JOP. J Pancreas (Online) 2013 Sep 10; 14(5):475-483.

-(.-/(.-0 120(3/4

Individual Patient Data Meta-Analysis of Organ Failure in Acute Pancreatitis: Protocol of the PANCREA II tudy
te!hanie "M Das#$ %eorge I Pa!achristou&$ 'ercio De Ca(!os)$ *o+efa Pane,-$ Ignasi Poves Pri(.$ Ale/andro erra0lo1$ Ro2an 3 Par,s4$ %eneroso 5o(o6$ *ohn A 3indsor#$ Ma7i( Petrov#$ on 0ehalf of the Pancreatitis Across Nations Clinical Research and Education Alliance 8PANCREA9
of !ur6er78 0he 9ni:ersit7 of 1uc;land. 1uc;land8 New <ealand. $5i:ision of .astroenterolo678 -epatolo67 and Nutrition8 5epart"ent of =edicine8 9ni:ersit7 of Pitts#ur6h =edical 3enter. Pitts#ur6h8 P18 9!1. &5epart"ent of !ur6er78 >!anta 3asa? !chool of =edical !ciences. !@o Paulo8 AraBil. 4!econd 5epart"ent of .eneral !ur6er78 Ja6iellonian 9ni:ersit7 =edical 3olle6e. 3racow8 Poland. 59nit of -epato-Ailiar7-Pancreatic !ur6er78 !er:ice of .eneral and 5i6esti:e !ur6er78 -ospital del =ar. Aarcelona8 !pain. C-PA !ur6ical 9nit8 =i6uel !er:et 9ni:ersit7 -ospital. <ara6oBa8 !pain. +5epart"ent of 3linical and !ur6ical !ciences D!ur6er7E8 9ni:ersit7 of 4din#ur6h8 2o7al (nfir"ar7 of 4din#ur6h. 4din#ur6h8 9nited Fin6do". *5epart"ent of (nternal =edicine8 3ardarelli -ospital. Naples8 (tal7
A: 'RAC' Conte7t Or6an failure is a "ajor deter"inant of "ortalit7 in patients with acute pancreatitis. 0hese patients usuall7 reGuire ad"ission to hi6h dependenc7 or intensi:e care units and consu"e considera#le health care resources. .i:en a low incidence rate of or6an failure and a lac; of lar6e non-inter:entional studies in the field of acute pancreatitis8 the characteristics of or6an failure that influence outco"es of patients with acute pancreatitis re"ain lar6el7 un;nown. 0herefore8 the Pancreatitis 1cross Nations 3linical 2esearch and 4ducation 1lliance DP1N3241E ai"s to conduct a "eta-anal7sis of indi:idual patient data fro" prospecti:e non-inter:entional studies to deter"ine the influence of ti"in68 duration8 seGuence8 and co"#ination of different or6an failures on "ortalit7 in patients with acute pancreatitis. Methods Pancreatolo6ists currentl7 acti:e with acute pancreatitis clinical research will #e in:ited to contri#ute. 0o #e eli6i#le for inclusion patients will ha:e to "eet the criteria of acute pancreatitis8 de:elop at least one or6an failure durin6 the first wee; of hospitaliBation8 and not #e enrolled into an inter:ention stud7. 2aw data will then #e collated and chec;ed. (ndi:idual patient data anal7sis #ased on a lo6istic re6ression "odel with adjust"ent for confoundin6 :aria#les will #e done. Hor all anal7ses8 correspondin6 )5I confidence inter:als and P :alues will #e reported. Conclusion 0his colla#orati:e indi:idual patient data "eta-anal7sis will answer i"portant clinical Guestions re6ardin6 patients with acute pancreatitis that de:elop or6an failure. (nfor"ation deri:ed fro" this stud7 will #e used to opti"iBe routine clinical "ana6e"ent and i"pro:e care strate6ies. (t can also help :alidate outco"e definitions8 allow co"para#ilit7 of results and for" a "ore accurate #asis for patient allocation in further clinical studies.
15epart"ent

