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1412 n engl j med 370;15 nejm.org april 10, 2014

The New England Journal of edi!ine

"ownloaded from nejm.org on #ep$em%er 3, 2014. &or per'onal u'e onl(. No o$her u'e' wi$hou$ permi''ion.

)op(righ$ * 2014 a''a!hu'e$$' edi!al #o!ie$(. +ll righ$' re'ered.

T h e n e w e n g l a n d j o u r n a l o f m e d i !in e

or iginal ar $i!le

+l%umin -epla!emen$ in a$ien$'

wi$h #eere #ep'i' or #ep$i! #ho!/ ie$ro )aironi, ."., ianni Tognoni, ."., #erge a''on, h."., -o%er$o

&umagalli, ."., +n$onio e'en$i, ."., arilena -omero, h."., )a$erina

&ania, .#$a$., ui'a )a'pani, ."., #$efano &aena, ."., ia!omo

ra''elli, ."., ae$ano api!hino, ."., a''imo +n$onelli, ."., ieri

arrini, ."., il%er$o &iore, ."., -o%er$o a$ini, .".,

and u!iano a$$inoni, ."., for $he +236# #$ud( ne'$iga$or'

+ 5 # T - +) T

&rom "ipar$imen$o di &i'iopa$ologia

edi8 !o8)hir urgi!a e dei Trapian$i,&ondaione '$i$u$o di -i!oero e )ura a

)ara$$ere #!i8 en$ifi!o 9-))#: )a;r anda < 6' pedale aggiore oli!lini!o,

=nier'i$> degli #$udi di ilano 9.).,

.., 2..:, "ipar$imen$o di +ne'$e'ia,

-ianimaione e Terapia del "o8 lore,

&ondaione -))# )a; r anda <

6'pedale aggiore oli!lini!o 9.).,

2.)., 2..:, 3-))#<3'$i$u$o di -i!er!he

&ar ma!o8 logi!he ario Negri 9#..,-.2.:, "i par $i8 men$o di #!iene della

#alu$e, =nier 'i$> degli #$udi di ilano

i!o!!a 9-.&., +..:, and "ipar$imen$o di

Emergena <=r gena, +ienda6'pedaliera #. aolo<olo =ni8 er'i$ario

9..:, ilan, )on'orio ar io Negri

#ud, #an$a aria m%aro 9.T., .-.,

).&.:, +ne'$e'iologia e -ianimaione,

"i8 par$imen$o Emergena<=rgena,

)hir urg8 ia enerale e dei Trapian$i,

oli!lini!o =ni8 er'i$ario #. 6r'ola

alpighi, 5ologna 9#.&.:, "ipar$imen$o di

Emergena < =rgen8 a, +ienda

6'pedaliera #. erardo, on8 a 9..:,

oli!lini!o =nier'i$ario +. e8 melli,

=nier'i$> )a$$oli!a, -ome 9.+.:,6'pedale del ugello < +ienda #ani$ar ia

di &irene, &loren!e 9..:, and 6'pedale

#. )ro!e, on!alieri 9.&.: ? all in 3$al(.

+d8 dre'' reprin$ re@ue'$' $o "r.

a$$inoni a$ $he "ipar$imen$o di

&i'iopa$ologia edi8 !o8)hir urgi!a e dei

Trapian$i, &ondaione -))# )a;r anda < 6' pedale aggior e oli!lini!o,

=nier'i$> degli #$udi di ila8 no, ia &.

#fora 35, 20122 ilan, 3$al(, or a$ga$$inonA poli!lini!o.mi.i$.

ne'$iga$or' of $he +l %umin 3$alian6u$!ome #ep'i' 9+236#: '$ud( ar e

li'$ed in $he #upplemen$ar ( + ppendiB,

aaila%le a$ NEJ.org.

Thi' ar$i!le wa' pu%li'hed on ar!h 1C,

2014, a$ NEJ.org.

N Engl J Med 2014;370 :1412-

21. DOI:

10.1056/ NEJMoa1305727

Copyright © 2014 Massac husett s Medi cal S ociet y.

mailto:[email protected]































+ l %umin - e pl a!emen$ in #e er e #e p'i' or #e p $i! #ho!/

or de!ade', human al %umin ha'

%een admini'$ered $o pa$ien$' $o pr oide

ade@ua$e on!o$i! pre''ure and

in$r aa'!ular olume.1

n 1C, howeer , a repor$ from $he )o!hrane

3n8 jurie' roup +l%umin -eiewer' indi!a$ed

$ha$ $he admini'$ra$ion of al%umin ma( %e

po$en$ial8 l( harmful in !ri$i!all( ill pa$ien$', a'

!om par ed wi$h $he admini'$ra$ion of !r ('$alloid'olu$ion'.2

#u%'e@uen$ me$a8anal('e' repor$ed

!on$r adi!$or ( f inding'.3,4

To !larif( $hi' i''ue, a large, dou%le8 %lind,randomied $rial 9$he #aline er 'u' +l%umin

&luid Ealua$ion H#+&EI '$ud(:5 wa' !ondu!$ed,

in whi!h

4D al%umin 'olu$ion wa' !ompared wi$h

nor mal 'aline a' f luid repla!emen$ in

!ri$i!all( ill pa8 $ien$', wi$h re'ul$' indi!a$ing

$ha$ al%umin ad8 mini'$ra$ion wa' 'afe. +

pr edef ined 'u%gr ou p anal('i' 'howed $ha$ pa$ien$' wi$h 'eere 'e p'i' r e!eiing al%umin

were a$ a lower, al$hough no$ 'ignif i!an$l(

lower, ri'/ for dea$h $han $ho'e re!eiing

normal 'aline. n addi$ion, a 'u%'e@uen$ '$ud(

poin$ed ou$ a po$en$ial %enefi$ of main$ain8 ing

'erum al%umin a$ a leel of more $han 30 g per

li$er in !ri$i!all( ill pa$ien$'.

There i' a !onin!ing ra$ionale for $he po$en8

$ial adan$age' of al%umin admini'$ra$ion

dur ing 'eere 'ep'i'.7 +l%umin i' $he main

pro$ein r e8 'pon'i%le for pla'ma !olloid

o'mo$i! pr e''ur eC; i$ a!$' a' a !arrier for 'eeral

endogenou' and eB8 ogenou' !ompound', wi$h

an$ioBidan$ and an$i8 inf lamma$or ( proper$ie',

and a' a '!aenger of rea!$ie oB(gen10,11 and

ni$rogen12 'pe!ie' and opera$e' a' a %uffer

mole!ule for a!id<%a'e e@ui8 li%rium.13 Ke

$herefore !ondu!$ed a r andomied, !on$rolled

$rial $o ine'$iga$e $he effe!$' of $he

admini'$ra$ ion of al%umin and !r ('$alloid', a'

!ompared wi$h !r ('$alloid' alone, $arge$ing a 'e8

rum al%umin leel of 30 g per li$er or more in a

popula$ion of pa$ien$' wi$h 'eere 'e p'i'.

