The

new engl and jour nal

of

medicine

original ar#icle

)lucocor#icoid" !lu" N*'ce#ylcy"#eine in &e(ere 'lcoholic +e!a#i#i"

Eric Nguyen*,hac, M.D., -h.D., Thierry The(eno#, M.D., Marie*'"#rid -i.ue#, M.D., -h.D., &a/d 0enferha#, M.D., 1dile )oria, M.D., Deni" $ha#elain, M.D., -h.D., 0lai"e Tramier, M.D., ran2oi" Dewaele, M.D., &alah )hri3, M.D., Mari4a 5udler, M.D., Nicola" $ar3onell, M.D., +er(6 To""ou, M.D., '3de"lam 0en#al, M.D., 0rigi##e 0ernard*$ha3er#, M.D., and Jean*7oui" Du!a", M.D., for #he ''+*N'$ &#udy )rou!8

'3"#r ac#
Background

Mor#ali#y among !a#ien#" wi#h "e(ere acu#e alcoholic he!a#i#i" i" high, e(en among #ho"e #rea#ed wi#h glucocor#icoid". 9e in(e"#iga#ed whe#her com3ina#ion #hera!y wi#h glucocor#icoid" !lu" N*ace#ylcy"#eine would im!ro(e "ur(i(al.
Methods

9e randomly a""igned 1:4 !a#ien#" #o recei(e !redni"olone !lu" N* ace#ylcy"#eine ;<= !a#ien#"> or only !redni"olone ;<9 !a#ien#">. 'll !a#ien#" recei(ed 4 wee4" of !red* ni"olone. The !redni"olone?N*ace#ylcy"#eine grou! recei(ed in#ra(enou" N*ace#ylcy"* #eine on day 1 ;a# a do"e of 1=0, =0, and 100 mg !er 4ilogram of 3ody weigh# in 2=0, =00, and 1000 ml of =@ gluco"e "olu#ion o(er a !eriod of A0 minu#e", 4 hour", and 1B hour", re"!ec#i(ely> and on day" 2 #hrough = ;100 mg !er 4ilogram !er day in 1000 ml of =@ gluco"e "olu#ion>. The !redni"olone*only grou! recei(ed an infu"ion in 1000 ml of =@ gluco"e "olu#ion !er day on day" 1 #hrough =. The !rimary ou#come wa" B*mon#h "ur(i(al. &econdary ou#come" included "ur(i(al a# 1 and A mon#h", he!a#i#i" com!lica#ion", ad(er"e e(en#" rela#ed #o N*ace#ylcy"#eine u"e, and change" in 3iliru3in le(el" on day" : and 14.
Results

increa"ed 1*mon#h "ur(i(al among !a#ien#" wi#h "e(ere acu#e alcoholic he!a#i#i", B*mon#h "ur* (i(al, #he !rimary ou#come, wa" no# im!ro(ed. ; unded 3y -rogramme +o"!i#alier de 5echerche $lini.ueF ''+*N'$ $linicalTrial".go( num3er, N$T00<BA:<=.>

Mor#ali#y wa" no# "ignifican#ly lower in #he !redni"olone?N*ace#ylcy"#eine grou! #han in #he !redni"olone*only grou! a# B mon#h" ;2:@ (". A<@, - C 0.0:>. Mor#ali#y wa" "ignifican#ly lower a# 1 mon#h ;<@ (". 24@, - C 0.00B> 3u# no# a# A mon#h" ;22@ (". A4@, - C 0.0B>. Dea#h due #o #he he!a#orenal "yndrome wa" le"" fre.uen# in #he !redni"olone? N*ace#ylcy"#eine grou! #han in #he !redni"olone*only grou! a# B mon#h" ;9@ (". 22@, - C 0.02>. Dn a mul#i(aria#e analy"i", fac#or" a""ocia#ed wi#h B*mon#h "ur(i(al were a younger age ;-E0.001>, a "hor#er !ro#hrom3in #ime ;-E0.001>, a lower le(el of 3iliru* 3in a# 3a"eline ;-E0.001>, and a decrea"e in 3iliru3in on day 14 ;-E0.001>. Dnfec#ion" were le"" fre.uen# in #he !redni"olone?N*ace#ylcy"#eine grou! #han in #he !red* ni"olone*only grou! ;- C 0.001>F o#her "ide effec#" were "imilar in #he #wo grou!".
Conclusions

'l#hough com3ina#ion

#hera!y wi#h !redni"olone

!lu" N*ace#ylcy"#eine

The New England Journal of Medicine Downloaded from nejm.org on January 29, 2014. or !er"onal u"e only. No o#her u"e" wi#hou# !ermi""ion. $o!yrigh# % 2011 Ma""achu"e##" Medical &ocie#y. 'll righ#" re"er(ed.

rom &er(ice dG+6!a#o*)a"#roen#6rolo* gie ;E.N.*,., .D., J.*7.D.> and -a#hology &er(ice ;D.$.>, 'mien" Hni(er"i#y +o"!i* #al, and E.ui!e 56gion DN&E5M 24, Hni* (er"i#y of -icardy ;E.N.*,.> I 3o#h in 'mien"F &er(ice dG+6!a#ologie, 0e"an2on Hni(er"i#y +o"!i#al, 0e"an2on ;T.T.>F &er* (ice dG+6!a#o* )a"#roen#6rologie, $aen Hni(er"i#y +o"!i#al, $aen ;M.*'.-.>F &er* (ice dG+6!a#o*)a"#roen#6rologie, &ain#* Juen#in )eneral +o"!i#al, &ain#*Juen#in ;&.0.>F &er(ice dG+6!a#o*)a"#roen#6rolo* gie, 5ouen Hni(er"i#y +o"!i#al, 5ouen ;1.).>F 0io"#a#i"#ic" De!ar#men#, 'u3a* gne )eneral +o"!i#al, 'u3agne ;0.T.>F &er* (ice dG+6!a#o*)a"#roen#6rologie, $am3rai )eneral +o"!i#al, $am3rai ;&.).>F &er* (ice dG+6!a#o* )a"#roen#6rologie, -i#i6? &al!K#riLre Hni(er"i#y +o"!i#al ;M.5.> and &er(ice dG+6!a#ologie, &ain#*'n#oine Hni* (er"i#y +o"!i#al ;N.$.> I 3o#h in -ari"F &er(ice dG+6!a#o*)a"#roen#6rologie, 0eau* (ai" )eneral +o"!i#al, 0eau(ai" ;+.T.>F &er(ice dG+6!a#o*)a"#roen#6rologie, '3* 3e(ille )eneral +o"!i#al, '33e(ille ;'.0.>F and &er(ice dG+6!a#o*)a"#roen#6rologie, 5eim" Hni(er"i#y +o"!i#al, 5eim" ;0.0.*$.> I all in rance. 'ddre"" re!rin# re.ue"#" #o Dr. Nguyen*,hac a# #he +e!a#o*)a"#ro* en#erology &er(ice,

'mien" Hni(er"i#y +o"* !i#al, -l. Mic#or -auche#, *<00=4 'mien" $EDEN 01 rance, or a# nguyen*4hac .ericOchu*amien".fr. 8The mem3er" of #he 'cu#e 'lcoholic +e!a#i#i"?N*'ce#ylcy"#eine ;''+*N'$> &#udy )rou! are li"#ed in #he &u!!lemen* #ary '!!endiP, a(aila3le a# NEJM.org. N Engl J Med 2011FAB=Q1:<1*9.
Copyright 2011 Massachusetts Medical Society.