IN'ROD5C'ION Or6an failure is a "ajor deter"inant of "ortalit7 '18 $8 &8 48 5, in patients with acute pancreatitis and this
;ey2ords =eta-1nal7sis as 0opicK =ortalit7K =ultiple Or6an HailureK Or6an 57sfunction !coresK Pancreatitis8 1cute NecrotiBin6 /co"plications A00reviations (P5: indi:idual patient dataK !OH1: !epsisrelated Or6an Hailure 1ssess"ent Corres!ondence =ax ! Petro: 1uc;land 3it7 -ospitalK 2oo" 1$.%)$8 /e:el 1$ !upport Auildin6K Pri:ate Aa6 )$%1)8 Victoria !treet LestK 1uc;land 114$K New <ealand Phone: MC4-)).$&$.++CK Hax: MC4-)&.++).C5C 4-"ail: "ax.petro:N6"ail.co"

has #een hi6hli6hted in the new international "ultidisciplinar7 classification of acute pancreatitis se:erit7 as the >s7ste"ic? deter"inant '18 $,. Patients who de:elop or6an failure usuall7 reGuire ad"ission to hi6h dependenc7 unit or intensi:e care unit D(39E. 0hese patients are a"on6 the "ost resource de"andin6 in health care s7ste"s 'C8 +,. (39s currentl7 represent the lar6est clinical cost depart"ent in hospitals8 with expenses esti"ated to #e up to $%I of a hospitalJs #ud6et '*8 ),8 and costs per da7 is three to fi:e-fold 6reater than in 6eneral wards '1%8 118 1$,. !e:eral aspects of or6an failure ha:e #een studied8 althou6h "an7 Guestions re"ain.

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#9 Dyna(ics of Organ Failure (t is widel7 accepted that local pancreatic infla""ation is the initiatin6 sti"ulus for a s7ste"ic infla""ator7 response. 0his8 in turn8 "a7 result in the de:elop"ent of or6an failure and contri#ute to death in patients with acute pancreatitis. 0he i"portance of the duration and re:ersi#ilit7 of or6an failure has #een well reco6niBed in the last decade. (t has #een shown that patients with worsenin6 or6an failure as well as those with persistent or6an failure ha:e a si6nificantl7 hi6her "ortalit7 rate '1&8 148 158 1C8 1+,. 1 stud7 fro" the 9nited Fin6do" '14, enrolled $)% patients across 1* centers and found that resolution of or6an failure within 4* hours was associated with a #etter pro6nosis co"pared to patients with or6an failure for "ore than 4* hours. 0his was irrespecti:e of whether the or6an failure was present on ad"ission or de:eloped later. 1nother stud7 conducted in !cotland '1&, on 1$1 patients found that patients with worsenin6 or6an failure and poor response to treat"ent ha:e a hi6her "ortalit7 rate. 1 stud7 fro" New <ealand also de"onstrated that the initial ph7siolo6ical response to intensi:e care treat"ent was a #etter predictor of outco"e and "ortalit7 in patients with acute pancreatitis '1+,. 0hese studies underscore the d7na"ic nature of or6an failure and the i"portance of "onitorin6 the response to treat"ent. &9 Nu(0er of Failed Organs 0he concept of "ultiple or6an failure was first descri#ed in the 1)+%s '1*,8 since then8 a lar6e nu"#er of definitions and acron7"s ha:e #een proposed '1),. 1 "odern definition for "ultiple or6an failure in patients with acute pancreatitis refers to the failure of two or "ore or6an s7ste"s '$%,. =ultiple or6an failure has #een shown to #e the leadin6 cause of death in a :ariet7 of clinical settin6s '$18 $$,. =ortalit7 rate in acute pancreatitis patients with "ultiple or6an failure has #een reported to #e up to 1%%I '$%8 $&8 $48 $58 $C, and there is a si6nificant correlation #etween the nu"#er of or6an failures and "ortalit7 '$+,. 1 lar6e population #ased retrospecti:e cohort stud7 on all deaths due to acute pancreatitis in !cotland included data fro" 18%$4 patients and found that C&I of fatalities had failure of at least two or6an s7ste"s '$*,. )9 3hich Organs Fail 0he 1tlanta classification for se:erit7 of acute pancreatitis ad:ocated four or6an s7ste"s Dcardio:ascular8 pul"onar78 renal and 6astrointestinal #leedin6E to classif7 the se:erit7 of acute pancreatitis '$$,. 0he 4uropean !ociet7 of (ntensi:e 3are =edicine since ad:ocated a scorin6 s7ste"

