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$$' edi!al #o!ie$(. +ll righ$' re'er,ed.
T he n e w e n g l a n d j o u r n a l of m e d i !i n e
original ar$i!le
+l%umin -epla!emen$ in .a$ien$'
wi$h #e,ere #ep'i' or #ep$i! #ho!/
.ie$ro )aironi, ."., 0ianni Tognoni, ."., #erge a''on, .h."., -o%er$o
&umagalli, ."., +n$onio .e'en$i, ."., arilena -omero, .h."., )a$erina
&ani11a, .#$a$., 2ui'a )a'pani, ."., #$efano &aen1a, ."., 0ia!omo
0ra''elli, ."., 0ae$ano 3api!hino, ."., a''imo +n$onelli, ."., 4ieri
.arrini, ."., 0il%er$o &iore, ."., -o%er$o 2a$ini, .".,
and 2u!iano 0a$$inoni, ."., for $he +2536# #$ud( 3n,e'$iga$or'7
+ 5 # T - +) T
&rom "ipar$imen$o di &i'iopa$ologia
edi8 !o8)hirurgi!a e dei Trapian$i,
&onda1ione 3'$i$u$o di -i!o,ero e )ura a
)ara$$ere #!i8 en$ifi!o 93-))#: )a;
0randa<6'pedale aggiore .oli!lini!o,
=ni,er'i$> degli #$udi di ilano 9..).,
0.3., 2.0.:, "ipar$imen$o di +ne'$e'ia,
-ianima1ione e Terapia del "o8 lore,
&onda1ione 3-))# )a; 0randa<
6'pedale aggiore .oli!lini!o 9..).,
2.)., 2.0.:, 3-))#<3'$i$u$o di -i!er!he
&arma!o8 logi!he ario Negri 9#..,
-.2.:, "ipar$i8 men$o di #!ien1e della
#alu$e, =ni,er'i$> degli #$udi di ilano
5i!o!!a 9-.&., +...:, and "ipar$imen$o di
Emergen1a<=rgen1a, +1ienda
6'pedaliera #. .aolo<.olo =ni8 ,er'i$ario
90.3.:, ilan, )on'or1io ario Negri
#ud, #an$a aria 3m%aro 90.T., .-.,
).&.:, +ne'$e'iologia e -ianima1ione,
"i8 par$imen$o Emergen1a<=rgen1a,
)hirurg8 ia 0enerale e dei Trapian$i,
.oli!lini!o =ni8 ,er'i$ario #. 6r'ola
alpighi, 5ologna 9#.&.:, "ipar$imen$o di
Emergen1a<=rgen8 1a, +1ienda
6'pedaliera #. 0erardo, on8 1a 90.0.:,
.oli!lini!o =ni,er'i$ario +. 0e8 melli,
=ni,er'i$> )a$$oli!a, -ome 9.+.:,
6'pedale del ugello<+1ienda #ani$aria
di &iren1e, &loren!e 94...:, and 6'pedale
#. )ro!e, on!alieri 90.&.: ? all in 3$al(.
+d8 dre'' reprin$ re@ue'$' $o "r.
0a$$inoni a$ $he "ipar$imen$o di
&i'iopa$ologia edi8 !o8)hirurgi!a e dei
Trapian$i, &onda1ione 3-))# )a;
0randa<6'pedale aggiore .oli!lini!o,
=ni,er'i$> degli #$udi di ila8 no, 4ia &.
#for1a 35, 20122 ilan, 3$al(, or a$
g a $ $in o nA p o li! lin i! o .m i.i$ .
73n,e'$iga$or' of $he +l%umin 3$alian
6u$!ome #ep'i' 9+2536#: '$ud( are
li'$ed in $he #upplemen$ar( +ppendiB,
a,aila%le a$ NEJ.org.
Thi' ar$i!le wa' pu%li'hed on ar!h 1C,
2014, a$ NEJ.org.
N Engl J Med 2014;370:1412-
21. DOI:
10.1056/NEJMoa1305727
Copyright 2014 Massachusetts Medical Society.
1412
n engl j med 370;15 nejm.org april 10, 2014
The New England Journal of edi!ine
"ownloaded from nejm.org on #ep$em%er 3, 2014. &or per'onal u'e onl(. No o$her u'e' wi$hou$ permi''ion.
)op(righ$ * 2014 a''a!hu'e$$' edi!al #o!ie$(. +ll righ$' re'er,ed.
B
A
C

!
"
O
#
N
D
+l$hough pre,iou' '$udie' ha,e
'ugge'$ed $he po$en$ial
ad,an$age' of al%umin ad8
mini'$ra$ion in pa$ien$' wi$h
'e,ere 'ep'i', i$' effi!a!( ha'
no$ %een full( e'$a%li'hed.
M
E
$
%
O
D
&
3n $hi' mul$i!en$er, open8la%el
$rial, we randoml( a''igned
1C1C pa$ien$' wi$h 'e8 ,ere
'ep'i', in 100 in$en'i,e !are
uni$' 93)=':, $o re!ei,e ei$her 20D al%umin and !r('$alloid 'olu$ion or
!r('$alloid 'olu$ion alone. 3n $he al%umin group, $he $arge$ 'erum al%umin
!on!en$ra$ion wa' 30 g per li$er or more un$il di'!harge from $he 3)= or 2C da('
af$er randomi1a$ion. The primar( ou$!ome wa' dea$h from an( !au'e a$ 2C da('.
#e!ondar( ou$!ome' were dea$h from an( !au'e a$ E0 da(', $he num%er of
pa$ien$' wi$h organ d('fun!$ion and $he degree of d('fun!$ion, and leng$h of
'$a( in $he 3)= and $he ho'pi$al.
"E&#'$&
"uring $he f ir'$ 7 da(', pa$ien$' in $he al%umin group, a' !ompared wi$h $ho'e
in $he !r('$alloid group, had a higher mean ar$erial pre''ure 9. F 0.03: and
lower ne$ f luid %alan!e 9.G0.001:. The $o$al dail( amoun$ of admini'$ered f luid
did no$ differ 'ignif i!an$l( %e$ween $he $wo group' 9. F 0.10:. +$ 2C da(', 2C5
of CE5 pa$ien$' 931.CD: in $he al%umin group and 2CC of E00 932.0D: in $he
!r('$alloid group had died 9rela$i,e ri'/ in $he al%umin group, 1.00; E5D !onf
iden!e in$er,al H)3I, 0.C7 $o
1.14; . F 0.E4:. +$ E0 da(', 3J5 of CCC pa$ien$' 941.1D: in $he al%umin group and
3CE of CE3 943.JD: in $he !r('$alloid group had died 9rela$i,e ri'/, 0.E4; E5D )3,
0.C5 $o
1.05; . F 0.2E:. No 'ignif i!an$ differen!e' in o$her 'e!ondar( ou$!ome' were
o%8 'er,ed %e$ween $he $wo group'.