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The New England Journal of Medicine Downloaded from nejm.org on January 29, 2014. or !er"onal u"e only. No o#her u"e" wi#hou# !ermi""ion. $o!yrigh# % 2011 Ma""achu"e##" Medical &ocie#y. 'll righ#" re"er(ed.

The

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e(ere acu#e alcoholic he!a#i#i" i" a life*#hrea#ening alcoholic li(er di"ea"e.1 'l* #hough glucocor#icoid #rea#men# i" recom* mended2,A and im!ro(e" "ur(i(al,4*11 mor#ali#y remain" high, wi#h A=@ of !a#ien#" dying wi#hin B mon#h".1 7ong*#erm alcohol con"um!#ion increa"e" in* #e"#inal !ermea3ili#y, wor"en" endo#oPemia,12 "#imula#e" ,u!ffer cell",1A and #hu" increa"e" !ro* duc#ion of !roinf lamma#ory cy#o4ine".14 +igh le(el" of #umor necro"i" fac#or R ;TN *R> ac#i(a#e cell*dea#h !a#hway" and induce #he !roduc#ion of reac#i(e oPygen "!ecie", no#a3ly "u!eroPide anion", 3y #he he!a#ocy#e mi#ochondria, leading #o cell dea#h. Thi" "i#ua#ion i" accom!anied 3y "e(ere mi#ochondrial de!le#ion of glu#a#hione,1= #he !ri* mary an#ioPidan# in cell". ur#hermore, he!a#o* cy#e" are much more "en"i#i(e #o TN *R when #heir an#ioPidan# re"er(e" are low.1B $om3ina#ion #hera!y wi#h an an#ioPidan# and glucocor#icoid" would ha(e #he ad(an#age of 3o#h ac#ing on #he inf lamma#ory !roce"" and recon"#i#u#ing cellu* lar glu#a#hione re"er(e". N*ace#ylcy"#eine could ha(e (alue a" an an#ioPi* dan# in #he #rea#men# of acu#e alcoholic he!a#i#i", 3ecau"e #he #hiol grou! in N* ace#ylcy"#eine i" a3le #o reduce le(el" of free radical". 'dmini"#ra#ion of N*ace#ylcy"#eine migh# recon"#i#u#e #he glu#a#hione "#oc4" of #he he!a#ocy#e". '# !re"en#, N*ace#ylcy"* #eine i" u"ed in #he #rea#men# of ace#amino!hen* induced he!a#i#i". 9e conduc#ed a #rial #o e(alua#e #he efficacy of glucocor#icoid" !lu" N* ace#ylcy"#e* ine, a" com!ared wi#h glucocor#icoid" alone, in !a#ien#" wi#h "e(ere acu#e alcoholic he!a#i#i".

func#ion of A2 or more, and li(er hi"#ologic f inding" con"i"#en# wi#h alcoholic he!a#i#i" ;Mallory 3odie" "urrounded 3y !olymor* !honuclear neu#ro!hil">. MaddreyG" di"criminan# func#ion i" calcula#ed a" T4.B U ;!a#ien#G" !ro#hrom*

Me#hod "
Patients

The com!le#e "#udy !ro#ocol i" a(aila3le ;in rench> wi#h #he full #eP# of #hi" ar#icle a# NEJM.org. rom 2004 #hrough 2009, !a#ien#" ho"!i#aliSed for "e(ere acu#e alcoholic he!a#i#i" a# 11 rench uni(er"i#y ho"!i#al" were e(alua#ed for eligi3ili#y. The inclu* "ion cri#eria were an age of 1< year" or older, an a(erage alcohol in#a4e of more #han =0 g !er day during #he A mon#h" 3efore enrollmen#, a Mad* dreyG" di"criminan#

3in #ime V con#rol !ro#hrom3in #ime, in "econd">W X "erum 3iliru3in le(el, in milligram" !er decili#er. ' (alue of A2 or more clearly iden#if ie" !a#ien#" wi#h a high ri"4 of early dea#h.: ,ey ePclu"ion cri#eria were #he he!a#orenal "yndrome, he!a#ocellular carcinoma, uncon#rolled 3ac#erial infec#ion or ga"#roin#e"#inal hemor* rhage in #he !re(iou" 4 day", infec#ion wi#h he!a#i#i" $ (iru" ;+$M>, he!a#i#i" 0 (iru" ;+0M>, human immunodef iciency (iru" ;+DM> infec#ion, au#oimmune he!a#i#i", hemochroma#o"i", 9il* "onG" di"ea"e, al!ha1*an#i#ry!"in deficiency, ace#a* mino!hen*induced he!a#i#i", cancer, N*ace#yl* cy"#eine allergy, and "eriou" cardiac, re"!ira#ory, or neurologic di"ea"e.
Study Design

9e !erformed a mul#icen#er, randomiSed, con* #rolled #rial. -a#ien#" who me# #he eligi3ili#y cri#eria were randomly a""igned #o recei(e ei#her !redni"* olone !lu" N*ace#ylcy"#eine or only !redni"olone. 5andomiSa#ion wa" !erformed cen#rally in 3loc4" of four 3y mean" of a com!u#eriSed !rocedure, wi#h "#ra#ifica#ion according #o cen#er. The #rea#men# a"* "ignmen#" were no# concealed from #he in(e"#iga* #or" or #he !a#ien#". The "#udy wa" conduc#ed in com!liance wi#h #he !ro#ocol. The ini#ial e(alua#ion included #ran"jugular or !ercu#aneou" li(er 3io!"y, ul#ra"onogra!hy of #he li(er, and e"o!hageal