that includes six "ajor or6an s7ste"s to descri#e as Guantitati:el7 and o#jecti:el7 as possi#le the de6ree of or6an d7sfunction o:er ti"e in criticall7 ill patients '$),. 0his scorin6 s7ste"8 ter"ed the !epsis-related Or6an Hailure 1ssess"ent D!OH1E score8 has #een widel7 used in a :ariet7 of disease settin6s '&%8 &18 &$,. 0he or6an s7ste"s used in the !OH1 score are respirator78 cardio:ascular8 coa6ulation8 hepatic8 renal and central ner:ous s7ste"s. 0he nu"#er of or6an s7ste"s that ha:e #een included in studies ha:e :aried fro" three '4,8 four '$+8 &&,8 six '&48 &5, to ei6ht '$+,. Aased on the $%11 6lo#al sur:e7 of pancreatolo6ists '&C,8 the consensus is that three or6an s7ste"s Drespirator78 cardio:ascular and renalE fail "ost freGuentl7 in patients with acute pancreatitis and is of "uch "ore pro6nostic i"portance than failure of other s7ste"s '48 &58 &+8 &*,. Presence/a#sence of or6an failure in each of these three s7ste"s is used in the new international "ultidisciplinar7 classification of acute pancreatitis se:erit7 '1,. -9 Co(0ination and e<uence of Organ Failures 1 prospecti:e "ulticenter inception cohort anal7sis '&), of 1+844% (39 ad"issions Dall cases and not confined to patients with acute pancreatitisE treated fro" 1)** to 1))% and 58C++ (39 ad"issions treated fro" 1)+) to 1)*$ found that co"#inations of or6an s7ste"s and the or6an s7ste" that failed had an i"pact on outco"e. 0he7 found that the profile of ph7siolo6ic a#nor"alities su#stantiall7 influences "ortalit7. Hor exa"ple8 "ortalit7 rate for patients with two or6an s7ste" failures :aried fro" $%I Dco"#ination of he"atolo6ic and cardio:ascular failureE to +CI Dco"#ination of cardio:ascular and neurolo6ic failuresE. (n patients with acute pancreatitis8 a retrospecti:e stud7 #7 -alonen et al. '&5, de"onstrated that different co"#inations of two or6an s7ste" failures ha:e different "ortalit7 rates with the hi6hest "ortalit7 rate D)1IE associated with the co"#ination of hepatic and renal failures. 0he7 also showed that hepatic failure8 renal failure8 pre:ious cardio:ascular "edication and cardio:ascular failure were independent factors that are associated with hospital "ortalit7. !o"e li"itations of this stud7 include the retrospecti:e desi6n8 the relati:el7 s"all cohort of patients DnO11&E and a selection #ias #ecause not all patients with or6an failure were included. 1nother stud7 loo;ed at seGuential s7ste" failure in patients with acute renal failure after rupture of a#do"inal aortic aneur7s"s '4%,. 0he authors showed that there was a si"ilar pro6ression of or6an s7ste" failures in all patients. 0his seGuence unfolded "ore slowl7 in patients that sur:i:ed lon6er and de:eloped "ore Guic;l7 in those sur:i:in6 for shorter periods. 0his >predicta#ilit7?

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of seGuence failure in or6an failure8 if confir"ed8 "a7 ha:e i"portant i"plications in the allocation of resource and tar6eted treat"ents directed towards slowin6 disease pro6ression and reducin6 "ortalit7. "i(itations of Current ;no2ledge A0out Organ Failure Hirst8 "ost studies ha:e #een sin6le center cohort studies '158 1C8 418 4$8 4&8 44, without sufficient statistical power to in:esti6ate all aspects of or6an failure and their effect on "ortalit7. 0his is li;el7 #ecause of relati:el7 low incidence of acute pancreatitis patients with or6an failure. 0he annual incidence rate in the 9nited !tates is $-4 cases of co"plicated acute pancreatitis per 7ear per 1%%8%%% adults8 and onl7 a fraction of the" de:elop or6an failure '45,. !econd8 there are so"e studies in which the cohorts fro" lar6er "ulti-center studies are part of inter:entional studies '148 4C, which "a;es an7 inference a#out disease course and outco"es in 6eneral8 and or6an failure in particular8 inherentl7 #iased. 0his is #ecause an7 studied inter:ention is desi6ned to alter the natural course of the disease. Other lar6er studies are li"ited #7 selection #ias8 such as usin6 preselected cohorts of patients with other deter"inants of outco"e De.6.8 pancreatic necrosisE or onl7 selected patients who had a contrast enhanced 30 scan '&&8 4+8 4*8 4),. 0his selection #ias does not allow a :alid inference a#out the course and outco"es of or6an failure. 0hird8 there is a relati:el7 li"ited #od7 of e:idence in the literature a#out the relati:e i"portance of different characteristics of or6an failure such as nu"#er8 ti"in68 duration8 seGuence8 and

