Hydroxyethyl Starch 130-0.4 (Voluven) Monograph

6% Hydroxyethyl Starch 130/0.4 in 0.
9% NaCl (Voluven
6% Hydroxyethyl Starch 130/0.4 in 0.9% Sodiu! Chloride (Voluven"

National #ru$ %ono$ra&h Se&te!'er (011 V) *har!acy +ene,it- %ana$e!ent Service-. %edical )dvi-ory *anel and V/SN *har!aci-t 0xecutiveThe purpose of VA PBM Services drug monographs is to provide a comprehensive drug review for making formulary decisions. These documents will be updated when new clinical data warrant additional formulary decision. ocuments will be placed in the Archive section when the information is deemed to be no longer current.
010C23/V0 S2%%)45 #e-cri&tion6 The FDA approved hydroxyethyl starch 6% 130/0.4 (Voluven ! "n late #00$ %or the prophylax"s and treat&ent o% hypovole&"a. 't "s a&on( a nu&)er o% hydroxyethyl starch solut"ons ava"la)le "n the *+. ,ydroxyethyl 6% 130/0.4 "s o%ten re%erred to as a th"rd-(enerat"on or ne.er (enerat"on starch and .as developed ."th the (oal o% reduc"n( /no.n adverse e%%ects that can occur ."th older hydroxyethyl starch solut"ons0 "nclud"n( severe0 delayed-onset prur"t"s0 "&pa"red coa(ulat"on and renal dys%unct"on. +tarches ."th h"(her &olecular .e"(ht0 h"(her de(ree o% &olar su)st"tut"on and h"(her 1#/16 rat"o have (reater pers"stence ."th"n the "ntravascular space )ut are also )el"eved to )e assoc"ated ."th a (reater r"s/ %or t"ssue accu&ulat"on and adverse events. ,ydroxyethyl starch 130/0.4 has a lo.er &olecular .e"(ht0 a lo.er de(ree o% &olar su)st"tut"on )ut a h"(her 1#/16 rat"o. #o-in$6 ,ydroxyethyl starch 130/0.4 "s ut"l"2ed %or &a"nta"n"n( and/or restor"n( "ntravascular volu&e and "s ad&"n"stered )y "ntravenous "n%us"on. The da"ly dose and "n%us"on rate depend upon an "nd"v"dual3s )lood loss0 on the &a"ntenance or restorat"on o% he&odyna&"cs and on he&od"lut"on. The ad&"n"strat"on o% hydroxyethyl starch 130/0.4 can )e repeated over several days. 4ecause there "s a r"s/ %or anaphylacto"d react"ons ."th Voluven 0 the "n"t"al 10-#0 &l should )e "n%used slo.ly .h"le care%ully o)serv"n( the pat"ent %or adverse events. 'n adults0 up to 50 &l//( o% )ody .e"(ht can )e ad&"n"stered da"ly result"n( "n an approx"&ate &ax"&u& da"ly dose o% 30500 &l o% Voluven "n a $0 /( person. 0,,icacy (Critically /ll/Se&tic or Sur$ical 6 A nu&)er o% cl"n"cal tr"als have )een conducted "n .h"ch the e%%"cacy and sa%ety o% ,6+ 130/0.4 .as co&pared to a var"ety o% crystallo"d (e.(.0 nor&al sal"ne0 7"n(er3s lactate0 etc.! or collo"dal (e.(.0 other starches0 al)u&"n0 (elat"n 8not ava"la)le "n the *+9 and dextran! solut"ons "n the sett"n( o% cr"t"cal "llness/seps"s or sur(ery. (Because of the serious allegations against r. !oachim Boldt of fabricating evidence" not obtaining #$B approval" etc." none of the trials in which r. Boldt is listed as a contributor were included.% 'n cr"t"cally "ll or sept"c pat"ents0 there are l"&"ted data co&par"n( 6% ,6+ 130/0.4 to other collo"ds or crystallo"ds (ava"la)le "n the *+!. There%ore "t "s d"%%"cult to deter&"ne .hether ,6+ 130/0.4 o%%ers any advanta(e or d"sadvanta(es over the other products used %or %lu"d resusc"tat"on "n sept"c pat"ents. Ava"la)le (u"del"nes support the use o% e"ther collo"ds or crystallo"ds ."thout a pre%erence %or %lu"d type due to a lac/ o% ev"dence prov"n( d"%%erences "n relevant outco&es )et.een products. 4ecause o% "ncons"stent data re(ard"n( the e%%ect o% ,6+ solut"ons on renal %unct"on "n pat"ents ."th seps"s0 t.o cl"n"cal tra"ls have )een des"(ned and are under.ay to help ans.er that :uest"on; &'S(Scandinavian Starch for Severe Sepsis)Septic Shock Trial* comparing '+ ,-S ./0)0.1 to crystalloids in 200 patients with severe sepsis. The primary outcome measure in this trial is a composite of mortality and end(stage kidney failure. A second trial &3rystalloid versus ,ydro4yethyl Starch Trial 53,-ST%* is comparing '+ ,-S ./0)0.1 to crystalloids 5saline% in 6"000 critically ill patients in the intensive care unit. The primary endpoint of this trial is death from all causes at 70 days. Secondary endpoints include renal failure" S89A score" use of renal replacement therapy" #3: stay" etc. The 3,-ST study began in April ;0.0.
*pdated vers"ons &ay )e %ound at ....p)&.va.(ov or va...p)&.va.(ov (+epte&)er #011!
6% Hydroxyethyl Starch 130/0.4 in 0.9% NaCl (Voluven 'n the s"x "ncluded cl"n"cal tr"als "nvolv"n( sur("cal pat"ents0 cl"n"cal outco&es d"d not d"%%er s"(n"%"cantly )et.een 6% ,6+ 130/0.4 and e"ther crystallo"d or collo"ds ad&"n"stered (,6+ 6$0/0.$50 al)u&"n0 6% Dextran $0! "n per"operat"ve or postoperat"ve )lood loss0 trans%us"on re:u"re&ents or or(an %unct"on. 'n several stud"es0 d"%%erences "n certa"n var"a)les (e.(.0 levels o% #-hour postoperat"ve nad"r Factor V''' or von <"lle)rand Factor (v<F!0 sl"(htly "ncreased '=70 etc.! .ere o)served )ut the cl"n"cal s"(n"%"cance o% these d"%%erences "s un/no.n. 'n the study co&par"n( 6% ,6+ 130/0.4 to 6% ,etastarch (6$0/0.$5!0 althou(h so&e d"%%erences .ere o)served "n secondary endpo"nts0 the FDA &ed"cal rev"e.er co&&ented that sa%ety endpo"nts "n th"s part"cular tr"al .ere cons"dered "n a se:uent"al &anner0 so "% one endpo"nt .as not stat"st"cally d"%%erent0 analys"s o% su)se:uent endpo"nts could only )e cons"dered exploratory. The FDA rev"e.er concluded that super"or sa%ety could not )e proven )ased upon data %ro& the tr"al. A 1ochrane rev"e. o% %lu"d replace&ents "n a)do&"nal aort"c sur(ery %ound a lac/ o% ev"dence to support one %lu"d as the opt"&al %lu"d replace&ent "n pat"ents hav"n( a)do&"nal aort"c sur(ery. 6x"st"n( (u"del"nes %or %lu"d replace&ent "n adult sur("cal pat"ents do not reco&&end a part"cular %lu"d replace&ent )ut reco&&end that e"ther )alanced crystallo"ds or a >su"ta)le? collo"d )e used to replace lost )lood. F"nally0 in vitro coa(ulat"on stud"es de&onstrate that 6% ,6+ 130/0.4 does have an e%%ect on platelet %unct"on/coa(ulat"on as assessed )y thro&)elasto(raphy (T6@! &easure&ents. 4ased upon th"s "n%or&at"on0 "t "s unclear "% 6% ,6+ 130/0.4 o%%ers any advanta(e or d"sadvanta(e over crystallo"ds or other collo"ds %or %lu"d replace&ent "n sur("cal pat"ents. Sa,ety6 <"th re(ard to adverse e%%ects0 ava"la)le ev"dence "s lac/"n( %ro& cl"n"cal tr"als to support a clear sa%ety advanta(e o% 6% ,6+ 130/0.4 over other hydroxyethyl starches. Contraindication-6 The use o% 6% ,6+ 130/0.4 "s contra"nd"cated "n the %ollo."n( s"tuat"ons; Ano.n hypersens"t"v"ty to ,6+ 'n %lu"d overloaded pat"ents (e.(.0 pul&onary ede&a0 con(est"ve heart %a"lure! 'n pat"ents ."th renal %a"lure ."th ol"(ur"a or anur"a unrelated to hypovole&"a Bat"ents rece"v"n( d"alys"s 'n pat"ents ."th severe hypernatre&"a or severe hyperchlore&"a 'n pat"ents ."th "ntracran"al )leed"n( 7arnin$- and *recaution-6 Anaphylacto"d react"ons have )een reported "n assoc"at"on ."th ,6+ solut"ons. The "n"t"al 10-#0 &l should )e "n%used slo.ly .h"le care%ully o)serv"n( the pat"ent %or adverse events. '% hypersens"t"v"ty occurs0 ,6+ 130/0.4 should )e pro&ptly d"scont"nued and treat&ent %or the aller("c react"on should cont"nue unt"l sy&pto&s have resolved. Flu"d status should )e &on"tored on a re(ular )as"s dur"n( treat&ent ."th ,6+ 130/0.4 espec"ally "n those pat"ents ."th card"ac "nsu%%"c"ency or severe renal "&pa"r&ent. 'n severely dehydrated pat"ents0 crystallo"d solut"ons should )e ad&"n"stered pr"or to ,6+ solut"ons. +u%%"c"ent %lu"d should )e ad&"n"stered to prevent dehydrat"on. Added caut"on "s adv"sed .hen ad&"n"ster"n( ,6+ 130/0.4 to pat"ents ."th severe l"ver d"sease or severe )leed"n( d"sorders (e.(.0 severe cases o% von <"lle)rand3s d"sease!. Con"tor"n( o% the pat"ent3s cl"n"cal status as .ell as la)oratory tests (e.(.0 electrolytes0 renal %unct"on0 ac"d-)ase status and coa(ulat"on para&eters! "s .arranted dur"n( prolon(ed use o% ,6+ and/or .henever the pat"ent3s cond"t"on d"ctates close &on"tor"n(. +eru& a&ylase &ay )e "ncreased te&porar"ly a%ter use o% ,6+ 130/0.4 and &ay "nter%ere ."th the d"a(nos"s o% pancreat"t"s. At h"(h doses o% ,6+ 130/0.40 d"lut"onal e%%ects &ay result "n reduced levels o% clott"n( %actors0 other plas&a prote"ns and a reduct"on "n he&atocr"t. As ."th all plas&a su)st"tutes0 "n%us"on o% excess"ve ,6+ can lead to overload"n( o% the c"rculatory syste&. '% th"s occurs0 the "n%us"on should )e stopped and d"uret"cs ad&"n"stered. *pdated vers"ons &ay )e %ound at ....p)&.va.(ov or va...p)&.va.(ov (+epte&)er #011!
6% Hydroxyethyl Starch 130/0.4 in 0.9% NaCl (Voluven *lace in 3hera&y6 At present0 the place "n therapy %or 6% ,6+ 130/0.4 (Voluven ! "s unclear0 as "t has not )een sho.n to )e super"or "n sa%ety or e%%"cacy co&pared to other a(ents and )ecause data are very l"&"ted0 part"cularly "n pat"ents ."th seps"s. +"nce the &ax"&u& approved da"ly dose %or %lu"d resusc"tat"on "s h"(her %or 6% ,6+ 130/0.4 (50 &l//(/day! than other ava"la)le starches (#0&l//(/day!0 6% ,6+ 130/0.4 "s an opt"on %or those pat"ents re:u"r"n( lar(e a&ounts o% crystallo"d and/or collo"d solut"ons (D #0&l//(/day! or as an alternat"ve to al)u&"n. ,o.ever0 s"nce there are also l"&"ted pu)l"shed data "n pat"ents rece"v"n( &ax"&u& da"ly doses o% 6% ,6+ 130/0.4 (Voluven !0 pat"ents rece"v"n( these h"(her doses should )e closely &on"tored %or adverse events "nclud"n( )leed"n(0 delayed onset prur"t"s and renal "&pa"r&ent. /N348#2C3/8N For years0 there has )een on(o"n( de)ate re(ard"n( the "deal %lu"d replace&ent strate(y %or "ntravascular %lu"d resusc"tat"on "n cr"t"cally "ll pat"ents. For exa&ple0 use o% collo"ds versus crystallo"ds and &ore recently0 collo"d versus collo"d due to the ."despread use o% collo"dsE a (ro."n( nu&)er o% ava"la)le collo"d products (e.(. hydroxyethyl starches F,6+G0 dextran and al)u&"n!E and the assu&pt"on that collo"ds are &ore e%%ect"ve than crystallo"ds at restor"n( "ntravascular %lu"d volu&e desp"te a lac/ o% ev"dence to support that assu&pt"on. There are a nu&)er o% ,6+ products ava"la)le "n the *n"ted +tates. The"r a)"l"ty to pers"st "n the "ntravascular space "s dependent upon a nu&)er o% %actors "nclud"n( &ean &olecular .e"(ht (to a lesser de(ree!0 &olar su)st"tut"on0 and pattern o% hydroxyethylat"on o% (lucose su)un"ts (rat"o o% 1#/16!. ,6+ products ."th a h"(her &ean &olecular .e"(ht0 a h"(her de(ree o% &olar su)st"tut"on and a h"(her rat"o o% 1#/16 have lon(er hal%-l"ves and pers"st lon(er "n the "ntravascular space. These %actors are also thou(ht to contr")ute to (reater t"ssue accu&ulat"on o% ,6+ and a (reater r"s/ %or "&pa"r&ent o% coa(ulat"on and renal %unct"on. Voluven has a lo.er &ean &olecular .e"(ht than other ava"la)le ,6+ products0 a lo.er de(ree o% &olecular su)st"tut"on )ut a h"(her 1#/16 rat"o. 't .as developed ."th the (oal that these character"st"cs &"(ht result "n a s"&"lar volu&e )ene%"t %or %lu"d resusc"tat"on or volu&e replace&ent )ut a lo.er r"s/ %or adverse events0 espec"ally on coa(ulat"on and /"dney %unct"on. The purposes o% th"s &ono(raph are to (1! evaluate the ava"la)le ev"dence o% sa%ety0 tolera)"l"ty0 e%%"cacy0 cost0 and other phar&aceut"cal "ssues that .ould )e relevant to evaluat"n( 6% hydroxyethyl starch 130/0.4 "n 0.H% sod"u& chlor"de (Voluven ! %or poss")le add"t"on to the VA =at"onal For&ularyE (#! de%"ne "ts role "n therapyE and (3! "dent"%y para&eters %or "ts rat"onal use "n the VA. *H)4%)C898:5/*H)4%)C8;/N03/CS1<6. ,ydroxyethyl starch (,6+! solut"ons0 such as Voluven 0 are ad&"n"stered "ntravenously to expand plas&a volu&e. There are a nu&)er o% volu&e expand"n( starch solut"ons ava"la)le )ut each d"%%ers "n ter&s o% "ts &ean &olecular .e"(ht0 &olar su)st"tut"on (nu&)er o% hydroxyethyl (roups/10 su)un"ts o% (lucoseE Voluven has 4 hydroxyethyl (roups/10 su)un"ts o% (lucoseI0.4! and 1#/16 rat"o (hydroxyethyl (roups attached to car)ons #0 3 or 6 o% the (lucose &olecule0 Voluven3s 1#/16 rat"o "s H;1!. Colar su)st"tut"on and 1#/16 rat"o0 to a (reater de(ree than &olecular .e"(ht0 deter&"ne in vivo )ehav"or and rate o% el"&"nat"on or de(radat"on o% ,6+ products (re%er to ta)les 1-3!. D"%%erences "n these character"st"cs are thou(ht to )e respons")le %or the var"at"on "n vascular pers"stence0 t"ssue accu&ulat"on and adverse events )et.een products. ,ydroxyethyl starches solut"ons ."th a h"(her &ean &olecular .e"(htE a h"(her de(ree o% &olar su)st"tut"onE and a h"(her rat"o o% 1#/16 are &eta)ol"2ed &ore slo.ly result"n( "n a prolon(ed vascular pers"stence and potent"ally a h"(her "nc"dence o% adverse events. 't should )e e&phas"2ed that vascular pers"stence does not necessary correlate ."th >volu&e expand"n( e%%"cacy? (de(ree and durat"on o% volu&e e%%ect! s"nce stud"es have sho.n a s"&"lar durat"on o% volu&e e%%"cacy ."th rap"dly de(rada)le (Voluven ! versus slo.ly de(rada)le ,6+ solut"ons.#6 @enerally a%ter #4 hours0 no cons"dera)le volu&e e%%ect has )een proven. As a result0 %or &a"nta"n"n( volu&e expans"on "n appropr"ate pat"ents0 repeat ad&"n"strat"on o% ,6+ "s necessary. Accu&ulat"on and t"ssue stora(e o% ,6+ products are )el"eved to contr")ute to ,6+ related adverse e%%ects such as prur"t"s.3 3a'le 16 Characteri-tic- 8, Hydroxyethyl Starche- (H0S *roduct- 1.4
7ei$ht %ean %axi!u! #aily
6% Hydroxyethyl Starch 130/0.4 in 0.9% NaCl (Voluven