endo"co!y. The clinical eP* amina#ion included #he recording of cardiac fre.uency, 3lood !re""ure, #em!era#ure, and a"* "e""men# for he!a#ic ence!halo!a#hy, a"ci#e", ga"* #roin#e"#inal hemorrhage, and jaundice. 'lcohol u"e wa" e(alua#ed wi#h #he 'lcohol H"e Di"order" Dden#ifica#ion Te"# ;'HDDT>1: and #he $')E .ue"* #ionnaire.1< 'HDDT "core", which range from 0 #o 40, are de#ermined 3y 10 "#andardiSed .ue"#ion" on #he u"e of alcoholic 3e(erage" during #he !a"# yearF a "core of more #han < indica#e" haSardou" and harmful alcohol u"e. $')E "core" range from 0 #o 4, and each of #he le##er" in #he acronym re* fer" #o one of #he four .ue"#ion"F a "core of 2 #o 4 "ugge"#" alcohol a3u"e. 7a3ora#ory #e"#" mea"ured !ro#hrom3in #imeF le(el" of 3iliru3in, a"!ar#a#e amino#ran"fera"e, Y*glu#amyl#ran"fera"e, al4aline !ho"!ha#a"e, al* 3umin, crea#inine, "odium, !o#a""ium, !ho"!ho* ru", hemoglo3in, iron, #ran"ferrin, ferri#in, al!ha1* an#i#ry!"in, and cerulo!la"minF !la#ele#, whi#e*cell, and !olymor!honuclear* neu#ro!hil coun#"F and

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)lucocor#icoid" !lu" n *'ce # y l c y" #eine in ' l coholic +e!a#i#i"

an#inuclear, an#i?"moo#h mu"cle, an#imi#ochon* drial, and an#i?li(er?4idney micro"omal an#i3od* ie". -a#ien#" were #e"#ed for +0M, +$M, and +DM. &creening for 3ac#erial infec#ion" included urine, a"ci#e", and 3lood cul#ure", a" well a" che"# radi* ogra!hy. The $hild?-ugh "core ;which ran4" #he "e(eri#y of cirrho"i"> and MaddreyG" di"criminan# func#ion were calcula#ed. The $hild?-ugh "coring "y"#em a""ign" 1 #o A !oin#" for each of fi(e (ari* a3le" ;!ro#hrom3in #ime, al3umin le(el, 3iliru3in le(el, a"ci#e", and he!a#ic ence!halo!a#hy>, wi#h A !oin#" indica#ing #he mo"# "e(ere derangemen#. ' $hild?-ugh "core of = or B indica#e" cla"" ' di"ea"e ;#he lea"# "e(ere>, : #o 9 !oin#" cla"" 0 ;modera#ely "e(ere>, and 10 #o 1= !oin#" cla"" $ ;#he mo"# "e(ere>. Each in(e"#iga#or de#ermined #he dura#ion of ho"!i#aliSa#ion. -a#ien#" were moni#ored wee4ly during #he f ir"# mon#h and #hen mon#hly un#il mon#h B. Each (i"i# included a clinical ePamina* #ion, "creening for com!lica#ion" ;ga"#roin#e"#inal hemorrhage, #he he!a#orenal "yndrome, he!a#ic ence!halo!a#hy, "!on#aneou" 3ac#erial !eri#oni#i", and o#her infec#ion">, e(alua#ion of com!liance wi#h #rea#men# and a3"#inence from alcohol con* "um!#ion, la3ora#ory #e"#" ;!ro#hrom3in #imeF le(el" of 3iliru3in, al3umin, a"!ar#a#e amino#ran"* fera"e, Y*glu#amyl#ran"fera"e, al4aline !ho"!ha* #a"e, and crea#inineF and whi#e*cell and !olymor* !honuclear*neu#ro!hil coun#">, and calcula#ion of #he $hild?-ugh "core and MaddreyG" di"criminan# func#ion. 'll !a#ien#" were followed for B mon#h" or un#il dea#h. The "#a#u" ;ali(e or dead> of !a* #ien#" lo"# #o follow*u! wa" a""e""ed 3y #ele!hon* ing a family mem3er or 3y con#ac#ing #he dea#h regi"#ry a# #he !a#ien#G" 3ir#h!lace.
Study Treatments

#hrough =, #hey recei(ed 100 mg !er 4ilogram !er day in 1000 ml of gluco"e "olu#ion. The !a#ien#" in #he

0o#h grou!" recei(ed 40 mg of oral !redni"olone !er day for 2< day". or #he f ir"# = day", !a#ien#" in #he !redni"olone?N* ace#ylcy"#eine grou! re* cei(ed in#ra(enou" infu"ion" of N*ace#ylcy"#eine ; luimucil, Zam3on )rou!>. 1n day 1, #hey re* cei(ed 1=0 mg !er 4ilogram of 3ody weigh# in 2=0 ml of =@ gluco"e "olu#ion o(er a !eriod of A0 minu#e", =0 mg !er 4ilogram in =00 ml of gluco"e "olu#ion o(er a !eriod of 4 hour", and 100 mg !er 4ilogram in 1000 ml of gluco"e "olu* #ion o(er a !eriod of 1B hour". 1n day" 2

!redni"olone*only grou! recei(ed an infu"ion in 1000 ml of =@ gluco"e "olu#ion !er day on day" 1 # h r o u g h = . The #rea#men# of a"ci#e" wi#h diure#ic", al3u* min, and "odium re"#ric#ion wa" allowed, a" wa" #he u"e of 3e#a* 3loc4er" for !or#al hy!er#en"ion. Managemen# of alcohol addic#ion wa" lef# #o #he indi(idual cen#er. The u"e of ace#amino!hen, !en#* oPifylline, or an#i?TN *R #rea#men#" wa" !rohi3* i#ed. 'll !a#ien#" recei(ed normal ho"!i#al nu#ri#ion ;1<00 #o 2000 4cal !er day>.
S t u d y O u t c o m e s

The !rimary ou#come wa" "ur(i(al a# B mon#h". -rogno"#ic fac#or" for B*mon#h mor#ali#y were eP* amined. The "econdary ou#come" were "ur(i(al a# 1 and A mon#h", change" in 3iliru3in le(el" af#er : and 14 day" of #rea#men#, occurrence of he!a#i* #i" com!lica#ion", and ad(er"e e(en#" rela#ed #o N*ace#ylcy"#eine u"e. 7i(er #ran"!lan#a#ion or u"e of #he molecular ad"or3en# recircula#ing "y"#em ;M'5&> during #he #rial wa" #rea#ed a" a mor#ali#y end !oin# in "ur(i(al analy"e".
Study Oversight

The "#udy wa" a!!ro(ed 3y #he in"#i#u#ional re(iew 3oard a# 'mien" Hni(er"i#y +o"!i#al and wa" con* duc#ed in com!liance wi#h #he rench +urie#? &6ru"cla# legi"la#ion on medical re"earch and #he Declara#ion of +el"in4i. 'll !a#ien#" !ro(ided wri##en informed con"en# 3efore enrollmen#. ; or !a#ien#" wi#h he!a#ic ence!halo!a#hy, informed con"en# wa" o3#ained from #he neP# of 4in.>
Statistical Analysis

