rillation rarely con erts spontaneously) and the su#sequent rapid de elop!ent of cardio ascular collapse de!ands pro!pt therapy. In the patient "ith acute !yocardial in2ury) pre!ature entricular co!ple*es !ay lead to entricular tachyarrhyth!ias. Intra enous lidocaine usually is the initial treat!ent and also is gi en after cardio ersion to pre ent recurrent entricular fi#rillation. %retyliu! tosylate has #een useful in treating life/ threatening entricular tachyarrhyth!ias that are unresponsi e to lidocaine or class Ia agents) such as procaina!ide. >o" cardiac output "ith entricular rates less than GC #eatsK!in !ay occur in patients "ith i!paired cardiac perfor!ance. Stroke olu!e cannot increase to co!pensate for the pathologic #radycardia. Electrical pacing of the heart at a rate of HC to :CC #eatsK!in can restore sufficient cardiac output "hether the underlying !echanis! is sinus #radycardia) atrial fi#rillation "ith slo" entricular rate 3e.g.) digitalis to*icity4) or atrio entricular dissociation. Neurogenic Shock Neurogenic shock 3,pri!ary shock. in the older classification4 is the for! of shock that occurs after serious interference "ith the #alance of asodilator and asoconstrictor influences to the arterioles and enules. This is the shock that is seen "ith clinical syncope'the sudden e*posure to unpleasant e ents) such as the sight of #lood) the hearing of #ad tidings) or the sudden onset of pain. Si!ilarly) neurogenic shock often is o#ser ed "ith serious paralysis of aso!otor influences) as in high spinal anesthesia or in2ury to the spinal cord. The refle* interruption of ner e i!pulses also occurs "ith acute gastric dilatation. The clinical picture of neurogenic shock is quite different fro! that classically seen in hypo ole!ic shock. 0hile the #lood pressure !ay #e e*tre!ely lo") the pulse rate usually is slo"er than nor!al and is acco!panied #y dry) "ar!) and e en flushed skin. 6easure!ents !ade during neurogenic shock indicate a reduction in cardiac output) #ut this is acco!panied #y a decrease in resistance of arteriolar essels and a decrease in the enous tone. $onsequently) there appears to #e a nor!o ole!ic state "ith a greatly increased reser oir capacity in the arterioles and enules) there#y inducing a decreased enous return to the right side of the heart and hence a reduction in cardiac output.

If neurogenic shock is not corrected) a reduction of #lood flo" to the kidneys and da!age to the #rain result) and the ra ages of hypo ole!ic shock appear. Treat!ent of neurogenic shock usually is o# ious. Aastric dilatation can #e treated rapidly "ith nasogastric suction. Shock due to high spinal anesthesia can #e treated effecti ely "ith ad!inistration of fluids and a asopressor) such as ephedrine or phenylephrine 3Neo/ Synephrine4. These drugs "ill increase cardiac output) restore enous tone) and ele ate syste!ic #lood pressure #y arteriolar constriction. 0ith the !ilder for!s of neurogenic shock) such as fainting) si!ply re!o ing the patient fro! the sti!ulus) relie ing the pain) and ele ating the legs is adequate therapy "hile the asoconstrictor ner es regain the a#ility to !aintain nor!al arteriolar and enous resistance. There is rarely a need for he!odyna!ic !easure!ent in this usually self/ li!ited for! of hypotension. An e*ception is "hen this for! of shock results fro! in2ury) as "ith spinal cord transection fro! trau!a. In this instance there !ay #e significant loss of #lood and e*tracellular fluid into the area of in2ury surrounding the cord and erte#ral colu!n. $onsidera#le confusion can arise as to the relati e need for fluid replace!ent or for asopressor drugs under these circu!stances. Si!ilarly) if surgical inter ention for any reason #eco!es necessary) he!odyna!ic !easure!ents !ay #e of great alue in the !anage!ent of these patients. In unco!plicated neurogenic shock) central enous pressure should #e slightly lo") "ith a near/nor!al cardiac output. If hypo ole!ia ensues) central enous pressure and cardiac output decrease. $areful !onitoring of central enous pressure !ay #e necessary. Fluid ad!inistration "ithout asopressors in this for! of hypotension !ay produce a gradually rising arterial pressure and cardiac output "ithout ele ation of central enous pressure #y