co"#ination '1,. =oreo:er8 there is li"ited e:idence to :alidate the definitions of these characteristics. Valid outco"e definitions are essential for Gualit7 research8 allowin6 co"para#ilit7 of results a"on6 centers and the a#ilit7 to "onitor chan6es in #etween different centers o:er ti"e '5%,. 5nans2ered =uestions A0out Organ Failure /i"itations and #ias in the existin6 literature hi6hli6hts the need for purportedl7 desi6ned noninter:entional studies to answer a nu"#er of ;e7 Guestions relatin6 to the characteristics of or6an failure in acute pancreatitis '51, and how the7 are lin;ed to "ortalit7 DHi6ure 1E. 0hese include8 #ut are not li"ited to the followin6 Guestions:

1E Lhat is the relati:e incidence of each or6an failureP $E Lhat is the relationship #etween nu"#er of or6an failures and "ortalit7P &E Lhat is the "ost co""on seGuence in failin6 s7ste"sP 4E Lhat is the ti"in6 of onset for each or6an failure and its effect on "ortalit7P 5E -ow is "ortalit7 affected #7 the duration of each s7ste" failureP CE Lhat is the relati:e incidence of the specific seGuences of or6an failure and its effect on "ortalit7P +E Lhat is the relati:e incidence of each co"#ination of two s7ste" failures and its effect on "ortalit7P
Ans2ering the =uestions 0y Conducting an Individual Patient Data Meta-Analysis Pooled anal7sis of prospecti:e data fro" indi:idual patients in all the a:aila#le studies has #een re6arded as the 6old standard in e:idence s7nthesis 6eneration '5$8 5&, and has pro:ided the #est approach to answer Guestions pertinent to the natural course of disease '54,. 0he "ethods and ad:anta6es of indi:idual patient data D(P5E "etaanal7sis ha:e #een well descri#ed '558 5C,. (P5 "eta-anal7sis pro:ides the least #iased and "ost relia#le "eans of addressin6 Guestions not satisfactoril7 answered #7 indi:idual clinical studies '5+,. 0his is #ecause it does not rel7 on pu#lished infor"ation alone and includes all a:aila#le stud7 data8 thus allowin6 for detailed chec;s of the inte6rit7 and co"pleteness of data and also reducin6 selection and pu#lication #ias. A7 includin6 data fro" "ultiple centers8 it pro:ides a stron6er endorse"ent of results8 #etter clarification and pro:ision of updated follow up infor"ation8 as well as a colla#oration for further research '5*,. (n

Figure #> 3urrent ;nowled6e and unanswered Guestions re6ardin6 patients with acute pancreatitis that de:elop or6an failure.

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'a0le #> .eo6raphic distri#ution of the P1N3241 colla#orators. 1r6entina =ala7sia 1ustralia =exico 1ustria Netherlands Ael6iu" New <ealand Aosnia and -erBe6o:ina Norwa7 AraBil Peru 3anada Philippines 3hina Poland 3roatia 2o"ania 3Bech 2epu#lic 2ussia 5en"ar; !er#ia and =ontene6ro 467pt !lo:a;ia Hinland !lo:enia Hrance !pain .er"an7 !weden .reece !witBerland -un6ar7 0aiwan (ndia 0hailand (ran 0ur;e7 (srael 9;raine (tal7 9nited 1ra# 4"irates Japan 9nited Fin6do" /at:ia 9nited !tates /ithuania 9ru6ua7 VeneBuela