CONC'#&ION&
3n pa$ien$' wi$h 'e,ere 'ep'i', al%umin repla!emen$ in addi$ion $o !r('$alloid', a'
!ompared wi$h !r('$alloid' alone, did no$ impro,e $he ra$e of 'ur,i,al a$ 2C and
E0 da('. 9&unded %( $he 3$alian edi!ine' +gen!(; +2536# )lini!alTrial'.go,
num%er, N)T00707122.:
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'er,ed.
+ l%umin - epl a!emen$ in #e , er e #ep'i' or #ep $i! #ho!/
or de!ade', human al%umin ha'
%een admini'$ered $o pa$ien$' $o pro,ide
ade@ua$e on!o$i! pre''ure and
in$ra,a'!ular ,olume.
1
3n 1EEC, howe,er, a repor$ from $he )o!hrane
3n8 jurie' 0roup +l%umin -e,iewer' 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'
!ompared wi$h $he admini'$ra$ion of !r('$alloid
'olu$ion'.
2
#u%'e@uen$ me$a8anal('e' repor$ed
!on$radi!$or( finding'.
3,4
To !larif( $hi' i''ue, a large, dou%le8%lind,
randomi1ed $rial 9$he #aline ,er'u' +l%umin
&luid E,alua$ion H#+&EI '$ud(:
5
wa' !ondu!$ed,
in whi!h
4D al%umin 'olu$ion wa' !ompared wi$h
normal '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. +
predef ined 'u%group anal('i' 'howed $ha$
pa$ien$' wi$h 'e,ere 'ep'i' re!ei,ing al%umin
were a$ a lower, al$hough no$ 'ignif i!an$l(
lower, ri'/ for dea$h $han $ho'e re!ei,ing
normal 'aline. 3n addi$ion, a 'u%'e@uen$ '$ud(
poin$ed ou$ a po$en$ial %enefi$ of main$ain8 ing
'erum al%umin a$ a le,el of more $han 30 g per
li$er in !ri$i!all( ill pa$ien$'.
J
There i' a !on,in!ing ra$ionale for $he po$en8
$ial ad,an$age' of al%umin admini'$ra$ion
during 'e,ere 'ep'i'.
7
+l%umin i' $he main
pro$ein re8 'pon'i%le for pla'ma !olloid
o'mo$i! pre''ure
C
; i$ a!$' a' a !arrier for 'e,eral
endogenou' and eB8 ogenou' !ompound',
E
wi$h
an$ioBidan$ and an$i8 inf lamma$or( proper$ie',
and a' a '!a,enger of rea!$i,e oB(gen
10,11
and
ni$rogen
12
'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 randomi1ed, !on$rolled
$rial $o in,e'$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 le,el of 30 g per li$er or more in a
popula$ion of pa$ien$' wi$h 'e,ere 'ep'i'.
E TL 6
"#
&$#D( O)E"&I!%$ AND DE&I!N
Ke !ondu!$ed $he +l%umin 3$alian 6u$!ome
#ep8 'i' 9+2536#: '$ud( ? an in,e'$iga$or8
ini$ia$ed, mul$i!en$er, open8la%el, randomi1ed,
!on$rolled $rial ? in 100 in$en'i,e !are uni$'
93)=': in 3$al(. The mem%er' of $he '$eering
!ommi$$ee 9'ee $he #upplemen$ar( +ppendiB,
a,aila%le wi$h $he full $eB$ of $hi' ar$i!le a$ NEJ.org:
de'igned $he
&
The New England Journal of edi!ine
"ownloaded from nejm.org on #ep$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$$' edi!al #o!ie$(. +ll righ$' re'er,ed.
'$ud(, were re'pon'i%le for i$'
eBe!u$ion and for $he da$a
anal('i', made $he de!i'ion $o
'u%mi$ $he manu'!rip$ for
pu%li!a$ion, and a''ume
re'pon8 'i%ili$( for $he f ideli$(
of $he '$ud( $o $he pro$o!ol
9a,aila%le a$ NEJ.org:.
The $rial wa' funded %( $he
3$alian edi!ine' +gen!(,
whi!h had no role in $he
!ondu!$ of $he '$ud(, $he
repor$ing of $he da$a, or $he
'uppl( of '$ud( f luid'.
+l%umin admini'$ered during
$he '$ud( wa' pro,ided %( ea!h
par$i!ipa$ing in'$i$u8 $ion a'
par$ of $he !lini!al $rea$men$
of !ri$i!all( ill pa$ien$'. The
'$ud( pro$o!ol and $he
informed8 !on'en$ pro!e''
were appro,ed %( $he e$hi!'
!ommi$$ee a$ ea!h par$i!ipa$ing
in'$i$u$ion. Kri$$en informed
!on'en$ or deferred !on'en$
wa' o%8 $ained from ea!h
pa$ien$.
-andomi1a$ion wa'
performed !en$rall(, wi$h $he
u'e of a !ompu$er8genera$ed
and %linded a'8 'ignmen$
'e@uen!e. -andomi1a$ion wa'
'$ra$ified a!!ording $o $he
par$i!ipa$ing 3)= and $he in$er,al %e$ween $he
$ime $ha$ $he pa$ien$ me$ $he !lini!al !ri$eria for
'e,ere 'ep'i' and randomi1a$ion. The !ondu!$ of
$he $rial wa' o,er'een %( $he da$a and 'afe$(
moni$oring %oard, whi!h performed an in8 $erim
anal('i' af$er $he enrollmen$ of 700 pa$ien$'.
*A$IEN$&
.a$ien$' 1C (ear' of age or older who me$ $he
!lini!al !ri$eria for 'e,ere 'ep'i'
14
wi$hin $he
pre8 ,iou' 24 hour' a$ an( $ime during $heir
'$a( in $he 3)= were enrolled in $he '$ud(
af$er %eing '!reened for eligi%ili$( !ri$eria.
"e$ail' of $he in8 !lu'ion and eB!lu'ion !ri$eria
are pro,ided in $he #upplemen$ar( +ppendiB.
&$#D( $"EA$MEN$&
.a$ien$' were randoml( a''igned $o re!ei,e
ei$her
20D al%umin and !r('$alloid 'olu$ion 9al%umin
group: or !r('$alloid 'olu$ion alone
9!r('$alloid group: from randomi1a$ion un$il
da( 2C or di'8 !harge from $he 3)=, whi!he,er
!ame f ir'$. "ur8 ing $he earl( pha'e of ,olume
re'u'!i$a$ion, f lu8 id' were admini'$ered in
%o$h group' a!!ording $o earl( goal8dire!$ed
$herap(.