gradually ,filling. the e*panded ascular poolD caution !ust #e used during fluid ad!inistration. In !anaging these patients) slight olu!e o ere*tension is !uch less deleterious than e*cessi e asopressor ad!inistration. The latter decreases organ perfusion in the presence of inadequate fluid replace!ent) particularly in the #ody pro*i!al to the cord in2ury. %alance is #est o#tained #y !aintaining a nor!al central enous pressure that rises slightly "ith rapid fluid ad!inistration 3ensuring adequate olu!e4 and using a asopressor such as phenylephrine 2udiciously to support arterial pressure. Septic Shock Sepsis) the sepsis syndro!e) and septic shock define the continuu! of hu!an response to infection. Although any agent capa#le of producing infection) including iruses) parasites) and fungi) !ay generate septic shock) the !ost frequent causati e organis!s in the anti#iotic era are gra!/negati e #acteria) and occasionally gra!/ positi e #acteria. The initial infectious process appears to #e only a sti!ulus for a series of host responses that !ay cul!inate in death) e en in the a#sence of infection at the ti!e of death. O er the past fe" decades) the incidence of gra!/ negati e sepsis has risen dra!atically) fro! fe"er than :CC reported cases in the early :;BCs to an esti!ate of 9CC)CCC cases per year) of "hich appro*i!ately :CC)CCC episodes of septic shock are treated in the 7nited States. E en in the !ost recent series) o erall !ortality e*ceeds <C percent) "ith !ortalities o er HC percent in co!plicated cases "ith associated !ultiple organ syste! failure. Ara!/negati e organis!s supplanted gra!/positi e organis!s as the predo!inant cause of septic shock after the "idespread application of effecti e anti#iotics for

gra!/positi e infections. Despite increasingly po"erful gra!/negati e anti#iotics) the incidence of gra!/negati e sepsis continues to rise. @roposed causes for this increasing incidence include a de eloping reser oir of resistant and irulent organis!s) concentration of infected patients in critical/care settings) !ore e*tensi e operations in elderly and poor/risk patients) initial sal age of the se erely in2ured) and a gro"ing population of patients i!!unosuppressed #y organ transplant protocols) radiotherapy) and che!otherapy. The !ost co!!on source of gra!/negati e infection is the genitourinary syste!. This frequently follo"s instru!entation of the urinary tract) "hich is perfor!ed in up to one/third of hospitalized patients. The second !ost frequent site of origin is the respiratory syste!) follo"ed #y the ali!entary syste!) including the #iliary tract. Increasing and prolonged use of ind"elling catheters for !onitoring and hyperali!entation is responsi#le for !any #loodstrea! infections. The early and aggressi e use of appropriate anti#iotic therapy "ith other treat!ents outlined #elo" ha e a crucial role in fa ora#le outco!e. @atients "ith a surgically correcta#le focus of infection ha e a !ore fa ora#le prognosis. $linical 6anifestations Ara!/negati e infections frequently are heralded #y the onset of chills and te!perature ele ations a#o e <HQ$ 3:C:QF4. The patient !ay rapidly progress to e idence of altered organ function) !ost often renal and pul!onary in nature. This clinical situation plus the de elop!ent of hypotension co!pletes the picture of septic shock. 7nlike !ost other for!s of shock) the patient "ho is nor!o ole!ic has hypotension despite an increased cardiac output and a reasona#le filling pressure. The peripheral resistance is lo" and produces the parado*ical ,"ar! shock. "ith pink) dry e*tre!ities. The high cardiac output often is associated "ith a decrease in o*ygen utilization and a narro"ed arterio enous o*ygen difference. In a patient "ho is initially hypo ole!ic or persists in the shock state) a hypodyna!ic pattern e!erges that is characterized #y a falling cardiac output) lo" central pressures) and increased peripheral resistance "ith !ore typical cold) pale e*tre!ities consistent "ith glo#al hypoperfusion. Early olu!e replace!ent frequently increases cardiac output and produces a hyperdyna!ic circulation) "hile the patient later in shock is unresponsi e to olu!e replace!ent and has a lo" cardiac output "ith increasing !eta#olic acidosis. $onco!itant la#oratory tests usually sho" an ele ation in the "hite #lood cell count) #ut leukopenia !ay #e present in i!!unosuppressed and de#ilitated patients or those "ith o er"hel!ing "hite cell consu!ption fro! sepsis. Thro!