4xposure: respirator78 renal8 and/or cardio:ascular or6an failureK Outco"e: in-hospital "ortalit7K !tud7 period: conducted fro" the 7ear $%%% onwards. !tudies/indi:idual data will #e excluded if: Participants were enrolled into an inter:entional stud7K 5ata do not contain the essential infor"ation reGuired Dsee #elowE. Collection of Data and Manage(ent 4ssential and optional data to #e collected are shown in 0a#le $. 1ll the contri#utors will #e as;ed to pro:ide de-identified data #7 uploadin6 the" into a standardiBed data collection for" or in an7 con:enient for"at #7 encr7pted8 electronic transfer where possi#le or #7 other "eans as reGuired8 dependin6 on site issues. 0he ori6inal data collection files sent #7 the authors will #e ;ept in their ori6inal :ersion and will #e sa:ed on a password-protected ser:er at the 9ni:ersit7 of 1uc;land8 and #ehind the firewall to ensure securit7. Onl7 the in:esti6ators of P1N3241 (( stud7 will ha:e direct access to indi:idual data prior to pu#lication of the final report. 'ransfer of Data 0he data will #e transferred to a secure passwordprotected we# ser:er at 9ni:ersit7 of 1uc;land or #7 pri:ac7 encr7pted e-"ail. 0his per"its a secure and identifia#le connection and "ini"iBes the possi#ilit7 of data loss. Data Chec,ing !tud7 in:esti6ators will perfor" data :alidation usin6 a cop7. 0he data will #e chec;ed independentl7 with respect to ran6e8 internal
'a0le &> 5ata to #e collected. Essential data 5ate of ad"ission 16e !ex 4tiolo67 D1lcohol8 Ailiar78 Other or 9n;nownE Presence/1#sence of or6an failure in each of three or6an s7ste"s studied in the first wee; of hospital sta7 O!tional data 5uration of s7"pto"s prior to ad"ission 0otal duration of sta7 in intensi:e care unit 0otal hospital sta7 1P13-4 (( score on ad"ission 30 findin6s D30 se:erit7 index8 AalthaBar score8 etc.E Presence/1#sence of infected pancreatic necrosis Presence/1#sence of extra pancreatic infectious co"plications

addition to this8 it allows for "ore powerful and flexi#le anal7sis of su#6roups and testin68 adjustin6 for confounders. O:*EC'I?E 0he ai" of the proposed stud7 is to perfor" an (P5 "eta-anal7sis to deter"ine the relati:e incidence of each or6an failure8 and the i"pact that the nu"#er8 ti"in68 duration8 seGuence8 and co"#ination of different indi:idual or6an failures on "ortalit7 in patients with acute pancreatitis. ME'@OD AND DE I%N tudy Design 0he stud7 desi6n will #e an indi:idual patient data "eta-anal7sis '558 5C8 5+8 5*,. Identification of tudies 1ll participants of the recentl7 conducted first 6lo#al sur:e7 of pancreatolo6ists8 who are acti:e in clinical research8 will #e in:ited to contri#ute indi:idual patient data to this stud7 '&C,. 0a#le 1 presents the 6eo6raphic distri#ution of participants in the 6lo#al sur:e7. Pancreatolo6ists are also encoura6ed to contact the correspondin6 author of this article if the7 are interested in contri#utin6 to this project. Eligi0ility Criteria 0o #e included8 studies will ha:e to "eet the followin6 criteria: 5esi6n: prospecti:e cohortK Population: patients with acute pancreatitis who presented with or de:eloped or6an failure durin6 first wee; of hospital ad"issionK

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consistenc78 "issin6 or extre"e :alues8 errors and consistenc7 with pu#lished reports. !tud7 details8 such as selection "ethods and outco"e details will #e crossed-chec;ed a6ainst pu#lished reports8 stud7 protocols and data collection spread sheets. 1pparent inconsistencies8 i"plausi#ilities8 or o"issions will #e clarified with colla#orators and8 where appropriate8 rectified. !u""ar7 ta#les and listin6 of the :aria#les used in planned anal7ses will #e supplied to colla#orators for chec;in6. 1n7 discrepancies will #e resol:ed #7 discussion. 3olla#orators will #e as;ed to :erif7 all recorded data #efore an7 anal7sis and the data will not #e used for an7 other purposes without per"ission fro" all the colla#orators. Core Data et and ?aria0les 1ll :erified data will #e entered into a "aster 4xcel spread sheet. 1 uniGue identification nu"#er will #e allocated to each patient entered into the core data set. 0his nu"#er will easil7 correspond to patients fro" :erified data fro" indi:idual studies. 0he essential and optional data will #e "anuall7 entered into "aster spread sheet8 and chec;ed. Definitions 1cute pancreatitis will #e dia6nosed #7 the presence two of the followin6 three features: a#do"inal pancreatitisK pain characteristic of acute