H0S Solution (+rand Voluven Concentration and Solvent 6% "n 0.H% =a1l %olecular 7ei$ht (=ilodalton130 %olar Su'-titutiona 0.4 C(/C6 4atio' H/1 #o-e (,a-t or -lo> de$radation
50 &l//(0 3500 &J0 (%ast! ,extend 6% "n )alanced 6$0 0.$5 4.5/1 #0 &l//(0 1500 &J0 electrolytes (slo.! ,etastarch 6% "n 0.H% =a1l 450 0.$ 5/1 #0 &l//(0 1500 (slo.! ,espan 6% "n 0.H% =a1l 600 0.$5 5/1 #0 &l//(0 1500 &J0 (slo.! 6% solut"ons are "so-oncot"c0 10% solut"ons are hyperoncont"c (volu&e e%%ect exceed"n( "n%used volu&e! in vivo a Colar su)st"tut"on (hydroxylat"on o% (lucose un"ts! slo.s do.n de(radat"on o% the ,6+ &olecule )y alpha-a&ylase and prolon(s "ntravascular retent"on. ) Battern o% hydroxylat"on can s"(n"%"cantly alter phar&aco/"net"cs (1# vs. 16 car)on ato&s!. 'nh")"t"on o% en2y&at"c de(radat"on o% the ,6+ &olecule )y alpha-a&ylase "s "nh")"ted to a (reater de(ree "% hydroxylat"on occurs at the 1# vs. 16 car)on ato&. There%ore0 solut"ons ."th a h"(her 1#/16 rat"o are expected to )e de(raded &ore slo.ly.
3a'le (6 *har!aco=inetic- (*; o, Hydroxyethyl Starche- (H0S *roduct- (Sin$le /n,u-ion in Healthy Volunteer-4
H0S Solution #o-e. :ra! C!ax (!$/!l 3 ? (hr Clearance (!l/!in 31.4 /n,u-ion 3i!e (!in
Voluven #6.3 3.$ 1#.K 30 (130/0.4! ,extend 0.6//( 13 46.4LL 0.HK #0 (6$0/0.$5! ,etastarch 30 $.K 300LL =7 60 (450/0.$! L,espan =7 =7 =7 =7 =7 (600/0.$5! L=7Inot reported0 )ut &ay assu&e s"&"lar phar&aco/"net"cs to ,extend s"nce C<0 C+ and de(ree o% su)st"tut"on are s"&"lar. D"%%erence "s )alanced solut"on vs. sal"ne solut"on LL7eported &ean T1/# at $-10 days %or ,extend and $-#K days a%ter ,etastarch. ,al%-l"ves should not )e "nterpreted as durat"on o% volu&e e%%ect.
3a'le 36 *har!aco=inetic- (*; o, Hydroxyethyl Starche- (H0S *roduct- (%ulti&le /n,u-ion- in Healthy Volunteer-4
H0S Solution Cu!ulative #o-e. :ra! (day- treated 500 (10! *la-!a Conc. (4 hr- a,ter la-t do-e (!$/!l M0.5 3 ? (hr Clearance (!l/!in ##.K )2C (!$/!l #ay 1 v-. 9a-t #ay 3#.K vs. 35.$
Voluven H.1 (130/0.4! ,extend =' =' =' =' =' (6$0/0.$5! ,etastarch H0 (3! H.6 =7 M1 =7 vs. D than on day (450/0.$! 1 L,espan =7 =7 =7 =7 =7 (600/0.$5! L=7Inot reported0 )ut &ay assu&e s"&"lar phar&aco/"net"cs to ,extend s"nce C<0 C+ and de(ree o% su)st"tut"on are s"&"lar. D"%%erence "s )alanced solut"on vs. sal"ne solut"on. ='Inot "ncluded "n study. ,al%-l"ves should not )e "nterpreted as durat"on o% volu&e e%%ect.
'n%or&at"on %ro& the &anu%acturer states that %ollo."n( "sovole&"c exchan(e o% 500 &J o% ,6+ 130/0.4 "n healthy volunteers0 )lood volu&e "s &a"nta"ned %or approx"&ately s"x hours. 4ased upon the "n%or&at"on "n Ta)les # and 30 ,6+ 130/0.4 does not appear to accu&ulate ."th &ult"ple "n%us"ons. ,o.ever0 cl"n"cal data are needed to deter&"ne .hether s"(n"%"cant advanta(es o% ,6+ 130/0.4 ex"st over other ,6+ products "n ter&s o% sa%ety and e%%"cacy. *pdated vers"ons &ay )e %ound at ....p)&.va.(ov or va...p)&.va.(ov (+epte&)er #011!
6% Hydroxyethyl Starch 130/0.4 in 0.9% NaCl (Voluven @#) )**48V0# /N#/C)3/8NS 6% hydroxyethyl starch 130/0.4 "n 0H% sod"u& chlor"de (Voluven ! .as approved )y the FDA "n late #00$ %or the prophylax"s and treat&ent o% hypovole&"a. *830N3/)9 8@@<9)+09 2S0S *n/no.n. C2440N3 V) @84%29)45 )9304N)3/V0S =on-synthet"c collo"ds; ,u&an al)u&"n (4-5%0 #0-#5%! +ynthet"c collo"ds; Dextran 10% 400 ,etastarches (e.(.0 ,espan0 ,extend! #8S):0 )N# )#%/N/S34)3/8N ,ydroxyethyl starch 130/0.4 "s ut"l"2ed %or &a"nta"n"n( and/or restor"n( "ntravascular volu&e and "s ad&"n"stered )y "ntravenous "n%us"on. The da"ly dose and "n%us"on rate depend upon an "nd"v"dual3s )lood loss0 on the &a"ntenance or restorat"on o% he&odyna&"cs and on he&od"lut"on. The ad&"n"strat"on o% hydroxyethyl starch 130/0.4 can )e repeated over several days. 4ecause there "s a r"s/ %or anaphylacto"d react"ons ."th Voluven 0 the "n"t"al 10-#0 &J should )e "n%used slo.ly .h"le care%ully o)serv"n( the pat"ent %or adverse events. 'n adults0 up to 50 &J//( o% )ody .e"(ht can )e ad&"n"stered da"ly result"n( "n an approx"&ate &ax"&u& da"ly dose o% 30500 &J o% Voluven "n a $0 /( person. '+ ,ydro4yethyl Starch ./0)0.1 5' gm% in 0.7+ Sodium 3horide 5700 mg% in water for in<ection -lectrolytes 5m-=)>%? @a .A1" 3l .A1" p, 1(A.A. 3alculated osmolarity /02 m8smol)> p, ad<usted with sodium hydro4ide or hydrochloric acid. 0@@/C)C5 6FF'1A1N C6A+*76+ 'n the sett"n( o% sur(ery0 trau&a or cr"t"cal "llness0 a)solute or relat"ve "ntravascular volu&e de%"c"ts re:u"re restorat"on to prevent hypovole&"a-related conse:uences. Absolute volume deficits can occur with blood loss while relative hypovolemia can occur due to vasodilation or in response to inflammation causing changes in the endothelial barrier leading to diffuse capillary leakage and movement of fluid from the intravascular into the e4travascular space 5interstitual compartment%. Ade:uate &ana(e&ent o% hypovole&"a "s necessary to prevent or l"&"t the )ody3s co&pensatory response (e.(.0 red"str")ut"on o% )lood %lo.0 a.ay %ro& /"dney0 (ut and s/"n0 act"vat"on o% the sy&pathet"c nervous syste& and ren"naldosterone-an("otens"n syste& 87AA+90 etc.!. '% "nade:uately treated0 volu&e de%"c"ts can lead to &ult"ple or(an "&pa"r&ent and death. +eps"s/1r"t"cally 'll; +e:uent"al Or(an Fa"lure Assess&ent (+OFA! +core-Developed "n order to create a s"&ple0 rel"a)le0 cont"nuous score %or &easur"n( %unct"on/%a"lure o% s"x or(ans (e.(.0 lun(s0 clott"n( syste&0 l"ver0 card"ovascular0 central nervous syste& and /"dneys!. Funct"onal"ty o% each or(an "s (raded on a 5 po"nt scale (0Inor&al0 4I&ost a)nor&al!. An "ncrease "n +OFA dur"n( the %"rst 4K hours "n the "ntens"ve care un"t ('1*! pred"cts &ortal"ty o% at least 50%. Therapeut"c 'ntervent"on +cor"n( +yste& (T'++!-Ceasure o% necessary '1* "ntervent"ons (e.(.0 &echan"cal vent"lat"on0 chest tu)es0 etc.! "n car"n( %or pat"ents. T'++ score should (o do.n as pat"ent "&proves. Acute Bhys"olo(y and 1hron"c ,ealth 6valuat"on (ABA1,6 ''!-sever"ty o% d"sease scor"n( syste& used "n '1* pat"ents. +cores can ran(e %ro& 0 to $1 ."th h"(her scores "nd"cat"n( &ore severe d"sease and a h"(her r"s/ o% death. *pdated vers"ons &ay )e %ound at ....p)&.va.(ov or va...p)&.va.(ov (+epte&)er #011!
6% Hydroxyethyl Starch 130/0.4 in 0.9% NaCl (Voluven Ceasures o% t"ssue per%us"on-&ean arter"al pressure (CAB!0 lactate0 central venous oxy(en saturat"on0 central venous pressure (1VB!0 stro/e volu&e (+V!0 pul&onary cap"llary .ed(e pressure (B1<B!0 card"ac "ndex (1'!0 card"ac output (1O!0 heart rate (,7!0 pul&onary artery pressure (BAB!0 )lood (ases0 etc.
+ur(ery; Ber"operat"ve and postoperat"ve )lood loss Volu&e o% collo"d or crystallo"d "n%used0 ur"ne output Trans%us"on o% )lood products (e.(.0 erythrocytes0 .hole )lood0 %resh %ro2en plas&a0 salva(ed )lood0 etc.! Ceasure&ent o% stren(th/"nte(r"ty o% %or&ed clots (C1F! (Thro&)elasto(raphy or T6@-analy2es platelet %unct"on! and rate o% clot %or&at"on (1T!. Ja)oratory &easure&ents-electrolytes0 hepat"c and renal %unct"on0 coa(ulat"on tests0 pro-"n%la&&atory &ar/ers0 etc. +*CCA7N OF 6FF'1A1N F'=D'=@+ 'n th"s rev"e.0 only those stud"es exa&"n"n( the use o% 6% ,6+ 130/0.4 vs. crystallo"d solut"ons or collo"dal solut"ons ava"la)le "n the *n"tes +tates .ere "ncluded. +"nce (elat"n "s not ava"la)le "n the *+0 stud"es co&par"n( ,6+ 130/0.4 to (elat"n as the only co&parator .ere not "ncluded. 'n add"t"on0 those stud"es co&par"n( ,6+ 130/0.4 to other ,6+ solut"ons not ava"la)le "n the *+ (as the only co&parator! .ere not "ncluded. #n 8ctober ;0.0" a study comparing cardiopulmonary bypass pump priming using a high dose of balanced ,-S 5not available in the :S% versus albumin was retracted by editors of Anesthesia and Analgesia. ./(.1 The retraction was prompted by an investigation by the $heinland State Medical Board revealing that there was no #$B approval" informed consent" randomiBation process or follow(up =uestionnaire as described in the study..A The investigation was initiated because several readers who =uestioned the plausibility of the results contacted the editor with their concerns. .'(.6 Since that time" at least 22 studies in which r. !oachim Boldt was included as an author have been retracted by a number of <ournals because #$B approval could not be verified. .2 r. Boldt contributed many of the studies supporting improved safety of modern ,-S solutions 5,-S ./0)0.1% leading clinicians to =uestion the validity of the literature on the safety and efficacy of '+ ,-S ./0)0.1 solution./2 As a result" many consensus guidelines" systematic reviews" meta(analyses involving colloidal solutions will be revised e4cluding the retracted studies. Because of the serious allegations of scientific misconduct against r. Boldt" those studies in which r. Boldt is listed as an investigator will not be considered as part of this review. On(o"n( de)ate cont"nues re(ard"n( the opt"&al %lu"d therapy %or restorat"on o% hypovole&"a. Desp"te the extens"ve nu&)er o% pu)l"shed tr"als0 a lac/ o% ev"dence to support one %lu"d therapy (crystallo"d vs. collo"d or collo"d vs. collo"d! as )e"n( super"or %or replac"n( volu&e de%"c"ts st"ll ex"sts. 5030-31 'n add"t"on0 the (oals o% %lu"d replace&ent &ay vary depend"n( upon the sett"n( (e.(.0 type o% sur("cal procedure or syste&"c "n%la&&at"on0 etc.!.4 As a result0 "t "s reco&&ended that (u"dance %or %lu"d therapy )e procedure or sett"n( spec"%"c and .hen ev"dence "s not ava"la)le0 "nd"v"dual0 (oal-d"rected %lu"d ad&"n"strat"on has )een reco&&ended )y a nu&)er o% authors. 40K-1# 'n &any o% these (oal-d"rected %lu"d &ana(e&ent tr"als0 the type o% %lu"d prov"ded "s not the "ntervent"on0 )ut "nstead ut"l"2"n( para&eters "nd"cat"ve o% %lu"d status such as stro/e volu&e0 B1<B0 1VB0 etc. to (u"de %lu"d therapy vs. convent"onal %lu"d ad&"n"strat"on. +eps"s; 1l"n"cal Tr"als; T.o stud"es co&par"n( the ad&"n"strat"on o% 6% ,6+ 130/0.4 vs. nor&al sal"ne solut"on (=++! or hu&an al)u&"n "n cr"t"cally "ll pat"ents ."th seps"s .ere "ncluded. 'n )oth stud"es0 collo"d or crystallo"d %lu"ds .ere ad&"n"stered to &a"nta"n t"ssue per%us"on us"n( CAB0 1VB0 B1<B0 etc. to (u"de %lu"d replace&ent. 4oth stud"es .ere s&all (nI#50 #0! and conducted over a per"od o% #4 hrs #1 to 5 days.#3 The %"rst study .as a p"lot study "n .h"ch su)l"n(ual &"croc"rculat"on (as a &ar/er o% t"ssue per%us"on! .as co&pared )et.een ,6+ 130/0.4 and =++. C"crovascular %lo. "ndex (CF'!0 percent o% per%used cap"llar"es *pdated vers"ons &ay )e %ound at ....p)&.va.(ov or va...p)&.va.(ov (+epte&)er #011!
6% Hydroxyethyl Starch 130/0.4 in 0.9% NaCl (Voluven and per%used cap"llary dens"ty .as (reater "n the ,6+ vs. =++ (roup (pM0.005!. #1 ,o.ever0 other outco&e &easures such as +OFA0 T'++ and ac"d-)ase para&eters .ere not d"%%erent. J"&"tat"ons o% th"s study "nclude lac/ o% val"dated &easure&ents %or su)l"n(ual &"croc"rculat"on (as a &ar/er %or t"ssue per%us"on! at the t"&e o% study co&&ence&ent. +a&ple s"2e .as adPusted do.n.ard once &ore data %or th"s &easure .as pu)l"shed. F"nally0 pat"ents "n the =++ (roup had )asel"ne h"(her seru& creat"n"ne values than ,6+ rec"p"ents (#.# vs. 1.#0 respect"vely! and conse:uently &ay have )een a s"c/er (roup o% pat"ents. 'n the second study0 #0 pat"ents ."th seps"s .ere %ollo.ed %or %"ve days "n the "ntens"ve care un"t. Bat"ents .ere rando&"2ed to rece"ve 6% ,6+ 130/0.4 or #0% hu&an al)u&"n (,A! (u"ded )y &easures o% he&odyna&"c status (B1<B!. 'n the study0 "t .as not clear o% the h"erarchy o% endpo"nts or outco&e &easures stud"ed )ut &easures o% he&odyna&"c status0 t"ssue oxy(enat"on and ABA1,6 '' scores .ere &on"tored. <"th the except"on o% card"ac "ndex ("ncreased vs. )asel"ne0 pM0.05! and r"(ht ventr"cular ePect"on %ract"on ("&proved vs.. )asel"ne and vs. ,A0 pM0.05!!0 other &easures o% he&odyna&"c status .ere not d"%%erent (e.(.0 CAB0 ,70 BAB0 B1<B0 1VB0 ur"ne output! %ro& )asel"ne or )et.een (roups. Analys"s o% t"ssue per%us"on us"n( )lood (ases sho.ed "&prove&ent %ro& )asel"ne "n the ,6+ (roup .h"le the ,A (roup re&a"ned unchan(ed. F"nally0 ABA1,6 '' scores decreased s"(n"%"cantly "n the ,6+ (roup .h"le the ,A (roup re&a"ned unchan(ed. +even pat"ents d"ed0 no &ent"on o% nu&)er per (roup. FDA 7ev"e.; The FDA approved 6% ,6+ 130/0.4 ."th t.o post-&ar/et"n( co&&"t&ents0 as %ollo.s;#H Co!&letion o, a clinical trial in &atient- >ith -e&-i-. >ith or >ithout renal di-ea-e . There is one trial &'S(Scandinavian Starch for Severe Sepsis)Septic Shock Trial* underway comparing ,-S ./0)0.1 to crystalloids in 200 patients with severe sepsis. The primary outcome measure in this trial is a composite of mortality and end(stage kidney failure. 3# A second trial &3rystalloid versus ,ydro4yethyl Starch Trial 53,-ST%* is also underway comparing ,-S ./0)0.1 to crystalloids 5saline% in 6"000 critically ill patients in the intensive care unit. The primary endpoint of this trial is death from all causes at 70 days. Secondary endpoints include renal failure" S89A score" use of renal replacement therapy" #3: stay" etc. The 3,-ST study began in April ;0.0./6 Co!&letion o, a clinical trial to exa!ine the -a,ety and e,,icacy o, 6% H0S 130/0.4 in &ediatric &atient- ((<1( year- old under$oin$ o&en<heart -ur$ery. @u"del"nes %or Flu"d 7eplace&ent "n 1r"t"cally 'll Bat"ents; Survivin$ Se&-i- Ca!&ai$n6 /nternational :uideline- ,or %ana$e!ent o, Severe Se&-i- and Se&tic Shoc=6 (00A33 o 7eco&&endat"on; Flu"d resusc"tat"on ."th e"ther natural/art"%"c"al collo"ds or crystallo"ds. There "s no ev"dence-)ased support %or a part"cular %lu"d over another. ,6+ ad&"n"strat"on "n pat"ents ."th seps"s &ay "ncrease r"s/ %or acute renal %a"lure0 "ncons"stent ev"dence prevents de%"n"t"ve reco&&endat"ons. 0vidence<+a-ed Colloid 2-e in the Critically /ll6 )!erican 3horacic Society Con-en-uState!ent.34 +elected +u&&ary Bo"nts (related to seps"s!; o All collo"ds a%%ect the coa(ulat"on syste&0 dextran and starch predo&"nantly. o 1ollo"ds restore "ntravascular volu&e &ore rap"dly than crystallo"ds "n all shoc/ states. o 1on%l"ct"n( ev"dence that ,6+ "ncreases r"s/ o% )leed"n( "n card"opul&onary )ypass sur(ery. o ,6+ &ay "ncrease r"s/ %or acute renal %a"lure "n pat"ents ."th seps"s.35 o Ceta-analyses o% collo"d use "n cr"t"cally "ll pat"ents are con%l"ct"n( due to tr"al hetero(ene"ty and var"a)le &eta-analyt"c &ethods used. ,o.ever a lar(e0 prospect"ve study (+AF6! 36 de&onstrated a neutral "n%luence o% collo"ds (al)u&"n! vs. crystallo"ds on cl"n"cal outco&es. Therapeut"c '&pl"cat"ons (related to seps"s!; o 1rystallo"ds should )e ad&"n"stered %"rst "n nonhe&orrha("c shoc/ resusc"tat"on. o ,6+ solut"ons should )e used caut"ously "n card"opul&onary )ypass and "n pat"ents ."th seps"s. Future 'nvest"(at"ons (related to seps"s!; o 1l"n"cal tr"als are needed to deter&"ne the cl"n"cal s"(n"%"cance o% )as"c sc"ence propert"es *pdated vers"ons &ay )e %ound at ....p)&.va.(ov or va...p)&.va.(ov (+epte&)er #011!
6% Hydroxyethyl Starch 130/0.4 in 0.9% NaCl (Voluven d"%%erences )et.een collo"ds. o Tr"als %ocused on outco&es ."th appropr"ate po.er to d"scern a &ortal"ty )ene%"t o% collo"d resusc"tat"on "n sept"c or he&orrha("c shoc/ ."th "nte(rated phar&acoecono&"c analyses. o 1l"n"cal tr"als des"(ned to exa&"ne )oth cl"n"cally relevant outco&es and phys"olo("c e%%ects o% collo"ds and crystallo"ds on or(an %unct"on "nclud"n( lun( %lu"d )alance "n pat"ents ."th or at r"s/ %or acute lun( "nPury (AJ'! or adult resp"ratory d"stress syndro&e (A7D+!. +eps"s +u&&ary; There are l"&"ted data co&par"n( 6% ,6+ 130/0.4 to other collo"ds or crystallo"ds ava"la)le "n the *+. There%ore "t "s d"%%"cult to deter&"ne .hether ,6+ 130/0.4 o%%ers any advanta(e or d"sadvanta(es over the other products used %or %lu"d resusc"tat"on "n sept"c pat"ents. Ava"la)le (u"del"nes support the use o% e"ther collo"ds or crystallo"ds ."thout a pre%erence %or %lu"d type due to a lac/ o% ev"dence prov"n( d"%%erences "n relevant outco&es )et.een products. 4ecause o% "ncons"stent data re(ard"n( the e%%ect o% ,6+ solut"ons on renal %unct"on "n pat"ents ."th seps"s0 t.o cl"n"cal tra"ls have )een des"(ned and are under.ay to help ans.er that :uest"on. +ur(ery; 1l"n"cal Tr"als; +"x stud"es co&par"n( 6% ,6+ 130/0.4 to crystallo"ds or other collo"ds "n pat"ents under(o"n( elect"ve sur(ery .ere "ncluded.#4-#60#K03H-40 +tudy endpo"nts "ncluded one or &ore o% the %ollo."n(; sur("cal )lood loss0 need %or trans%us"on o% )lood products0 in vitro assess&ent o% e%%ect on coa(ulat"on (us"n( thro&)elasto(raphy 8T6@9!0 volu&e o% collo"d or crystallo"d "n%used0 and renal %unct"on. 'n (eneral0 the stud"es .ere s&all and o% short durat"on ran("n( %ro& 36-140 pat"ents and %ollo.ed %or 1-#K days post-op. 'n add"t"on0 althou(h &ax"&u& doses o% ,6+ 130/0.4 are 50 &l//(/day (approx"&ately 3500 &l "n a $0 /( pat"ent!0 &ost stud"es "n%used )et.een 500 and 1500 &l ."th the except"on o% the study )y @handh"0 et al0 #6 and Cu/htar#K0 et al. "n .h"ch &ax"&u& da"ly doses .ere exa&"ned. T.o o% the s"x stud"es "nvolve a co&par"son o% 6% ,6+ 130/0.4 to lactated r"n(ers (7J! (nI1400 1A4@ sur(ery!#4 or 5% al)u&"n (nI360 &"tral valve sur(ery! #5 as a co&ponent o% card"opul&onary )ypass pr"&"n( solut"ons. 'n the ,6+ 130/0.4 vs. 7J co&par"son0 no d"%%erences .ere o)served "n post-op )lood loss0 use o% %resh %ro2en plas&a0 t"&e to extu)at"on0 '1* stay0 creat"n"ne clearance or t"&e to d"schar(e. At #4 hrs post-op0 4*= and seru& creat"n"ne (+1r! .ere stat"st"cally h"(her "n the ,6+ vs. 7J (roup (46 vs. 3# &(/dJ and 1.4 vs. 1.1 &(/dJ0 respect"vely0 pI0.001!. 1reat"n"ne clearance .as not d"%%erent at $# hours )et.een (roups )ut )asel"ne values .ere h"(her "n the ,6+ vs. 7J (roup (4asel"ne; $6 &l/&"n 7J vs. K# &l/&"n ,6+0 $# hrs post-op; 6K &l/&"n 7J vs. 64 &l/&"n ,6+!. 'nternat"onal nor&al"2ed rat"o ('=7! values .ere h"(her "n the 7J (roup vs. ,6+ at 1# and #4 hours post-op (1.3H vs. 1.05 81# hr9 and 1.3K vs. 1.1# 8#4 hr!0 respect"vely )ut d"%%erences "n )lood loss .ere not o)served. 'n the second )ypass pr"&"n( study0 ,6+ 130/0.4 .as co&pared to 5% al)u&"n "n 36 pat"ents hav"n( elect"ve &"tral valve replace&ent. #5 'n th"s study0 there .ere no d"%%erences "n rate o% clot develop&ent or stren(th o% clot ()oth .ere e:ually reduced %ro& )asel"ne!0 %lu"ds ad&"n"stered or )lood products "n%used or chan(e "n pro-"n%la&&atory &ar/ers )et.een (roups. The re&a"n"n( %our stud"es are "ncluded "n Ta)le 4 )elo.; 3a'le 46 Su!!ary o, H0S 130/0.4 v-. Colloid or Cry-talloid- in *atient- havin$ 0lective Sur$ery
:handi(6 (nB100 CaPor orthoped"c sur(ery0 h"p and sp"ne &ost co&&on (4K hrs post-op0 #K days post-op %or sa%ety! /ntervention ,6+ 130/0.4 (Voluven! vs. ,6+ 6$0/0.$5 (6% ,etastarch! 0nd&oint-/4e-ultBr"&ary; Total volu&e o% collo"d re:u"red %or volu&e expans"on. =o d"%%erences %ound. Other; Total %lu"d "nput/output0 use o% vasoact"ve &eds. =o d"%%erence "n %lu"d "nput or ur"ne output "n the "ntent to treat populat"on and .hen ad&"n"strat"on o% "nd"v"dual types o% %lu"d or )lood products .as assessed. ,o.ever0 .hen the "n%used totals o% p741s0 .hole )lood and salva(ed )lood .ere co&)"ned0 there .as a d"%%erence "n %avor o% Co!!entAlthou(h sl"(ht d"%%erences "n # hr post-op nad"r FV''' and von <"lle)rand Factor .ere o)served "n %avor o% ,6+ 1300 no d"%%erence "n )lood loss or "n%us"on o% "nd"v"dual )lood co&ponents .as reported. There .ere 3 cases o% ser"ous coa(ulopath"es "n the ,6+ 6$0 (roup and none "n the ,6+ 130 (roup. All o% these pat"ents rece"ved D30000 &l