#ocytopenia !ay #e an early indicator of gra!/negati e sepsis) particularly in pediatric and #urn patients. 6ild hypo*ia "ith co!pensatory hyper entilation and respiratory alkalosis are co!!on early findings) despite clinical or radiological e idence of intrinsic pul!onary disease. Although the onset of hypotension !ay #e coincident "ith these clinical signs of infection) a patient can ha e relati ely su#tle findings of hyper entilation) respiratory alkalosis) and altered sensoriu! for a prolonged period #efore shock #egins. Septic shock is the result of nu!erous co!ple* interactions #et"een e*ogenous and endogenous !ediators and host responses to these sti!uli. The "ide indi idual

ariation in septic shock and in response to arious inter entions in hu!an and e*peri!ental studies ser es to underscore this intricate and poorly understood pathogenesis. Necessary host responses to local in2ury and infection for! the local defenses against progression to syste!ic illness. 0hen the a#ility to contain local infection is o er"hel!ed) syste!ic illness !ay result fro! the inappropriate syste!ic effects of these !ediators. At the organ le el) cardio ascular response to syste!ic infection) in the a#sence of hypo ole!ia) is the de elop!ent of a hyperdyna!ic state. A nu!#er of asoregulatory !ediators co!#ine to produce a net decrease in syste!ic ascular resistance. This is quite distinct fro! the increased ascular resistance seen in responses to hypoperfusion in other for!s of shock. As cardiac inde* increases) the arterial/ enous o*ygen difference narro"s. An apparent effect in peripheral o*ygen e*traction "as originally ascri#ed to pathologic arterio enous shunting. +o"e er) !icro ascular #lood flo" in !any capillary #eds does not appear to #e altered in septic shock. Additionally) neither cellular hypo*ia nor any defects in the energy/ producing !eta#olic path"ays ha e #een docu!ented #y studies using in i o nuclear !agnetic resonance spectroscopy. Despite increased cardiac inde* and decreased o*ygen e*traction) no direct e idence for cellular hypo*ia "as detected. Although patients "ith hyperdyna!ic septic shock ha e an increased cardiac output) detailed studies in patients and ani!als report a depression in !yocardial function. The long/postulated !yocardial depressant factor) although poorly characterized #ioche!ically) appears to #e a reasona#le e*planation for docu!ented decreases in left entricular e2ection fraction despite accepta#le filling pressures. The pathophysiologic !echanis!s that produce organ dysfunction in the septic state) prior to the onset of hypotension) are co!pounded #y the de elop!ent of refractory hypotension) "ith tissue ische!ia pro#a#ly contri#uting a co!ponent of cell death in end/stage hypodyna!ic septic shock. @athophysiology 6any studies suggested that the agents responsi#le for the induction of fe er "ere endogenous products) and this led to the concept of endogenous !ediators of the action of endoto*in. 0hile early studies de!onstrated that interleukin/: 3I>/:4 "as an endogenous !ediator of infection) recent studies #y %eutler and co"orkers and #y Tracey and co"orkers de!onstrated that cachectin/TNF is a central and pro*i!al !ediator of the host response to endoto*e!ia and #actere!ia. $achectin is a cytokine secreted #y acti ated !acrophagesD it "as purified to ho!ogeneity #y %eutler and $era!i "hile they "ere looking for a factor that !ediated cache*ia. This protein) "hich is produced predo!inantly #y cells of !acrophage lineage) "as purified and characterized #y Aggar"al and associates. It is a :G/kD protein "ith EC percent ho!ology "ith ly!photo*in) a ly!phokine "ith "hich it shares !any properties. %ecause of the si!ilarity of function) ly!photo*in has #een called TNF/#) and TNF/ cachectin is referred to as TNF/a. After protein and co!ple!entary DNA 3cDNA4 sequence analysis "as co!pleted) it #eca!e apparent that cachectin "as identical to a factor called tu!or necrosis factor) isolated for its a#ility to !ediate endoto*in/induced tu!or cytoto*icity.