insufficienc7 defined as PaO$ of C% ""-6 or less8 renal failure defined as a creatinine le:el 6reater than 1++ Q"ol// D$ "6/d/E after reh7drationK a !OH1 score of $ or "ore for each indi:idual s7ste" '$),K a =arshall score of $ or "ore for each indi:idual s7ste" '5),. 0he or6an s7ste"s that will #e reported on include respirator78 cardio:ascular and renal s7ste"s. 0he definitions used in relation to the ti"in68 duration8 seGuence and co"#ination of or6an failures are 6i:en in Hi6ure $. 0otal hospital sta7 will #e defined as the nu"#er of consecuti:e da7s the patient was in hospital. 5uration of s7"pto"s will #e defined as the nu"#er of consecuti:e full da7s D$4 hoursE the patient had s7"pto"s #efore the da7 of ad"ission8 excludin6 the da7 of ad"ission. Planned tatistical Analysis 5ue to the co"plexit7 of the statistical anal7ses8 the followin6 section represents the planned principal anal7sesK so"e "odifications and secondar7 anal7ses are li;el7 to e"er6e durin6 the project. -owe:er8 a detailed statistical anal7sis plan will #e produced #efore the anal7sis. 1n7 anal7sis conducted will #e #ased on the chec;ed and updated (P5 fro" all a:aila#le studies. Primary nalysis 1 >one-sta6e? approach will #e used #ecause of its increased power and a#ilit7 to test for nonlinear relationships for continuous :aria#les and a#ilit7 to control for a66re6ation #ias '5&8 5*8 C%8 C18 C$,. 0he "odel used will #e #ased on a lo6istic re6ression "odel '5$, adjusted for confoundin6 :aria#les includin6 a6e8 sex8 etiolo678 etc. 0he dependent :aria#le will #e "ortalit7 and independent :aria#les will initiall7 include the characteristics of or6an failure Dti"in68 duration8 seGuence8 and co"#ination of or6an failuresE. 0he 2 $.15.$ fra"ewor; D2 Houndation for !tatistical 3o"putin68 Vienna8 1ustriaE will #e used for statistical anal7sis 'C&,. !u""ar7 statistics with correspondin6 )5I confidence inter:als D3(sE will #e calculated. 0his will include the pooled incidence of each s7ste" failure. Patients will #e 6rouped accordin6 to total nu"#er of or6an failures at an7 point and pooled incidence for one8 two8 three or6an failures will #e calculated with correspondin6 "ortalit7 rates. Patients will also #e 6rouped accordin6 to ti"in6 of first Dan7E or6an failure and "ortalit7 rates and relati:e ris;s will #e calculated accordin6 to or6an failure occurrin6 at an7 particular da7 durin6 the first wee;. Hurther anal7sis will #e perfor"ed #ased

seru" a"7lase and/or lipase & ti"es the upper li"it of nor"alK and characteristic findin6s of acute pancreatitis on to"o6raph7 D30E scan. Or6an failure will #e defined as the presence of worsened or6an function in an acutel7 ill acute pancreatitis patient usin6 one of the followin6 criteria: >#reachin6 of thresholds? as descri#ed #7 Aradle7 et al. '$$, with shoc; defined as a s7stolic #lood pressure less than )% ""-68 pul"onar7

Figure &> Outco"e definitions for the studied characteristics of or6an failure.