-rimary and "econdary ou#come" were com!ared 3e#ween #he #wo #rea#men# grou!". Juan#i#a#i(e (aria3le", eP!re""ed a" mean" [&D, were com!ared wi#h #he u"e of #he 9ilcoPon #e"#, ,ru"4al?9alli" #e"#, or &#uden#G" #*#e"#, a" a!!ro!ria#e. Juali#a#i(e (aria3le", eP!re""ed a" !ercen#age", were com!ared wi#h #he u"e of a chi*".uare #e"# or i"herG" ePac# #e"#. ,a!lan? Meier "ur(i(al cur(e" were !lo##ed for u! #o 1<0 day" and com!ared wi#h #he u"e of a log* ran4 #e"#. ac#or" #ha# were "ignifican#ly !redic#i(e of mor#ali#y in a uni(aria#e analy"i" ;-E0.0=> were included in a mul#i(aria#e $oP logi"#ic* regre""ion analy"i" wi#h "#e!wi"e elimina#ion. ' 3iliru3in de* crea"e on day : or 14 wa" def ined a" a lower a3* "olu#e (alue #han on day 0. Dn "econdary analy"e" #ha# were no# !re"!ecif ied in #he "#udy !ro#ocol,

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4A0 -a#ien#" were a""e""ed for eligi3ili#y

2=0 9ere ePcluded 1B1 Did no# mee# inclu"ion cri#eria A: Declined #o !ar#ici!a#e =2 +ad o#her rea"on"

1<0 Hnderwen# randomiSa#ion

<9 9ere a""igned #o recei(e !redni"olone !lu" N*ace#ylcy"#eine

91 9ere a""igned #o recei(e !redni"olone only

4 Did no# recei(e "#udy drug 2 Me# ePclu"ion cri#eria 1 +ad he!a#ocarcinoma 1 +ad lung cancer 2 +ad o#her rea"on"

2 Did no# recei(e "#udy drug 1 Me# ePclu"ion cri#eria ;he!a#ocarcinoma> 1 +ad o#her rea"on

<= 5ecei(ed "#udy drug and were included in #he in#en#ion*#o*#rea# !o!ula#ion

<9 5ecei(ed "#udy drug and were included in #he in#en#ion*#o*#rea# !o!ula#ion

< Di"con#inued glucocor#icoid" : Died wi#hin #he fir"# mon#h 1 +ad "!on#aneou" 3ac#erial !eri#oni#i" A Di"con#inued "#udy drug af#er #he fir"# do"e owing #o a ra"h 11 9ere lo"# #o follow*u! 2 'f#er 14 day" 9 'f#er a median of 90 day"

2A Di"con#inued glucocor#icoid" 20 Died wi#hin #he fir"# mon#h 1 9a" #rea#ed wi#h M'5& on day 2: 1 +ad "!on#aneou" 3ac#erial !eri#oni#i" 1 +ad a lung infec#ion 1A 9ere lo"# #o follow*u! 1 'f#er : day" 4 'f#er 14 day" 1 'f#er 21 day" : 'f#er a median of B0 day"

<= 9ere included in #he analy"i"

<9 9ere included in #he analy"i"

Figure 1 !nrollment and Outcomes Da#a on mor#ali#y were a(aila3le for all !a#ien#" in #he in#en#ion*#o*#rea# !o!ula#ion, including #ho"e lo"# #o follow*u!. M'5& deno#e" molecular ad"or3en# recircula#ing "y"#em.

we com!ared cau"e" of dea#h 3e#ween #he #wo grou!" and ePamined #he effec# of change in 3ili* ru3in le(el" o(er #ime on "ur(i(al. 'n in#ermedia#e "afe#y analy"i" wa" !erformed af#er =0@ of #he enrolled !a#ien#" had com!le#ed B mon#h" of fol* low*u! ;wi#h -E0.0= cho"en a" #he #hre"hold for "#a#i"#ical "ignif icance>. or #he f inal analy"i", a - (alue of le"" #han 0.02= wa" u"ed. 'll #he "#a* #i"#ical analy"e" were !erformed in #he modif ied

in#en#ion*#o*#rea# !o!ula#ion. 'll re!or#ed (alue" are #wo*"ided. The re.uired "am!le "iSe wa" calcula#ed on #he a""um!#ion #ha# #he "ur(i(al ra#e would 3e B:@ a# B mon#h" in #he !redni"olone*only grou!.1 9i#h an al!ha error of 0.0=, a 3e#a error of 0.10, and a hy!o#he#ical im!ro(emen# in "ur(i(al of 20@ a# mon#h B for #he !redni"olone?N*ace#ylcy"#eine grou!, #he re.uired "am!le "iSe wa" 1:4 !a#ien#".

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Ta"le 1 Baseline Characteristics o# the Patients $ Re#erence Range Prednisolone Only '( ) *+, =2.2[<.= =0 ;=B> :.9[B.: 10<.<[==.A 22.B[:.4 A.2[0.9 11.A[1.A =<.2[20.0 A9 ;44> B2 ;:0> :0?100 0?19 A:?4= EA=?4= 0?<= 0?240 4=?120
A

Characteristic 'ge I yr Male "eP I no. ;@> Time 3e#ween ho"!i#al admi""ion and "#ar# of #rea#men# in #rial I day" 'lcohol in#a4e I g\day 'HDDT "core] $')E "core^ $hild?-ugh "core_ MaddreyG" di"criminan# func#ion` +e!a#ic ence!halo!a#hy I no. ;@> '"ci#e" I no. ;@> -ro#hrom3in #ime I @ of normal 0iliru3in I amol\li#er 'l3umin I g\li#er '"!ar#a#e amino#ran"fera"e I H\li#er Y*)lu#amyl#ran"fera"e I H\li#er 'l4aline !ho"!ha#a"e I H\li#er $rea#inine I amol\li#er 9hi#e*cell coun# I !er mm -olymor!honuclear*neu#ro!hil coun# I !er mmA

Prednisolone% N&Acetylcysteine '( ) *-, =2.<[<.: == ;B=> :.2[B.B 10:.2[=<.0 22.=[:.4 A.A[0.9 11.0[1.= =4.0[1<.2 A< ;4=> =9 ;B9> A9.9[10.9 2A<.1[1AB.0 24.A[=.9 12:.=[<A.9 A0<.9[2<9.0 1:4.<[<A.< :A.A[29.9 10,=2<[B=A4 :=A0[B2=4

P .alue 0.BB 0.2= 0.4= 0.<B 0.91 0.2< 0.A= 0.11 0.4B 1.00 0.12 0.A= 0.42 0.10 0.0= 0.90 0.9B 0.B9 0.4<