Early studies #y Shires and colleagues recognized that cellular dysfunction acco!panying acute he!orrhagic shock is associated "ith a reduction in the transcellular !e!#rane potential. Su#sequent studies in ani!al !odels of septic shock #y Illner and associates and a pri!ate !odel of septic shock #y Trunkey and associates de!onstrated that si!ilar changes in the transcellular !e!#rane potential occurred during septic shock and that the reduction in the !e!#rane potential preceded the onset of hypotension. A si!ilar decrease in the trans!e!#rane potential occurred in hu!an olunteers in response to endoto*in infusion. To understand the etiology of the reduction in cellular !e!#rane potential during sepsis) the effects of TNF/a on skeletal !uscle !e!#rane potentials "ere studied. It "as found that TNF/a "as capa#le of inducing !e!#rane depolarization in itro. 7sing the in itro !easure!ent of skeletal !uscle !e!#rane potentials as a #ioassay) Tracey and colleagues "ere a#le to de!onstrate that plas!a fro! critically ill patients "ith septice!ia in a surgical intensi e care unit contained a circulating factor that caused !uscle !e!#rane depolarization. @reincu#ation of the plas!a sa!ples "ith a !onoclonal anti#ody to hu!an TNF/a "as a#le to a#rogate the in itro decrease in the !e!#rane potential. Infusion of TNF/aintraarterially in dogs induced a rapid decrease in skeletal !uscle !e!#rane potential and e*tre!ity lactate efflu*) si!ilar to that seen in sepsis #efore the onset of shock. These changes preceded the onset of hypertension #y B to < h and "ere associated "ith an increased fluid require!ent secondary to third/space losses. The ti!e course of these changes) i.e.) skeletal !uscle !e!#rane depolarization and lactic acide!ia preceding circulatory co!pro!ise) is consistent "ith clinical o#ser ations of the de elop!ent of septic shock. These initial studies) confir!ed #y Schir!er and associates) suggested that TNF/a "as an i!portant !ediator of septic shock. To assess the role of TNF/a in #actere!ic shock in pri!ates) !onoclonal anti#odies RF3a#14B frag!entsS to hu!an TNF/a "ere ad!inistered to #a#oons B h #efore challenge "ith a lethal dose of Escherichia coli. The ad!inistration of anti&TNF/a anti#odies pre ented the de elop!ent of su#sequent septic shock and associated organ dysfunction. Su#sequent analysis of plas!a sa!ples fro! these #a#oons re ealed that anti&TNF/a !onoclonal anti#ody pretreat!ent #efore the infusion of E. coli a#rogated the increases in circulating interleukin/: 3I>/:4 and I>/F seen in the untreated ani!als 3Fig. 9/:<4. In a si!ilar study) 6athison and colleagues de!onstrated that ad!inistration of anti&TNF/aanti#odies protected ra##its fro! lethal shock induced #y endoto*e!ia. These studies esta#lished the role of TNF/a as a central and pro*i!al !ediator of e*peri!ental septic shock. $irculating TNF/a can #e found in response to endoto*in ad!inistration in hu!an #eings and peak le els !ay correlate "ith sepsis and o erall !ortality "hen detected in hu!an disease states. Although endoto*in or gra!/ negati e #acteria infusions !ay not accurately reproduce the !ode of onset of clinical septice!ia) the fact that TNF/a is present in hu!an critical disease states strongly supports an i!portant role of TNF/ a in the pathophysiology of septic shock in hu!an #eings. The !echanis!s through "hich TNF/a induces the pathophysiologic changes associated "ith shock are #eing studied. TNF/ainduces the synthesis and secretion of a ariety of secondary !ediators) including other cytokines) prostaglandins) leukotrienes) platelet/acti ating factor) co!ple!ent co!ponents) and acti ation of the

clotting cascade) that possess to*ic properties capa#le of causing "idespread tissue da!age if li#erated syste!ically. In addition) lipopolysaccharide 3>@S4 !ay synergize "ith TNF/a to induce !any of the to*ic effects !ediated #y TNF/a. The TNF/ a/induced release of these factors !ay #e responsi#le for pathologic changes seen in the lungs) li er) #o"el) and kidneys in response to sepsis and septic shock. Discrepancies in TNF/a detection in the circulation !ay #e partially e*plained #y the presence of circulating TNF receptors that !ay interfere "ith the !easure!ent of TNF/a in the plas!a. These receptors can neutralize TNF/a cytoto*icity) !easured #y #ioassay) and interfere "ith the detection of TNF/a #y enzy!e/linked i!!unosor#ent