E TL 6" #

&$#D( O)E"&I!%$ AND DE&I!N

Ke !ondu!$ed $he +l%umin $alian 6u$!ome

#ep8 'i' 9+236#: '$ud( ? an ine'$iga$or 8

ini$ia$ed, mul$i!en$er, open8la%el, randomied,

!on$r olled $rial ? in 100 in$en'ie !are uni$'

93)=': in 3$al(. The mem%er' of $he '$eering

!ommi$$ee 9'ee $he #u pplemen$ar ( +ppendiB,

aaila%le wi$h $he full $eB$ of $hi' ar$i!le a$ NEJ.or g:

de'igned $he

&






'$ud(, were re'pon'i%le for i$'

eBe!u$ion and f or $he da$a

anal('i', made $he de!i'ion $o

'u%mi$ $he manu'!rip$ for

pu%li!a$ion, and a''ume

r e'pon8 'i%ili$( for $he f ideli$(

of $he '$ud( $o $he pr o$o!ol

9aaila%le a$ NEJ.or g:.

The $rial wa' funded %( $he

$alian edi!ine' +gen!(,

whi!h had no role in $he!ondu!$ of $he '$ud(, $he

repor$ing of $he da$a, or $he

'u ppl( of '$ud( f luid'.

+l%umin admini'$ered during

$he '$ud( wa' pr oided %( ea!h

par$i!ipa$ing in'$i$u8 $ion a'

par$ of $he !lini!al $rea$men$

of !r i$i!all( ill pa$ien$'. The

'$ud( pro$o!ol and $he

inf or med8 !on'en$ pro!e''

were a ppr oed %( $he e$hi!'

!ommi$$ee a$ ea!h par$i!ipa$ing

in'$i$u$ion. Kri$$en informed

!on'en$ or deferred !on'en$

wa' o %8 $ained from ea!h

pa$ien$.

-andomia$ion wa'

performed !en$r all(, wi$h $he

u'e of a !ompu$er8genera$ed

and %linded a'8 'ignmen$

'e@uen!e. -andomia$ion wa'

'$r a$if ied a!!ording $o $he

par$i!ipa$ing 3)= and $he in$er al %e$ween $he

$ime $ha$ $he pa$ien$ me$ $he !lini!al !ri$eria for

'eere 'ep'i' and randomia$ion. The !ondu!$ of

$he $rial wa' oer 'een %( $he da$a and 'afe$(

moni$oring %oard, whi!h performed an in8 $erim

anal('i' af$er $he enrollmen$ of 700 pa$ien$'.

*A$IEN$&

a$ien$' 1C (ear' of age or older who me$ $he

!lini!al !ri$eria for 'eere 'ep'i'14 wi$hin $he

pr e8 iou' 24 hour' a$ an( $ime during $heir '$a( in $he )= were enrolled in $he '$ud(

af$er %eing '!reened for eligi%ili$( !ri$eria.

"e$ail' of $he in8 !lu'ion and eB!lu'ion !ri$eria

are pr oided in $he #u pplemen$ar ( +ppendiB.

&$#D( $"EA$MEN$&

a$ien$' were r andoml( a''igned $o re!eie

ei$her

20D al%umin and !r ('$alloid 'olu$ion 9al %umin

group: or !r ('$alloid 'olu$ion alone

9!r ('$alloid group: from randomia$ion un$il

da( 2C or di'8 !harge from $he )=, whi!heer

!ame f ir'$. "ur8 ing $he earl( pha'e of olume

re'u'!i$a$ion, f lu8 id' were admini'$ered in

%o$h group' a!!or ding $o earl( goal8dire!$ed

$her a p(.15

+f$er randomia$ion, pa$ien$' in $he

al %umin group re!eied 300 ml of 20D al%umin

'olu$ion. &rom da( 1 un$il da( 2C or 3)=

di'!harge 9whi!h8 eer !ame f ir'$:, 20D

al%umin wa' admini'$er ed on a dail( %a'i', $o

main$ain a 'erum al %umin leel of 30 g per

li$er or more. n %o$h gr ou p',

n engl j med 370;15 nejm.org april 10, 2014 1413



T he n e w e n g l a n d j o u r n a l o f m e d i !in e

!r ('$alloid' were admini'$ered wheneer i$ wa'

!lini!all( indi!a$ed %( $he a$$ending ph('i!ian.

The admini'$ra$ion of '(n$he$i! !olloid' wa' no$

allowed. +ll o$her $rea$men$' were a$ $he

di'!r e8 $ion of $he a$$ending ph('i!ian.

O#$COME&

The pr imar ( ou$!ome mea'ure wa' dea$h f r om

an( !au'e a$ 2C da(' af$er randomia$ion. The prin!ipal 'e!ondar ( ou$!ome mea'ure wa' dea$h

from an( !au'e a$ 0 da(' af$er r andomia$ion.

+ddi$ional 'e!ondar ( ou$!ome' were $he

num%er of pa$ien$' wi$h organ d('f un!$ion

and $he de8 gree of d('f un!$ion and $he leng$h

of '$a( in $he )= and $he ho'pi$al. The

'eeri$( of '('$emi! illne'' wa' a''e''ed wi$h

$he u'e of $he #impli8 fied +!u$e h('iolog(

#!ore, wi$h '!ore' r anging from 0 $o 13 and

higher '!ore' indi!a$ing mor e 'eere illne''.1

6rgan fun!$ion wa' a''e''ed dail( wi$h $he

u'e of $he #e@uen$ial 6rgan &ailure +''e''men$

9#6&+: '!ore,17 whi!h range' f r om

0 $o 4 for ea!h of f ie !omponen$'

9r e'pir a$or (, !oagula$ion, lier, !ar dioa'!ular ,

and renal !om8 ponen$':, wi$h higher '!ore'

indi!a$ing mor e 'eere organ d('f un!$ion

9Ta%le #1 in $he #up8 plemen$ar ( +ppendiB:.

New organ failure' were def ined a' a !hange

in a !omponen$ '!ore dur 8 ing $he '$ud( from a

%a'eline '!ore of 0, 1, or 2 $o a '!ore of 3 or

4.5,1C,1 Ter$iar( ou$!ome', whi!h were a''e''ed

in po'$ ho! anal('e', in!luded $he

u'e of renal8repla!emen$ $hera p(, $he in!iden!e

of a!u$e / idne( in jur (, $he dura$ion of

me!hani!al en$ila$ion, and $he $ime $o

'u'pen'ion of $he ad8 mini'$ra$ion of

a'o pr e''or or ino$ropi! agen$'.

&$A$I&$ICA' ANA'(&I&

Ke or iginall( de$ermined $ha$ a 'ample of 1350

pa8 $ien$' would pr oide $he '$ud( wi$h C0D

power $o de$e!$ an a%'olu$e %e$ween8group

differen!e of 7.5 per!en$age poin$' in mor$ali$(

a$ 2C da(', on $he %a'i' of an e'$ima$ed %a'eline

mor$ali$( of

45D, wi$h a $wo8'ided alue of le'' $han 0.05

indi!a$ing '$a$i'$i!al 'ignif i!an!e. The '$ud(

pr o8 $o!ol 'pe!if ied $he po''i%ili$( of

in!rea'ing $he 'ample $o 1C00 pa$ien$' on $he

%a'i' of a r e!om8 menda$ion %( $he da$a and

'afe$( moni$or ing %oard during an in$erim

anal('i'.

+ll $he anal('e' were !ondu!$ed on an

in$en8 $ion8$o8$rea$ %a'i'. inar( ou$!ome'

were !om8 pared wi$h $he u'e of $he !hi8

'@uare $e'$, and !on$inuou' ou$!ome' wi$h $he

u'e of $he Kil!oBon ran/8'um $e'$.