,6+ 130 (pI0.0#H6!. # hr post-op nad"r %actor V''' .as 1H% lo.er "n ,6+ 130 vs. 6$0 (pI0.04HH!. 'n pat"ents rece"v"n( D1000 &l o% study collo"d0 # hr post-op FV''' nad"r .as lo.er "n the ,6+ 6$0 vs. 130 (pI0.04H! and nad"r von <"lle)rand %actor .as lo.er as .ell (pI0.00K! Br"&ary +a%ety Outco&e; 1alculated and est"&ated )lood loss0 no d"%%erence "n "ntent to treat populat"on or "n the "n%us"on o% "nd"v"dual )lood co&ponents )et.een (roups. <hen "n%us"on volu&es o% p741s0 .hole )lood and salva(ed )lood .ere totaled0 there .ere lo.er co&)"ned totals "n the ,6+ 130 vs. 6$0 (roup. Br"&ary; 6%%ect on renal %unct"on 1-4 days post-op. =o d"%%erence "n +cr0 1r1l0 or cystat"n 1 plas&a levels )et.een (roups. One pat"ent "n each (roup re:u"red renal replace&ent therapy Other; Volu&e o% collo"d ad&"n"stered .as s"(n"%"cantly h"(her "n the ,6+ vs. ,A (roup (6##H &( vs. 4636 &l0 respect"vely!. D"uret"c use .as also h"(her "n ,6+ vs. ,A. =o d"%%erence "n use o% crystallo"ds0 741s0 FFB and ur"ne output Br"&ary; D"%%erence "n per"operat"ve )lood loss. =o d"%%erence )et.een (roups Other; =o d"%%erence "n trans%used p7410 FFB or nu&)er o% pat"ents re:u"r"n( trans%us"on. One pat"ent on ,6+ developed renal %a"lure re:u"r"n( d"alys"s. =o d"%%erences "n e%%ect o% these %lu"ds on the coa(ulat"on syste& (assessed us"n( thro&)elasto(raphy! Br"&ary; +ur("cal )lood loss0 volu&e expans"on %ro& collo"ds0 e%%ect on coa(ulat"on syste& us"n( thro&)elasto(raphy (h"erarch o% endpo"nts unclear!. =o d"%%erence "n )lood loss0 volu&e e%%ect "ncreased )y &ore than 14% %or all collo"ds and decreased over t"&e "n all (roups except Dextran. For all collo"ds0 clott"n( t"&e .as reduced and stren(th o% clots .as .ea/ened Br"&ary; Cax"&al clot %"r&ness (C1F! &easured )y thro&)elasto&etry (7OT6C!; At 30% d"lut"on ."th ,6+ 130/0.4 "n )oth (roups0 C1F .as s"(n"%"cantly reduced (.ea/ened clot!. 'n the %")r"no(en concentrate (roup0 C1F "ncreased (clot stren(th! s"(n"%"cantly vs. place)o. +econdary; 4lood loss0 trans%us"on re:u"re&ents and other thro&)elasto-&etry para&eters (thro&)"n (enerat"on and platelet %unct"on!; 4lood loss and trans%us"on re:u"re&ents d"d not d"%%er )et.een (roups. Bostoperat"vely0 K/10 pat"ents "n the place)o (roup re:u"red 741 trans%us"on vs. #/10 "n the (roup treated ."th %")r"no(en. o% study collo"d. =o other deta"ls ("ven. FDA rev"e.er co&&ented that sa%ety endpo"nts .ere cons"dered "n a se:uent"al &anner so "% one sa%ety endpo"nt .as not s"(. d"%%erent0 analys"s o% the su)se:uent sa%ety endpo"nt could only )e cons"dered explanatory. The FDA rev"e.er concluded that )ecause o% th"s0 super"or sa%ety o% ,6+ 130 over ,6+ 6$0 could not )e concluded )ased upon these data. Cost pat"ents "n the study had nor&al renal %unct"on. Authors unsure .hat e%%ect ,6+ ."ll have "n those ."th &ore severely "&pa"red renal %unct"on.
%u=htar(A (nB40 J"v"n( donor l"ver transplantat"on (*p to 4 days post-op!
,6+ 130/0.4 vs. 5% al)u&"n (,A!
9ee39 (nB106 7ec"p"ents o% dual ant"platelet therapy and hav"n( o%%-pu&p coronary artery )ypass sur(ery (#4 hr %ollo.up! Cdol-e=40 (nBDA ,"p sur(ery us"n( sp"nal anesthes"a (4-5 hr post-op %ollo.-up!
,6+ 130/0.4 vs. 1rystallo"d (Blas&a solut"on A!
Cax doses o% 30 &l//(/d .ere used "nstead o% FDA approved &ax doses o% 50 &(//(/d. *nsure o% e%%ect on outco&es "% a h"(her dose o% ,6+ .ere used.
,6+ 130/0.4#0 ,6+ 130/0.40 ,6+ #00/0.50 Dextran $0 6%
=o s"(n"%"cant d"%%erences )et.een collo"ds "n )lood loss0 coa(ulat"on (all reduced t"&e to clot and produced .ea/ened clot stren(th! and expanded plas&a volu&e. 1ollo"dal hal%-l"%e &ay expla"n the var"ed e%%ect on post-op and durat"on o% volu&e expans"on. ,6+ 130/0.4 .as selected as the collo"dal plas&a expander s"nce "t "s the &ost co&&only used "n 6urope. 'nvest"(ators selected ,6+ 130 as a volu&e expander to sho. "ts a%%ect on C1F and the use o% %")r"no(en vs. place)o to "&prove or reduce the e%%ect o% th"s collo"d on para&eters o% coa(ulat"on ("n v"vo &easure&ent!. =o collo"dal control (roup as"de %ro& ,6+130. Authors concluded that resusc"tat"on ."th ,6+ 130 dur"n( sudden excess"ve )leed"n( "nduces coa(ulopathy )y reduc"n( C1F. 1ould ,6+ 130/0.4 )een chosen )ecause o% "ts pred"cted >less e%%ect
@en$er<0ri=-en 41 (nB(0 4leed"n( pat"ents under(o"n( rad"cal cystecto&y (,e&atocr"t reduced 30% %ro& )asel"ne! (4K hr post-op %ollo.-up!
4lood loss replaced 1;1 ."th ,6+ 130/0.4 "n )oth (roups. *se o% a %")r"no(en concentrate .as the "ntervent"on vs. place)o.