assay 3E>ISA4 if the anti#odies used do not recognize TNF/a&solu#le receptor co!ple*es. It also has #een noted that co!petiti e radioi!!unoassays 3=IAs4 !ay o eresti!ate TNF/a concentrations in the presence of solu#le TNF receptors. =IA #inding of the la#eled antigen to the solu#le receptors reduces #inding to the anti#ody. This results in a lo" !easured alue and a correspondingly high calculated alue for the concentration of unla#eled TNF/a. $oncentrations of solu#le receptors found in endoto*e!ic olunteers or critically ill patients are sufficient to neutralize or attenuate the cytoto*icity associated "ith TNF/a concentrations o#ser ed in !ild infla!!ation. Such le els apparently are inadequate to neutralize the to*icity associated "ith the e*cessi e or persistent TNF/a acti ity found during o er"hel!ing sepsis. E idence of the therapeutic potential of TNF/a#lockade "as o#tained #y Tracey) "ho ad!inistrated !onoclonal !urine antihu!an TNF/aanti#odies to #a#oons #efore ad!inistering a lethal dose of li e E. coli and de!onstrated sur i al for at least 9H h. In addition to the difference in sur i al) anti&TNF/a anti#odies attenuated the leukopenia and the release of cata#olic stress hor!ones 3epinephrine) norepinephrine) and glucagon4 that nor!ally acco!pany such a lethal #actere!ia. The appearance of other cytokines kno"n to #e produced during sepsis 3I>/:# and I>/F4 also "as significantly reduced. A different approach to achie ing #lockade of e*cessi e TNF/a has #een pro ided #y the recent identification of naturally occurring inhi#itors of TNF/a acti ity in hu!an seru! and urine. The isolation and characterization of these inhi#itors re ealed the! to #e the e*tracellular do!ains of the type I and type II TNF receptors) "hich are shed fro! the cell surface in response to so!e of the sa!e infla!!atory sti!uli kno"n to induce TNF/a production. %oth naturally occurring solu#le TNF receptors 3sTNF=/I and sTNF=/II4 can #e found in hu!an olunteers after endoto*in ad!inistration. To in estigate the therapeutic potential of e*ogenous solu#le TNF receptors) reco!#inant solu#le TNF=/I 3rsTNF=/I4 "as ad!inistered to #a#oons "ith a lethal #actere!ia. The #a#oons recei ed an intra enous #olus of li e E. coli 3>D:CC4) follo"ed #y a </h pri!ed continuous infusion of rsTNF=/I sufficient to pro ide a <CC/fold !olar e*cess of sTNF=/I o er the !a*i!u! TNF/a plas!a concentration. Ad!inistration of rsTNF=/I significantly reduced the olu!e of resuscitation fluid required to !aintain he!odyna!ic sta#ility and the !a*i!u! decline in !ean arterial pressure 36A@4 3Fig. 9/:94.

The ter! interleukin/: applies to t"o different polypeptides) I>/:a and I>/ :#. These #ioche!ically distinct for!s share only BF percent a!ino acid ho!ology) #ut #oth arieties #ind to the sa!e cell/surface receptors and induce the sa!e #iologic responses. I>/I) like TNF/a) is one of the key !ediators of the host response to infection) infla!!ation) and in2ury. The t"o cytokines ha e #een found to ha e !any o erlapping #iologic functions. %ecause !uch of the circulating I>/: is thought to represent e*cess local tissue production) the infrequent detection of I>/: in the circulation during clinical sepsis is not surprising. There is e idence that local production of I>/ : and TNF/a is increased in infla!!ation e en in the a#sence of circulating cytokine) suggesting that assays of local tissue le els !ay #e !ore appropriate than !easure!ent of circulating concentrations. A naturally occurring inhi#itor of I>/: "as identified in the urine of fe#rile patients as "ell as in the plas!a of endoto*e!ic olunteers and critically ill patients. This inhi#itor is a :G/kD polypeptide "ith BF percent and :; percent sequence ho!ology to I>/:# and I>/:a) respecti ely) "hich #inds to I>/: cell/surface receptors. Despite the sequence ho!ology and the protein1s a#ility to #ind to #oth types of I>/: receptors) it has no agonist acti ity) and it "as ter!ed interleukin/: receptor antagonist 3I>/:ra4. I>/:ra #locks !any functions of I>/: in itro) including- ly!phocyte proliferationD increased adhesion of endothelial cells for neutrophils and eosinophilsD synthesis of I>/:) TNF/a) I>/F) and I>/H #y !onocytesD and nitric o*ide production in hu!an s!ooth !uscle cells. Fischer and associates in estigated the potential #enefit of e*ogenous I>/ :ra in se ere sepsis #y ad!inistering a lethal #actere!ia