)ompari'on' of f luid olume' and

ph('iologi!al da$a oer $ime were per f or med

wi$h $he u'e of a $wo8fa!$or anal('i' of ar ian!e

for repea$ed mea'uremen$'. Ke !al!ula$ed 'ur 8

ial e'$ima$e' a!!ording $o $he Maplan<eier

me$hod and !ompared $hem u'ing a log8r an/

$e'$. Ke performed an adju'$ed anal('i'u'ing ro%u'$ oi''on regre''ion for %inar (

ou$!ome'. n a po'$ ho! anal('i', $he pr imar (

and pr in!i pal

$a+le 1. C,a-a./e-/. o /,e *a/en/ a/ Baelne.

Al+n !-o C-/allod !-oC,a-a/e-/ 8N 9 :03; 8N 9 :07;

+ge ? (r

edian 70

n$er@uar$ile range 57<77 5<77

&emale 'eB ? no. 9D: 30 93.: 357 93E.4:

od(8ma'' indeB 27O 27O

-ea'on for 3)= admi''ion ? no. 9D:

edi!al 511 95.: 51C 957.1:

Ele!$ie 'urger( 97.: 5C 9J.4:

Emergen!( 'urger( 323 935.C: 331 93J.5:

reeBi'$ing !ondi$ion ? no. 9D:P

2ier di'ea'e 13 91.4: 14 91.5:

)6" 113 912.5: 10C 911.E:

)hroni! renal failure 44 94.: 32 93.5:

mmunodefi!ien!( 115 912.7: 12C 914.1:

)onge'$ie or i'!hemi! hear$ di'ea'e 14 91.5: 15 91C.2:

#+# '!oreQ

edian 4C 4C





$a+le 1. 8Con/ned.;

Al+n !-o C-/allod !-oC,a-a/e-/ 8N 9 :03; 8N 9 :07;

h('iologi!al aria%leR

Lear$ ra$e ? %ea$'Smin 105O22 10O20

ean ar$erial pre''ure ? mm Lg 74O1 73O15

)en$ral enou' pre''ure ? mm Lg 10.0O4. .CO4.7=rine ou$pu$ ? mlShr

edian 50 50


a!$a$e ? mmolSli$er

edian 2.3 2.5

n$er@uar$ile range 1.4<4.2 1.<4.3

#erum al%umin ? gSli$er 24.1O.3 24.2O.2

Lemoglo%in ? gSdl 10.O2.1 11.0O2.0

)en$ral enou' oB(gen 'a$ura$ion ? D

edian 73 73

n$er@uar$ile range 5<7 C<C0

#6&+ '!ore‖edian C C

n$er@uar$ile range <10 5<10

6rgan d('fun!$ion ? no. 9D:

1 organ 1CC 920.C: 20C 922.E:

2 organ' 31 940.0: 303 933.4:

3 organ' 23 92.1: 24C 927.3:

4 organ' C 9.: 115 912.7:

5 organ' 2 93.2: 33 93.J:

#ho!/ ? no. 9D: 55 92.: 570 9J2.C:

e!hani!al en$ila$ion ? no. 9D: 70 97C.5: 737 9C1.3:

&luid admini'$ra$ion in preiou' 24 hr ? no. 9D:

+l%umin 153 91.: 17 91E.4:#(n$he$i! !olloid' 452 950.1: 47 952.C:

lu'<minu' alue' are mean' O#". There were no 'ignifi!an$ differen!e' %e$ween $he $wo group' eB!ep$ wi$h re'pe!$$o !en$ral enou' oB(gen 'a$ura$ion 9 F 0.02: and num%er of pa$ien$' wi$h organ d('fun!$ion 9 F 0.04:. )6"deno$e' !hroni! o%'$ru!$ie pulmonar( di'ea'e, and )= in$en'ie !are uni$.

The %od(8ma'' indeB i' $he weigh$ in /ilogram' diided %( $he '@uare of $he heigh$ in me$er'.P +mong preeBi'$ing !ondi$ion', lier di'ea'e wa' defined a' $he pre'en!e of !irrho'i', por$al h(per$en'ion, or preiou'

epi'ode' of lier in'uffi!ien!(; immunodefi!ien!( a' $he !on!urren$ pre'en!e of immuno'uppre''ie di'ea'e' or re!eip$of immuno'uppre''ie $herapie'; and !onge'$ie or i'!hemi! hear$ di'ea'e a' New or/ Lear$ +''o!ia$ion !la'' .

Q The #implified +!u$e h('iolog( #!ore 9#+# :1 wa' u'ed $o a''e'' $he 'eeri$( of '('$emi! illne'' a$ %a'eline.#!ore' range from 0 $o 13, wi$h higher '!ore' indi!a$ing more 'eere illne''.

R "a$a on !en$ral enou' pre''ure were aaila%le for C41 pa$ien$' in $he al%umin group and C5C in $he !r('$alloid

group; da$a on la!$a$e leel, for C74 and C7, re'pe!$iel(; da$a on 'erum al%umin leel, for C21 and C13, re'pe!$iel(;da$a on hemoglo%in leel, for C3 and C4, re'pe!$iel(; and da$a on !en$ral enou' oB(gen 'a$ura$ion, for 7C andC02, re'pe!$iel(.

‖ The #e@uen$ial 6rgan &ailure +''e''men$ 9#6&+: '!ore17 in!lude' 'u%'!ore' ranging from 0 $o 4 for ea!h of fie!omponen$' 9re'pira$or(, !oagula$ion, lier, !ardioa'!ular, and renal !omponen$':, wi$h higher '!ore' indi!a$ingmore 'eere organ d('fun!$ion. The '!oring wa' modified %( eB!luding $he a''e''men$ of !ere%ral failure 9$hela'gow )oma #!ale:, whi!h wa' no$ performed in $he'e pa$ien$', and %( de!rea'ing $o 5 mm Lg $he mean ar$erial

pre''ure $hre'hold for a !ardioa'!ular 'u%'!ore of 1, for !on'i'$en!( wi$h $he hemod(nami! $arge$' a' defineda!!ording $o $he earl( goal8dire!$ed $herap(.15

6rgan d('fun!$ion' were defined a' a #6&+ '!ore of 2 or more on $he re'pira$or( !omponen$; 2 or more on $he !o8agula$ion !omponen$; 2 or more on $he lier !omponen$; 1, 3, or 4 on $he !ardioa'!ular !omponen$; and 2 or moreon $he renal !omponen$.5 + '!ore of 2 on $he !ardioa'!ular !omponen$ wa' no$ in!luded %e!au'e $ha$ '!ore i' a'8'igned for $he u'e of a'opre''or drug' a$ low do'e' 9a !ondi$ion no$ !on'idered $o %e '$ri!$l( rela$ed $o !ardioa'!u8lar d('fun!$ion:.