15
+f$er randomi1a$ion, pa$ien$' in $he
al%umin group re!ei,ed 300 ml of 20D al%umin
'olu$ion. &rom da( 1 un$il da( 2C or 3)=
di'!harge 9whi!h8 e,er !ame f ir'$:, 20D
al%umin wa' admini'$ered on a dail( %a'i', $o
main$ain a 'erum al%umin le,el of 30 g per
li$er or more. 3n %o$h group',
n engl j med 370;15 nejm.org april 10, 2014
1413
T he n e w e n g l a n d j o u r n a l of m e d i !i n e
!r('$alloid' were admini'$ered whene,er i$ wa'
!lini!all( indi!a$ed %( $he a$$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'!re8 $ion of $he a$$ending ph('i!ian.
O#$COME&
The primar( ou$!ome mea'ure wa' dea$h from
an( !au'e a$ 2C da(' af$er randomi1a$ion. The
prin!ipal 'e!ondar( ou$!ome mea'ure wa' dea$h
from an( !au'e a$ E0 da(' af$er randomi1a$ion.
+ddi$ional 'e!ondar( ou$!ome' were $he
num%er of pa$ien$' wi$h organ d('fun!$ion
and $he de8 gree of d('fun!$ion and $he leng$h
of '$a( in $he 3)= and $he ho'pi$al. The
'e,eri$( of '('$emi! illne'' wa' a''e''ed wi$h
$he u'e of $he #impli8 fied +!u$e .h('iolog(
#!ore, wi$h '!ore' ranging from 0 $o 1J3 and
higher '!ore' indi!a$ing more 'e,ere illne''.
1J
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' from
0 $o 4 for ea!h of f i,e !omponen$'
9re'pira$or(, !oagula$ion, li,er, !ardio,a'!ular,
and renal !om8 ponen$':, wi$h higher '!ore'
indi!a$ing more 'e,ere organ d('fun!$ion
9Ta%le #1 in $he #up8 plemen$ar( +ppendiB:.
New organ failure' were def ined a' a !hange
in a !omponen$ '!ore dur8 ing $he '$ud( from a
%a'eline '!ore of 0, 1, or 2 $o a '!ore of 3 or
4.
5,1C,1E
Ter$iar( ou$!ome', whi!h were a''e''ed
in po'$ ho! anal('e', in!luded $he
u'e of renal8repla!emen$ $herap(, $he in!iden!e
of a!u$e /idne( injur(, $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'opre''or or ino$ropi! agen$'.
&$A$I&$ICA' ANA'(&I&
Ke originall( de$ermined $ha$ a 'ample of 1350
pa8 $ien$' would pro,ide $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(
pro8 $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 re!om8 menda$ion %( $he da$a and
'afe$( moni$oring %oard during an in$erim
anal('i'.
+ll $he anal('e' were !ondu!$ed on an
in$en8 $ion8$o8$rea$ %a'i'. 5inar( 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 o,er $ime were performed
wi$h $he u'e of a $wo8fa!$or anal('i' of ,arian!e
for repea$ed mea'uremen$'. Ke !al!ula$ed 'ur8
,i,al e'$ima$e' a!!ording $o $he Maplan<eier
me$hod and !ompared $hem u'ing a log8ran/
$e'$. Ke performed an adju'$ed anal('i'
u'ing ro%u'$ .oi''on regre''ion for %inar(
ou$!ome'. 3n a po'$ ho! anal('i', $he primar(
and prin!ipal
$a+le 1. C,a-a./e-01/0.1 o2 /,e *a/0en/1 a/ Ba1el0ne.3
Al+450n !-o46 C-71/allo0d !-o46
C,a-a./e-01/0. 8N 9 :03; 8N 9 :07;
+ge ? (r
edian 70 JE
3n$er@uar$ile range 57<77 5E<77
&emale 'eB ? no. 9D: 3J0 93E.E: 357 93E.4:
5od(8ma'' indeBN 27OJ 27OJ
-ea'on for 3)= admi''ion ? no. 9D:
edi!al 511 95J.J: 51C 957.1:
Ele!$i,e 'urger( JE 97.J: 5C 9J.4:
Emergen!( 'urger( 323 935.C: 331 93J.5:
.reeBi'$ing !ondi$ion ? no. 9D:P
2i,er di'ea'e 13 91.4: 14 91.5:
)6." 113 912.5: 10C 911.E:
)hroni! renal failure 44 94.E: 32 93.5:
3mmunodefi!ien!( 115 912.7: 12C 914.1:
)onge'$i,e or i'!hemi! hear$ di'ea'e 14E 91J.5: 1J5 91C.2:
#+.# 33 '!oreQ
edian 4C 4C
3n$er@uar$ile range 37<5E 37<J0
1414
n engl j med 370;15 nejm.org april 10, 2014
+ l%umin - epl a!emen$ in #e , er e #ep'i' or #ep $i! #ho!/
$a+le 1. 8Con/0n4ed.;
Al+450n !-o46 C-71/allo0d !-o46
C,a-a./e-01/0. 8N 9 :03; 8N 9 :07;
.h('iologi!al ,aria%leR
Lear$ ra$e ? %ea$'Smin 105O22 10JO20
ean ar$erial pre''ure ? mm Lg 74O1J 73O15
)en$ral ,enou' pre''ure ? mm Lg 10.0O4.E E.CO4.7
=rine ou$pu$ ? mlShr
edian 50 50
3n$er@uar$ile range 20<100 25<100
2a!$a$e ? mmolSli$er
edian 2.3 2.5
3n$er@uar$ile range 1.4<4.2 1.J<4.3
#erum al%umin ? gSli$er 24.1OJ.3 24.2OJ.2
Lemoglo%in ? gSdl 10.EO2.1 11.0O2.0
)en$ral ,enou' oB(gen 'a$ura$ion ? D
edian 73 73
3n$er@uar$ile range J5<7E JC<C0
#6&+ '!ore
edian C C
3n$er@uar$ile range J<10 5<10
6rgan d('fun!$ion ? no. 9D:77
1 organ 1CC 920.C: 20C 922.E:
2 organ' 3J1 940.0: 303 933.4:
3 organ' 23J 92J.1: 24C 927.3:
4 organ' CE 9E.E: 115 912.7:
5 organ' 2E 93.2: 33 93.J:
#ho!/ ? no. 9D:NN 5J5 9J2.J: 570 9J2.C:
e!hani!al ,en$ila$ion ? no. 9D: 70E 97C.5: 737 9C1.3:
&luid admini'$ra$ion in pre,iou' 24 hr ? no. 9D:
+l%umin 153 91J.E: 17J 91E.4:
#(n$he$i! !olloid' 452 950.1: 47E 952.C:
7 .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!$i,e pulmonar( di'ea'e, and 3)= in$en'i,e !are uni$.
N The %od(8ma'' indeB i' $he weigh$ in /ilogram' di,ided %( $he '@uare of $he heigh$ in me$er'.
P +mong preeBi'$ing !ondi$ion', li,er di'ea'e wa' defined a' $he pre'en!e of !irrho'i', por$al h(per$en'ion, or pre,iou'
epi'ode' of li,er in'uffi!ien!(; immunodefi!ien!( a' $he !on!urren$ pre'en!e of immuno'uppre''i,e di'ea'e' or re!eip$
of immuno'uppre''i,e $herapie'; and !onge'$i,e or i'!hemi! hear$ di'ea'e a' New Tor/ Lear$ +''o!ia$ion !la'' 33.