on coa(ulat"on? to "&prove )ene%"t o% study "ntervent"onQ *nl"/ely s"nce coa(ulat"on "n )oth (roups .ould )e less a%%ected.
Bu)l"shed 7ev"e.s o% Flu"ds *sed Dur"n( +ur(ery; There are three pu)l"shed rev"e.s o% the use o% 6% ,6+ 130/0.4 "n pat"ents under(o"n( sur(ery. 7ev"e.s0 pooled analyses or &eta-analyses co&par"n( ,6+ 130/0.4 to a s"n(le replace&ent %lu"d not ava"la)le "n the *.+. .ere not "ncluded. +ee Ta)le 5 %or deta"ls; 3a'le E. *u'li-hed 4evie>- o, H0S 130/0.4 in Sur$ical *atient3oo!ton$. et al4( (009 'V %lu"ds %or a)do&"nal aort"c sur(ery #e-cri&tion/@indin$-3K tr"als0 15KH pat"ents "ncluded. -1o&pare the phys"olo("c e%%ects o% crystallo"d and collo"d replace&ent %lu"ds to deter&"ne "% there "s ev"dence to support an opt"&al %lu"d %or replace&ent %or a)do&"nal aort"c sur(ery. -Br"&ary outco&e co&pared .as death. -Other para&eters co&pared; card"ac0 resp"ratory0 he&atolo("c0 and len(th o% stay. Authors co&&ents; -Jac/ o% stud"es report"n( death as pr"&ary outco&e -Jac/ o% ev"dence to support a >)est %lu"d? replace&ent dur"n( or a%ter a)do&"nal aort"c sur(ery. -=o s"n(le %lu"d a%%ected any outco&e &easure &ore than another %lu"d across a ran(e o% outco&es -Cany d"%%erent %lu"d replace&ents used0 so %e. results could )e pooled. -'&portant outco&e &easures should "nclude need %or allo(ene"c )lood trans%us"on0 or(an %a"lure0 len(th o% stay "n '1* or hosp"tal. -7ev"e. o% e%%"c"ency o% ,6+ 130/0.4 o% plas&a su)st"tut"on vs. other collo"ds -4lood loss and r"s/ o% )leed"n( ."th ,6+ 130/0.4e%%ect on coa(ulat"on (la) &easures-T6@! &"n"&al. -7enal sa%ety o% ,6+ 130.0.4-"nade:uate ev"dence .hether d"%%erences ex"st )et.een ,6+ products -Bul&onary &echan"cs o% ,6+ 130/0.4 vs. other collo"ds-type o% %lu"d does not a%%ect pul&onary per&ea)"l"ty/ede&a0 ,6+ &ay reduce per&ea)"l"ty -'n%la&&atory response to sur(ery- ,6+ &ay reduce "n%la&&atory response a%ter sur(ery vs. crystallo"ds (paper used to support .as retracted! -1# relevant papers .ere "ncluded (H cl"n"cal tr"als0 3 in vitro stud"es! -3 in vitro stud"es; de&onstrate no s"(n"%"cant a%%ect on platelet var"a)les (T6@! and %aster clot %or&at"on ."th ,6+ 130/0.4 -H cl"n"cal stud"es; ,6+ 130/0.40 ,6+ #00/0.50 and (elat"n all a%%ect coa(ulat"on s"&"larly result"n( "n no d"%%erences "n )lood loss a%ter card"ac sur(ery. Co!!ent-1ochrane 7ev"e. -Jac/ o% ev"dence support"n( clear advanta(es o% one %lu"d replace&ent therapy over another -Althou(h ,6+ 130/0.4 .as "ncluded "n the rev"e.0 l"&"ted nu&)er o% stud"es.
*iaFFa. et al43 (010 6%%"cacy0 sa%ety o% ,6+
-+u)Pect"ve0 not syste&at"c rev"e. o% ,6+ 130/0.4 dur"n( sur(ery -+everal o% the retracted papers0 "nclud"n( 4oldt as an author0 .ere "ncluded "n the rev"e. and helped to support so&e o% the conclus"ons (e.(.0 "n%la&&atory response to sur(ery0 etc.!
4aGa. et al44 (011 1ard"ac sur(ery0 does ,6+ 130/0.4 "&pa"r coa(ulat"on less than other collo"dsQ
-'ncluded tr"als used pr"&ar"ly ,6+ 130/0.4 vs. other collo"ds not ava"la)le "n the *+. ,o.ever0 s"nce crystallo"ds and al)u&"n .ere co&parators0 the rev"e. .as "ncluded. -Althou(h surro(ate &easures o% coa(ulat"on (T6@ para&eters! .ere not s"(n"%"cantly a%%ected )y ,6+ 130/0.40 d"%%erences "n )leed"n( outco&es d"d not d"%%er %ro& ,6+ #00/0.5 and (elat"n (ne"ther ava"la)le "n the *+!
@u"del"nes %or Flu"d 7eplace&ent "n +ur("cal Bat"ents; +riti-h Con-en-u- :uideline- on /ntravenou- @luid 3hera&y ,or )dult Sur$ical *atient-< ,ypovole&"a due predo&"nantly to )lood loss should )e treated ."th e"ther a )alanced crystallo"d solut"on or a su"ta)le collo"d unt"l pac/ed red cells are ava"la)le.45-46 *pdated vers"ons &ay )e %ound at ....p)&.va.(ov or va...p)&.va.(ov (+epte&)er #011!
10
6% Hydroxyethyl Starch 130/0.4 in 0.9% NaCl (Voluven #n Vitro +tud"es o% ,6+ 6%%ect on 1oa(ulat"on "n +ur("cal Bat"ents; There have )een three in vitro stud"es exa&"n"n( the e%%ect o% 6% ,6+ 130/0.4 on coa(ulat"on (us"n( thro&)elasto(raph 8T6@9 &easure&ents! "n pat"ents under(o"n( a sur("cal procedure. 'n the %"rst study0 H5 pat"ents0 scheduled %or l"ver transplantat"on0 had the"r )lood d"luted )y 11%0 ##% and 33% ."th ,6+ 130/0.4 or nor&al sal"ne to deter&"ne the e%%ect o% ,6+ he&od"lut"on0 &easured us"n( T6@ analys"s. 4$ +al"ne served as the control. At 33% he&od"lut"on ."th sal"ne0 only the react"on t"&e to clot %or&at"on .as "ncreased vs. )asel"ne. <"th ,6+0 a)nor&al"t"es "n T6@ &easure&ents .ere o)served ."th 11% he&od"lut"on ."th the ult"&ate stren(th o% the %")r"n clot stat"st"cally reduced %ro& )asel"ne (pI0.003!. At 33% d"lut"on0 the rate o% clot %or&at"on .as reduced as .ell as clot stren(th %ro& )asel"ne and vs. sal"ne control. 'n the second study0 30 pat"ents0 ."th )lood Type non-O and 15 ."th Type O0 scheduled %or sp"nal sur(ery had 30% o% the"r )lood re&oved a%ter "nduct"on o% anesthes"a and replaced ."th 6% ,6+ 130/0.4. 1oa(ulat"on pro%"les .ere deter&"ned 30 &"nutes pr"or to and a%ter acute nor&ovole&"c he&od"lut"on. 4K The "nvest"(ators expected that s"nce "nd"v"duals ."th Type O )lood have a tendency to.ards reduced Factor V''' and von <"lle)rand Factor (v<F!0 they &ay )e &ore vulnera)le to coa(ulopathy ."th ,6+ he&od"lut"on Althou(h the levels o% these %actors .ere lo.er "n the Type O (roup0 there .ere no d"%%erences )et.een (roups "n )lood loss or the need %or pac/ed red cells. Overall0 Factor V'''/v<F decreased &ore than expected ."th he&od"lut"on. 1lot stren(th .as also reduced ."th he&od"lut"on "n )oth (roups o% pat"ents. The authors caut"on that pat"ents ."th Type O )lood &ay )e &ore vulnera)le to )leed"n( .hen exposed to ,6+ he&od"lut"on s"nce the levels o% certa"n coa(ulat"on %actors .ere reduced )elo. the nor&al ran(eE ho.ever the &a(n"tude o% the reduct"on d"d not d"%%er )et.een )lood types stud"ed. 'n the th"rd study0 act"v"ty o% t"ssue-type plas&"no(en act"vator (t-BA! and plas&"no(en act"vator "nh")"tor1 (BA'-1! .ere &easured "n 66 pat"ents hav"n( orthoped"c sur(ery rando&"2ed to (elat"n0 ,6+ 6% 130/0.4 or 7"n(er3s lactate solut"on.4H The purpose o% the study .as to explore the e%%ects o% collo"d and crystallo"d solut"ons on act"vat"on o% %")r"nolys"s and deter&"ne "% ad&"n"stered %lu"ds %ac"l"tate clot d"ssolut"on at a certa"n %")r"nolyt"c act"v"ty. There .ere no d"%%erences "n %")r"nolyt"c act"v"ty )et.een %lu"d (roups. ,o.ever0 dur"n( hyper%")r"nolys"s0 the presence o% ,6+ or (elat"n %ac"l"tated clot d"s"nte(rat"on vs. 7"n(er3s lactate solut"on s"nce .ea/er %or&ed clots lead to &ore rap"d clot d"ssolut"on. +ur(ery +u&&ary; 'n the s"x cl"n"cal tr"als0 cl"n"cal outco&es d"d not d"%%er s"(n"%"cantly )et.een 6% ,6+ 130/0.4 and e"ther crystallo"d or collo"ds ad&"n"stered (,6+ 6$0/0.$50 Al)u&"n0 6% Dextran $0! "n per"operat"ve or postoperat"ve )lood loss0 trans%us"on re:u"re&ents or or(an %unct"on. 'n several stud"es0 d"%%erences "n certa"n var"a)les (e.(.0 levels o% #-hour postoperat"ve nad"r Factor V''' or von <"lle)rand Factor (v<F!0 sl"(htly "ncreased '=70 etc.! .ere o)served )ut the cl"n"cal s"(n"%"cance o% these d"%%erences "s un/no.n. 'n the study co&par"n( 6% ,6+ 130/0.4 to 6% ,etastarch (6$0/0.$5!0 althou(h so&e d"%%erences .ere o)served "n secondary endpo"nts0 the FDA &ed"cal rev"e.er co&&ented that sa%ety endpo"nts "n th"s part"cular tr"al .ere cons"dered "n a se:uent"al &anner0 so "% one endpo"nt .as not stat"st"cally d"%%erent0 analys"s o% su)se:uent endpo"nts could only )e cons"dered exploratory. The FDA rev"e.er concluded that super"or sa%ety could not )e proven )ased upon data %ro& the tr"al. A 1ochrane rev"e. o% %lu"d replace&ents "n a)do&"nal aort"c sur(ery %ound a lac/ o% ev"dence to support one %lu"d as the opt"&al %lu"d replace&ent "n pat"ents hav"n( a)do&"nal aort"c sur(ery. 6x"st"n( (u"del"nes %or %lu"d replace&ent "n adult sur("cal pat"ents do not reco&&end a part"cular %lu"d replace&ent )ut reco&&end that e"ther )alanced crystallo"ds or a >su"ta)le? collo"d )e used to replace lost )lood. F"nally0 in vitro coa(ulat"on stud"es de&onstrate that 6% ,6+ 130/0.4 does have an a%%ect on platelet %unct"on/coa(ulat"on as assessed )y T6@ &easure&ents. 4ased upon th"s "n%or&at"on0 "t "s unclear "% 6% ,6+ 130/0.4 o%%ers any advanta(e or d"sadvanta(e over crystallo"ds or other collo"ds %or %lu"d replace&ent "n sur("cal pat"ents. )#V04S0 0V0N3S D6AT,+ A=D OT,67 +67'O*+ ADV67+6 6V6=T+ To date0 no deaths have )een attr")uted d"rectly to ,6+ 130/0.4. +er"ous adverse events &ay "nclude rare *pdated vers"ons &ay )e %ound at ....p)&.va.(ov or va...p)&.va.(ov (+epte&)er #011!
11
6% Hydroxyethyl Starch 130/0.4 in 0.9% NaCl (Voluven anaphylacto"d react"ons (D0.01 to M0.1%!. '% th"s type o% react"ons occurs0 ,6+ 130/0.4 should )e d"scont"nued "&&ed"ately and e&er(ency support"ve &easures "nst"tuted. OT,67 ADV67+6 6V6=T+ *ruriti-6 Brolon(ed ad&"n"strat"on o% ,6+ type products &ay cause prur"t"s that "s delayed "n onset (1-6 .ee/s!0 can last %or .ee/s to &onths0 can )e severe and re%ractory to treat&ent and can s"(n"%"cantly a%%ect :ual"ty o% l"%e. One author rev"e."n( the pu)l"shed l"terature on ,6+ assoc"ated prur"t"s co&&ented that >The true "nc"dence o% th"s co&pl"cat"on has l"/ely )een underest"&ated s"nce the onset o% prur"t"s "s delayed0 "t &ay )e &"ssed "n cl"n"cal tr"als o% short durat"on and &ay not )e reco(n"2ed as )e"n( assoc"ated ."th ad&"n"strat"on o% ,6+ .ee/s earl"er.?50 Althou(h th"s adverse event "s )el"eved to result %ro& t"ssue depos"t"on o% the ,6+ &olecule and so&e theor"2e that "ts occurrence0 sever"ty and/or durat"on &ay )e reduced ."th certa"n later (enerat"on ,6+ products0 "t "s reportedly o)served ."th all ,6+ products and has )een reported even ."th usual doses o% ,6+. To date0 there "s no ev"dence to support a lo.er "nc"dence o% ,6+-"nduced prur"t"s ."th ne.er (enerat"on ,6+ products such at 6% ,6+ 130/0.4. 0,,ect on Coa$ulation (Su!!ary6 in vitro trial- 6 3a'le 66 /n Vitro Studie- HCoa$ulation 0,,ect o, 6% H0S 130/0.4
0ntholFner (000E( =I30 volunteers /ntervention/0nd&oint 30% he&od"lut"on ."th; ,6+ 130/0.4 ,6+ #00/0.5 ,6+ 450/0.$ =or&al sal"ne *nd"luted (roup (control! 'ntr"ns"c and extr"ns"c thro&)elasto(raphy (T6@! and coa(ulat"on tests (BT and aBTT! @indin$-/Conclu-ionaBTT not chan(ed vs. control BT prolon(ed vs. control "n all (roups (All ,6+ (roups pM0.05 vs. control and vs. sal"ne0 sal"ne &ost prolon(ed!. 6xtr"ns"c T6@ test"n( sho.ed s"(n"%"cant prolon(at"on o% t"&e to )e("n clot %or&at"on0 t"&e to coa(ulat"on and reduced clot stren(th "n all ,6+ (roups vs. control and ,6+ #00 and 450 vs. place)o. 'ntr"ns"c T6@ test"n( d"d not sho. a delay "n react"on t"&e to )e("n clot %or&at"on )ut coa(ulat"on t"&e and reduced clot stren(th occurred "n all ,6+ (roups. -+&all sa&ple o% volunteers -#n vitro tests0 no "nd"cat"on o% cl"n"cal s"(n"%"cance -=o d"%%erence )et.een ,6+ (roups "n all T6@ var"a)les tested vs. control or vs. place)o except extr"ns"c T6@ "n .h"ch ,6+ 130 .as not d"%%erent vs. sal"ne "n clot stren(th )ut .as reduced vs. control +tren(th o% clot and propa(at"on o% clot .ere s"(n"%"cantly reduced ."th all collo"ds vs. sal"ne ."th no d"%%erences )et.een the ,6+ (roups or Dextran. -+&all sa&ple s"2e -+"(n"%"cant he&od"lut"on used "n th"s study vs. &oderate "n other stud"es (e.(.0 30%!
@en$er<0ri=-on (00EE3 =I#0 healthy volunteers 1o&par"son o% e%%ect o% collo"ds on .hole )lood coa(ulat"on and resolut"on )y %")r"no(en concentrate or Factor V'''
55% ,e&od"lut"on ."th; =or&al sal"ne ,6+ #00/0.5 ,6+ 130/0.4 Dextran $0 <hole )lood clot %or&at"on us"n( T6@. Ad&"n"strat"on o% e4 vivo %")r"no(en concentrate or Factor V''' as a strate(y to reduce )leed"n( co&pl"cat"ons "nduced )y collo"d ad&"n"strat"on.
There are %our other tr"als co&par"n( the e%%ects o% 6% ,6+ 130/0.4 and 6% ,6+ #00/0.5 (not ava"la)le "n the *+0 ."dely used "n 6urope! on )lood and )lood coa(ulat"on. 54-5$ 'n (eneral0 the authors o)served a *pdated vers"ons &ay )e %ound at ....p)&.va.(ov or va...p)&.va.(ov (+epte&)er #011!
12
6% Hydroxyethyl Starch 130/0.4 in 0.9% NaCl (Voluven s"(n"%"cant e%%ect o% )oth ,6+ products on clot %or&at"on0 he&od"lut"on and/or )lood v"scos"ty %ro& )asel"ne )ut overall no s"(n"%"cant d"%%erence )et.een (roups. +leedin$ (Clinical 3rial- 6 Overall0 no s"(n"%"cant d"%%erences "n per"operat"ve or postoperat"ve )lood loss or need %or trans%us"on o% )lood products .ere o)served "n cl"n"cal tr"als co&par"n( ,6+ 6% 130/0.4 to other %lu"d therap"es. (+ee Ta)le 4 and Append"x %or deta"ls! 0,,ect on 4enal @unction6 There have )een three syste&at"c rev"e.s o% ,6+ products and the"r e%%ect on renal outco&es.5K-60 'n the %"rst syste&at"c rev"e./&eta-analys"s0 authors "dent"%"ed t.enty-t.o tr"als "n .h"ch ,6+ .as co&pared to an alternat"ve %lu"d %or acute volu&e resusc"tat"on "n 1K65 cr"t"cally "ll pat"ents.5K Fro& the"r analys"s0 the authors %ound that pat"ents rece"v"n( ,6+ .ere &ore l"/ely to have rece"ved renal replace&ent therapy (77T! vs. an alternat"ve %lu"d type (e.(.0 al)u&"n0 (elat"n or crystallo"ds! (O7 1.H00 H5% 1' 1.##-#.H60 =I$4H! )ut there .ere no d"%%erence "n overall &ortal"ty (O7 1.0$0 H5% 1' 0.K5-1.340 =I165$!. ,o.ever0 "n h"(h :ual"ty0 &ult"center tr"als that enrolled pat"ents ."th severe seps"s/sept"c shoc/0 there .as a trend to.ards "ncreased r"s/ o% death "n the ,6+ (roup. O% "&portance0 only one o% the "ncluded stud"es used 6% ,6+ 130/0.4. 5The authorsC analysis and conclusions are being revised since !oachim Boldt authored seven of the included studies. r. Boldt is accused of fabricating evidence for other studies" not obtaining #$B approval and forging names of co(authors on manuscript submissions. #nvestigations into these allegations are underway%. The second syste&at"c rev"e. .as %ro& the 1ochrane 1olla)orat"on and "nvolved rev"e. o% ,6+ products versus other %lu"d therap"es and a co&par"son o% the"r e%%ect on renal %unct"on. 5H The rev"e. "ncluded th"rty-%our tr"als "nvolv"n( #060$ pat"ents. Author-de%"ned /"dney %a"lure .as h"(her "n the ,6+ (roup vs. other %lu"d therap"es (77 1.50 H5% 1' 1.#-1.K$0 nI11HH!. There .as a trend to.ards h"(her 77T "n the ,6+ vs. other %lu"d therapy (roups (77 1.3K0 H5% 1' 0.KH-#.160 nI1#36! )ut the d"%%erence .as not stat"st"cally s"(n"%"cant. +u)(roup analys"s sho.ed a h"(her r"s/ "n sept"c pat"ents co&pared to sur("cal or trau&a pat"ents. Authors caut"oned o% an "ncreased r"s/ %or acute /"dney "nPury "n sept"c pat"ents .hen .e"(h"n( the r"s/s and )ene%"ts o% %lu"d resusc"tat"on ."th ,6+ type products "n these pat"ents. The authors also state that there "s "nade:uate cl"n"cal ev"dence to support cla"&s o% d"%%erences "n sa%ety )et.een ,6+ products. 'n the th"rd0 co&parat"ve rev"e. o% %lu"d &ana(e&ent ."th var"ous collo"ds and the "&pact on renal %unct"on0 the authors report an adverse "&pact on renal %unct"on %or &ost ,6+ products ("nclud"n( 6% ,6+ 130/0.4! and conclude that there "s "nade:uate proo% that ne.er products are %ree %ro& renal e%%ects. 60 9a'oratory 0,,ect-6 Dur"n( treat&ent ."th ,6+ products0 seru& a&ylase can r"se and &ay con%use the d"a(nos"s o% pancreat"t"s.1051 'n add"t"on0 clott"n( %actors0 other plas&a prote"ns and a reduct"on "n he&atocr"t &ay )e co&&only o)served.1 8ther6 There are t.o pu)l"shed rev"e.s o% ,6+ products0 one spec"%"cally address"n( sa%ety o% ,6+ 6% 130/0.4 "n .h"ch the authors cons"der the total"ty o% the ev"dence and conclude that there "s a lac/ o% conv"nc"n( ev"dence that 6% ,6+ 130/0.4 "s sa%er than other ,6+ solut"ons.61-6# FDA F'=D'=@+ Follo. up o% adverse events0 as part o% the &anu%acturer3s co&&"t&ent to prov"de all reported adverse events "nvolv"n( ped"atr"c pat"ents s"nce approval (1#-0$ throu(h 6-0H!0 d"d not reveal any unexpected adverse events and none that .ere not already l"sted "n the pac/a(e la)el"n(. Adverse events reported throu(h the FDA3s Adverse 6vents 7eport"n( +yste& (A67+0 nI10! and Ber"od"c +a%ety *pdate 7eport"n( (B+*7s0 #004-#00H0 nI#31! su)&"tted )y the &anu%acturer .ere cons"dered to )e lo. relat"ve to the est"&ated lar(e d"str")ut"on o% 6% ,6+ 130/0.4.$ C8N34)/N#/C)3/8NS The use o% 6% ,6+ 130/0.4 "s contra"nd"cated "n the %ollo."n( s"tuat"ons; Ano.n hypersens"t"v"ty to ,6+ 'n %lu"d overloaded pat"ents (e.(.0 pul&onary ede&a0 con(est"ve heart %a"lure! 'n pat"ents ."th renal %a"lure ."th ol"(ur"a or anur"a unrelated to hypovole&"a *pdated vers"ons &ay )e %ound at ....p)&.va.(ov or va...p)&.va.(ov (+epte&)er #011!
13
6% Hydroxyethyl Starch 130/0.4 in 0.9% NaCl (Voluven Bat"ents rece"v"n( d"alys"s 'n pat"ents ."th severe hypernatre&"a or severe hyperchlore&"a 'n pat"ents ."th "ntracran"al )leed"n(
7)4N/N:S )N# *40C)23/8NS Anaphylacto"d react"ons have )een reported "n assoc"at"on ."th ,6+ solut"ons. The "n"t"al 10-#0 &J should )e "n%used slo.ly .h"le care%ully o)serv"n( the pat"ent %or adverse events. '% hypersens"t"v"ty occurs0 ,6+ 130/0.4 should )e pro&ptly d"scont"nued and treat&ent %or the aller("c react"on should cont"nue unt"l sy&pto&s have resolved. Flu"d status should )e &on"tored on a re(ular )as"s dur"n( treat&ent ."th ,6+ 130/0.4 espec"ally "n those pat"ents ."th card"ac "nsu%%"c"ency or severe renal "&pa"r&ent. 'n severely dehydrated pat"ents0 crystallo"d solut"ons should )e ad&"n"stered pr"or to ,6+ solut"ons. +u%%"c"ent %lu"d should )e ad&"n"stered to prevent dehydrat"on. Added caut"on "s adv"sed .hen ad&"n"ster"n( ,6+ 130/0.4 to pat"ents ."th severe l"ver d"sease or severe )leed"n( d"sorders (e.(.0 severe cases o% von <"lle)rand3s d"sease!. Con"tor"n( o% the pat"ent3s cl"n"cal status as .ell as la)oratory tests (e.(.0 electrolytes0 renal %unct"on0 ac"d-)ase status and coa(ulat"on para&eters! "s .arranted dur"n( prolon(ed use o% ,6+ and/or .henever the pat"ent3s cond"t"on d"ctates close &on"tor"n(. +eru& a&ylase &ay )e "ncreased te&porar"ly a%ter use o% ,6+ 130/0.4 and &ay "nter%ere ."th the d"a(nos"s o% pancreat"t"s. At h"(h doses o% ,6+ 130/0.40 d"lut"onal e%%ects &ay result "n reduced levels o% clott"n( %actors0 other plas&a prote"ns and a reduct"on "n he&atocr"t. As ."th all plas&a su)st"tutes0 "n%us"on o% excess"ve ,6+ can lead to overload"n( o% the c"rculatory syste&. '% th"s occurs0 the "n%us"on should )e stopped and d"uret"cs ad&"n"stered. S*0C/)9 *8*29)3/8NS Bre(nancy cate(ory 1. =o ade:uate0 .ell-controlled stud"es "n pre(nant .o&en. *se only .hen the potent"al )ene%"t out.e"(hs the potent"al r"s/. 'n cl"n"cal tr"als0 no d"%%erences "n sa%ety or e%%ect"veness .ere noted "n pat"ents 65 years and older )ut the nu&)ers exposed "s l"&"ted. As a result0 a (reater sens"t"v"ty o% so&e older "nd"v"duals to ,6+ 130/0.4 cannot )e ruled out. 7"s/ o% adverse events &ay )e (reater "n those pat"ents ."th renal "&pa"r&ent s"nce ,6+ 130/0.4 "s excreted pr"&ary )y the /"dneys. Volu&e status0 rate o% "n%us"on and ur"ne output should )e &on"tored closely. +"nce older pat"ents are &ore l"/ely to have "&pa"red renal %unct"on0 these %actors should )e cons"dered .hen select"n( doses "n "nd"v"dual pat"ents. *8S3%)4;03/N: 01*04/0NC0 (8*3/8N)9 +a%ety pro%"le "s s"&"lar to that o)served "n cl"n"cal tr"als o% ,6+ 130/0.4. ,ypersens"t"v"ty react"ons0 urt"car"a0 )ronchospas& or hypotens"on .ere the &ost %re:uently reported ser"ous adverse events )ased upon spontaneous reports. D"stur)ances "n )lood coa(ulat"on can occur and appear to )e dose-dependent. S0N3/N09 0V0N3S There have )een no sent"nel events assoc"ated ."th ad&"n"strat"on o% 6% ,6+ 130/0.4. 988;<)9/;0/S82N#<)9/;0 (9)/S) 04484 4/S; *830N3/)9 As part o% a standard %or The Ro"nt 1o&&"ss"on (TR1!0 JA+A na&es are assessed dur"n( the %or&ulary select"on o% dru(s. 4ased on cl"n"cal Pud(&ent and an evaluat"on o% JA+A "n%or&at"on %ro& %our data sources (Jex"-1o&p0 *+B Onl"ne JA+A F"nder0 F"rst Data)an/0 and '+CB 1on%used Dru( =a&e J"st!0 the %ollo."n( dru( na&es &ay cause JA+A con%us"on; JA/+A %or (ener"c na&e (,ydroxyethyl starch0 ,6+ 130/0.40 class"%"ed as tetrastarch!; Tetraca"ne0 ,espan0 *pdated vers"ons &ay )e %ound at ....p)&.va.(ov or va...p)&.va.(ov (+epte&)er #011!
14
6% Hydroxyethyl Starch 130/0.4 in 0.9% NaCl (Voluven ,extend and hetastarch. JA/+A %or trade na&e (Voluven !; Volu&en0 Voltaren #42: /N304)C3/8NS D7*@-D7*@ The sa%ety o% co&pata)"l"ty o% dru(s or other su)stances added to ,6+ 130/0.4 has not )een esta)l"shed. D7*@-JA4 +eru& a&ylase &ay )e "ncreased te&porar"ly a%ter use o% ,6+ 130/0.4 and &ay "nter%ere ."th the d"a(nos"s o% pancreat"t"s. At h"(h doses o% ,6+ 130/0.40 d"lut"onal e%%ects &ay result "n reduced levels o% clott"n( %actors0 other plas&a prote"ns and a reduct"on "n he&atocr"t. )CI2/S/3/8N C8S3S 3a'le D6 Colloidal Solution Voluven He-&an 6% Hextend 6% (electrolyteHeta-tarch 6% #extran 40 )l'u!in E% ((E0<E00 !l )l'u!in (E% (E0<100 !l V) *24CH)S0S 3a'le A6 Kune<)u$u-t (011 H0S Solution Voluven (ca-e o, 1E He-&an (ca-e o, 1( Hextend 6% (ca-e o, 1( Heta-tarch 6% (ca-e o, 1( #extran 40 (ca-e o, 1( )l'u!in E% )l'u!in (E% *H)4%)C80C8N8%/C )N)95S/S =one pu)l"shed. C8NC92S/8NS The FDA approved hydroxyethyl starch 6% 130/0.4 (Voluven ! "n late #00$ %or the prophylax"s and treat&ent o% hypovole&"a. 't "s a&on( a nu&)er o% hydroxyethyl starch solut"ons ava"la)le "n the *+. ,ydroxyethyl 6% 130/0.4 "s o%ten re%erred to as a th"rd-(enerat"on or ne.er (enerat"on starch and .as developed ."th the (oal o% reduc"n( /no.n adverse e%%ects that can occur ."th older hydroxyethyl starch solut"ons0 "nclud"n( severe0 delayed-onset prur"t"s0 "&pa"red coa(ulat"on and renal dys%unct"on. +tarches ."th h"(her &olecular .e"(ht0 h"(her de(ree o% &olar su)st"tut"on and h"(her 1#/16 rat"o have (reater pers"stence ."th"n the "ntravascular space )ut are also )el"eved to )e assoc"ated ."th a (reater r"s/ %or t"ssue accu&ulat"on and adverse events. ,ydroxyethyl 130/0.4 has a lo.er &olecular .e"(ht0 a lo.er de(ree o% &olar su)st"tut"on )ut a h"(her 1#/16 rat"o. A nu&)er o% cl"n"cal tr"als have )een conducted "n .h"ch the e%%"cacy and sa%ety o% ,6+ 130/0.4 .as *pdated vers"ons &ay )e %ound at ....p)&.va.(ov or va...p)&.va.(ov (+epte&)er #011!
Co-t/2nit (J 3#.H3 (500 &l! $.KH (500 &l! 15.34 (500 &l! $.$6-11.K0 (500 &l! 16.0K (500 &l! #5.0H-4H.H# 1$.H#-3$.43
Co-t/#ay (J (2-in$ !ax. daily do-e in D0 =$ *t. #30.50L #3.6$ 46.0# #3.#$-35.40 4K.#4 ---
Co-t/*atient (J (!ean. a--u!in$ 1E00 !l/day in ,ir-t (4 hrHK.K0 #3.6$ 46.0# #3.#$-35.40 4K.#4 14H.$6 1K$.15 (500 &l!
LCax"&u& da"ly dose "s h"(her ."th Voluven vs. other ,6+ products (50 &l//(/day vs. #0 &l//(/day0 respect"vely!.
3otal 2nit#10 K5# 1#36 4536 46K ---
3otal Co-t (J 6055H 603$H #00664 3303K1 110061 #KH0505 K500$00
15
6% Hydroxyethyl Starch 130/0.4 in 0.9% NaCl (Voluven co&pared to a var"ety o% crystallo"d (e.(.0 nor&al sal"ne0 7"n(er3s lactate0 etc.! or collo"dal (e.(.0 other starches0 al)u&"n0 (elat"n 8not ava"la)le "n the *+9 and dextran! solut"ons "n the sett"n( o% cr"t"cal "llness/seps"s or sur(ery. Because of the serious allegations against r. !oachim Boldt of fabricating evidence" not obtaining #$B approval and forging names of co(authors" none of the trials in which r. Boldt is listed as a contributor were included. 'n cr"t"cally "ll or sept"c pat"ents0 there are l"&"ted data co&par"n( 6% ,6+ 130/0.4 to other collo"ds or crystallo"ds (ava"la)le "n the *+!. There%ore "t "s d"%%"cult to deter&"ne .hether ,6+ 130/0.4 o%%ers any advanta(e or d"sadvanta(es over the other products used %or %lu"d resusc"tat"on "n sept"c pat"ents. Ava"la)le (u"del"nes support the use o% e"ther collo"ds or crystallo"ds ."thout a pre%erence %or %lu"d type due to a lac/ o% ev"dence prov"n( d"%%erences "n relevant outco&es )et.een products. 4ecause o% "ncons"stent data re(ard"n( the e%%ect o% ,6+ solut"ons on renal %unct"on "n pat"ents ."th seps"s0 t.o cl"n"cal tra"ls have )een des"(ned and are under.ay to help ans.er that :uest"on; &'S(Scandinavian Starch for Severe Sepsis)Septic Shock Trial* comparing '+ ,-S ./0)0.1 to crystalloids in 200 patients with severe sepsis. The primary outcome measure in this trial is a composite of mortality and end(stage kidney failure. A second trial &3rystalloid versus ,ydro4yethyl Starch Trial 53,-ST%* is comparing '+ ,-S ./0)0.1 to crystalloids 5saline% in 6"000 critically ill patients in the intensive care unit. The primary endpoint of this trial is death from all causes at 70 days. Secondary endpoints include renal failure" S89A score" use of renal replacement therapy" #3: stay" etc. The 3,-ST study began in April ;0.0. 'n the s"x "ncluded cl"n"cal tr"als "nvolv"n( sur("cal pat"ents0 cl"n"cal outco&es d"d not d"%%er s"(n"%"cantly )et.een 6% ,6+ 130/0.4 and e"ther crystallo"d or collo"ds ad&"n"stered (,6+ 6$0/0.$50 al)u&"n0 6% Dextran $0! "n per"operat"ve or postoperat"ve )lood loss0 trans%us"on re:u"re&ents or or(an %unct"on. 'n several stud"es0 d"%%erences "n certa"n var"a)les (e.(.0 levels o% #-hour postoperat"ve nad"r Factor V''' or von <"lle)rand Factor (v<F!0 sl"(htly "ncreased '=70 etc.! .ere o)served )ut the cl"n"cal s"(n"%"cance o% these d"%%erences "s un/no.n. 'n the study co&par"n( 6% ,6+ 130/0.4 to 6% ,etastarch (6$0/0.$5!0 althou(h so&e d"%%erences .ere o)served "n secondary endpo"nts0 the FDA &ed"cal rev"e.er co&&ented that sa%ety endpo"nts "n th"s part"cular tr"al .ere cons"dered "n a se:uent"al &anner0 so "% one endpo"nt .as not stat"st"cally d"%%erent0 analys"s o% su)se:uent endpo"nts could only )e cons"dered exploratory. The FDA rev"e.er concluded that super"or sa%ety could not )e proven )ased upon data %ro& the tr"al. A 1ochrane rev"e. o% %lu"d replace&ents "n a)do&"nal aort"c sur(ery %ound a lac/ o% ev"dence to support one %lu"d as the opt"&al %lu"d replace&ent "n pat"ents hav"n( a)do&"nal aort"c sur(ery. 6x"st"n( (u"del"nes %or %lu"d replace&ent "n adult sur("cal pat"ents do not reco&&end a part"cular %lu"d replace&ent )ut reco&&end that e"ther )alanced crystallo"ds or a >su"ta)le? collo"d )e used to replace lost )lood. F"nally0 in vitro coa(ulat"on stud"es de&onstrate that 6% ,6+ 130/0.4 does have an e%%ect on platelet %unct"on/coa(ulat"on as assessed )y T6@ &easure&ents. 4ased upon th"s "n%or&at"on0 "t "s unclear "% 6% ,6+ 130/0.4 o%%ers any advanta(e or d"sadvanta(e over crystallo"ds or other collo"ds %or %lu"d replace&ent "n sur("cal pat"ents. <"th re(ard to adverse e%%ects0 ava"la)le ev"dence "s lac/"n( %ro& cl"n"cal tr"als to support a sa%ety advanta(e o% 6% ,6+ 130/0.4 over other hydroxyethyl starches. +"nce the &ax"&u& approved da"ly dose %or %lu"d resusc"tat"on "s h"(her %or 6% ,6+ 130/0.4 (50 &l//(/day! than other ava"la)le starches (#0&l//(/day!0 "t "s conce"va)le that 6% ,6+ 130/0.4 &"(ht )e an opt"on %or those pat"ents re:u"r"n( lar(e a&ounts o% crystallo"d and/or collo"d solut"ons (D #0&l//(/day! or as an alternat"ve to al)u&"n. ,o.ever0 there are l"&"ted pu)l"shed data "n pat"ents rece"v"n( &ax"&u& da"ly doses o% 6% ,6+ 130/0.4 (Voluven ! so pat"ents rece"v"n( these h"(her doses should )e closely &on"tored %or adverse events "nclud"n( )leed"n(0 delayed onset prur"t"s and renal "&pa"r&ent. 40@040NC0S 1. Voluven (6% hydroxyethyl starch 130/0.4 "n 0.H% sod"u& chlor"de %or "nPect"on! Broduct 'n%or&at"on. Dece&)er #00$. ,osp"ra0 'nc. Ja/e Forest0 'll"no"s 60045. #. 4oldt R0 +uttner +. Blas&a +u)st"tutes. C"nerva Anesth #005E$1;$41-$5K. 3. Ao2e/-Jan(enec/er +A. 6%%ects o% ,ydroxyethyl +tarch +olut"ons on ,e&ostas"s. Anesthes"olo(y #005E103;654-660. 4. <estphal C0 Ra&es CFC0 Ao2e/-Jan(enec/er A0 et al. ,ydroxyethyl +tarches. Anesthes"olo(y *pdated vers"ons &ay )e %ound at ....p)&.va.(ov or va...p)&.va.(ov (+epte&)er #011!
16
6% Hydroxyethyl Starch 130/0.4 in 0.9% NaCl (Voluven 5. 6. #00HE111;1K$-#0#. 4unn F0 Tr"ved" D0 Ashra% +. 1ollo"dal +olut"ons %or Flu"d 7esusc"tat"on. 1ochrane Data)ase o% +yste&at"c 7ev"e.s #0110 'ssue 30 Art. =o.;1D00131H. DO'; 10.100#/14651K5K.1D00131H.pu)3. Run(he"rnr"ch 10 +auer&ann .0 4epperl"n( F0 Vo(t =,. Volu&e 6%%"cacy and 7educed 'n%luence on Ceasures o% 1oa(ulat"on us"n( ,ydroxyethyl +tarch 130/0.4 (6%! ."th an Opt"&"2ed "n v"vo Colecular <e"(ht "n Orthoped"c +ur(ery; A 7ando&"2ed0 Dou)le-4l"nd +tudy. Dru(s 7 D #004E5;1-H. http;//....%da.(ov/do.nloads/Adv"sory1o&&"ttees/1o&&"tteesCeet"n(Cater"als/Bed"atr"cAdv" sory1o&&"ttee/*1C1H#0$#.pd% (Accessed 4-13-11! @an TR0 +opp"tt A0 Caroo% C. @oal-D"rected Flu"d Ad&"n"strat"on 7educes Jen(th o% ,osp"tal +tay A%ter CaPor +ur(ery. Anesthes"olo(y #00#EH$;K#0-K#6 Cayer R0 4oldt R0 Cen("stu AC. @oal-D"rected 'ntraoperat"ve Therapy 4ased on Autocal")rated Arter"al Bressure <ave%or& Analys"s 7educes ,osp"tal +tay "n ,"(h-7"s/ +ur("cal Bat"ents; A 7ando&"2ed0 1ontrolled Tr"al. 1r"t"cal 1are #010E14;71K epu) 4enes R0 1hytra '0 Alt&an B0 et al. 'ntraoperat"ve Flu"d Opt"&"2at"on *s"n( +tro/e Volu&e var"at"on "n ,"(h 7"s/ +ur("cal Bat"ents; 7esults o% Brospect"ve 7ando&"2ed +tudy. 1r"t"cal 1are #010E14(3!;711K 6pu) #010 Rune 16. RhanP" +0 V"v"an-+&"th A0 Jucena-A&aro +0 et al. ,ae&odyna&"c Opt"&"2at"on '&proves T"ssue C"crovascular Flo. and Oxy(enat"on A%ter CaPor +ur(ery; A 7ando&"2ed 1ontrolled Tr"al. 1r"t"cal 1are #010E14;7151 6pu). 7"vers 60 =(uyen 40 ,avstad +0 et al. 6arly @oal-D"rected Therapy "n the Treat&ent o% +evere +eps"s and +ept"c +hoc/. =6RC #001E345;136K-13$$ http;//....anesthes"a-anal(es"a.or(/content/10H/6/1$5#.lon( (Accessed 5-3-11! http;//....nc)".nl&.n"h.(ov/pu)&ed/1HH#3501 (Accessed 5-3-11! http;//....ne.s."se.co&/art"cles/v"e./5$04$$Qpr"nt-art"cle (Accessed 5-3-11! http;//....tele(raph.co.u//health/K36066$/C"ll"ons-o%-sur(ery-pat"ents-at-r"s/-"n-dru(-research%raud-scandal.ht&l (Accessed 5-3-11! http;//....&edpa(etoday.co&/Anesthes"olo(y/Anesthes"olo(y/#51HK (Access 5-3-11! http;//Pournals.l...co&/anesthes"olo(y/Docu&ents/6'1%#0Ro"nt%#0+tate&ent%#0on %#07etract"ons%#01#Car#011.pd% (Accessed 5-3-11! Run(he"nr"ch 10 +charp% 70 <ar(enau C0 et al. The Bhar&aco/"net"cs and Tolera)"l"ty o% an 'ntravenous 'n%us"on o% the =e. ,ydroxyethyl +tarch 130/0.4 (6%0 500 &J! "n C"ld-to-+evere 7enal '&pa"r&ent. Anesth Anal( #00#EH5;544-551. http;//....&ed"calcr"ter"a.co&/s"te/"ndex.phpQv"e.Iart"cleScat"dI4$%3Acr"t"calcareS"dI#66%3Aut"so%aSt&plIco&ponentSpr"ntI1Spa(eISopt"onIco&TcontentS'te&"dIK0S lan(Ien (Accessed 5-4-11! Du)"n A0 Bo2a CO0 1asa)ella 1A0 et al. 1o&par"son o% 6% ,ydroxyethyl +tarch 130/0.4 and +al"ne +olut"on %or 7esusc"tat"on o% the C"croc"rculat"on Dur"n( the 6arly @oal-D"rected Therapy o% +ept"c Bat"ents. R 1r"t 1are #010E#5;65He1-65HeK. A&er"can 1olle(e o% 1hest Bhys"c"ans/+oc"ety o% 1r"t"cal 1are Ced"c"ne 1onsensus 1on%erence 1o&&"ttee %or De%"n"t"on o% +eps"s. De%"n"t"ons %or +eps"s and Or(an Fa"lure and @u"del"nes %or the *se o% 'nnovat"ve Therap"es. 1HH#E#0;K64-K$4. Balu&)o D0 +erv"llo @0 D3A&ato J0 et al. The 6%%ects o% ,ydroxyethyl +tarch +olut"on "n 1r"t"cally 'll Bat"ents. C"nerva Anestes"ol #006E$#;655-664. T"rya/"o(lu O0 N"ld"2 @0 Vural ,0 et al. ,ydroxyethyl +tarch versus 7"n(er +olut"on "n 1ard"opul&onary 4ypass Br"&e +olut"ons (A 7ando&"2ed 1ontrolled Tr"al!. Rournal o% 1ard"othorac +ur( #00KE3;45. 1ho" N+0 +h"& NA0 ,on( +<0 et al. 1o&par"n( the 6%%ects o% 5% Al)u&"n and 6% ,ydroxyethyl +tarch 130/0.4 on 1oa(ulat"on and 'n%la&&atory 7esponse .hen used as Br"&"n( +olut"ons %or 1ard"opul&onary 4ypass. C"nerva Anesthes"ol #010E$6;1-K. @andh" +D0 <e"s/op% 740 Run(he"nr"ch 10 et al. Volu&e 7eplace&ent Therapy dur"n( CaPor Orthoped"c +ur(ery *s"n( Voluven (,ydroxyethyl +tarch 130/0.4! or ,etastarch. Anesthes"olo(y #00$E106;11#0-11#$.
7.
K. H. 10. 11. 1#. 13. 14. 15. 16. 1$. 1K. 1H. #0. #1. ##. #3. #4. #5. #6.
17
27. http;//....%da.(ov/4"olo("cs4loodVacc"nes/4lood4loodBroducts/ApprovedBroducts/=e.Dru(A
ppl"cat"ons=DAs/uc&163H11.ht& (Accessed 5-11-11! #K. Cu/htar A0 A)oul%etouh F0 O)ayah @0 et al. The +a%ety o% Codern ,ydroxyethyl +tarch "n J"v"n( Donor J"ver Transplantat"on; A 1o&par"son ."th ,u&an Al)u&"n. Anesth Anal( #00HE10H;H#4H30. 29. http;//....%da.(ov/4"olo("cs4loodVacc"nes/4lood4loodBroducts/ApprovedBroducts/=e.Dru(A ppl"cat"ons=DAs/uc&0K3364.ht& (Accessed 5-11-11! 30. Berel B0 7o)erts '0 Bearson C. 1ollo"ds versus 1rystallo"ds %or Flu"d 7esusc"tat"on "n 1r"t"cally 'll Bat"ents. 1ochrane Data)ase o% +yste&at"c 7ev"e.s #00$0 'ssue 4. Art. =o.; 1D00056$. DO'; 10.100#/14651K5K.1D00056$.pu).3. 31. Dunn0 F0 Tr"ved" D0 Ashra% +. 1ollo"d +olut"ons %or Flu"d 7esusc"tat"on. 1ochrane Data)ase o% +yste&at"c 7ev"e.s #00KE'ssue 1EArt. =o; 1D00131H. DO'; 10.100#/14651K5K.1D00131H.pu)#. 3#. Berner A0 ,aase =0 <etterslev R0 et al. 1o&par"n( the 6%%ect o% ,ydroxyethyl +tarch 130/0.4 ."th 4alanced 1rystallo"d +olut"on on Cortal"ty and A"dney Fa"lure "n Bat"ents ."th +evere +eps"s (6++cand"nav"an +tarch %or +evere +eps"s/+ept"c +hoc/ Tr"al!; +tudy Brotocol0 Des"(n and 7at"onale %or a Dou)le-4l"nded0 7ando&"2ed 1l"n"cal Tr"al. Tr"als #011E1#;#4. 33. Dell"n(er 7B0 Jevy CC0 1arlet RC0 et al. +urv"v"n( +eps"s 1a&pa"(n; 'nternat"onal @u"del"nes %or Cana(e&ent o% +evere +eps"s and +ept"c +hoc/; #00K. 'ntens"ve 1are Ced #00KE34;1$-60. 34. 6v"dence-4ased 1ollo"d *se "n the 1r"t"cally 'll; A&er"can Thorac"c +oc"ety 1onsensus +tate&ent. A& R 7esp"r 1r"t 1are Ced #004E1$0;1#4$-1#5H. 35. +chort(en F0 Jacherade R10 4runeel F0 et al. 6%%ects o% ,ydroxyethyl +tarch and @elat"n on 7enal Funct"on "n +evere +eps"s; A Cult"center 7ando&"2ed +tudy. Jancet #001E35$;H11-H16. 36. +AF6 study "nvest"(ators. A 1o&par"son o% Al)u&"n and +al"ne %or Flu"d 7esusc"tat"on "n the 'ntens"ve 1are *n"t. = 6n(l R Ced #004E350;##4$-##56. 3$. The 1rystallo"d versus ,ydroxyethyl +tarch Tr"al; Brotocol %or a Cult"-1enter 7ando&"2ed0 1ontrolled Tr"al o% Flu"d 7esusc"tat"on ."th 6% ,ydroxyethyl +tarch (,6+! 1o&pared to 0.H% +od"u& 1hlor"de (+al"ne! "n 'ntens"ve 1are Bat"ents on Cortal"ty. 'ntens"ve 1are Ced #011E3$;K16-K#3. 3K. 7e"nhart A0 Ta/ala R. ,ydroxyethyl +tarches; <hat Do <e +t"ll Ano.Q Anesthes"a Anal( #011E11#;50$-511. 3H. Jee R+0 Ahn +<0 +on( R<0 et al. 6%%ect o% ,ydroxyethyl +tarch 130/0.4 on 4lood Joss and 1oa(ulat"on "n Bat"ents <"th 7ecent 6xposure to Dual Ant"platelet Therapy *nder(o"n( O%%Bu&p 1oronary Artery 4ypass @ra%t +ur(ery. 1"rc R #011E Au( #nd 8epu) ahead o% pr"nt9. 40. Udolse/ ,R0 Ve(%ors T0 J"ndahl J0 et al. ,ydroxyethyl +tarches and Dextra Dur"n( ,"p 7eplace&ent +ur(ery; 6%%ects on 4lood Volu&e and 1oa(ulat"on. Acta Anaesthes"ol +cand #011E55;6$$-6K5. 41. Fen(er-6r"/son 10 Rensen TC0 Ar"stensen 4+0 et al. F")r"no(en +u)st"t"on '&proves <hole 4lood 1lot F"r&ness a%ter D"lut"on ."th ,ydroxyethyl +tarch "n 4leed"n( Bat"ents *nder(o"n( 7ad"cal 1ystecto&y; A 7ando&"2ed0 Blace)o-1ontrolled 1l"n"cal Tr"al. R Thro&) and ,ae&ost #00HE$;$H5-K0#. 4#. Too&ton( 70 +u/so&pon( +. 'ntravenous Flu"ds %or A)do&"nal Aort"c +ur(ery. 1ochrane Data)ase o% +yste&at"c 7ev"e.s #0100'ssue 1.Art.=o; 1D000HH1. DO'; 10;100#/14651K5K.1D000HH1.pu).#. 43. B"a22a O0 +carpat" @0 Tu%ano 7. *pdate on Trans%us"on +olut"ons dur"n( +ur(ery; 7ev"e. o% ,ydroxyethyl +tarches 130/0.4. 'nt R @en Ced #010E3;#K$-#H5. 44. 7aPa +@0 A/htar +0 +hah)a2 N0 Casood A. 'n 1ard"ac +ur(ery Bat"ents Does Voluven '&pa"r 1oa(ulat"on Jess Than Other 1ollo"dsQ 'nteract"ve 1ard"o and Thorac +ur( #011E1#;10##-10#$. 45. http;//....reduc"n(len(tho%stay.or(/doc/03@'FTA+*Bsu&&aryla"doutF'=AJ.pd% (Accessed H##-11! 46. http;//Pournal."cs.ac.u//pd%/1001013.pd% (Accessed H-##-11! 4$. 4an( +70 A"& N,0 A"& @+. The 6%%ects on in vitro ,e&od"lut"on ."th 6% ,ydroxyethyl +tarch (,6+! (130/0.4! +olut"on on Thro&)elasto(raph Analys"s "n Bat"ents *nder(o"n( J"ver Transplantat"on. 1l"n Transplant #011E#5;450-456. *pdated vers"ons &ay )e %ound at ....p)&.va.(ov or va...p)&.va.(ov (+epte&)er #011!
18
6% Hydroxyethyl Starch 130/0.4 in 0.9% NaCl (Voluven 4K. Aa(n R@0 Ahn ,R0 A"& +@0 et al. The ,e&ostat"c Bro%"les o% Bat"ents ."th Type O and =on-O 4lood A%ter Acute =or&ovole&"c ,e&od"lut"on ."th 6% ,ydroxyethyl +tarch (130/0.4!. Anesth Anal( #006E103;1543-154K. 4H. C"tter&ayr C0 +tre"% <0 ,aas T0 et al. 6%%ects o% 1ollo"d and 1rystallo"d +olut"ons on 6ndo(enous Act"vat"on o% F")r"nolys"s and 7es"stance o% Boly&er"2ed F")r"n to 7eco&)"nant T"ssue Blas&"no(en Act"vator added e4 vivo. 4r R Anaesth #00KE100;30$-314. 50. 4or/ A. Brur"t"s Brec"p"tated )y ,ydroxyethyl +tarch; A 7ev"e.. 4r R Der&atol #005E15#;3-1#. 51. Cueller T0 +ch"&etta <0 D"epl"n(er0 40 et al. 'n%luence o% ,ydroxyethyl +tarch (6% ,6+ 130/0.4! Ad&"n"strat"on on ,e&atolo(y and 1l"n"cal 1he&"stry Bara&eters. 1l"n 1he& Ja) Ced #00KE46;55K-56#. 5#. 6hthol2ner 6A0 C"el/e JJ0 1alat2"s A=0 et al. 1oa(ulat"on 6%%ect o% a 7ecently Developed ,ydroxyethyl +tarch (,6+ 130/0.4! 1o&pared to ,ydroxyethyl +tarches ."th ,"(her Colecular <e"(ht. Acta Anaesthes"ol +cand #000E44;1116-11#1. 53. Fen(er-6r"/son 10 An/er-Coller0 60 ,eslop R0 et al. Thro&)elasto(raph"c <hole 4lood 1lot For&at"on A%ter -4 Vivo Add"t"on o% Blas&a +u)st"tutes; '&prove&ents o% the 'nduced 1oa(ulopathy ."th F")r"no(en 1oncentrate. 4r R Anaesth #005EH4;3#4-3#H. 54. J"u F10 J"ao 1,0 1han( N<0 et al. ,ydroxyethyl +tarch 'nter%eres ."th ,u&an 4lood -4 Vivo 1oa(ulat"on0 Blatelet Funct"on and +ed"&entat"on. Acta Anaesthes"ol Ta".an #00HE4$;$1-$K. 55. Ra&n"c/" C0 Uoll"n(er A0 +e"%ert 40 et al. 1o&pro&"sed 4lood 1oa(ulat"on; An #n Vitro 1o&par"son o% ,ydroxyethyl +tarch 130/0.4 and ,ydroxyethyl +tarch #00/0.5 *s"n( Thro&)elasto(raphy. Anesth Anal( 1HHKEK$;HKH-HH3. 56. =e%% TA0 F"schler J0 Car/ C0 et al The 'n%luence o% T.o D"%%erent ,ydroxyethyl +tarch +olut"ons (6% ,6+ 130/0.4 and #00/0.5! on 4lood V"scos"ty. 5$. +ossdor% C0 Carx +0 +chaarsch&"dt 40 et al. ,6+ 130/0.4 '&pa"rs ,ae&ostas"s and +t"&ulates Bro-'n%la&&atory 4lood Blatelet Funct"on. 1r"t"cal 1are #00HE13;7#0K. 5K. Uarychans/" 70 Tur(eon AA0 Fer(usson0 DA0 et al. 7enal Outco&es and Cortal"ty Follo."n( ,ydroxyethyl +tarch 7esusc"tat"on o% 1r"t"cally 'll Bat"ents; +yste&at"c 7ev"e. and CetaAnalys"s o% 7ando&"2ed Tr"als. Open Ced"c"ne #00HE3;61H6-#0H. 5H. Dart A40 Cutter T10 7uth 1A0 Ta)ac/ +B. ,ydroxyethyl +tarch (,6+! Versus Other Flu"d Therap"es; 6%%ects on A"dney Funct"on. 1ochrane Data)ase o% +yste&at"c 7ev"e.s #0100 'ssue 1. Art. =o.; 1D00$5H4. DO'; 10.100#/14651K5K.1D00$5H4.pu)#. 60. Dav"dson 'R. 7enal '&pact o% Flu"d Cana(e&ent ."th 1ollo"ds; A 1o&parat"ve 7ev"e.. 6ur R Anaesth #006E#3;$#1-$3K. 61. <"eder&ann 1R. ,ydroxyethyl +tarch; 1an the +a%ety Bro)le&s )e '(noredQ <"en Al"n <ochenschr #004E1K;5K3-5H4. 6#. ,arto( 1+0 Aohl C0 7e"nhart A. A +yste&at"c 7ev"e. o% Th"rd-@enerat"on ,ydroxyethyl +tarch (,6+ 130/0.4! "n 7esusc"tat"on; +a%ety =ot Ade:uately Addressed. Anesth Anal( #011E11#;635645.
)**0N#/1 (Only those rando&"2ed tr"als co&par"n( ,6+ 130/0.4 to crystallo"ds0 al)u&"n or other ,6+ solut"ons ava"la)le "n the *+ have )een cons"dered. 'n add"t"on0 those stud"es l"st"n( Dr. Roach"& 4oldt as an author have )een excluded %ro& the rev"e. 8see %ootnote )elo.L9. The FDA .e)s"te .as searched %or relevant approval and overs"(ht "n%or&at"on! 3a'le 16 Clinical 3rial- o, H0S 130/0.4
Clinical 3rial #u'in(1 70 10 )l"nded o)server0 B"lot0 # hosp"tals0 nI#50 #4 hrs *o&ulation Se&tic /C2 &atient'nclus"on; 1K or older0 'n%ect"on ."th # or D s"(ns o% +'7+ (as de%"ned )y /ntervention/*ri!ary 8utco!e %ea-ure H0S 130/0.4 v-. NSS (alon( ."th vasopressors0 do)uta&"ne0 or )lood trans%ust"ons0 prn! to 4e-ultNB(E. 4 died (( each $rou& . 1 ,6+ excluded due to B6 and seps"s .as ruled out as cause o% shoc/. Br"&ary Outco&e at #4 hrs (,6+ vs. )dver-e 0vent-/ Co!!ent=o AD6s reported d"rectly attr")uta)le to "ntervent"on 1o&&ents;
19