#ho!/ a$ $he $ime of randomia$ion wa' defined a' a '!ore of 3 or 4 on $he !ardioa'!ular !omponen$ of $he #6&+.5





A

34

32

30

2C

2

24

22

20

1C

1

14

G0.001

0

+l%umin

)r('$alloid'

<g-e 1. &e- Al+n 'e=el1 /,-og, Da 2>

and Ne/ <ld Balan.e /,-og, Da 7.

anel + 'how' $he 'erum al%umin !on!en$r a$ion

$hrough da( 2C in pa$ien$' re!eiing al%umin and !r ('8

$alloid' or !r ('$alloid' alone. "a( 0 wa' defined a' $he

$ime of randomia$ion. "a$a are median', wi$h %ar '

indi!a$ing in$er@uar$ile range'. The alue i' for $he

%e$ween8gr oup !ompari'on performed wi$h $he u'e

of a $wo8f a!$or anal('i' of arian!e for repea$ed mea8

'uremen$' $o $e'$ $ime 92 da(' for 'erum al %umin,

in!luding da( 0: and group ef fe!$'. anel 'how' $he

ne$ f luid %alan!e $hrough da( 7 for pa$ien$' re!eiing

al%umin and !r ('$alloid' or !r ('$alloid' alone. The

dail( ne$ f luid %alan!e wa' !al!ula$ed a' $he diff er en!e

%e$ween $he $o$al amoun$ of admini'$ered f luid 9in8

No. a/ "?

0 4 C 12 1

&/d Da

20 24 2C !luding 20D al%umin; !r ('$alloid'; o$her %lood pr od8

u!$', 'u!h a' pa!/ed red !ell', f r e'h8f r oen pla'ma, or

pla$ele$'; and o$her f luid': and $he $o$al amoun$ of

eB!r e$ed f luid ea!h da( 9in!luding urinar ( ou$pu$ and+l%umin

)r('$alloid'

B5000

C21C13

773

4C344

335303

23217

1C15

14C130

+l%umin

107104

o$her f luid lo''e', 'u!h a' f luid' po$en$iall( r emoed

wi$h !on$inuou' r enal8r e pla!emen$ $her ap(, f luid' lo'$

a' fe!e', a'pira$ed ga'$ri! !on$en$, drainage f luid',

and in'en'i%le per'pira$ion:. &or da( 1, $he ne$ f luid %alan!e wa' !ompu$ed from $he $ime of r andomia8

4000

3000

2000

1000

0

)r('$alloid' $ion $o da( 1, whi!h aeraged 1 hour' in $he $wo '$ud(

group'. The horion$al line in $he %oBe' indi8 !a$e' $he

median, $he $op and %o$$om of $he %oB $he

in$er @uar $ile range, and %ar' $he 5$h and 5$h per 8

!en$ile range. The alue i' for $he %e$ween8gr oup

!ompari'on performed wi$h $he u'e of $he $wo8f a!$or

anal('i' of arian!e for repea$ed mea'uremen$' $o $e'$

$ime 97 da(': and group eff e!$'.

U1000

U2000

U3000

No. a/ "?

G0.001

1 2 3 4 5 7

&/d Da

l( a''igned $o re!eie 20D al%umin and !r ('$al8

loid 'olu$ion 910 pa$ien$': or !r ('$alloid

'olu$ion alone 90C: for f luid repla!emen$. er

pr o$o!ol, pa$ien$ enrollmen$ wa' '$r a$if ieda!!ording $o $he in$er al %e$ween $he $ime

$he pa$ien$ me$ $he !lini!al !ri$eria for 'eere

'ep'i' and r andom8+l%umin

)r('$alloid'C40C44

7C75

742735

701C5

335

5C5C7

54252 ia$ionV hour' or le'' 957 pa$ien$' H31.CDI:

er'u' more $han hour' 9123 HC.2DI:. + $o$al

of C pa$ien$' were eB!luded from $he anal('i'

'e!ondar ( ou$!ome' were a''e''ed in pa$ien$'

who had 'ep$i! 'ho!/ and $ho'e who did no$

hae 'ep$i! 'ho!/ a$ $he $ime of enr ollmen$.

Le$er ogenei$( of $rea$men$ effe!$' among 'u%8

group' wa' a''e''ed wi$h $he u'e of $he $e'$ f or

a !ommon rela$ie ri'/. #+# 'of$ware, er'ion.2 9#+# n'$i$u$e:, wa' u'ed for all $heanal('e'.

- E # = 2 T#

&$#D( *O*#'A$ION

&rom +ugu'$ 200C $hrough &e %r uar ( 2012, a

$o$al of 1C1C pa$ien$' wi$h 'eere 'ep'i' were

r andom8

92 pa$ien$' in $he al%umin group owing $o wi$h8

drawal of !on'en$, and 5 in $he al%umin gr ou p

and 1 in $he !r ('$alloid group owing $o a r an8

domia$ion error: 9&ig. #1 in $he

#u pplemen$ar ( +ppendiB:.

+f$er follow8up, da$a regarding dea$h a$ 0

da(' were aaila%le for CCC of 03 pa$ien$'

9C.3D: in $he al%umin group and for C3 of

07 9C.5D: in $he !r ('$alloid group. a'eline

!hara!$eri'$i!' were 'imilar %e$ween $he $wo

'$ud( group', eB!ep$ for a 'ligh$ im%alan!e in

$he num%er of pa$ien$' wi$h organ d('f un!$ion

and alue' of !en$ral enou' oB(gen 'a$ura$ion

9Ta%le 1:. The pr imar ( 'i$e of


& e - 4 5 A

l + 4 5 0 n 8 g / l 0 e - ;

N e < l 4 0 d B a l a n . e 8 5 l ;




infe!$ion, $he $(pe of iden$if ied

mi!r oor gani'm, and $he propor$ion of

pa$ien$' r e!eiing an$i8 %io$i!' were 'imilar in

$he $wo group' 9Ta%le #2 in $he #u pplemen$ar (

+ppendiB:.

<'#ID $%E"A*( AND $"EA$MEN$ E<<EC$&

"uring $he f ir'$ 7 da(', $he al%umin group,

a' !ompared wi$h $he !r ('$alloid group, re!eieda 'ignif i!an$l( larger olume of 20D al%umin

'olu8 $ion 9G0.001: and le'' !r ('$alloid

'olu$ion 9G0.001:. n $he al%umin group, $he

admini'$r a8 $ion of 20D al%umin 'olu$ion

a!!oun$ed for a median dail( aerage of

4.3D 9in$er @uar $ile range, 2. $o 5.C: of $he

$o$al admini'$ered f luid'. The $o$al dail(

amoun$ of admini'$ered f luid' in $he f ir'$ 7

da(' did no$ differ 'ignif i!an$l( %e8 $ween $he

al%umin group and $he !r ('$alloid group

9373C ml Hin$er@uar$ile range, 3174 $o

4437I and 3C25 ml Hin$er@uar$ile range, 3205$o

4533I, re'pe!$iel(; F 0.10: 9Ta%le #3 in $he

#up8 plemen$ar ( +ppendiB:.

The 'erum al%umin leel wa' 'ignif

i!an$l( higher in $he al%umin group $han in $he

!r ('$al8 loid group from da( 1 $o da( 2C

9G0.001: 9&ig.

1+:. "uring $he f ir'$ 7 da(', pa$ien$' in $he

al8 %umin group had a 'ignif i!an$l( lower hear$

r a$e $han $ho'e in $he !r ('$alloid group 9 F

0.002:, a' well a' a 'ignif i!an$l( higher mean

ar$erial pr e'8 'ure 9 F 0.03: 9Ta%le #4 and

&ig. #2 in $he #u pplemen$ar ( +ppendiB:.