Q The #implified +!u$e .h('iolog( #!ore 9#+.# 33:
1J
wa' u'ed $o a''e'' $he 'e,eri$( of '('$emi! illne'' a$ %a'eline.
#!ore' range from 0 $o 1J3, wi$h higher '!ore' indi!a$ing more 'e,ere illne''.
R "a$a on !en$ral ,enou' pre''ure were a,aila%le for C41 pa$ien$' in $he al%umin group and C5C in $he !r('$alloid
group; da$a on la!$a$e le,el, for C74 and CJ7, re'pe!$i,el(; da$a on 'erum al%umin le,el, for C21 and C13, re'pe!$i,el(;
da$a on hemoglo%in le,el, for CE3 and CE4, re'pe!$i,el(; and da$a on !en$ral ,enou' oB(gen 'a$ura$ion, for 7EC and
C02, re'pe!$i,el(.
The #e@uen$ial 6rgan &ailure +''e''men$ 9#6&+: '!ore
17
in!lude' 'u%'!ore' ranging from 0 $o 4 for ea!h of fi,e
!omponen$' 9re'pira$or(, !oagula$ion, li,er, !ardio,a'!ular, and renal !omponen$':, wi$h higher '!ore' indi!a$ing
more 'e,ere organ d('fun!$ion. The '!oring wa' modified %( eB!luding $he a''e''men$ of !ere%ral failure 9$he
0la'gow )oma #!ale:, whi!h wa' no$ performed in $he'e pa$ien$', and %( de!rea'ing $o J5 mm Lg $he mean ar$erial
pre''ure $hre'hold for a !ardio,a'!ular 'u%'!ore of 1, for !on'i'$en!( wi$h $he hemod(nami! $arge$' a' defined
a!!ording $o $he earl( goal8dire!$ed $herap(.
15
77 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 !o8
agula$ion !omponen$; 2 or more on $he li,er !omponen$; 1, 3, or 4 on $he !ardio,a'!ular !omponen$; and 2 or more
on $he renal !omponen$.
5
+ '!ore of 2 on $he !ardio,a'!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 !ardio,a'!u8
lar d('fun!$ion:.
NN #ho!/ a$ $he $ime of randomi1a$ion wa' defined a' a '!ore of 3 or 4 on $he !ardio,a'!ular !omponen$ of $he #6&+.
5
n engl j med 370;15 nejm.org april 10, 2014
1415
T he n e w e n g l a n d j o u r n a l of m e d i !i n e
A
34
32
30
2C
2J
24
22
20
1C
1J
14
.G0.001
0
+l%umin
)r('$alloid'
<0g4-e 1. &e-45 Al+450n 'e=el1 /,-o4g, Da7 2>
and Ne/ <l40d Balan.e /,-o4g, Da7 7.
.anel + 'how' $he 'erum al%umin !on!en$ra$ion
$hrough da( 2C in pa$ien$' re!ei,ing al%umin and !r('8
$alloid' or !r('$alloid' alone. "a( 0 wa' defined a' $he
$ime of randomi1a$ion. "a$a are median', wi$h 3 %ar'
indi!a$ing in$er@uar$ile range'. The . ,alue i' for $he
%e$ween8group !ompari'on performed wi$h $he u'e
of a $wo8fa!$or anal('i' of ,arian!e for repea$ed mea8
'uremen$' $o $e'$ $ime 92E da(' for 'erum al%umin,
in!luding da( 0: and group effe!$'. .anel 5 'how' $he
ne$ f luid %alan!e $hrough da( 7 for pa$ien$' re!ei,ing
al%umin and !r('$alloid' or !r('$alloid' alone. The
dail( ne$ f luid %alan!e wa' !al!ula$ed a' $he differen!e
%e$ween $he $o$al amoun$ of admini'$ered f luid 9in8
No. a/ "01?
0 4 C 12 1J
&/4d7 Da7
20 24 2C
!luding 20D al%umin; !r('$alloid'; o$her %lood prod8
u!$', 'u!h a' pa!/ed red !ell', fre'h8fro1en pla'ma, or
pla$ele$'; and o$her f luid': and $he $o$al amoun$ of
eB!re$ed f luid ea!h da( 9in!luding urinar( ou$pu$ and
+l%umin
)r('$alloid'
B 5000
C21
C13
J77
JJ3
4C3
4J4
335
303
23E
217
1EC
15E
14C
130
+l%umin
107
104
o$her f luid lo''e', 'u!h a' f luid' po$en$iall( remo,ed
wi$h !on$inuou' renal8repla!emen$ $herap(, 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 randomi1a8
4000
3000
2000
1000
0
)r('$alloid' $ion $o da( 1, whi!h a,eraged 1J hour' in $he $wo '$ud(
group'. The hori1on$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 3 %ar' $he 5$h and E5$h per8
!en$ile range. The . ,alue i' for $he %e$ween8group
!ompari'on performed wi$h $he u'e of $he $wo8fa!$or
anal('i' of ,arian!e for repea$ed mea'uremen$' $o $e'$
$ime 97 da(': and group effe!$'.
U1000
U2000
U3000
No. a/ "01?
.G0.001
1 2 3 4 5 J 7
&/4d7 Da7
l( a''igned $o re!ei,e 20D al%umin and !r('$al8
loid 'olu$ion 9E10 pa$ien$': or !r('$alloid
'olu$ion alone 9E0C: for f luid repla!emen$. .er
pro$o!ol, pa$ien$ enrollmen$ wa' '$ra$if ied
a!!ording $o $he in$er,al %e$ween $he $ime
$he pa$ien$ me$ $he !lini!al !ri$eria for 'e,ere
'ep'i' and random8
+l%umin
)r('$alloid'
C40
C44
7CE
7E5
742
735
701
JC5
J3E
J35
5CJ
5C7
542
52E
i1a$ionV J hour' or le'' 957E pa$ien$' H31.CDI:
,er'u' more $han J hour' 9123E HJC.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 $ho'e who did no$
ha,e 'ep$i! 'ho!/ a$ $he $ime of enrollmen$.
Le$erogenei$( of $rea$men$ effe!$' among 'u%8
group' wa' a''e''ed wi$h $he u'e of $he $e'$ for
a !ommon rela$i,e ri'/. #+# 'of$ware, ,er'ion
E.2 9#+# 3n'$i$u$e:, wa' u'ed for all $he
anal('e'.
- E # = 2 T
#
&$#D( *O*#'A$ION
&rom +ugu'$ 200C $hrough &e%ruar( 2012, a
$o$al of 1C1C pa$ien$' wi$h 'e,ere 'ep'i' were
random8
92 pa$ien$' in $he al%umin group owing $o wi$h8
drawal of !on'en$, and 5 in $he al%umin group
and 1 in $he !r('$alloid group owing $o a ran8
domi1a$ion error: 9&ig. #1 in $he
#upplemen$ar( +ppendiB:.