+u)l"n(ual &"croc"rculat"on o% sept"c pat"ents (S0*S/S the A& 1oll 1hest Bhys"c"ans/ +oc"ety o% 1r"t. 1are Ced cr"ter"a!##0 CAB M65 && ,( desp"te a #0 &J//( crystallo"d challen(e or )lood lactate o% 4 &&ol/J orD 6xclus"on; +tro/e0 A1+0 pul& ede&a0 status asth&at"cus0 card"ac arrhyth&"a0 @' )leed"n(0 se"2ures0 )urns0 trau&a0 rece"ved &ore than 1500 &J o% %lu"d0 etc. &a"nta"n 1VB K-1# && ,(0 CAB 65 && ,( or D0 +cv0# $0% or D Br"&ary Outco&e; C"croc"rculatory para&eters a%ter #4 hrs o% resusc"tat"on as assessed )y su)l"n(ual &"croc"rculat"on evaluated )y s"destrea& dar/ %"eld "&a("n(; -V"deo "&a(es %ro& at least 5 d"%%erent s"tes -A value .as ass"(ned depend"n( upon the %lo. "n each vessel (no %lo. to cont"nuous! -CF' "s the &ean o% %lo. scores -Vascular dens"ty .as :uant"%"ed as the nu&)er o% vessels/&&# +econdary Outco&es; +OFA0 T'++ H0S 130/0.4 v-. H) (0% 6very day0 pat"ents rece"ved ,6+ or ,A at a volu&e to &a"nta"n B1<B )et.een 15 and 1K &&,( Br"&ary Outco&e; Ceasures o% he&odyna&"c status0 t"ssue oxy(enat"on status and ABA1,6 '' scores +econdary Outco&es; *nclear (see co&&ents! =++!; 1ap"llary dens"tyI=+ 1ap"llary CF'I#.5 vs. 1.6 % per%used cap"llar"esIK4% vs. 53% Ber%used cap"llary dens"tyI1H vs. 11 vessels/&&# (all pM0.005! +econdary Outco&es; +OFAI=+0 T'++I=+0 ac"d-)ase para&etersI=+ Core %lu"d %or volu&e expans"on "n =++ (roup vs. ,6+ (rat"o #.4;1! -B"lot study0 no val"d para&eters re(ard"n( &"cro-c"rculatory values "n 6@DT sept"c shoc/. +a&ple s"2e adPusted do.n.ard once &ore pu)l"shed "n%o .as ava"la)le. -+cr .as #.1 "n =++ (roup vs. 1.# "n ,6+ (roup (pI0.04K! and sho.ed a tendency to.ard a h"(her a&ount o% &eta)ol"c ac"dos"s and rece"ved &ore vasopressors on day 1. 't "s poss")le that pat"ents "n the =++ (roup .ere s"c/er and .ould have .orse &"croc"rculatory &easure&ents. -*n/no.n cl"n"cal s"(n"%"canceIs&all sa&ple s"2e0 no d"%%erence "n outco&es (+OFA0 T'++!0 relevance o% d"%%erences %ound =o AD6s reported d"rectly attr")uta)le to "ntervent"on 1o&&ents; -Br"&ary outco&e &easure not clearly stated. A l"st o% &easures .as prov"ded )ut h"erarchy o% "&portance .as not. -7esults sect"on prov"ded l"&"ted d"scuss"on o% results and .hether the stat"st"cal co&par"sons .ere &ade )et.een %lu"d replace&ent treat&ents or %ro& )asel"ne -+even pat"ents d"ed0 ho.ever unsure o% nu&)er per (roup. =o AD6s reported d"rectly attr")uta)le to "ntervent"on 1o&&ents; -un)l"nded0 unclear "% rando&"2ed (do not th"n/ so!. -+cr0 (#4 hrs! and 4*= (1# and #4 hrs! "ncreased s"(n"%"cantly "n ,6+ vs.
*alu!'o(3 70 s"n(le-center =I#00 5 days (S0*S/S
Se&tic /C2 &atient'nclus"on; #1 and older0 severe seps"s 6xclus"on; +crD#0 4*= D150 &(/dJ0 ur"ne output M#0 &l/h desp"te d"uret"cs0 severe l"ver %a"lure0 D'10 ter&"nal
NB(0 (10 !en. 10 >o!en . $ pat"ents d"ed0 unsure o% nu&)er per (roup. Br"&ary Outco&e ,6+ vs. ,A; -,e&odyna&"c para&eters; Te&p0 heart rate0 CAB0 BAB0 B1<B0 1VB *r"ne output (=+! Only 7V6F and 1' .ere s"(n"%"cantly "&proved %ro& )asel"ne or vs. ,A (pM0.05! -Oxy(enat"on para&eters; 'ncreased s"(n"%"cantly only "n the ,6+ (roup (pM0.05! althou(h unsure "% d"%%erent %ro& )asel"ne or %ro& ,A. -ABA1,6 '' scores; reduced "n the ,6+ (roup )ut "ncreased "n the ,A (roup. (pM0.05!
3irya=io$lu(4 Q 7 ((roups strat"%"ed )y r"s/ %actors! +"n(le center0 =I1400 $# hrs (C* +y&a-*ri!in$ Solution-
*atient- havin$ C)+: -ur$ery 'nclus"on; elect"ve 1A4@0 no others stated 6xclus"on; Breoperat"ve renal "nsu%%"c"ency
H0S 130/0.4 v-. 49 1500 &J ,6+ or 7J used "n 1B )ypass pr"&"n( V #00 &l &ann"tol and 60 &( sod"u& )"car)onate Br"&ary Outco&e; Ja)s; 6lectrolytes0 renal and l"ver %unct"on he&ostat"c para&eters0 a&ount o% pr"&e
NB140 (4asel"ne +cr; 1 &(/dJ 7J0 vs. 1.1 &(/dJ ,6+! ,6+ vs. ,A at 1# and #4 hrs; Only stat"st"cally d"%%erent values are reported; 1# hrs; '=7; 1.3H 7J vs. 1.05 ,6+ (pI0.0001! 4*=; 30 &(/dJ 7J vs. 41 &(/dJ ,6+ (pI0.0001! #4 hrs;
20