A:.=[9.9 2B0.1[1:1.0 24.9[=.4 109.9[49.1 22A.0[240.0 1:B.<[1B1.= :A.1[21.0 10,901[=B40 <1:9[=20=

4000?10,000 1400?:=00

8 -lu"?minu" (alue" are mean" [&D. 5eference range" are from #he lowe"# reference (alue u"ed 3y any of #he cen#er" #o #he highe"# (alue u"ed 3y any cen#er. ] The 'lcohol H"e Di"order" Dden#ifica#ion Te"# ;'HDDT>, de(elo!ed 3y #he 9orld +eal#h 1rganiSa#ion, a""e""e" ePce""i(e drin4ing wi#h a "#andardiSed in#er(iew #ha# include" 10 .ue"#ion" on #he u"e of alcoholic 3e(erage" during #he !re(iou" year. ' "core of more #han < indica#e" haSardou" and harmful alcohol u"e ;"core range, 0 #o 40>. ^ The $')E .ue"#ionnaire include" 4 .ue"#ion" on u"e of alcoholic 3e(erage". ' "core of 2 or more indica#e" alcohol a3u"e ;"core range, 0 #o 4>. _ The $hild?-ugh "core ran4" #he "e(eri#y of cirrho"i" 3y a""igning 1 #o A !oin#" for each of fi(e (aria3le" ;!ro#hrom3in #ime, al3umin le(el, 3iliru3in le(el, !re"ence or a3"ence of a"ci#e", and !re"ence or a3"ence of he!a#ic ence!halo!a#hy>, wi#h A !oin#" indica#ing #he mo"# "e(ere derangemen#. ' $hild?-ugh "core of = or B indica#e" cla"" ' di"ea"e ;#he lea"# "e(ere>, : #o 9 !oin#" cla"" 0 ;modera#ely "e(ere>, and 10 #o 1= !oin#" cla"" $ ;#he mo"# "e(ere>. ` MaddreyG" di"criminan# func#ion i" calcula#ed a" T4.B U ;!a#ien#G" !ro#hrom3in #ime ? con#rol !ro#hrom3in #ime, in "ec* ond">W X "erum 3iliru3in le(el, in milligram" !er decili#er. ' (alue of A2 indica#e" "e(ere acu#e alcoholic he!a#i#i" wi#h a high ri"4 of early dea#h.

3a"eline charac#eri"#ic" of #he !a#ien#" did no# dif* fer "ignifican#ly 3e#ween #he #wo grou!", Study Po/ulation wi#h #he ePce!#ion of a "ligh#ly higher Y* glu#amyl#ran"* ' #o#al of 4A0 !a#ien#" were e(alua#ed for from '33e(ille, 2 from 0eau(ai", and 1 from 5eim">. The eligi3ili#y ; ig. 1>. 'f#er ePclu"ion of 2=0 !a#ien#" who did no# mee# #he inclu"ion cri#eria or for o#her rea"on", 1<0 underwen# randomiSa#ion. The final analy"i" wa" !erformed wi#h 1:4 !a#ien#" ;:A from 'mien", A9 from 0e"an2on, 20 from $aen, 1= from &ain#* Juen#in, 11 from 5ouen, : from $am3rai, 2 from &ain#*'n#oine, 2 from -i#i6*&al!K#riLre, 2

5e"ul# "

fera"e le(el in #he !redni"olone?N*ace#ylcy"#eine grou! ;- C 0.0=> ;Ta3le 1>. The re"ul#" of #he "ched* uled in#erim analy"i" ha(e 3een !u3li"hed !re(i* ou"ly.19

Mortality

Dn regard #o #he !rimary ou#come, =: !a#ien#" had died 3y B mon#h". The mor#ali#y ra#e wa" A<@ in #he !redni"olone*only grou! ;A4 of <9> and 2:@ in
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1.0 0.9

infec#ion" accoun#ed for 9@ of !a#ien#" in #he !red* ni"olone*only grou! ;< of <9> and <@ of #ho"e in

#he !redni"olone*N*ace#ylcy"#eine grou! ;: of <=>;odd" ra#io, 0.91F 9=@ $D, 0.2< #o

-redni"olone? N*ace#ylcy"#eine

0.:

0.B 0.=

-redni"olone only - C 0.0: 3y log*ran4 #e"#

0.4 0.A 0.2 0.1 0.0 0 A0 B0 90 120 1=0 1<0

Days (o at Risk

-redni"olone only <9 -redni"olone? <= N*ace#ylcy"#eine

B9 :<

B1 :A

B0 BB

=B BA

== BA

4B 4<

2.9AF - C 0.<=>, wi#h a mean #ime #o dea#h of A1[22 day" and =B[4= day", re"!ec#i(ely ;- C 0.0=>. Dn #he !redni"o* lone*only grou!, 4 !a#ien#" died from "e!#ic "hoc4, A from lung infec#ion", and 1 from "!on#aneou" 3ac#erial !eri#oni#i"F in #he !redni"olone?N* ace#yl* cy"#eine grou!, 2 !a#ien#" died from "e!#ic "hoc4, 2 from lung infec#ion", and 1 each from "u3!hren* ic a3"ce"", "!on#aneou" 3ac#erial !eri#oni#i", and !yelone!hri#i". The o#her cau"e" of dea#h in #he !redni"olone*only grou! were e"o!hageal (ariceal hemorrhage ;1 !a#ien#>, e"o!hageal ulcer hemor* rhage ;1>, hemorrhagic "#ro4e ;1>, #or"ade de !oin#e" ;1>, and #erminal li(er failure ;1>F in addi#ion, 1 !a* #ien# wa" #rea#ed wi#h M'5& on day 2:. Dn #he !red* ni"olone?N*ace#ylcy"#eine grou!, #he o#her cau"e" of dea#h were e"o!hageal (ariceal hemorrhage ;= !a#ien#"> ;- C 0.11>, hemorrhagic "#ro4e ;1>, and #erminal li(er failure ;1>F in addi#ion, 1 !a#ien# un* derwen# li(er #ran"!lan#a#ion on day 1:0.
Adverse !vents

Pro/ortion Surviving

Figure 0 1a/lan%Meier Curves #or 2&Month Survival in the 3ntention&to& Treat Po/ulation