+f$er follow8up, da$a regarding dea$h a$ E0
da(' were a,aila%le for CCC of E03 pa$ien$'
9EC.3D: in $he al%umin group and for CE3 of
E07 9EC.5D: in $he !r('$alloid group. 5a'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('fun!$ion
and ,alue' of !en$ral ,enou' oB(gen 'a$ura$ion
9Ta%le 1:. The primar( 'i$e of
141J
n engl j med 370;15 nejm.org april 10, 2014
&
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
;
+ l%umin - epl a!emen$ in #e , er e #ep'i' or #ep $i! #ho!/
infe!$ion, $he $(pe of iden$if ied
mi!roorgani'm, and $he propor$ion of
pa$ien$' re!ei,ing an$i8 %io$i!' were 'imilar in
$he $wo group' 9Ta%le #2 in $he #upplemen$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!ei,ed
a 'ignif i!an$l( larger ,olume of 20D al%umin
'olu8 $ion 9.G0.001: and le'' !r('$alloid
'olu$ion 9.G0.001:. 3n $he al%umin group, $he
admini'$ra8 $ion of 20D al%umin 'olu$ion
a!!oun$ed for a median dail( a,erage of
4.3D 9in$er@uar$ile range, 2.E $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
$o
4533I, re'pe!$i,el(; . F 0.10: 9Ta%le #3 in $he
#up8 plemen$ar( +ppendiB:.
The 'erum al%umin le,el wa' 'ignif
i!an$l( higher in $he al%umin group $han in $he
!r('$al8 loid group from da( 1 $o da( 2C
9.G0.001: 9&ig.
1+:. "uring $he f ir'$ 7 da(', pa$ien$' in $he
al8 %umin group had a 'ignif i!an$l( lower hear$
ra$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 pre'8 'ure 9. F 0.03: 9Ta%le #4 and
&ig. #2 in $he #upplemen$ar( +ppendiB:.
"ail( ne$ f luid %al8 an!e' were lower in $he
al%umin group $han in $he !r('$alloid group
9.G0.001: 9&ig. 15:. The median !umula$i,e
ne$ 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, U32JJ $o
4042I ,'. 1220 ml Hin$er@uar$ile range, U27J7 $o
5034I, . F 0.004: 9Ta%le #5 in $he
#upplemen$ar( +ppendiB:.
O#$COME&
+$ 2C da(' af$er randomi1a$ion, 2C5 of CE5 pa8
$ien$' 931.CD: in $he al%umin group and 2CC
of
E00 932.0D: in $he !r('$alloid group had
died 9rela$i,e ri'/ in $he al%umin group, 1.00;
E5D !onf iden!e in$er,al H)3I, 0.C7 $o 1.14; .
F 0.E4: 9Ta%le 2:. +$ E0 da(' of follow8up, 3J5
of CCC pa$ien$' 941.1D: in $he al%umin group
and 3CE of
CE3 943.JD: in $he !r('$alloid group had
died 9rela$i,e ri'/, 0.E4; E5D )3, 0.C5 $o 1.05; .
F 0.2E:. No 'ignif i!an$ differen!e in $he pro%a%ili$( of
'ur,i,al wa' o%'er,ed %e$ween $he al%umin
group and $he !r('$alloid
group during $he E0 da(' af$er
randomi1a$ion 9. F 0.3E: 9&ig.
2:.
No 'ignifi!an$ differen!e
wa' o%'er,ed %e$ween $he $wo
'$ud( group' wi$h re'pe!$ $o
ei$her $he num%er of newl(
de,eloped organ failure' or $he
median #6&+ '!ore 9Ta%le
2:. +nal('i' of $he #6&+ '!ore
for ea!h organ '('$em re,ealed
$ha$, a' !ompared wi$h $he
!r('$alloid group, $he al8
%umin group had a lower
!ardio,a'!ular '!ore 9. F 0.03:,
a higher !oagula$ion '!ore 9.
F 0.04:, and a higher li,er
'!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 group 9.
F 0.007: 9Ta%le 2:.
3n 'u%group anal('e', no
'ignif i!an$ differ8 en!e wa'
o%'er,ed in $he pre'pe!if ied
'u%group' $ha$ were '$ra$ified
a!!ording $o $he in$er,al %e8
$ween $he $ime $he pa$ien$ me$
$he !lini!al !ri$e8 ria for 'e,ere 'ep'i' and
randomi1a$ion 9&ig. #3 in $he #upplemen$ar(
+ppendiB:. )on,er'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$h JJ0 wi$h8 ou$ 'ep$i! 'ho!/,
a$ $he $ime of enrollmen$ 9rela8 $i,e ri'/ wi$h
'ep$i! 'ho!/, 0.C7; E5D )3, 0.77 $o
0.EE; rela$i,e ri'/ wi$hou$ 'ep$i! 'ho!/,
1.13;
E5D )3, 0.E2 $o 1.3E; . F 0.03 for
he$erogenei$(: 9&ig. #3 in $he #upplemen$ar(
+ppendiB:. +dju'$8 men$ for %a'eline
!o,aria$e' did no$ 'ignif i8 !an$l( modif(
$he'e re'ul$' 9Ta%le #J in $he #upplemen$ar(
+ppendiB:.
" 3 # ) = # #
36N
The main re'ul$' of $hi' large8'!ale $rial pro,ide
e,iden!e regarding %o$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$ional '$ra$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 $rea$8 men$ $o main$ain a 'erum
al%umin le,el of 30 g per li$er or more i' 'afe %u$
doe' no$ pro,ide a 'ur,i,al ad,an$age o,er
!r('$alloid' alone, o,er a follow8up period of
E0 da('. #imilar f inding' were o%'er,ed in $he
'u%group '$ra$if ied a!!ord8 ing $o $he in$er,al
%e$ween $he $ime $he pa$ien$ me$ $he !lini!al
!ri$eria for 'e,ere 'ep'i' and $rea$men$
appli!a$ion.
n engl j med 370;15 nejm.org april 10, 2014
1417
T he n e w e n g l a n d j o u r n a l of m e d i !i n e
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'$ed a 'ur8 ,i,al ad,an$age wi$h an
al%umin8%a'ed '$ra$eg( during 'e,ere 'ep'i'.
The plau'i%ili$( of $hi' h(8 po$he'i' wa'
'uppor$ed %( $he 'ignif i!an$ hemo8 d(nami!
ad,an$age' o%'er,ed
23
and %( fur$her
in,e'$iga$ion' 'howing $ha$ $he !orre!$ion of
h(poal%uminemia redu!ed $he 'e,eri$( of organ
d('fun!$ion.
4,J
#imilar %enef i!ial effe!$'
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! ad,an$age'. + 'ignif i!an$l(
grea$er pro8 por$ion of pa$ien$' in $he al%umin
group $han in
$a+le 2. O4/.o5e1.