solut"on0 post-op dra"na(e0 )lood co&ponents trans%used at 1# and #4 hrs. At $# hrs0 1r 1l +econdary Outco&e; Q Br"&ary and secondary outco&es not clearly del"neated. Blatelets; 14K 103/ul 7J vs. 1KH ,6+ (pI0.001! '=7; 1.3K 7J vs. 1.1# ,6+ (pI0.001! 4*=; 3# &(/dJ 7J vs. 46 &(/dJ ,6+ (pI0.001! +cr; 1.1 &(/dJ 7J vs. 1.4 &(/dJ ,6+ (pI0.001! 1r1J $# hrs; 6K &l/&"n 7J vs. 64 &l/&"n ,6+ (=+! (4asel"ne 1r1lI$6 &l/&"n 7J vs. K# &l/&"n ,6+! Operat"ve and Bost-op Data; Only stat"st"cally d"%%erent values are reported; Flu"d added to pu&p dur"n( 1B4; 1360 &l 7J vs. 0 ,6+ L=o d"%%erence "n post-op )lood or FFB trans%us"ons. =o d"%%erence "n extu)at"on t"&e0 '1* stay0 creat"n"ne clearance or d"schar(e t"&e. 7J. -At $# hrs0 creat"n"ne clearance .as s"&"lar and stated to have )een >o)ta"ned.? *nsure ho. the values .ere o)ta"ned (est"&ated or calculated!. -4asel"ne 1r1l "n ,6+ .as K# &l/&"n vs. 64 &l/&"n at $# hrs post-op. 7J 1r1l .as $# &l/&"n )asel"ne vs. 6K &l/&"n $# hrs post-op -4*= h"(her "n ,6+ (roup. 1ould that )e expla"ned "n part due to no add"t"onal %lu"d ad&"n"stered dur"n( 1B4 vs. added %lu"d "n 7J (roupQ -'=7 .as s"(n"%"cantly h"(her "n 7J vs. ,6+ )ut no d"%%erences "n trans%us"on re:u"re&ents0 )leed"n(0 etc. -'% outco&es are s"&"lar0 .hy not use crystallo"dsQ =o AD6s reported d"rectly attr")uta)le to "ntervent"on. 1o&&ents; Authors report that 1B4 does lead to an e%%ect on coa(ulat"on. There%ore0 "t "s des"ra)le to choose pr"&"n( solut"ons hav"n( l"ttle to no add"t"onal e%%ect on coa(ulat"on. 'n add"t"on0 he&od"lut"on can lead to an e%%ect on clot stren(th. 'n th"s study0 there .as no d"%%erence "n any outco&e &easure )et.een (roups. ,o.ever0 there .ere d"%%erences %ro& )asel"ne. 5 pts "n ,6+ 130 had H ser"ous AD6s vs. H pts "n ,6+ 6$0 had 11 ser"ous AD6s. 3 ser"ous coa(ulopath"es .ere reported "n ,6+ 6$0 and none "n ,6+
Choi(E 70 4l"nded0 10 s"n(le-center0 =I360 #4 hrs postop (C* +y&a-*ri!in$ Solution-
*atient- -cheduled ,or elective !itral valve -ur$ery 'nclus"on; 6lect"ve &"tral valve sur(ery 6xclus"on; e&er(ency sur(ery0 /no.n 1AD0 "n%ect"ve endocard"t"s0 "n%la&&at"on0 coa(ulat"on d"sorder0 ant"platelet dru(s ."th"n the past 5 days0 l"ver d"sease0 +cr D1.40 JV6F M50%0 h() M10 &(/dJ
:andhi 70 D40 C10 =I1000 up to 4K hrs post-op and #K days post-op %or AD6s
26
*atient- -cheduled ,or !aGor ortho&edic -ur$ery >ith ex&ected 'lood lo-- LE00 !l 'nclus"on; under(o"n( elect"ve
H0S 130/0.4 v-. H) E% 500 &J o% ,6+ or 500 &J o% 5% ,A. Br"&"n( solut"on also conta"ned &ann"tol0 hepar"n0 su%entan"l0 &"da2ola&0 and 7"n(er3s solut"on. Outco&e Ceasures; -+tren(th o% %or&ed clots us"n( T6@ trac"n( on collected sa&ples o% )lood at 4 hrs a%ter 1B4 -1han(e "n he&ostat"c var"a)les (BJT0 ,1T0 BT0 aBTT! -=eed %or %lu"ds or )lood products -1han(e "n pro"n%la&&atory &ar/ers ('J-60 'J-K0 T=F-W0 <41! H0S 130/0.4 v-. H0S 6D0/0.DE 1ollo"d ad&"n"strat"on deter&"ned )y 1VB and arter"al )lood pressure. (1VB M10 &&,(0 collo"ds
NB36 T6@ trac"n(s; the rate o% clot develop&ent and stren(th o% %")r"n clot .ere reduced at 4 hrs vs. )asel"ne (pM0.05! "n )oth (roups. ,e&ostat"c para&eters; =o d"%%erence )et.een (roups0 )ut BJT and ,1T values .ere s"(n"%"cantly reduced %ro& )asel"ne (pM0.05! Flu"d or )lood products; =o d"%%erence )et.een (roups "n a&ounts o% crystallo"d or collo"dal %lu"d "n%used. =o d"%%erence "n trans%us"on o% )lood products 1han(e "n pro-"n%la&&atory &ar/ers; =o d"%%erence )et.een (roups )ut 'J-60 'J-K0 T=F .ere all s"(n"%"cantly "ncreased 0.5 hrs a%ter 1B40 and 'J-60 'J-K0 T=F and <41 .ere s"(n"%"cantly elevated %ro& )asel"ne at 4 and 1# hrs a%ter 1B4. NB110 enrolled. 10 >ithdra>n 'e,ore -ur$ery. NB100 co!&leted -tudy. Cost co&&on sur(ery .as o% the h"p or sp"ne. Br"&ary Outco&e; ,6+ 130; 16#3 &l ,6+ 6$0; 15K4 &l (=+!
21