to nonhu!an pri!ates. Ad!inistration of I>/:ra significantly decreased the hypotension and fall in cardiac output o#ser ed in controls and i!pro ed sur i al. In addition) circulating le els of I>/:# and I>/F "ere significantly reduced. TNF/ a le els "ere unchanged #y I>/:ra) leading to the conclusion that the control !echanis!s of these t"o cytokines are independent 3Fig. 9/:E4. These ani!al !odels pro ided the #asis for initiating clinical trials of I>/:ra in the treat!ent of sepsis. In patients in "ho! I>/: acti ity is adequately #alanced #y endogenous I>/:ra) ad!inistration of e*ogenous I>/:ra !ay not #e #eneficial and !ay potentially e*acer#ate certain types of infection. Since endoto*in is the #acterial co!ponent largely responsi#le for the to*ic effects of gra!/negati e infection) !ethods of #locking endoto*in are #eing in estigated. One approach is the ad!inistration of antiendoto*in anti#odies. Niegler and co"orkers reported an i!pro e!ent in sur i al in a su#set of patients "ith sepsis "ho had docu!ented gra!/negati e #actere!ia and "ere treated "ith +A/:A) a hu!an !onoclonal Ig6 anti#ody) against the lipid A portion of endoto*in. There "as no i!pro e!ent in those patients "ithout positi e #lood cultures. Another report sho"ed i!pro ed sur i al in patients "ith gra!/negati e sepsis 3"ith positi e cultures4 #ut "ithout shock "ho "ere treated "ith EE) a !urine !onoclonal Ig6 anti#ody also against lipid A. A follo"/up study failed to confir! the #eneficial effects of EE.

Endogenous >@S/#inding proteins !ay #e used to #lock the effects of endoto*in. One such protein) first isolated fro! neutrophil granules) is #actericidalKper!ea#ility/ increasing protein 3%@I4. This peptide specifically #inds to >@S and has #een sho"n to inhi#it endoto*in/!ediated TNF/a release in itro #y peripheral #lood !ononuclear cells and in i o in the !urine lung. %@I) "hen preincu#ated "ith >@S) #locks >@S/ !ediated pyrogenicity in ra##its. Early data suggest that %@I !ay ha e therapeutic potential in the treat!ent of gra!/negati e sepsis. The a#o e factors are only so!e of the likely !ediators of the host response to o er"hel!ing sepsis and septic shock. $lassic hor!onal responses in septic shock are si!ilar to those o#ser ed in he!orrhagic shock. Other potential !ediators of septic shock include the kinins) endogenous opiates) and a nu!#er of recently purified cytokines #elie ed to !ediate host infla!!atory responses. Therapy The control of infection #y anti#iotic treat!ent and early surgical de#ride!ent or radiologically guided drainage represent definiti e therapy. Other reco!!ended !easures) including fluid therapy and the use of asoacti e drugs) represent ad2uncti e for!s of therapy. Ad2uncti e therapies are useful in preparing patients for surgical or radiologic inter ention or supporting patients until the infectious process can #e controlled) #ut if the infection cannot #e adequately controlled) the death of the patient is ine ita#le. It is essential that a pro!pt search for the source of infection #e !ade as soon as infection #eco!es e ident. It is ad isa#le to institute supporti e !easures so that arterial and central enous or pul!onary capillary "edge pressures can #e !easured directly) and urine output and arterial and central enous #lood gases should #e !easured) if indicated. If the infectious process requires drainage) operation should #e perfor!ed as soon as possi#le after the patient has #een sta#ilized) #ecause so!e conditions) such as septic shock secondary to ascending cholangitis) "ill respond only #riefly to ad2uncti e !easures. Anti#iotic treat!ent should #e #ased on the results of cultures and sensiti ity tests "hen possi#le) #ut in the a#sence of these data #road/ spectru! anti#iotics should #e started) including co erage for anaero#ic organis!s such as %acteroides species or fungi) if clinically indicated. Anti#iotic therapy should #e ad2usted "hen culture and sensiti ity reports #eco!e a aila#le. $orrection of pree*isting fluid deficits is essential in the septic patient and should proceed rapidly) though carefully) using pul!onary capillary "edge pressure and cardiac output as a guide to target appropriate replace!ent olu!es) so that the detri!ental pul!onary effects of fluid o erload can #e a oided. 6onitoring is essential) #ecause fluid require!ents !ay #e !assi e in these patients. =esuscitation require!ents in e*cess of :C> of lactated =inger1s solution are co!!on. The use of corticosteroids in the treat!ent of septic shock "as contro ersial until data fro! t"o "ell/controlled) prospecti e clinical trials de!onstrated that the use of high/ dose corticosteroids did not confer a sur i al ad antage o er non/steroid/treated controls 3Fig. 9/:F4. The only indications for steroid treat!ent in patients "ith septic shock are hypoadrenalis! and for stress co erage in patients taking steroids 3or "ho