"ela/0=e "01?
O4/.o5e Al+450n !-o46 C-71/allo0d !-o46 8:5@ CI; * )al4e
.rimar( ou$!omeV dea$h a$ 2C da(' ? no.S$o$al no. 9D: 2C5SCE5 931.C: 2CCSE00 932.0: 1.00 90.C7<1.14: 0.E4
#e!ondar( ou$!ome'
"ea$h a$ E0 da(' ? no.S$o$al no. 9D: 3J5SCCC 941.1: 3CESCE3 943.J: 0.E4 90.C5<1.05: 0.2E
New organ failure' ? no.S$o$al no. 9D:7 0.EE
None 372SC3J 944.5: 3C3SC41 945.5:
1 organ 2C3SC3J 933.E: 2C7SC41 934.1:
2 organ' 130SC3J 915.J: 123SC41 914.J:
3 organ' 40SC3J 94.C: 3JSC41 94.3:
4 organ' 10SC3J 91.2: 11SC41 91.3:
5 organ' 1SC3J 90.1: 1SC41 90.1:
#6&+ '!oreN ? 0.23
edian J.00 5.J2
3n$er@uar$ile range 4.00<C.50 3.E2<C.2C
#6&+ 'u%'!oreN
)ardio,a'!ular ? 0.03
edian 1.20 1.42
3n$er@uar$ile range 0.4J<2.31 0.J0<2.50
-e'pira$or( ? 0.J3
edian 2.00 2.00
3n$er@uar$ile range 1.5J<2.4C 1.57<2.50
-enal ? 0.15
edian 0.C3 0.75
3n$er@uar$ile range 0.14<2.14 0.07<2.00
)oagula$ion ? 0.04
edian 0.J4 0.50
3n$er@uar$ile range 0.00<1.J2 0.00<1.5E
2i,er ? 0.02
edian 0.2C 0.20
3n$er@uar$ile range 0.00<1.00 0.00<0.E2
2eng$h of '$a( ? da('
3n 3)= ? 0.42
edian E E
3n$er@uar$ile range 4<1C 4<17
3n ho'pi$alP ? 0.J5
edian 20 20
3n$er@uar$ile range 10<3J E<3C
141C
n engl j med 370;15 nejm.org april 10, 2014
+ l%umin - epl a!emen$ in #e , er e #ep'i' or #ep $i! #ho!/
$a+le 2. 8Con/0n4ed.;
"ela/0=e "01?
O4/.o5e Al+450n !-o46 C-71/allo0d !-o46 8:5@ CI; * )al4e
Ter$iar( ou$!ome'Q
-enal8repla!emen$ $herap( ? no.S$o$al no. 9D:R 222SE03 924.J: 1E4SE07 921.4: 0.11
+!u$e /idne( injur( ? no.S$o$al no. 9D: 1C3SC34 921.E: 1E0SC37 922.7: 0.71
"ura$ion of me!hani!al ,en$ila$ion ? da('77 ? 0.50
edian J J
3n$er@uar$ile range 2<14 2<13
Time $o 'u'pen'ion of ,a'opre''or or ino$ropi! ? 0.007
agen$' ? da('NN
edian 3 4
3n$er@uar$ile range 1<J 2<7
7 New organ failure' were defined %( a !hange in a 'pe!ifi! !omponen$ of $he #6&+
17
from a '!ore of 0, 1, or 2 a$ %a'eline $o a '!ore of 3
or 4 during $he '$ud( period.
5,17,1C
N The ,alue' are $he median and in$er@uar$ile range of $he #6&+ '!ore, repre'en$ing $he a,erage of $he dail( #6&+ '!ore' for ea!h indi,idu8
al pa$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 $he 3)=.
Q Ter$iar( ou$!ome' were anal(1ed in po'$ ho! anal('e'.
R 3n!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$eria
20
for a!u$e /idne(
in8 jur( on $he %a'i' of dail( in!remen$al in!rea'e' in 'erum !rea$inine le,el' from %a'eline during $he '$ud( period.
77 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$.
NN 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 a,aila%le for 5C2 pa$ien$' in $he al%umin group
and 57J in $he !r('$alloid group.
$he !r('$alloid group rea!hed $he $arge$ed mean
ar$erial pre''ure wi$hin J hour' af$er random8
i1a$ion 9Ta%le #7 in $he #upplemen$ar(
+ppendiB:. "uring $he f ir'$ 7 da(', $he mean
ar$erial pre'8 'ure wa' higher, wherea' $he
hear$ ra$e and ne$ f luid %alan!e were lower, in
$he al%umin group $han in $he !r('$alloid
group. oreo,er, $he a,8 erage !ardio,a'!ular
#6&+ 'u%'!ore o,er $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'opre''or agen$' wa' 'hor$er, in8 di!a$ing a
de!rea'ed u'e of ,a'opre''or'. The'e effe!$'
were o%$ained wi$h 'imilar amoun$' of
admini'$ered f luid' in $he $wo '$ud(
group'. The'e f inding' !onf irm a
ph('iologi!al ad,an8 $age of al%umin
admini'$ra$ion during 'e,ere 'ep'i', in!luding a
larger f luid di'$ri%u$ion wi$hin $he in$ra,a'!ular
!ompar$men$ and, in addi$ion, po''i%le effe!$'
of al%umin a' a '!a,enger of ni8 $ri! oBide,
12
media$ing peripheral ,a'odila$a$ion during
'ep'i'.
25,2J
The 'e!ondar( ou$!ome' al'o pro,ide a de8
$ailed prof ile of $he 'afe$( of al%umin
admini'8
$ra$ion during 'e,ere '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 a,erage #6&+ 'u%'!ore' for li,er and
!oagula$ion in $he al%umin group, indi!a$ing a
higher 'erum %iliru%in and a lower pla$ele$
!oun$, re'pe!$i,el(, $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.J $o 1.7I
,'. 0.E mg per de!ili$er Hin$er@uar$ile range, 0.5
$o 1.5I, .G0.001: and wa' pro%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 group ma( %e a fur$her mar/er of a
larger eBpan'ion of $he in$ra,a'!ular
!ompar$men$ in $hi' group $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
#upplemen$ar( +ppendiB:.
.o'$ ho! uni,aria$e and mul$i,aria$e anal('e'
n engl j med 370;15 nejm.org april 10, 2014
141E
T he n e w e n g l a n d j o u r n a l of m e d i !i n e
1.0
0.E
0.C
0.7
0.J
0.5
0.4
0.3
0.0 0 10 20 30 40 50 J0 70 C0 E0
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$ra,a'!u8
lar ,olume. #e!ond, $he o%'er,ed mor$ali$( a$ 2C
da(' wa' lower $han originall( eBpe!$ed, $here%(
in!rea'ing $he li/elihood $ha$ $he '$ud( wa' un8
derpowered. &inall(, onl( approBima$el( one
$hird of $he pa$ien$' were enrolled during $he
earl( pha'e of 'e,ere 'ep'i'.