(%aGor ortho&edic -ur$ery orthoped"c sur(ery ."th an expected )lood loss o% D500 &l. 6xclus"on; Aller(y to ,6+0 coa(ulat"on d"sorder0 renal dys%unct"on or anur"a not related to hypovole&"a0 severe card"ac d"sease (=N,A class ''' or 'V!0 unsta)le an("na or pre(nancy. "n%used!. +tudy collo"ds .ere stopped %or 1VB D15 &&,( Br"&ary Outco&e; Total volu&e o% collo"d solut"on re:u"red %or "ntraoperat"ve volu&e resplace&ent +econdary Outco&e; Total %lu"d "nput/output0 use o% vasoact"ve &eds Br"&ary +a%ety Outco&e; Ber"operat"ve red )lood cell loss ("nduct"on o% anesthes"a to 4K hrs post-op0 nad"r %actor V''' act"v"ty0 nad"r v<F ant"(en conc ."th"n # hrs a%ter sur(ery0 use o% FFB A Br"or" su)(roup analys"s; 1! Bts he&odyna&"cally sta)le at end o% .ound close and "n post-anesthes"a care un"t #! Bts ."thout &aPor )lood loss and ."thout use o% other collo"ds. 3! Bts rece"ved D1000 &l ,6+ 130 or ,6+ 6$0 =o d"%%erence "n volu&es o% ,6+ "n%used "n any o% the 3 >A Br"or"? su)(roupsE no d"%%erence "n crystallo"d ad&"n or 1VB. +econdary Outco&e; =o d"%%erence "n %lu"d "nput )et.een (roups ."th the except"on o% .hen 741sV .hole )lood and salva(ed )lood .ere co&)"ned "n %avor o% ,6+ 130 (pI0.0#H6 only %or pts rece"v"n( the %lu"d type and pI0.1H16 %or all pts! 'n those pts rece"v"n( D1000 &l o% ,6+ 130 or 6$00 the only d"%%erence "n %lu"d "nput .as .hen 741s0 .hole )lood and salva(ed )lood .ere co&)"ned (pI0.0345 only "n pts rece"v"n( that %lu"d type0 pI0.140K %or all pts!. =o d"%%erence "n vasoact"ve therapy Br"&ary +a%ety Outco&es; 1alculated 741 loss and est"&ated )lood loss .ere not d"%%erent )et.een (roups. =ad"r %actor V''' .as 1H% lo.er "n the ,6+ 6$0 vs. ,6+ 130 (roup (&B0.0499! # hrs post-op. 'n the (roup rece"v"n( D1000 &l o% collo"d0 FV''' nad"r .as lo.er "n ,6+ 6$0 vs. 130 (roup (pI0.04H! # hrs post-op =ad"r v<F # hrs post-op lo.er "n ,6+ 6$0 vs ,6+ 130 (roup (pI0.00K! "n the su)set o% pts rece"v"n( D1000 &l o% collo"d. =o d"%%erence "n 'TT populat"on and nad"r v<F.. At #4 and 4K hrs0 FV''' and v<F .ere h"(her "n ,6+ 130 vs. 6$0 (roup (BM0.0001! =o d"%%erence "n FFB ad&"n M@ir-t value i- 'a-eline 130 6$0 pvalue a*33 #K.H #K.1 #4 hr #H.K 33.$ pM0.05 4K hr 30.3 3#.6 *3 11.H 1#.1 #4 hr 1#.K 14.1 pM0.05 4K hr 1#.5 13.H @V/// 146. 143 #4 hr 3 151. pM0.05 4K hr #44 1 315. ##K. 3 1 v7@ 13#. 134. #4 hr K 6 pM0.05 4K hr ##0. 146. 1 6 #5K. #10. H K 130 (roup. (All rece"ved D 3 l"ters o% ,6+ 6$0!. =o deta"ls prov"ded o% the ser"ous AD6s and .hether or not they .ere related to the "ntervent"on or deta"ls on the ser"ous coa(ulopath"es. 1o&&ents; =o d"%%erence "n volu&e expand"n( or replace&ent e%%"cacy. 'n those pts re:u"r"n( )lood0 there .ere no d"%%erences "n re:u"re&ents %or "nd"v"dual co&ponents (FFB0 7410 .hole )lood0 salva(ed )lood!. ,o.ever0 a d"%%erence d"d ex"st "n %avor o% ,6+ 130 .hen the ad&"n"strat"on o% 741s0 .hole )lood and salva(ed )lood .ere co&)"ned. The d"%%erence .as only present "n pts rece"v"n( these treat&ents and not the 'TT populat"on. There .as a d"%%erence "n the # hr nad"r FV''' "n the 'TT pop and "n the su)(roup o% pts rece"v"n(D1000 &l collo"d. There .as no d"%%erence "n # hr nad"r v<F "n 'TT pop )ut .as a d"%%erence "n D1000 &l su)(roup. +&all sa&ple s"2e o% pat"ents. The authors co&&ented that ,6+ 130 &"(ht )e an alternat"ve "n those pat"ents re:u"r"n( lar(e volu&e replace&ent. /n the @#)N- revie> o, thi- -tudy. -ince the -a,ety end&oint- >ere only con-idered in a -eOuential !anner. i, one -a,ety end&oint >a- not di,,erent. analy-i- o, the next -a,ety end&oint could only con-idered
22

ex&loratory and not con,ir!atory. )- a re-ult. the @#) revie>er concluded that the -u&erior -a,ety o, H0S 130 over H0S 6D0 could not 'e concluded 'a-ed u&on the-e data.(D =o AD6s reported d"rectly attr")uta)le to "ntervent"on. 1o&&ents; All 3 pat"ents ."th severe renal "&pa"r&ent (1r1lM30 &l/&"n! .ere rando&"2ed to ,6+ (roup. 1ystat"n 1 "s %"ltered %ro& the )lood )y (lo&erul"0 there%ore can )e used to &on"tor chan(es "n @F7. As @F7 decreases0 less cystat"n 1 "s %"ltered and the levels "ncrease. There "s st"ll uncerta"nly a)out .hen and ho. th"s test should )e used. D"d not study the "n%luence o% volu&e therapy on "nte(r"ty o% renal tu)ular %unct"on .h"ch can )e &easured us"n( &ar/ers such as =acetyl-4-D(lucosa&"n"dase and (lutath"one trans%erasealpha. Authors co&&ent that &ost pts "n the"r study had nearly nor&al renal %unct"on )e%ore transplant0 there%ore unsure o% the e%%ect o% ,6+ on pts ."th a populat"on ."th &ore severe renal d"sease than "ncluded. 'n add"t"on0 the nonrenal sa%ety o% ,6+ "n these pts "s not /no.n. Jon(-ter& %ollo. up data %ro& th"s tr"al "s lac/"n(. Authors reported "nc"dence o% AD6s .as not d"%%erent )et.een (roups.
%u=htar(A 70 =I400 up to 4 days post-op (*atientunder$oin$ livin$ donor liver tran-&lantation
*t- >ith end<-ta$e liver di-ea-e havin$ livin$ donor liver tran-&lantation 'nclus"on; Bts hav"n( l"ver transplant 6xclus"on; pts hav"n( retransplantat"on0 upper a)do&"nal sur(ery0 portal ve"n thro&)os"s0 M1K yrs0 pr"&ary renal dys%unct"on
H0S 130 v-. H) E% 4olus o% #50 &l o% e"ther ,6+ or ,A %ollo.ed )y up to &ax ad&"n o% 50 &l//(/d to &a"nta"n 1VB )et.een 5-$ &&,( dur"n( "ntra operat"ve per"od and 4 post-op days. 7J solut"on .as ad&"n at 10 &l//(/hr. Br"&ary Outco&e; 6%%ect on renal %unct"on (+cr0 seru& cystat"n 1 and calculated 1r1l post-op and days 1-4 post-op
NB40 =o d"%%erence "n "sche&"a or operat"ve t"&e0 durat"on o% &echan"cal vent"lat"on0 start o% enteral %eed"n(. =o d"%%erence "n '1* or hosp"tal stay. One pat"ent "n each (roup needed 77T. Cean volu&e o% "ntraoperat"ve collo"d; ,6+; 30K0 &l vs. ,A; 3500 (=+! Cean total volu&e post-op; ,6+; 6##H vs. ,A 4636 &l (pI0.003! =et cu&ulat"ve %lu"d )alance; ,6+; 304$ vs. ,A 1100 (pI0.0#H! *se o% crystallo"ds0 741s0 FFB and ur"ne output d"d not d"%%er. *se o% d"uret"cs .as h"(her "n ,6+ vs. ,A. (pM0.05! +cr and 1r1l d"d not d"%%er throu(hout study per"od. 1ystat"n 1 levels tended to )e h"(her on days # and 3 "n the ,6+ (roup (pI0.0K! )ut could )e expla"ned )y &ore severe renal d"sease "n ,6+ (roup (all 3 pts ."th severe renal d"sease "n ,6+!
9ee39 70 OJ ()l"nded endpo"nt!0 +1 nI106
*t- on #)*3 and under$oin$ 8*C)+ -ur$ery 'nclus"on; Bts hav"n(
H0S 130/0.4 v-. Cry-talloid (*la-!a Soln ) ,6+ 130/0.4 up to 30
NB106 Br"&ary Outco&e; Overall0 per"operat"ve )lood loss d"d not
23