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on duration of or6an failure. 2elati:e ris;s of death will #e calculated for patients with or6an failure for one da7 onl7 co"pared to or6an failure for "ore than one da7. 0he sa"e anal7sis will #e done for or6an failure for two da7s co"pared to or6an failure for "ore than two da7s and so on Dthree and four da7sE. Patients with two or three or6an failures with different seGuences of or6an failures will #e 6rouped to6ether and the pooled incidence of each seGuence of or6an failure will #e calculated. /astl78 patients will #e 6rouped accordin6 to different co"#inations of two or6an failure and relati:e ris;s of death will #e calculated. 0hese co"#inations will include cardio:ascular and respirator78 cardio:ascular and renal8 respirator7 and renal s7ste"s. S!"#r$!p nalysis 0he cohorts will #e 6rouped accordin6 to the pro:ision of optional data. 0hese will #e listed firstl7 in a su""ar7 ta#le with the followin6 headin6s: stud7 title8 nu"#er of patients8 data a:aila#le D7es/noE for co:ariates: durations of s7"pto"s8 1P13-4 (( score on ad"ission8 extent of necrosis on 308 30 se:erit7 index8 infectious pancreatic co"plications durin6 hospitaliBation8 other infectious co"plications durin6 hospitaliBation8 as well as data a:aila#le for secondar7 outco"es: duration of (39 sta7 and total hospital sta7. (f sufficient patient nu"#ers are a:aila#le8 anal7sis will then #e conducted for each co:ariate in separate su#6roups. 0he sa"e "odel used in the pri"ar7 anal7sis will also #e applied for secondar7 outco"es if sufficient data are a:aila#le. Sec$n%ary nalysis Hurther anal7ses "a7 include possi#le confoundin6 factors for the entire patient population identified fro" our su#6roups anal7sis. !u#seGuent anal7sis fro" the pri"ar7 anal7sis will adjust for an7 additional confounders usin6 "ulti:ariate re6ression to 6i:e esti"ates that are "ore rele:ant to indi:idual patients. Data Presentation Aaseline characteristics of patients will #e presented for indi:idual cohorts as well as o:erall su""ar7 statistics. 3ontinuous :aria#les will #e presented as "ean and standard de:iation Dor "edian and ran6e if not nor"all7 distri#utedE. Ainar7 and cate6orical outco"es will #e presented as freGuenc7 and percenta6es. Le will also report "ortalit7 rates #oth #efore and after adjust"ents for confounders. Hor all pri"ar7 and secondar7 anal7ses8 adjusted ris; ratios and correspondin6 )5I 3(s will #e presented8 alon6 with the correspondin6 P :alues. P

:alues less than %.%5 will #e re6arded as statisticall7 si6nificant. 0he final "eta-anal7sis will #e reported #ased on rele:ant 6uidelines 'C48 C5,. Pu0lication Policy 0he "ain results of this project will #e pu#lished and presented under the auspices of the Pancreatitis 1cross Nations 3linical 2esearch and 4ducation 1lliance DP1N3241E. 9p to two researchers fro" each contri#utin6 centre and the P1N3241 !teerin6 3o""ittee will #e in:ited to author the "anuscript. 2esults fro" further papers usin6 the sa"e data set will not #e pu#lished without appro:al fro" all colla#orators and will ac;nowled6e the P1N3241 colla#oration as the source of the data. 0he P1N3241 colla#oration will disse"inate the findin6s of its research widel7 at acade"ic conferences and in journal pu#lications. DI C5 ION

Or6an failure is one of "ain causes of death in patients with acute pancreatitis #ut8 to date8 there has #een a lac; of Gualit7 data on its natural course and characteristics that influence patientsJ outco"es. Part of the dri:e to i"pro:e patientsJ outco"es will reGuire a #etter understandin6 of the different characteristics of or6an failure. 0he #est wa7 to ad:ance this is to a66re6ate existin6 prospecti:e data fro" non-inter:entional studies under the auspice of an international colla#oration. 0his approach allows for "ore powerful and flexi#le anal7sis of su#6roups and testin68 adjustin6 for confounders and "ini"iBes pu#lication and reportin6 #ias 'CC, and has #een descri#ed as the >6old standard? of e:idence s7nthesis '558 5C8 5+,. 0he P1N3241 colla#oration has alread7 #een esta#lished and its first stud7 was to de:elop a new classification for the se:erit7 of acute pancreatitis '1,. 0his in:ol:ed se:eral sta6es. 0he first sta6e was an e:idence re:iew to reco6niBe a need for a new classification for the se:erit7 of acute pancreatitis and to hi6hli6ht the li"itations of pre:ious classifications. 0he second sta6e was conductin6 a world-wide sur:e7 of pancreatolo6ists. 0he third sta6e was to further discuss the proposed classification and see; accord on definitions at an international s7"posiu" durin6 the $%11 =eetin6 of the (nternational 1ssociation of Pancreatolo67 DFochi8 (ndiaE. 0he final docu"ent was pu#lished as a feature article in the worldJs pre"ier sur6ical journal and was acco"panied #7 a supporti:e editorial #7 the author of the 1tlanta classification 'C+,. 0he new classification has also #eco"e a:aila#le in se:eral lan6ua6es other than 4n6lish 'C*8 C)8 +%8 +1,. 0he stud7 descri#ed in this protocol will #e the second "ulticentre stud7 of the P1N3241 colla#orati:e DP1N3241 (( stud7E. (t will atte"pt to