3n !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 'e,ere 'ep'i' during $heir '$a(
in $he 3)= did no$ pro,ide a 'ur,i,al %enef i$ a$
2C or E0 da(', de'pi$e impro,emen$' in
hemod(nami! ,aria%le'. The !lini!al %enef i$
of al%umin $ha$
No. a/ "01?
Da71 10n.e
"ando50Aa/0on
wa' 'een in $he po'$ ho! anal('i' of $he 'u%group
of pa$ien$' wi$h 'ep$i! 'ho!/ warran$' fur$her
+l%umin
)r('$alloid'
E03
E07
733
72E
J47
J52
5E7
5EC
5J7
J7J
55J
551
545
53C
535
521
52E
511
523
504
!onf irma$ion.
#uppor$ed %( $he 3$alian edi!ine' +gen!(.
<0g4-e 2. *-o+a+0l0/7 o2 &4-=0=al 2-o5 "ando50Aa/0on /,-o4g, Da7 :0.
The graph 'how' $he Maplan<eier e'$ima$e' for $he pro%a%ili$( of 'ur8
,i,al among pa$ien$' re!ei,ing al%umin and !r('$alloid' and among $ho'e
re!ei,ing !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$ E0
da(' in $he al%umin group $han in $he !r('$alloid
group. )on,er'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$
pre'pe!if ied, and $herefore i$ ma( %e
!hara!$eri1ed %( well8 /nown %ia'e'.
None$hele'', a '$a$e of 'ho!/ a''o8 !ia$ed wi$h
'e,ere 'ep'i' repre'en$' a well8defined !lini!al
en$i$(. oreo,er, if $he on!o$i!, an$i8 inf
lamma$or(, and ni$ri! oBide<'!a,enging prop8
er$ie' of al%umin are of !lini!al impor$an!e,
$he'e ma( %e maBimall( eBploi$ed in $he !ondi8
$ion' $ha$ are $he mo'$ 'e,ere, 'u!h a' !ardio,a'8
!ular d('fun!$ion.
6ur $rial ha' !er$ain limi$a$ion'. &ir'$, we in8
!luded $he u'e of al%umin 'olu$ion' wi$h a
grea$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' pro,ided %( $he au$hor' are a,aila%le wi$h
$he full $eB$ of $hi' ar$i!le a$ NEJ.org.
Ke $han/ Ni!ola 5o$$ino, ."., 0iu'eppe 5reda, .".,
"a,ide )hiumello, ."., #$efania )ro$$i, ."., #ergio "e
)hiara, ."., +lfredo 2i''oni, ."., &ran!e'!a .agan, .".,
auro .anigada, ."., -i!!arda -u''o, ."., oni!a #a,ioli,
."., +l%er$o #i!ignano, ."., "aniela Tu%iolo, ."., and all
$he re'iden!( and nur'ing '$aff of $he -ianima1ione 0enerale
Emma 4e!la, &onda1ione 3'$i$u$o di -i!o,ero e )ura a )ara$$ere
#!ien$if i!o 93-))#: )a; 0randa<6'pedale aggiore
.oli!lini!o, ilan 9!oordina$ing !en$er:, for 'uppor$ in
moni$oring $he ran8 domi1a$ion pro!e'' and '$ud(
!omplian!e; .aola 5ru11one, ."., &ederi!o .olli, ."., and
&ederi!a Tallarini, ."., of $he "ipar$imen$o di +ne'$e'ia,
-ianima1ione e Terapia del "olore, &onda1ione 3-))# )a;
0randa<6'pedale aggiore .oli!lini!o, ilan, and Tomma'o
auri, ."., of $he "ipar$imen$o di edi!ina
.eriopera$oria e Terapia 3n$en'i,a, +1ienda 6'pedaliera #.
0erardo di on1a, for help in da$a8@uali$ ( a'8 'e''men$;
2ui'ella .iro11i of $he )on'or1io ario Negri #ud, #an$a
aria 3m%aro, and arina 2eonardelli of $he "ipar$imen$o di
+ne'$e'ia, -ianima1ione e Terapia del "olore, &onda1ione
3-))# )a; 0randa<6'pedale aggiore .oli!lini!o, ilan, for
'uppor$ in moni$oring '$ud( !omplian!e and re$rie,8 ing
ou$!ome da$a; .aolo )adringher and Eleonora )arle''o,
.#!., of $he "ipar$imen$o di &i'iopa$ologia edi!o8
)hirurgi!a e dei Trapian$i, &onda1ione 3-))# )a;
0randa<6'pedale aggiore .oli!lini!o, =ni,er'i$> degli #$udi,
ilan, for pri8 mar( 'uppor$ in !rea$ing and managing
ele!$roni! !lini!al re8 'ear!h form'; Jean82oui' 4in!en$, .".,
of $he "epar$men$ of 3n$en'i,e )are, Era'me =ni,er'i$ (
Lo'pi$al, =ni,er'i$W 2i%re de 5ruBelle', 5ru''el', .e$er .
#u$er, ."., of $he =ni,er'i$ ( of 0ene,a, 0ene,a, aria
0ra1ia 4al'e!!hi of $he "ipar$imen$o di edi!ina )lini!a e
.re,en1ione, =ni,er'i$> degli #$udi di ilano85i!o!!a, ilan,
and +medeo #an$o'uo''o of $he "ipar$imen$o di
0iuri'pruden1a, =ni,er'i$> degli #$udi di .a,ia, .a,ia, for
'er,ing on $he da$a and 'afe$ ( moni$oring %oard; $he '$ud(
pa$ien$' and $heir rela$i,e' for $heir par$i!ipa8 $ion; and $he
ph('i!ian' and nur'ing '$aff of $he par$i!ipa$ing !en$er' for
$heir !oopera$ion.
1420
n engl j med 370;15 nejm.org april 10, 2014
*
-
o
+
a
+
0
l
0
/
7

o
2

&
4
-
=
0
=
a
l
+l%umin

)r('$alloid'
.F0.3E
+ l%umin - epl a!emen$ in #e , er e #ep'i' or #ep $i! #ho!/
"E<E"ENCE &
1. Er'$ad 52, 0ale' 5J, -appapor$ K". 10. Ming T.. 6n $he 'ulf h(dr(l group of !en$er, pro'pe!$i,e '$ud(. )ri$ )are
ed The u'e of al%umin in !lini!al pra!$i!e. human pla'ma al%umin. J 5iol )hem 1EEC;2JV17E38C00.
+r!h 3n$ern ed 1EE1;151VE01811. 1EJ1;23JV.)5. 1:. oreno -, 4in!en$ J2, a$o' -, e$ al.