recently co!pleted a course of steroids4 for i!!unosuppression or anti/ infla!!atory purposes. Future clinical use of anti&TNF anti#odies) protein $) or other anti!ediator treat!ent regi!ens pro#a#ly "ill depend on early recognition of the sepsis syndro!e for success unless used prophylactically in a population of patients at high risk. @har!acologic Support Although fluid resuscitation re!ains the initial therapy for hypotension in sepsis) it is frequently necessary to ad!inister drugs "ith inotropic or asopressor acti ity. Dopa!ine is the initial inotropic agent used. As discussed a#o e in the section on cardiogenic shock) dopa!ine has so!e asopressor acti ity at higher doses that !ay #e required in the olu!e/ loaded patient "ith persistent profound hypotension. Aug!entation of the i!paired !yocardial perfor!ance in septic shock is a reasona#le goal. Do#uta!ine often increases cardiac input "ith less tachycardia and arrhyth!ia than dopa!ine. The #eta/adrenergic asodilatation fro! do#uta!ine infusion !ay not #e tolerated #y these hypotensi e patients. 8asodilator drugs ha e #een sho"n to i!pro e cardiac output and o*ygen deli ery in nor!otensi e septic patients. Their use in septic shock is li!ited #y lo" syste!ic pressure or decreased cardiac filling pressures. 6ore potent asopressors) despite their o# ious detri!ental effect on peripheral perfusion) !ay #e transiently una oida#le in patients "ho ha e persistent life/threatening hypotension) despite opti!al fluid and dopa!ine infusions. Norepinephrine is a potent alpha/receptor agonist that usually is effecti e in raising pressure in patients for "ho! the !easures descri#ed a#o e ha e failed. Its use is so!eti!es preferred o er high/dose dopa!ine #ecause the cardiac effects are less. Epinephrine) a catechola!ine "ith potent alpha/ and #eta/adrenergic acti ity) !ay support the #lood pressure in patients "ho do not respond to norepinephrine. @olyphar!acy frequently is ineffecti e and !ay #e har!ful in patients "ith co!ple* cardio ascular alterations. 7se of pressors is pri!arily for transient support "hile pri!ary definiti e therapy "ith anti#iotics and drainage of surgical infection are #eing instituted. 6anipulations of +u!oral =esponses Ai en the o# iously co!ple* and ill/defined interactions a!ong a large nu!#er of !ediators) therapy directed at any single agent is pro#a#ly ineffecti e. $arefully tailored !ultidrug or serial anti!ediator therapy e entually !ay allo" !odulation of the deleterious syste!ic effects of the necessary host responses to in2ury and infection. Initial trials of steroids) fi#ronectin) and nalo*one "ere disappointing. 6ore specific i!!unotherapy using !onoclonal Ig6 anti#odies to core lipopolysaccharide ha e #een co!pleted. Only s!all su#sets of patients fro! each study sho"ed statistical #enefit. Treat!ent "ith +A/:A i!pro ed sur i al and organ function in the presence of gra!/negati e #actere!ia "ith or "ithout shock. The EE trial "as #eneficial in patients "ith gra!/negati e #actere!ia only in the a#sence of shock. None of the anti#odies directed at lipid A or other epitopes of the core lipopolysaccharide are esta#lished therapeutic !odalities. The naturally occurring I>/: receptor antagonist has #een !anufactured #y reco!#inant technology. I>/:ra sho"ed #enefit in se eral ani!al !odels #ut failed to

sho" efficacy in hu!an sepsis. 6onoclonal anti#odies to TNF also are a aila#le and appear pro!ising in patients "ith septic shock. The use of anticoagulants such as anti&thro!#in III in the treat!ent of sepsis that is unassociated "ith shock is currently under in estigation. The persistent significant !or#idity and !ortality fro! sepsis) despite po"erful anti#iotic therapy) pro!pt surgery) and carefully titrated fluid and drug support suggest that the future for i!pro ed therapeutic results lies in these e*citing ne" treat!ents "ithin the ne*t decade. 3%i#lio