"ail( ne$ f luid %al8 an!e' were lower in $he

al%umin group $han in $he !r ('$alloid group

9G0.001: 9&ig. 1:. The median !umula$ie

ne$ f luid %alan!e wa' al'o 'ignif i!an$l( lower

in $he al%umin group $han in $he !r ('$alloid

group 9347 ml Hin$er @uar$ile range, U32 $o

4042I '. 1220 ml Hin$er @uar$ile range, U277 $o

5034I, F 0.004: 9Ta%le #5 in $he


O#$COME&

+$ 2C da(' af$er randomia$ion, 2C5 of C5 pa8

$ien$' 931.CD: in $he al%umin group and 2CC

of

00 932.0D: in $he !r ('$alloid group had

died 9rela$ie ri'/ in $he al%umin group, 1.00;

5D !onf iden!e in$er al H)I, 0.C7 $o 1.14;

F 0.4: 9Ta%le 2:. +$ 0 da(' of follow8up, 35

of CCC pa$ien$' 941.1D: in $he al%umin group

and 3C of

C3 943.D: in $he !r ('$alloid group had

died 9rela$ie ri'/, 0.4; 5D ), 0.C5 $o 1.05;

F 0.2:. No 'ignif i!an$ differen!e in $he pr o %a %ili$( of

'urial wa' o %'er ed %e$ween $he al %umin



group and $he !r ('$alloid

group during $he 0 da(' af$er

randomia$ion 9 F 0.3: 9&ig.

2:.

No 'ignifi!an$ differen!e

wa' o %'er ed %e$ween $he $wo

'$ud( group' wi$h re'pe!$ $o

ei$her $he num%er of newl(

deelo ped organ failure' or $he

median #6&+ '!ore 9Ta%le

2:. +nal('i' of $he #6&+ '!orefor ea!h organ '('$em reealed

$ha$, a' !ompared wi$h $he

!r ('$alloid group, $he al8

%umin group had a lower

!ar dioa'!ular '!or e 9 F 0.03:,

a higher !oagula$ion '!ore 9

F 0.04:, and a higher lier

'!ore 9 F 0.02:. No 'ignif

i!an$ differen!e' were

o %'er ed in o$her 'e!ondar (

and $er$iar ( ou$!ome', wi$h $he

eB!ep$ion of $he $ime $o

'u'pen'ion of $he

admini'$ra$ion of a8 'opre''or

or ino$ropi! agen$', whi!h wa'

'hor$er in $he al%umin group

$han in $he !r ('$alloid gr ou p 9

F 0.007: 9Ta%le 2:.

n 'u%group anal('e', no

'ignif i!an$ differ8 en!e wa'

o %'er ed in $he pr e'pe!if ied

'u%gr ou p' $ha$ were '$ra$ified

a!!ording $o $he in$er al %e8$ween $he $ime $he pa$ien$ me$

$he !lini!al !r i$e8 ria for 'eere 'ep'i' and

randomia$ion 9&ig. #3 in $he #u pplemen$ar (

+ppendiB:. )oner'el(, a 'ignif i!an$ differen!e

wa' o %'er ed in a po'$ ho! 'u%group anal('i'

$ha$ in!luded 1121 pa$ien$' wi$h 'ep$i! 'ho!/,

a' !ompared wi$h 0 wi$h8 ou$ 'ep$i! 'ho!/,

a$ $he $ime of enrollmen$ 9r ela8 $ie ri'/ wi$h

'ep$i! 'ho!/, 0.C7; 5D ), 0.77 $o

0.; rela$ie ri'/ wi$hou$ 'ep$i! 'ho!/,1.13;

5D ), 0.2 $o 1.3; F 0.03 for he$er ogenei$(: 9&ig. #3 in $he #u pplemen$ar (

+ppendiB:. +dju'$8 men$ for %a'eline

!oar ia$e' did no$ 'ignif i8 !an$l( modif (

$he'e re'ul$' 9Ta%le # in $he #u pplemen$ar (

+ppendiB:.

" 3 # ) = # #

6N

The main re'ul$' of $hi' large8'!ale $rial pr oide

eiden!e regarding %o$h $he eff i!a!( and

$he 'afe$( of $he u'e of human al%umin during

'e8 ere 'ep'i' ? an in$er en$ional '$r a$eg( $ha$

ha' long %een de%a$ed.21,22 The addi$ion of

al %umin $o !r ('$alloid' during $he f ir'$ 2C

da(' of $r ea$8 men$ $o main$ain a 'erum

al%umin leel of 30 g per li$er or more i' 'afe %u$

doe' no$ pr oide a 'urial adan$age oer

!r ('$alloid' alone, oer a follow8up period of

0 da('. #imilar f inding' were o %'er ed in $he

'u%group '$r a$if ied a!!or d8 ing $o $he in$er al

%e$ween $he $ime $he pa$ien$ me$ $he !lini!al

!ri$eria for 'eere 'ep'i' and $rea$men$a ppli!a$ion.





The f inding' in our $rial ma( appear $o

!on8 $radi!$ $ho'e of $he predefined 'u%group

anal('i' from $he #+&E '$ud(,5 whi!h

'ugge'$ed a 'ur 8 ial adan$age wi$h an

al%umin8%a'ed '$r a$eg( during 'eere 'ep'i'.

The plau'i%ili$( of $hi' h(8 po$he'i' wa'

'uppor$ed %( $he 'ignif i!an$ hemo8 d(nami!

adan$age' o %'er ed23 and %( f ur $her

ine'$iga$ion' 'howing $ha$ $he !orre!$ion of h( poal %uminemia redu!ed $he 'eeri$( of or gan

d('f un!$ion.4,J #imilar %enef i!ial effe!$'

were al'o 'ugge'$ed %( a large me$a8anal('i',whi!h !on!luded $ha$ $he u'e of al %umin8

!on$aining 'olu$ion' !ould %e a''o!ia$ed wi$h

lower mor$al8 i$( $han $ha$ 'een wi$h o$her f

luid regimen'.24

6ur re'ul$' !onf irm $ha$ admini'$ra$ion

of al%umin produ!e' 'mall %u$ 'ignif i!an$

hemod(8 nami! adan$age'. + 'ignif i!an$l(

grea$er pr o8 por$ion of pa$ien$' in $he al%umin

group $han in

$a+le 2. O4/o5e1.

"ela/=e "? O/oe Al+n !-o C-/allod !-o 85@ CI; * )ale

rimar( ou$!omeV dea$h a$ 2C da(' ? no.S$o$al no. 9D: 2C5SC5 931.C: 2CCS00 932.0: 1.00 90.C7<1.14: 0.4

#e!ondar( ou$!ome'

"ea$h a$ 0 da(' ? no.S$o$al no. 9D: 35SCCC 941.1: 3CSC3 943.: 0.4 90.C5<1.05: 0.2

New organ failure' ? no.S$o$al no. 9D: 0.