#he !redni"olone?N*ace#ylcy"#eine grou! ;2A of <=> ;haSard ra#io wi#h com3ina#ion #hera!y, 0.B2F 9=@ confidence in#er(al T$DW, 0.A: #o 1.0BF - C 0.0:> ; ig. 2>. The mean #ime #o dea#h wa" 40[A= day" ;medi* an, 2:F range, A #o 149> in #he !redni"olone*only grou! and =4[A: day" ;median, =0.=F range, = #o 149> in #he !redni"olone?N*ace#ylcy"#eine grou! ;- C 0.14>. Dn regard #o #he "econdary ou#come", #he re"!ec#i(e mor#ali#y ra#e" in #he !redni"olone* only and !redni"olone?N* ace#ylcy"#eine grou!" were 24@ ;21 of <9> and <@ ;: of <=> a# 1 mon#h ;haSard ra#io, 0.=<F 9=@ $D, 0.14 #o 0.:BF - C 0.00B> and A4@ ;A0 of <9> and 22@ ;19 of <=> a# A mon#h" ;haSard ra#io, 0.AAF 9=@ $D, 0.AA #o 1.04F - C 0.0B>.
Causes o# Death

'# B mon#h", #he ra#e of #he he!a#orenal "yn* '# B mon#h", 22@ of #he !a#ien#" in #he !redni"* olone* only grou! ;20 of <9> had died of #he he!a* #orenal "yndrome, (er"u" 9@ of #he !a#ien#" in #he !redni"olone?N*ace#ylcy"#eine grou! ;< of <=> ;odd" ra#io, 2.:9F 9=@ $D, 1.0< #o :.42F - C 0.02>F #he mean #ime #o dea#h wa" AB.=[2< day" and BB[AA day", re"!ec#i(ely ;- C 0.A0>. Dea#h" due #o

drome wa" 2=@ in #he !redni"olone*only grou! ;22 of <9 !a#ien#"> and 12@ in #he !redni"olone? N*ace#ylcy"#eine grou! ;10 of <=> ;odd" ra#io wi#h com3ina#ion #hera!y, 0.41F 9=@ $D, 0.1: #o 0.9<F - C 0.02> ;Ta3le 2>. The o(erall ra#e of infec#ion wa" 42@ in #he !redni"olone*only grou! ;A: of <9 !a* #ien#"> and 19@ in #he !redni"olone?N*ace#ylcy"* #eine grou! ;1B of <=> ;odd" ra#io, 0.AAF 9=@ $D, 0.1= #o 0.B<F - C 0.001>. The #wo grou!" did no# dif* fer "ignif ican#ly wi#h re"!ec# #o o#her com!lica* #ion". 'mong !a#ien#" wi#h rela!"e of alcohol u"e af#er 1 mon#h, 1A@ died in #he !redni"olone*only grou! ;2 of 1=> (er"u" :@ in #he !redni"olone?N* ace#ylcy"#eine grou! ;1 of 1=> ;- C 1.00>.
Predictive Factors #or Death

'# B mon#h", nine fac#or" were "ignifican#ly a""oci* a#ed wi#h mor#ali#y in a uni(aria#e analy"i" ;Ta3le A>. 'ge, he!a#ic ence!halo!a#hy, !ro#hrom3in #ime, 3a"eline 3iliru3in le(el, 3a"eline crea#inine le(el, MaddreyG" di"criminan# func#ion, $hild? -ugh "core, change from 3a"eline in #he 3iliru3in le(el on day :, change from 3a"eline in #he 3iliru3in le(el on day 14, and #rea#men# grou! were all included in a $oP model for mul#i(aria#e analy"i". Maria3le" inde!enden#ly a""ocia#ed wi#h increa"ed mor#ali#y were older age ;odd" ra#io, 1.0:F 9=@ $D, 1.0A #o

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1.11F -E0.001>, !rolonged !ro#hrom3in #ime ;odd" ra#io, 0.9AF 9=@ $D, 0.91 #o 0.9:F -E0.001>, higher 3a"eline 3iliru3in le(el ;odd" ra#io, 1.00:F 9=@ $D, 1.00= #o 1.009F -E0.001>, and #he a3"ence of a de* crea"e in #he 3iliru3in le(el on day 14 ;odd" ra#io, 0.2AF 9=@ $D, 0.12 #o 0.4=F -E0.001>.
Change over Time in Biliru"in 4evel and !##ect on Survival

Ta"le 0 Adverse !vents Prednisolone Prednisolone% Only N&Acetylcysteine '( ) *+, '( ) *-,

!vent

n
Dn !a#ien#" wi#h "e(ere acu#e alcoholic he!a#i#i", #he com3ina#ion of N*ace#ylcy"#eine and !redni"olone did no# "ignif ican#ly im!ro(e B*mon#h "ur(i(al, a" com!ared wi#h !redni"olone only. The ra#ionale for #he u"e of an#ioPidan#" in #he #rea#men# of acu#e alcoholic he!a#i#i" i" 3a"ed on #he !i(o#al role of oPida#i(e "#re"" in #he di"order. 7i(er !ro#ec#ion 3y N*ace#ylcy"#eine ha" 3een "hown in mou"e model" of acu#e and chronic alcoholic he!a#i#i".20*22 +ow*

The change in #he median 3iliru3in le(el in each grou! o(er #he cour"e of #he "#udy i" "hown in igure 1& in #he &u!!lemen#ary '!!endiP, a(ail* a3le a# NEJM.org. The difference wa" "ignif ican# only on day 14 ;1B0 amol !er li#er in #he !redni"* olone*only grou! (". 11= amol !er li#er in #he !redni"olone?N*ace#ylcy"#eine grou!, - C 0.00A> ;Ta3le 1& in #he &u!!lemen#ary '!!endiP>. or #he whole "#udy !o!ula#ion, da#a on #he 3iliru3in le(el on day : were a(aila3le for 1=9 !a* #ien#" ;2 !a#ien#" had died, and da#a were mi""ing for 1A o#her !a#ien#">. ' 3iliru3in decrea"e on day : wa" o3"er(ed in 12< !a#ien#" ;<1@>. The B* mon#h "ur(i(al ra#e wa" 90@ among !a#ien#" wi#h a 3ili* ru3in decrea"e on day : and 10@ among !a#ien#" wi#hou# a decrea"e ;odd" ra#io, :<F 9=@ $D, 29 #o 210F -E0.001>. 1n day 14, da#a on #he 3iliru3in le(el were a(aila3le for 14A !a#ien#" ;: !a#ien#" had died, and da#a were mi""ing for 24 o#her !a#ien#">. ' 3iliru3in decrea"e on day 14 wa" o3"er(ed in <0@ of #he !a#ien#". The B*mon#h "ur(i(al ra#e wa" <9@ among !a#ien#" wi#h a 3iliru3in decrea"e on day 14 and 11@ among !a#ien#" wi#hou# a decrea"e ;odd" ra#io, B1F 9=@ $D, 2A #o 1BBF -E0.001>. 1n day :, :<@ of !a#ien#" in #he !redni"olone*only grou! had a 3iliru3in decrea"e, (er"u" <1@ in #he !red* ni"olone?N*ace#ylcy"#eine grou! ;odd" ra#io, 1.A<F 9=@ $D, 0.=9 #o A.29F -C0.41>. 1n day 14, :4@ of !a#ien#" in #he !redni"olone*only grou! had a 3ili* ru3in decrea"e, (er"u" <:@ in #he !redni"olone? N*ace#ylcy"#eine grou! ;odd" ra#io, 2.4:F 9=@ $D, 0.9B #o B.49F - C 0.04>.