#4 hr %ollo. up (*atientreceivin$ #)*3 and under$oin$ 8*C)+ OB1A4 sur(ery and ta/"n( clop"do(rel and asp"r"n (DABT! ."th"n 5 days o% sur(ery. A s"n(le sur(eon per%or&ed all operat"ons. 6xclus"on; e&er(ency sur(ery0 C'0 h"story o% card"ac sur(ery0 h"story o% )leed"n( d"athes"s or l"ver dys%unct"on0 ePect"on %ract"on M40%0 h()M1# (/dl0 plts M1000000 &&30 a)nor&al aBTT0 '=70 +1r D1.4 &(/dl or uses o% (lycoprote"n '')/'''a "nh")"tors &l//(/d or crystallo"d to &a"nta"n 1' D#.# J/&"n0 +vO# D60%0 and ur"nary output 0.5 &l//(/h. 'n the ,6+ (roup0 "% &ax da"ly dose o% 30 &l//( d"d not &a"nta"n these he&odyna&"c para&eters0 a )alanced0 &ult"ple electrolyteconta"n"n( solut"on .as ("ven. =orep"nephr"ne0 n"tropruss"de and "% needed vasopress"n .ere used to &a"nta"n CAB )et.een 60-K0 &&,(. Br"&ary Outco&e; D"%%erence "n per"operat"ve )lood loss de%"ned as the )lood loss dur"n( sur(ery V."th"n the %"rst #4hr post-op Other Outco&es; Total "n%used %lu"d0 ur"ne output0 "ntraoperat"ve and #4hr post-op trans%us"on re:u"re&ents0 per&anent stro/e0 renal dys%unct"on (e"ther; +1r D# &l/dl0 D50% reduct"on "n est"&ated @F7 vs. )asel"ne and ne. re:u"re&ent %or 77T0 Bost-op C' and len(th o% hosp"tal"2at"on. T6@ var"a)les (sta(es o% )lood clot %or&at"on "n a (raph"c %or&at! .ere also &easured d"%%er )et.een (roups or .hen separated "nto )leed"n( "n the O7 or #4hr "n the '1*; Overall; 100#K &l (crystallo"d! vs. H$K &l (,6+!0 pI0.4K3 O7; #1K &l (crystallo"d! vs. #3# ,6+0 pI0.63$ '1* (#4 hr!; K10 &l (crystallo"d! vs. $53 (,6+!0 pI0.353 Other outco&e &easures; There .ere no d"%%erences "n trans%used p741s0 FFB or nu&)ers o% pat"ents re:u"r"n( trans%us"on o% e"ther )lood product. Core crystallo"d .as "n%used "n the crystallo"d vs. ,6+ (roup; K034# &l vs. 606H4 &l (pM0.001! Cean ,6+ volu&e ("ven; 1045K &l "n the ,6+ vs. none "n the crystallo"d (roup. (pM0.001! =o d"%%erences "n ur"ne output .ere noted. Authors noted that '=7 .as elevated post-op "n the ,6+ vs. crystallo"d (roup (pM0.0#K! )ut st"ll "n the nor&al ran(e. ,e&o(lo)"n levels .ere stat"st"cally lo.er "n the ,6+ vs. crystallo"d (roup. 4oth '=7 and he&o(lo)"n .ere s"&"lar )et.een (roups at )asel"ne. *se o% vasopressors .as not d"%%erent )et.een (roups. One pat"ent "n the ,6+ (roup developed renal %a"lure re:u"r"n( d"alys"s. Other endpo"nts %or &or)"d"ty d"d not d"%%er (e.(.0 len(th o% stay0 etc.!. T6@ &easure&ent de&onstrated s"&"lar e%%ects on coa(ulat"on "&pa"r&ent and durat"on o% e%%ect 1! t"&e to "n"t"al %")r"n %or&at"on0 #! rap"d"ty o% %")r"n crossl"n/"n(0 3! speed o% clot %or&at"on and 4! clot stren(th and act"v"ty o% %")r"n and platelets. 1o&&ents; *nsure .hat Blas&a +olut"on A conta"ns and .hether "t "s ava"la)le "n the *+. =ot clear "% )alanced &ult"ple-electrolyte "soton"c solut"on (crystallo"d! used "n ,6+ (roup .as the sa&e as the crystallo"d co&parator. ,6+ da"ly dose l"&"t .as lo.er "n th"s study vs. the FDA approved &ax dose (30 &l//(/d vs. 50 &l//(/d0 respect"vely!. 6%%ect on var"ous study var"a)les &"(ht )e d"%%erent ."th h"(her ,6+ doses. Bo.er calculat"ons .ere )ased solely upon the expectat"on o% a standard dev"at"on o% #50 &l and )lood loss o% 150 &l or (reater to )e cons"dered s"(n"%"cant. Bo.er calculat"ons .ere )ased upon pr"&ary endpo"nt o% )lood loss and not outco&es or other &easures. Overall0 no d"%%erence "n endpo"nts )et.een ,6+ and crystallo"d (roups "n pat"ents rece"v"n( DABT and hav"n( OB1A4 except '=7 .as sl"(htly h"(her and he&o(lo)"n lo.er "n the ,6+ vs. crystallo"d (roup. *nsure "% h"(her dose o% volu&e replace&ent us"n( ,6+ ."ll produce s"&"lar e%%ects. =o pat"ent re:u"re reoperat"on due to )leed"n(0 3 had post-op thro&)ot"c co&pl"cat"ons ."th"n one &onth a%ter sur(ery (#lun( e&)ol"0 1-,6+ 130/0.4# and 1-,6+ 130/0.40 and 1-stro/e0 1Dextran! 1o&&ent;
Cdol-e=40 70 OJ0 +10 =I$K0 30 days post-op %or AD6s (*atient-cheduled ,or elective hi& -ur$ery under -&inal ane-the-ia
*atient- E(<AD yrand -cheduled ,or elective hi& -ur$ery under -&inal ane-the-ia. 'nclus"on; A+A phys"cal status class"%"cat"on syste& ' (nor&al healthy! and # (&"ld syste&"c d"sease! and D1K yrs
H0S 130/0.4( (V@ . H0S/0.4 (VV . H0S (00/0.E (HS . #extran D0 6% (#ex 6 500 &l pre-op and as needed to &a"nta"n c"rculatory sta)"l"ty. Br"&ary Outco&e; +ur("cal )lood loss0 )lood volu&e expans"on %ro&
NBA4 rando!iFed. DA included in ,inal analy-i- (H0S 130/0.4B((. #extran D0 6%B1A. other colloid- not availa'le in 2S 'ut had 1A and (0 in tho-e $rou&-. (!l
Colloid Cry-tal +leedin$ Volu!e
VV
10( 3 11A 6 E11
#ex
A61 131 9 E(4
V@
AA6 131 6 E39
HS
A61 136E E9E
24

6xclus"on; A+A class ''' (severe syste&"c d"sease! or 'V (severe syste&"c d"sease constant threat to l"%e!0 heart or /"dney %a"lure0 rheu&ato"d arthr"t"s0 /no.n clott"n( d"sorder0 use o% (eneral anesthes"a0 use o% cell saver0 on .ar%ar"n or clop"do(rel or aller(y to study collo"ds. collo"ds and e%%ect on coa(ulat"on us"n( 7OT6C .as assessed. L*nclear the h"erarchy o% the endpo"nts.
0,,ect E00 !l *o-t<o& E9D 309 60D 6A0 E34 303 6A1 46E
=o d"%%erence "n )leed"n(0 volu&e e%%ect "ncreased )y 14% &ore than a&ount o% collo"d "n%used (60$ &l vs. only 500 &l "n%used!. Volu&e e%%ect reduced over t"&e )ut .as &a"nta"ned %or Dex vs. other collo"ds 6 pat"ents rece"ved p741s )ut no "n%o ("ven on .h"ch (roups the pat"ents .ere "n. 'n"t"al volu&e load"n( ."th VV and ,+ prolon(ed the aBTT and Dex prolon(ed aBTT a%ter sur(ery. BT-'=7 and Dd"&er "ncreased s"&"larly %or all 4 collo"ds. Thro&)"n-ant"thro&)"nco&plex (TAT! "ncreased ."th t."ce as &uch ."th VF and ,+ (ne"ther ava"l "n *+!. 1lott"n( t"&e .as reduced ."th all collo"ds and &ax clot %or&at"on (C1F! .as lo.er represent"n( .ea/ened clot stren(th %or all 4 collo"ds. Overall0 no s"(n"%"cant d"%%erences )et.een collo"ds on )lood loss0 coa(ulat"on (all reduce t"&e to clot and .ea/ened clot stren(th! and expanded plas&a volu&e. The hal%-l"%e o% the collo"ds &ay expla"n the var"ed e%%ects post-op on volu&e expans"on0 etc.
7ando&"2at"on .as done )y select"on o% one o% K0 envelopes (#0 o% each collo"d solut"on!. *nsure "% th"s &ethod "s val"d s"nce 6 pat"ents .ere re&oved %ro& study0 another 5 .ere added and the ne. 5 selected a d"%%erent envelope lead"n( to d"%%erent nu&)ers "n (roups. Althou(h no stats .ere prov"ded0 nu&)er o% %e&ales .as h"(h "n ,6+ 130/0.4 (roup vs. others and pat"ents .ere &uch youn(er "n th"s (roup (&ean 6$ years vs. $50 $3 and $1!. #/4 collo"ds stud"ed are not ava"la)le "n the *+. And there%ore .ere not "ncluded "n deta"l "n the results.
A1+Iacute coronary syndro&e0 aBTTIact"vated part"al thro&)oplast"n t"&e0 A+AIA&er"can +oc"ety o% Anesthes"olo("sts0 4*=I)lood urea n"tro(en0 1-controlled0 1A4@Icoronary artery )ypass (ra%t0 1ADIcoronary artery d"sease0 1'-card"ac "ndex0 1B4ypassIcard"opul&onary )ypass0 1r1lIcreat"n"ne clearance0 1VBIcentral venous pressure0 4DIdou)le-)l"nd0 DABTIdual ant"platelet therapy0 D'1Id"sse&"nated "ntravascular coa(ulat"on0 6@DT-early (oal d"rected therapy0 FFBI%resh %ro2en plas&a0 FV'''I%actor V'''0 @F7I(lo&erular %"ltrat"on rate0 @'I(astro"ntest"nal0 ,AIhu&an al)u&"n0 ,1TIhe&atocr"t0 '1*I"ntens"ve care un"t0 'J-6 or 'J-KI"nterlue/"n0 'TTI"ntent to treat0 CABI&ean arter"al pressure0 C1I&ult"center0 CF'I&"crovascular %lo. "ndex0 =+Inot s"(n"%"cant0 =++Inor&al sal"ne solut"on0 OJIopen-la)el0 OB1A4Io%%-pu&p coronary artery )ypass sur(ery0 BABIpul&onary artery pressure0 B1<BIpul&onary cap"llary .ed(e pressure0 B6Ipul&onary e&)ol"s&0 BJTIplatelets0 p741sIpac/ed red )lood cells0 B7=Ias needed0 BTIprothro&)"n t"&e0 7Irando&"2ed0 7JIr"n(er3s lactate solut"on0 77TIrenal replace&ent therapy0 7V6FIr"(ht ventr"cular ePect"on %ract"on0 +1Is"n(le center0 +crIseru& creat"n"ne0 +cv0#Icentral venous oxy(en saturat"on0 +'7+Isyste&"c "n%la&&atory response syndro&e0 +OFAIse:uent"al or(an %a"lure assess&ent0 T6@Ithro&)oelasto(raphy0 T'++Itherapeut"c "ntervent"on scor"n( syste&0 T=F-WItu&or necros"s %actor0 v<FIvon <"lle)rand Factor0 <41I.h"te )lood cell
M8ver the &a-t ,e> !onth-. it ha- co!e to the attention o, &u'li-her- and clinician- that a >idely &u'li-hed author (Koachi! +oldt in the area o, ,luid re&lace!ent ha- 'een accu-ed o, ,a'ricatin$ -tudie-. ,ailin$ to o'tain /4+ a&&roval and ,or$in$ na!e- o, co<author- on !anu-cri&t -u'!i--ion-. /nve-ti$ation- into the-e alle$ationare under>ay. )- a re-ult. &u'lication- in >hich #r. +oldt i- li-ted a- an author are not included in thi- revie>. 8n %arch 4. (011. the 0ditor- in Chie, ,or a lar$e nu!'er o, Gournal- relea-ed a li-t o, -tudie- &u'li-hed 'y +oldt. et al. that >ere 'ein$ retracted -ince /4+ a&&roval could not 'e veri,ied. 3he current li-t include- AA -tudie- in >hich #r. +oldt i- included a- an author. htt&6//>>>.ox,ordGournal-.or$/ourPGournal-/Gac/eic %(0Goint%(0-tate!ent%(0on%(0retraction-%(04!ar(011.&d,
25

Hydroxyethyl Starch 130-0.4 (Voluven) Monograph

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Hydroxyethyl Starch 130-0.4 (Voluven) Monograph

Uploaded by

Copyright:

Available Formats

6% Hydroxyethyl Starch 130/0.4 in 0.

6% Hydroxyethyl Starch 130/0.4 in 0.9% Sodiu! Chloride (Voluven"

*pdated vers"ons &ay )e %ound at ....p)&.va.(ov or va...p)&.va.(ov (+epte&)er #011!

*pdated vers"ons &ay )e %ound at ....p)&.va.(ov or va...p)&.va.(ov (+epte&)er #011!

6% Hydroxyethyl Starch 130/0.4 in 0.9% NaCl (Voluven

*pdated vers"ons &ay )e %ound at ....p)&.va.(ov or va...p)&.va.(ov (+epte&)er #011!

6% Hydroxyethyl Starch 130/0.4 in 0.9% NaCl (Voluven

%u=htar(A (nB40 J"v"n( donor l"ver transplantat"on (*p to 4 days post-op!

,6+ 130/0.4 vs. 5% al)u&"n (,A!

,6+ 130/0.4 vs. 1rystallo"d (Blas&a solut"on A!

,6+ 130/0.4#0 ,6+ 130/0.40 ,6+ #00/0.50 Dextran $0 6%

*pdated vers"ons &ay )e %ound at ....p)&.va.(ov or va...p)&.va.(ov (+epte&)er #011!

6% Hydroxyethyl Starch 130/0.4 in 0.9% NaCl (Voluven

*iaFFa. et al43 (010 6%%"cacy0 sa%ety o% ,6+

3otal 2nit#10 K5# 1#36 4536 46K ---

3otal Co-t (J 6055H 603$H #00664 3303K1 110061 #KH0505 K500$00

*pdated vers"ons &ay )e %ound at ....p)&.va.(ov or va...p)&.va.(ov (+epte&)er #011!

6% Hydroxyethyl Starch 130/0.4 in 0.9% NaCl (Voluven

*pdated vers"ons &ay )e %ound at ....p)&.va.(ov or va...p)&.va.(ov (+epte&)er #011!

6% Hydroxyethyl Starch 130/0.4 in 0.9% NaCl (Voluven

*alu!'o(3 70 s"n(le-center =I#00 5 days (S0*S/S

*pdated vers"ons &ay )e %ound at ....p)&.va.(ov or va...p)&.va.(ov (+epte&)er #011!

6% Hydroxyethyl Starch 130/0.4 in 0.9% NaCl (Voluven

Choi(E 70 4l"nded0 10 s"n(le-center0 =I360 #4 hrs postop (C* +y&a-*ri!in$ Solution-

*pdated vers"ons &ay )e %ound at ....p)&.va.(ov or va...p)&.va.(ov (+epte&)er #011!

6% Hydroxyethyl Starch 130/0.4 in 0.9% NaCl (Voluven

*pdated vers"ons &ay )e %ound at ....p)&.va.(ov or va...p)&.va.(ov (+epte&)er #011!

6% Hydroxyethyl Starch 130/0.4 in 0.9% NaCl (Voluven

%u=htar(A 70 =I400 up to 4 days post-op (*atientunder$oin$ livin$ donor liver tran-&lantation

9ee39 70 OJ ()l"nded endpo"nt!0 +1 nI106

*t- on #)*3 and under$oin$ 8*C)+ -ur$ery 'nclus"on; Bts hav"n(

H0S 130/0.4 v-. Cry-talloid (*la-!a Soln ) ,6+ 130/0.4 up to 30

NB106 Br"&ary Outco&e; Overall0 per"operat"ve )lood loss d"d not

*pdated vers"ons &ay )e %ound at ....p)&.va.(ov or va...p)&.va.(ov (+epte&)er #011!

6% Hydroxyethyl Starch 130/0.4 in 0.9% NaCl (Voluven

*pdated vers"ons &ay )e %ound at ....p)&.va.(ov or va...p)&.va.(ov (+epte&)er #011!

6% Hydroxyethyl Starch 130/0.4 in 0.9% NaCl (Voluven

*pdated vers"ons &ay )e %ound at ....p)&.va.(ov or va...p)&.va.(ov (+epte&)er #011!

You might also like

alu!'o(3 70 s"n(le-center =I#00 5 days (S0S/S

t- on #)3 and under$oin$ 8*C)+ -ur$ery 'nclus"on; Bts hav"n(