None 372SC3 944.5: 3C3SC41 945.5:

1 organ 2C3SC3 933.: 2C7SC41 934.1:

2 organ' 130SC3 915.: 123SC41 914.J:

3 organ' 40SC3 94.C: 3SC41 94.3:

4 organ' 10SC3 91.2: 11SC41 91.3:

5 organ' 1SC3 90.1: 1SC41 90.1:

#6&+ '!ore ? 0.23

edian .00 5.2

n$er@uar$ile range 4.00<C.50 3.2<C.2C

#6&+ 'u%'!ore

)ardioa'!ular ? 0.03

edian 1.20 1.42n$er@uar$ile range 0.4<2.31 0.0<2.50

-e'pira$or( ? 0.3

edian 2.00 2.00

n$er@uar$ile range 1.5<2.4C 1.57<2.50

-enal ? 0.15

edian 0.C3 0.75

n$er@uar$ile range 0.14<2.14 0.07<2.00

)oagula$ion ? 0.04

edian 0.4 0.50

n$er@uar$ile range 0.00<1.2 0.00<1.5

ier ? 0.02

edian 0.2C 0.20

n$er@uar$ile range 0.00<1.00 0.00<0.2

eng$h of '$a( ? da('

n )= ? 0.42

edian

n$er@uar$ile range 4<1C 4<17

n ho'pi$alP ? 0.5

edian 20 20

n$er@uar$ile range 10<3 <3C

141C n engl j med 370;15 nejm.org april 10, 2014




$a+le 2. 8Con/ned.;

"ela/=e "? O/oe Al+n !-o C-/allod !-o 85@ CI; * )ale

Ter$iar( ou$!ome'Q

-enal8repla!emen$ $herap( ? no.S$o$al no. 9D:R 222S03 924.: 14S07 921.4: 0.11

+!u$e /idne( injur( ? no.S$o$al no. 9D:‖ 1C3SC34 921.: 10SC37 922.7: 0.71

"ura$ion of me!hani!al en$ila$ion ? da(' ? 0.50

edian


Time $o 'u'pen'ion of a'opre''or or ino$ropi! ? 0.007agen$' ? da('

edian 3 4

n$er@uar$ile range 1< 2<7

New organ failure' were defined %( a !hange in a 'pe!ifi! !omponen$ of $he #6&+17 from a '!ore of 0, 1, or 2 a$ %a'eline $o a '!ore of 3or 4 during $he '$ud( period.5,17,1C

The alue' are $he median and in$er@uar$ile range of $he #6&+ '!ore, repre'en$ing $he aerage of $he dail( #6&+ '!ore' for ea!h indiidu8al pa$ien$ during hi' or her '$ud( period 9in!luding $he #6&+ '!ore a$ %a'eline:. No impu$a$ion wa' performed for mi''ing da$a.

P The leng$h of '$a( in $he ho'pi$al in!luded $he leng$h of '$a( in $he )=.Q Ter$iar( ou$!ome' were anal(ed in po'$ ho! anal('e'. R n!luded are pa$ien$' wi$h an( form of renal8repla!emen$ $herap( pre'!ri%ed %( $he a$$ending ph('i!ian during $he '$ud( period, in!luding

pa$ien$' wi$h !hroni! renal failure a$ %a'eline. ‖ +!u$e /idne( injur( wa' defined a!!ording $o $he ri'/, injur(, failure, lo'', and end8'$age /idne( injur( 9-3&2E: !ri$eria20 for a!u$e /idne(

in8 jur( on $he %a'i' of dail( in!remen$al in!rea'e' in 'erum !rea$inine leel' from %a'eline during $he '$ud( period. The dura$ion of en$ila$or( 'uppor$ in!lude' onl( $he $ime during $he '$ud( period, whi!h wa' no$ ne!e''aril( $he $o$al dura$ion of en$ila8

$or( 'uppor$. The $ime $o $he 'u'pen'ion of a'opre''or or ino$ropi! agen$' wa' a''e''ed a' $he num%er of da(' of admini'$ra$ion of a'opre''or or

ino$ropi! agen$' in pa$ien$' for whom 'u!h $rea$men$ wa' ongoing a$ %a'eline. "a$a were aaila%le for 5C2 pa$ien$' in $he al%umin groupand 57 in $he !r('$alloid group.

$he !r ('$alloid group rea!hed $he $arge$ed mean

ar$erial pre''ure wi$hin hour' af$er r andom8

ia$ion 9Ta%le #7 in $he #u pplemen$ar (

+ppendiB:. "uring $he f ir'$ 7 da(', $he mean

ar$erial pr e'8 'ure wa' higher, wherea' $he

hear$ ra$e and ne$ f luid %alan!e were lower, in

$he al%umin gr ou p $han in $he !r ('$alloid

group. or eoer , $he a8 erage !ar dioa'!ular

#6&+ 'u%'!ore oer $he !our'e of $he '$ud(

period wa' lower in $he al8 %umin group, and

$he $ime $o $he 'u'pen'ion of ino$ropi! or

a'o pr e''or agen$' wa' 'hor$er, in8 di!a$ing a

de!rea'ed u'e of a'o pr e''or'. The'e effe!$'

were o%$ained wi$h 'imilar amoun$' of

admini'$ered f luid' in $he $wo '$ud(

gr ou p'. The'e f inding' !onf irm a

ph('iologi!al adan8 $age of al%umin

admini'$ra$ion during 'eer e 'ep'i', in!luding a

larger f luid di'$ri%u$ion wi$hin $he in$r aa'!ular

!ompar$men$ and, in addi$ion, po''i%le effe!$'

of al%umin a' a '!aenger of ni8 $ri! oBide,12

media$ing peripheral a'odila$a$ion during

'e p'i'.25,2

The 'e!ondar ( ou$!ome' al'o pr oide a de8

$ailed pr of ile of $he 'afe$( of al%umin

admini'8

$ra$ion during 'eere 'ep'i'. The in!iden!e of

new organ failure' during $he '$ud( wa' 'imi8

lar in $he $wo group'. Ke o %'er ed 'ligh$l(

higher aerage #6&+ 'u%'!ore' for lier and

!oagula$ion in $he al%umin group, indi!a$ing a

higher 'erum %iliru%in and a lower pla$ele$

!oun$, re'pe!$iel(, $han were o %'er ed in $he

!r ('$alloid group. None$hele'', $he a %'olu$e

eB!e'' in $he 'erum %iliru%in !on!en$ra$ion in

$he al%umin group wa' marginal 9median, 1.0

mg per de!ili$er Hin$er@uar$ile range, 0. $o 1.7I

'. 0. mg per de!ili$er Hin$er@uar$ile range, 0.5

$o 1.5I, G0.001: and wa' pr o %a %l( rela$ed $o

$he me$hod' u'ed $o prepare al%umin 'olu8

$ion', whi!h ma( %e ineff i!ien$ in !learing

%ili8 ru%in !on$en$ from pla'ma.

21,27

The'ligh$ re8 du!$ion in pla$ele$ !oun$' in $he

al%umin gr ou p ma( %e a fur$her mar/er of a

larger eB pan'ion of $he in$r aa'!ular

!ompar$men$ in $hi' gr ou p $han in $he

!r ('$alloid group, wi$h a !on'e@uen$ dilu$ion of

$he hemoglo%in !on$en$ 9Ta%le #4 in $he


o'$ ho! uniar ia$e and mul$iar ia$e anal('e'





1.0

0.

0.C

0.7

0.