Di"cu""io

n o. (%) +e!a#orenal "yndrome8 22 ;2=> A: ;42> 9 ;10> < ;9> : ;<> A ;A> &#a!hylococcal 2 ;2> "e!#icemia 2 2 ;2> 1#i#i" 1 ;1> Dnfec#ion A ;A> ;9> 1 ;1> )a"#roduodenal 0 hemorrhage ;1> 0 4 ;4> Thigh ;2> 0 eP#erna 0 of 0 un4nown cau"e < E"o!hageal 0 "e!#icemia 2 ;2> )ram*nega#i(e 2 ;2> candidia"i" 10 ;12> 'll infec#ion"] 1B ;19> 3ac#erial !eri#oni#i" = ;B> 7ung infec#ion A ;4> Hrinary "y"#em infec#ion 4 ;=> Ery"i!ela"

0 0 1 ;1> 0 7um3ar (er#e3ral colla!"e $ere3ral hemorrhage $ancer of #he !harynP H#erine fi3roid hemorrhage $alf hema#oma Tor"ade de !oin#e"

1 ;1>

unc#ional 4idney failure

1 ;1> Dnguinal hernia occlu"ion 1 ;1> 2 ;2> 1 ;1> 1 ;1> 1 ;1> 1 ;1> 0 1 ;1> 0 1= ;1:> 1 ;1> 1 ;1> 0 0 0 0 A ;4> 0 1 ;1> 1= ;1<>

&!on#aneou"

5a"h af#er fir"# injec#ion of N*ace#ylcy"#eine M'5& u"e_ 7i(er #ran"!lan#a#ion_ 5ela!"e of alcohol u"e af#er 1 mon#h

E"o!hageal (ariceal hemorrhage 0 ulcer 0 hemorrhage 1 A ;4> Hm3ilical (ariceal

8 - C 0.02 for #he 3e#ween*grou! com!ari"on. ] - C 0.001 for #he 3e#ween*grou! com!ari"on. ^ +e!a#ic hydro#horaP wa" rela#ed #o !or#al hy!er#en"ion. _ 7i(er #ran"!lan#a#ion or u"e of #he molecular ad"or3en# recircula#ing "y"#em ;M'5&> wa" con"idered a !rimary*ou#come failure.

10 ;12> E"o!hageal ulcer hemorrhage

hema#oma

1 ;1> +e!a#ic ence!halo!a#hy A ;4> +e!a#ic hydro#horaP^

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e(er, in !a#ien#" wi#h "e(ere acu#e alcoholic he!a* #i#i", #he 3enef i#" of an#ioPidan#" ha(e no# 3een "hown. Dn a randomiSed #rial, a com3ina#ion of an* #ioPidan#" #ha# included N* ace#ylcy"#eine wa" "ig* nifican#ly wor"e #han !redni"olone wi#h re"!ec# #o "ur(i(al.2A &imilarly, in a "#udy wi#h a com!leP de*
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Ta"le 5 Factors Associated 6ith Mortality at 2 Months '7nivariate Analysis, $ Factor Dead 'ge I yr -ro#hrom3in #ime I @ of normal 0iliru3in I amol\li#er $rea#inine I amol\li#er +e!a#ic ence!halo!a#hy I no.\#o#al no. ;@> MaddreyG" di"criminan# func#ion $hild?-ugh "core 0iliru3in decrea"e on day : I no.\#o#al no. ;@> 0iliru3in decrea"e on day 14 I no.\#o#al no. ;@> 8 -lu"?minu" (alue" are mean" [&D. ==.B[B.9 A=.2[10.= AA0.4[1<2.1 <0.<[24.B 1<\=: ;A2> BB.A[1:.< 11.=[1.A A1\=1 ;B1> 29\4B ;BA> Status at 2 Mo 'li(e =0.9[<.9 40.A[10.1 209.9[122.< B9.4[2=.4 19\11B ;1B> =1.2[1:.9 10.9[1.4 9:\10< ;90> <B\9: ;<9> E0.001 0.00A E0.001 0.00= 0.0A E0.001 0.01 E0.001 0.001 P .alue

"ign, ano#her N*ace#ylcy"#eine*con#aining an#ioPi* dan# regimen ;wi#h or wi#hou# glucocor#icoid"> did no# im!ro(e B*mon#h "ur(i(al.24 inally, a random* iSed #rial "howed #ha# u"e of N*ace#ylcy"#eine for 14 day" did no# confer any "ur(i(al 3enefi#, a" com* !ared wi#h oral nu#ri#ional "u!!or#.2= 'l#hough #here wa" no "ignifican# difference in "ur(i(al a# B mon#h" 3e#ween our "#udy grou!", #here wa" a "hor#*#erm "ur(i(al 3enefi# a# 1 mon#h wi#h !redni"olone?N*ace#ylcy"#eine a" com!ared wi#h !redni"olone only. 9e u"ed N*ace#ylcy"#eine 3ecau"e i# ha" an#ioPidan# !ro!er#ie",2B decrea"e" le(el" of free radical", increa"e" glu#a#hione le(* el",2: and re!re""e" #he eP!re""ion of nuclear fac#or b0 and TN * R.2< The do"e, dura#ion, and admini"#ra#ion rou#e u"ed were #he "ame a" #ho"e u"ed for #he #rea#men# of drug in#oPica#ion29,A0 and #he he!a#orenal "yndrome.A1 '# A and B mon#h", we o3"er(ed a lower mor#ali#y ra#e in #he !redni"* olone?N*ace#ylcy"#eine grou! #han in #he !redni"* olone*only grou!, 3u# #he difference" were no# "ignif ican#. The"e f inding" may 3e rela#ed #o a lac4 of !ower. D# i" al"o !o""i3le #ha# = day" of N*ace#ylcy"#eine wa" no# enough. ' longer !eriod of in#ra(enou" N*ace#ylcy"#eine com3ined wi#h !redni"olone could !erha!" 3e con"idered, wi#h "u3"e.uen# oral admini"#ra#ion of N*ace#ylcy"#eine un#il 1 mon#h. The im!ro(emen# in "hor#*#erm "ur(i(al #ha# we o3"er(ed in our "#udy could 3e lin4ed, a# lea"# in !ar#, #o a reduced ri"4 of #he he!a#orenal "yn* drome in #he !redni"olone?N*ace#ylcy"#eine grou!. Dn a "#udy in(ol(ing 12 !a#ien#" wi#h #he