2. )o!hrane 3njurie' 0roup +l%umin 11. Xuinlan 0J, argar'on ., um%( The u'e of maBimum #6&+ '!ore $o @uan8
-e,iewer'. Luman al%umin admini'$ra8 #, E,an' TK, 0u$$eridge J. +dmini'$ra8 $if( organ d('fun!$ionSfailure in in$en'i,e
$ion in !ri$i!all( ill pa$ien$'V '('$ema$i! $ion of al%umin $o pa$ien$' wi$h 'ep'i' !areV re'ul$' of a pro'pe!$i,e, mul$i!en$re
re,iew of randomi'ed !on$rolled $rial'. '(ndromeV a po''i%le %enef i!ial role in '$ud(. Kor/ing 0roup on #ep'i' rela$ed
5J 1EEC;317V235840. pla'ma $hiol reple$ion. )lin #!i 92ond: .ro%lem' of $he E#3). 3n$en'i,e )are
3. Kil/e' , Na,i!/i' -J. .a$ien$ 'ur8 1EEC;E5V45E8J5. ed 1EEE;25VJCJ8EJ.
,i,al af$er human al%umin admini'$ra$ionV 12. #$amler J#, Jara/i 6, 6'%orne J, e$ al. 20. Mellum J+, 5ellomo -, -on!o ).
The
a me$a8anal('i' of randomi1ed, !on$rolled Ni$ri! oBide !ir!ula$e' in mammalian !on!ep$ of a!u$e /idne( injur( and $he
-3&2E
$rial'. +nn 3n$ern ed 2001;135V14E8J4. pla'ma primaril( a' an #8ni$ro'o addu!$ !ri$eria. )on$ri% Nephrol 2007;15JV108J.
4. 4in!en$ J2, "u%oi' J, Na,i!/i' -J, of 'erum al%umin. .ro! Na$l +!ad #!i 21. 4in!en$ J2. -ele,an!e of al%umin in
Kil/e' . L(poal%uminemia in a!u$e = # + 1EE2;CEV7J7487. modern !ri$i!al !are medi!ine. 5e'$ .ra!$
illne''V i' $here a ra$ionale for in$er,en8 13. -ee,e' -5. Tempera$ure8indu!ed -e' )lin +nae'$he'iol 200E;23V1C38E1.
$ionY + me$a8anal('i' of !ohor$ '$udie' !hange' in %lood a!id8%a'e '$a$u'V "on8 22. 4in!en$ J2, 0o$$in 2. T(pe of f luid in
and !on$rolled $rial'. +nn #urg 2003; nan r)l and red !ell ,olume. J +ppl .h('i8 'e,ere 'ep'i' and 'ep$i! 'ho!/. iner,a
237V31E834. ol 1E7J;40V7J287. +ne'$e'iol 2011;77V11E08J.
5. &infer #, 5ellomo -, 5o(!e N, &ren!h 14. 5one -), 5al/ -+, )erra &5, e$ al. "ef8 23. The #+&E #$ud( 3n,e'$iga$or'. 3mpa!$
of
J, (%urgh J, Nor$on -. + !ompari'on of ini$ion' for 'ep'i' and organ failure and al%umin !ompared $o 'aline on organ fun!8
al%umin and 'aline for f luid re'u'!i$a$ion guideline' for $he u'e of inno,a$i,e $hera8 $ion and mor$ali$( of pa$ien$' wi$h 'e,ere
in $he in$en'i,e !are uni$. N Engl J ed pie' in 'ep'i'. )he'$ 1EE2;101V1J44855. 'ep'i'. 3n$en'i,e )are ed 2011;37VCJ8EJ.
2004;350V224785J. 15. -i,er' E, Ngu(en 5, La,'$ad #, e$ al. 24. "elane( +., "an +, !)affre( J, &in8
6. "u%oi' J, 6rellana8Jimene1 ), elo$ Earl( goal8dire!$ed $herap( in $he $rea$8 fer #. The role of al%umin a' a re'u'!i$a8
), e$ al. +l%umin admini'$ra$ion im8 men$ of 'e,ere 'ep'i' and 'ep$i! 'ho!/. $ion f luid for pa$ien$' wi$h 'ep'i'V a '('8
pro,e' organ fun!$ion in !ri$i!all( ill h(8 N Engl J ed 2001;345V13JC877. $ema$i! re,iew and me$a8anal('i'. )ri$
poal%uminemi! pa$ien$'V a pro'pe!$i,e, 16. 2e 0all J-, 2eme'how #, #aulnier &. )are ed 2011;3EV3CJ8E1.
randomi1ed, !on$rolled, pilo$ '$ud(. )ri$ + new #implif ied +!u$e .h('iolog( #!ore 25. Lollen%erg #, .io$row'/i J, .ar8
)are ed 200J;34V253J840. 9#+.# 33: %a'ed on a EuropeanSNor$h +mer8 rillo JE. Ni$ri! oBide '(n$ha'e inhi%i$ion
7. Xuinlan 0J, ar$in 0#, E,an' TK. i!an mul$i!en$er '$ud(. J++ 1EE3;270V re,er'e' ar$eriolar h(pore'pon'i,ene'' $o
+l%uminV %io!hemi!al proper$ie' and 2E578J3. HErra$um, J++ 1EE4;271V1321.I endo$helin81 in 'ep$i! ra$'. +m J .h('iol
$herapeu$i! po$en$ial. Lepa$olog( 2005;41V 17. 4in!en$ J2, oreno -, Ta/ala J, e$ al. 1EE7;272V-EJE8-E74.
12118E. The #6&+ 9#ep'i'8rela$ed 6rgan &ailure 26. Ti$heradge +. Ni$ri! oBide in 'ep$i!
>. Keil L, Lenning -J, .uri 4M. )ol8 +''e''men$: '!ore $o de'!ri%e organ d('8 'ho!/. 5io!him 5ioph(' +!$a 1EEE;1411V
loid on!o$i! pre''ureV !lini!al 'ignifi!an!e. fun!$ionSfailure. 3n$en'i,e )are ed 437855.
)ri$ )are ed 1E7E;7V1138J. 1EEJ;22V707810. 27. !)ann M5, 4u!i!a T, &amulari #,
:. #udlow 0, 5ir/e$$ "J, Kade "N. The 1>. 4in!en$ J2, de endonZa +, )an$raine 5er$olini J. Effe!$ of pro!e''ing me$hod'
!hara!$eri1a$ion of $wo 'pe!if i! drug &, e$ 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. $he in!iden!e of organ d('fun!$ionSfailure prepara$ion'. 5iologi!al' 200E;37V328J.
ol .harma!ol 1E75;11VC24832. in in$en'i,e !are uni$'V re'ul$' of a mul$i8 Copyright 2014 Massachusetts Medical Society.
16e.0al/0e1 and /o60.1 a/ neB5.o-g
#pe!ial$( 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 and
non!lini!al $opi!', offer lin/' $o in$era!$i,e and mul$imedia !on$en$ and fea$ure
re!en$l( pu%li'hed ar$i!le' a' well a' ma$erial from $he NEJ ar!hi,e 91C12<1ECE:.
n engl j med 370;15 nejm.org april 10, 2014
1421