0.5

0.4

0.3

0.0 0 10 20 30 40 50 0 70 C0 0

edl( lower $han $ha$ admini'$ered in $he #+&E

'$ud(, 'in!e our goal wa' $o !orre!$ h( poal %u8

minemia and no$ $o dire!$l( repla!e in$r aa'!u8

lar olume. #e!ond, $he o %'er ed mor$ali$( a$ 2C

da(' wa' lower $han or iginall( eBpe!$ed, $her e %(

in!rea'ing $he li/elihood $ha$ $he '$ud( wa' un8

derpowered. &inall(, onl( a ppr oBima$el( one

$hird of $he pa$ien$' were enrolled during $he

earl( pha'e of 'eere 'e p'i'.n !on!lu'ion, $he u'e of al%umin in addi$ion

$o !r ('$alloid' $o !orre!$ h( poal %uminemia, a'

!ompared wi$h $he u'e of !r ('$alloid' alone, in

pa$ien$' wi$h 'eere 'ep'i' during $heir '$a(

in $he )= did no$ pr oide a 'urial %enef i$ a$

2C or 0 da(', de'pi$e im pr oemen$' in

hemod(nami! ar ia %le'. The !lini!al %enef i$

of al%umin $ha$

No. a/ "?

Da ne

"andoAa/onwa' 'een in $he po'$ ho! anal('i' of $he 'u%gr ou pof pa$ien$' wi$h 'ep$i! 'ho!/ warran$' f ur$her

+l%umin)r('$alloid'

0307

733

72

47

52

57

5C

57

7

55

551

545

53C

535

521

52

511

523

504!onf ir ma$ion.

#uppor$ed %( $he $alian edi!ine' +gen!(.

<g-e 2. *-o+a+l/ o &-==al 2 -o "andoa/on /,-og, Da :0.

The graph 'how' $he M aplan < eier e'$ima$e' for $he pr o %a %ili$( of 'ur 8

ial among pa$ien$' re!eiing al%umin and !r ('$alloid' and among $ho'e

re!eiing !r ('$alloid' alone. The alue wa' !al!ula$ed wi$h $he u'e of $he

log8ran/ $e'$.

of da$a from $he 1121 pa$ien$' wi$h 'ep$i! 'ho!/

'howed 'ignif i!an$l( lower mor$ali$( a$ 0

da(' in $he al%umin group $han in $he !r ('$alloid

gr ou p. )oner'el(, in $he 'u%group of pa$ien$'wi$h 'e8 ere 'ep'i' wi$hou$ 'ho!/, mor$ali$(

appeared $o %e higher among $ho'e who were

$rea$ed wi$h al%umin $han among $ho'e $rea$ed

wi$h !r ('$al8 loid' alone, al$hough $he differen!e

wa' far from 'ignif i!an$. Thi' anal('i' wa' no$

pr e'pe!if ied, and $herefore i$ ma( %e

!hara!$eried %( well8 /nown %ia'e'.

None$hele'', a '$a$e of 'ho!/ a''o8 !ia$ed wi$h

'eere 'ep'i' repre'en$' a well8defined !lini!al

en$i$(. or eoer , if $he on!o$i!, an$i8 inf

lamma$or (, and ni$ri! oBide< '!aenging pr o p8

er$ie' of al%umin are of !lini!al im por $an!e,$he'e ma( %e maBimall( eBploi$ed in $he !ondi8

$ion' $ha$ are $he mo'$ 'eer e, 'u!h a' !ar dioa'8

!ular d('f un!$ion.

6ur $rial ha' !er$ain limi$a$ion'. &ir'$, we in8

!luded $he u'e of al%umin 'olu$ion' wi$h a

gr ea$er !on!en$ra$ion $han $ho'e u'ed in $he

#+&E '$ud( 920D '. 4D:. )on'e@uen$l(, $he

olume of al %u8 min 'olu$ion $ha$ wa'

admini'$ered wa' mar / 8

"i'!lo'ure form' pr oided %( $he au$hor' are aaila%le wi$h

$he full $eB$ of $hi' ar$i!le a$ NEJ.or g.Ke $han/ Ni!ola o$$ino, ."., iu'eppe reda, .".,

"aide )hiumello, ."., #$efania )ro$$i, ."., #ergio "e

)hiara, ."., +lfredo 2i''oni, ."., &ran!e'!a agan, .".,

auro anigada, ."., -i!!arda -u''o, ."., oni!a #aioli,

."., +l%er$o #i!ignano, ."., "aniela Tu%iolo, ."., and all

$he r e'iden!( and nur'ing '$aff of $he -ianimaione ener ale

Emma e!la, &ondaione '$i$u$o di -i!oero e )ura a )ar a$$er e

#!ien$if i!o 93-))#: )a randa<6'pedale aggiore

oli!lini!o, ilan 9!oordina$ing !en$er:, for 'uppor$ in

moni$oring $he r an8 domia$ion pro!e'' and '$ud(

!omplian!e; aola 5r uone, ."., &ederi!o olli, ."., and

&ederi!a Tallarini, ."., of $he "ipar$imen$o di +ne'$e'ia,

-ianimaione e Terapia del "olor e, &ondaione 3-))# )a

randa<6'pedale aggiore oli!lini!o, ilan, and Tomma'o

auri, ."., of $he "ipar$imen$o di edi!ina

eriopera$oria e Terapia 3n$en'ia, +ienda 6'pedaliera #.

erardo di ona, for help in da$a8@uali$ ( a'8 'e''men$;

2ui'ella iroi of $he )on'orio ario Negri #ud, #an$a

aria m%aro, and arina 2eonardelli of $he "ipar$imen$o di

+ne'$e'ia, -ianimaione e Terapia del "olor e, &ondaione

3-))# )a randa<6'pedale aggiore oli!lini!o, ilan, for

'uppor$ in moni$oring '$ud( !omplian!e and r e$r ie8 ing

ou$!ome da$a; aolo )adringher and Eleonora )ar le''o,.#!., of $he "ipar$imen$o di &i'iopa$ologia edi!o8

)hirurgi!a e dei Trapian$i, &ondaione -))# )a

r anda < 6'pedale aggiore oli!lini!o, =nier'i$> degli #$udi,

ilan, for pr i8 mar ( 'uppor$ in !rea$ing and managingele!$roni! !lini!al r e8 'ear!h form'; Jean82oui' in!en$, .".,

of $he "epar$men$ of n$en'ie )are, Era'me =nier 'i$ (

Lo'pi$al, =nier'i$W 2i%re de ruBelle', ru''el', e$er .

#u$er, ."., of $he =nier'i$ ( of enea, enea, aria

raia al'e!!hi of $he "i par $imen$o di edi!ina )lini!a e

r eenione, =nier'i$> degli #$udi di ilano8i!o!!a, ilan,

and +medeo #an$o'uo''o of $he "ipar$imen$o di

iuri'prudena, =nier'i$> degli #$udi di aia, aia, for

'er ing on $he da$a and 'af e$ ( moni$or ing %oard; $he '$ud(

pa$ien$' and $heir r ela$ie' for $heir par $i!i pa8 $ion; and $he

ph('i!ian' and nur'ing '$af f of $he par $i!i pa$ing !en$er' for

$heir !oo per a$ion.


* - o + a + 0 l 0 / 7 o 2 & 4 - = 0 = a l

+l%umin

)r('$alloid'

F0.3




"E<E" ENCE &

1. Er'$ad 52, ale' 5J, -appapor$ K". 10. Ming T. 6n $he 'ulf h(dr(l group of !en$er, pr o'pe!$ie '$ud(. )ri$ )are

The u'e of al%umin in !lini!al pr a!$i!e. human pla'ma al%umin. J iol )hem 1C;2V1738C00.