he!a#o* renal "yndrome, #he "ur(i(al ra#e a# 1 mon#h af#er

N*ace#ylcy"#eine infu"ion wa" uneP!ec#edly high ;B:@>.A1 Dn regard #o mor3idi#y, #he !redni"olone? N*ace#ylcy"#eine grou! in our "#udy had "ignif i* can#ly fewer infec#iou" com!lica#ion" #han #he !redni"olone*only grou!. D# ha" 3een "hown #ha# !a#ien#" wi#h "e(ere alcoholic he!a#i#i" who do no# ha(e a re"!on"e #o #rea#men# ha(e "ignifican#ly more 3ac#erial infec#ion" #han !a#ien#" who ha(e a re"!on"e.A2 'l#erna#i(ely, N* ace#ylcy"#eine could ha(e 3enef icial effec#" 3y increa"ing 3lood f low #o #he li(er, im!ro(ing li(er func#ion, increa"ing #he cardiac indeP,AA and decrea"ing #he in#rahe* !a#ic lac#a#e le(el" "een in !a#ien#" wi#h "e!#ic "hoc4.A4 1ur "#udy !ro(ide" !ro"!ec#i(e (alida#ion of #he finding #ha# a decrea"e in #he 3iliru3in le(el af#er : day" of #rea#men# i" a""ocia#ed wi#h a fa(ora3le !rogno"i"A= and al"o "how" #ha# a decrea"e on day 14 i" a""ocia#ed wi#h increa"ed "ur(i(al. +ow* e(er, in a
1:<<

mul#i(aria#e analy"i", only a decrea"e in #he 3iliru3in le(el on day 14 remained "ignifican#, and #he decrea"e wa" more fre.uen# in #he !red* ni"olone?N*ace#ylcy"#eine grou! #han in #he !red* ni"olone*only grou!. Thu", for a =*day cour"e of !redni"olone?N*ace#ylcy"#eine #hera!y, #hera!eu* #ic eff icacy i" 3e##er e(alua#ed on day 14 #han on day :. Dn conclu"ion, we o3"er(ed im!ro(ed "ur(i(al a# 1 mon#h among !a#ien#" wi#h "e(ere acu#e alco* holic he!a#i#i" who recei(ed com3ina#ion #hera!y wi#h !redni"olone and N*ace#ylcy"#eine, a" com* !ared wi#h #ho"e who recei(ed !redni"olone only, 3u# B*mon#h mor#ali#y, our !rimary ou#come, wa" no# im!ro(ed wi#h com3ina#ion #hera!y.
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)lucocor#icoid" !lu" n *'ce # y l c y" #eine in ' l coholic +e!a#i#i"

&u!!or#ed 3y -rogramme +o"!i#alier de 5echerche $lini.ue, a !rogram of #he rench go(ernmen# #ha# "u!!or#" ho"!i#al* 3a"ed clinical re"earch. No !o#en#ial conf lic# of in#ere"# rele(an# #o #hi" ar#icle wa" re!or#ed. Re#erence s Ma#hurin -, Mendenhall $7, $ari#her" 57 Jr, e# al. $or#ico"#eroid" im!ro(e "hor#* #erm "ur(i(al in !a#ien#" wi#h "e(ere alco* holic he!a#i#i" ;'+>Q indi(idual da#a anal* y"i" of #he la"# #hree randomiSed !lace3o con#rolled dou3le 3lind #rial" of cor#ico* "#eroid" in "e(ere '+. J +e!a#ol 2002FABQ 4<0* :. 0 Dm!eriale T , 1G$onnor J0, Mc* $ullough 'J. $or#ico"#eroid" are effec#i(e in !a#ien#" wi#h "e(ere alcoholic he!a#i#i". 'm J )a"#roen#erol 1999F94QA0BB*<. 5 1G&hea 5&, Da"ara#hy &, Mc$ullough 'J. 'lcoholic li(er di"ea"e. +e!a#ology 2010F=1QA0:* 2<. 8 +elman 5', Tem4o M+, Nye &9, al* lon +J. 'lcoholic he!a#i#i"Q na#ural hi"#o* ry and e(alua#ion of !redni"olone #hera!y. 'nn Dn#ern Med 19:1F:4QA11*21. Maddrey 9$, 0oi#no## J,, 0edine M&, 9e3er 7 Jr, MeSey E, 9hi#e 5D Jr. $or#i* co"#eroid #hera!y of alcoholic he!a#i#i". )a"#roen#erology 19:<F:=Q19A* 9. 2 Mendenhall $7, 'nder"on &, )arcia* -on# -, e# al. &hor#*#erm and long*#erm "ur(i(al in !a#ien#" wi#h alcoholic he!a#i* #i" #rea#ed wi#h oPandrolone and !red* ni"olone. N Engl J Med 19<4FA11Q14B4* :0. 9 $ari#her" 57 Jr, +erlong + , Diehl 'M, e# al. Me#hyl!redni"olone #hera!y in !a#ien#" wi#h "e(ere alcoholic he!a#i#i"Q a randomiSed mul#icen#er #rial. 'nn Dn* #ern Med 19<9F110QB<=*90. * 5amond MJ, -oynard T, 5ueff 0, e# al. ' randomiSed #rial of !redni"olone in !a* #ien#" wi#h "e(ere alcoholic he!a#i#i". N Engl J Med 1992FA2BQ=0:*12. + Dm!eriale T , Mc$ullough 'J. Do cor* #ico"#eroid" reduce mor#ali#y from alco* holic he!a#i#i"c ' me#a*analy"i" of #he randomiSed #rial". 'nn Dn#ern Med 1990F 11AQ299* A0:. 1: Daure" J-, -eray -, 0orie" -, e# al. $or* #icoid #hera!y in #he #rea#men# of acu#e alcoholic he!a#i#i"Q re"ul#" of a me#a*anal* y"i". )a"#roen#erol $lin 0iol 1991F1=Q22A* <. ;Dn &!ani"h.> 11 5am3aldi ', &acona#o ++, $hri"* #en"en E, Thorlund ,, 9e##er"le( J, )luud $. &y"#ema#ic re(iewQ glucocor#ico"#e* roid" for alcoholic he!a#i#i" I a $ochrane +e!a#o*0iliary )rou! "y"#ema#ic re(iew wi#h me#a*analy"e" and #rial "e.uen#ial analy"e" of randomiSed clinical #rial". 'limen# -harmacol Ther 200<F2:Q11B:*:<. 10 Ma#hurin -, Deng J), ,e"ha(arSian
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