+r!h n$ern ed 11;151V01811. 11;23V)5. 1:. oreno -, in!en$ J2, a$o' -, e$ al.

2. )o!hrane njurie' roup +l%umin 11. Xuinlan J, argar'on , um %( The u'e of maBimum #6&+ '!ore $o @uan8

-eiewer'. Luman al%umin admini'$r a8 #, Ean' TK, u$$eridge J. +dmini'$r a8 $if( organ d('f un!$ionSf ailur e in in$en'ie

$ion in !ri$i!all( ill pa$ien$'V '('$ema$i! $ion of al%umin $o pa$ien$' wi$h 'e p'i' !areV re'ul$' of a pr o'pe!$ie, mul$i!en$r ereiew of randomi'ed !on$rolled $r ial'. '(ndr omeV a po''i%le %enef i!ial role in '$ud(. Kor/ing roup on #ep'i' r ela$ed

5J 1C;317V235840. pla'ma $hiol reple$ion. )lin #!i 92ond: ro%lem' of $he E#). 3n$en'ie )are

3. Kil/e' , Nai!/i' - J. a$ien$ 'ur 8 1C;5V4585. ed 1;25VC8.ial af$er human al%umin admini'$r a$ionV 12. #$amler J#, Jar a/ i 6, 6'%orne J, e$ al. 20. Mellum J+, ellomo -, -on!o ).

a me$a8anal('i' of randomied, !on$r olled Ni$ri! oBide !ir!ula$e' in mammalian !on!ep$ of a!u$e / idne( injur( and $he

$rial'. +nn n$ern ed 2001;135V1484. pla'ma pr imar il( a' an #8ni$ro'o addu!$ !ri$eria. )on$ri% Nephrol 2007;15V108.

4. in!en$ J2, "u%oi' J, Nai!/i' - J, of 'erum al%umin. ro! Na$l +!ad #!i 21. in!en$ J2. -elean!e of al%umin in

Kil/e' . L( poal %uminemia in a!u$e = # + 12;CV77487. modern !ri$i!al !are medi!ine. e'$ ra!$

illne''V i' $here a ra$ionale for in$er en8 13. -eee' -. Tem per a$ur e8indu!ed -e' )lin +nae'$he'iol 200;23V1C381.

$ionY + me$a8anal('i' of !ohor$ '$udie' !hange' in %lood a!id8%a'e '$a$u'V "on8 22. in!en$ J2, o$$in 2. T(pe of f luid in

and !on$rolled $rial'. +nn #urg 2003; nan r)l and red !ell olume. J +ppl h('i8 'eere 'ep'i' and 'ep$i! 'ho!/. iner a

237V31834. ol 17;40V7287. +ne'$e'iol 2011;77V1108.

5. &infer #, ellomo -, o(!e N, &r en!h 14. one -), al/ -+, )erra &, e$ al. "ef8 23. The #+&E #$ud( 3ne'$iga$or'. mpa!$

J, ( %ur gh J, Nor$on -. + !ompari'on of ini$ion' for 'ep'i' and organ failure and al%umin !ompared $o 'aline on organ f un!8

al%umin and 'aline for f luid r e'u'!i$a$ion guideline' for $he u'e of innoa$ie $her a8 $ion and mor $ali$( of pa$ien$' wi$h 'eer e

in $he in$en'ie !are uni$. N Engl J ed pie' in 'ep'i'. )he'$ 12;101V144855. 'ep'i'. 3n$en'ie )are ed 2011;37VC8.

2004;350V224785. 15. -ier' E, Ngu(en , La'$ad #, e$ al. 24. "elane( +, "an +, !)affre( J, &in8

6. "u%oi' J, 6r ellana8Jimene ), elo$ Earl( goal8dire!$ed $her a p( in $he $r ea$8 fer #. The role of al%umin a' a r e'u'!i$a8

), e$ al. +l%umin admini'$ra$ion im8 men$ of 'eere 'ep'i' and 'ep$i! 'ho!/ . $ion f luid for pa$ien$' wi$h 'ep'i'V a '('8 pr oe' organ fun!$ion in !ri$i!all( ill h(8 N Engl J ed 2001;345V13C877. $ema$i! reiew and me$a8anal('i'. )ri$

poal%uminemi! pa$ien$'V a pr o'pe!$ie, 16. 2e all J- , 2eme'how #, #aulnier &. )are ed 2011;3V3C81.

randomied, !on$rolled, pilo$ '$ud(. )ri$ + new #im plif ied +!u$e h('iolog( #!ore 25. Lollen%erg #, io$row'/i J, ar8

)are ed 200;34V253840. 9#+# : %a'ed on a EuropeanSNor$h +mer 8 rillo JE. Ni$ri! oBide '(n$ha'e inhi %i$ion7. Xuinlan J, ar$in #, Ean' TK. i!an mul$i!en$er '$ud(. J++ 13;270V r eer'e' ar$eriolar h( por e'pon'iene'' $o

+l%uminV %io!hemi!al proper$ie' and 25783. HErra$um, J++ 14;271V1321.I endo$helin81 in 'ep$i! ra$'. +m J h('iol

$herapeu$i! po$en$ial. Le pa$olog( 2005;41V 17. in!en$ J2, oreno -, Ta/ala J, e$ al. 17;272V-8-74.

12118. The #6&+ 9#ep'i'8rela$ed 6rgan &ailure 26. Ti$heradge +. Ni$ri! oBide in 'e p$i!

>. Keil L, Lenning - J, uri M . )ol8 +''e''men$: '!ore $o de'!ri%e organ d('8 'ho!/. io!him ioph(' +!$a 1;1411V

loid on!o$i! pre''ureV !lini!al 'ignifi!an!e. fun!$ionSfailure. 3n$en'ie )a re ed 437855.

)ri$ )are ed 17;7V1138. 1;22V707810. 27. !)ann M, u!i!a T, &amulari #,

:. #udlow , ir/e$$ "J, Kade "N. The 1>. in!en$ J2, de endonZa +, )an$r aine er$olini J. Effe!$ of pro!e''ing me$hod'

!hara!$eria$ion of $wo 'pe!if i! dr ug &, e$ al. ='e of $he #6&+ '!ore $o a''e'' on !oloura$ion of human 'erum al %umin

%inding 'i$e' on human 'erum al %umin. $he in!iden!e of organ d('f un!$ionSf ailur e prepara$ion'. iologi!al' 200;37V328.

ol harma!ol 175;11VC24832. in in$en'ie !are uni$'V re'ul$' of a mul$i8 Copyright© 2014 Massachusetts Medical Society.

16e.0al0e1 and o60.1 a/ ne 5.o-g

#pe!ial$( page' a$ $he Journal ;' we%'i$e 9NEJ.org: fea$ure ar$i!le' in !ardiolog(,

endo!rinolog(, gene$i!', infe!$iou' di'ea'e, nephrolog(, pedia$ri!', and man( o$her

medi!al 'pe!ial$ie'. The'e page', along wi$h !olle!$ion' of ar$i!le' on !lini!al andnon!lini!al $opi!', offer lin/' $o in$era!$ie and mul$imedia !on$en$ and fea$ure

re!en$l( pu%li'hed ar$i!le' a' well a' ma$erial from $he NEJar!hie 91C12<1C:.


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