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answer i"portant Guestions re6ardin6 the effect of ti"in68 duration8 seGuence and co"#ination of indi:idual or6an s7ste" failures on "ortalit7. (nfor"ation deri:ed fro" this stud7 will #e used to opti"iBe routine clinical "ana6e"ent and i"pro:e clinical care strate6ies. 0hese will then help in the direction of health resources and i"pro:e cost effecti:eness. (t can also help :alidate outco"e definitions8 allow co"para#ilit7 of results and for" a "ore accurate #asis for patient allocation in further clinical studies. Conflict of interest 0he authors ha:e no potential conflict of interest
References 1. 5ellin6er 4P8 Hors"ar; 348 /a7er P8 /R:7 P8 =ara:S-Po"a 48 Petro: =!8 et al. 5eter"inant-#ased classification of acute pancreatitis se:erit7: 1n international "ultidisciplinar7 consultation. 1nn !ur6 $%1$K $5C:*+5-*%. 'P=(5 $$+&5+15, $. Petro: =!8 Lindsor J18 /R:7 P8 Pancreatitis 1cross Nations 3linical 2esearch and 4ducation 1lliance DP1N3241E. New international classification of acute pancreatitis: "ore than just 4 cate6ories of se:erit7. Pancreas $%1&K 4$:&*)-)1. 'P=(5 $&4*C&C&, &. !te:enson F8 3arter 32. 1cute pancreatitis. !ur6er7 $%1&K &1:$)5-&%&. 4. 0handasser7 2A8 Tada: 058 5utta 98 1ppasani !8 !in6h F8 Fochhar 2. Prospecti:e :alidation of 4-cate6or7 classification of acute pancreatitis se:erit7. Pancreas $%1&K 4$:&)$-C. 'P=(5 $&4$)4)*, 5. Petro: =!8 Lindsor J1. 3onceptual fra"ewor; for classif7in6 the se:erit7 of acute pancreatitis. 3lin 2es -epatol .astroenterol $%1$K &C:&41-4. 'P=(5 $$551C4$, C. !i6urdsson .-. (ntensi:e care "ana6e"ent of acute pancreatitis. 5i6 !ur6 1))4K 11:$&1-41. +. =ara:S Po"a 48 <u#ia Olascoa6a H8 Petro: =!8 Na:arro !oto !8 /aplaBa !antos 38 =orales 1la:a H8 et al. !4=(3T93 $%1$. 2eco""endations for intensi:e care "ana6e"ent of acute pancreatitis. =ed (ntensi:a $%1&K &+:1C&-+). 'P=(5 $&541%C&, *. -alpern N18 Aettes /8 .reenstein 2. Hederal and nationwide intensi:e care units and healthcare costs: 1)*C-1))$. 3rit 3are =ed 1))4K $$:$%%1-+. 'P=(5 +)**14%, ). 3halfin 5A. 3ost-effecti:eness anal7sis in health care. -osp 3ost =ana6 1ccount 1))5K +:1-*. 'P=(5 1%14&&$1, 1%. Oosten#rin; JA8 Auijs-Van der Loude 08 :an 16tho:en =8 Foop"anschap =18 2utten HH. 9nit costs of inpatient hospital da7s. Phar"acoecono"ics $%%&K $1:$C&-+1. 'P=(5 1$C%%$$1, 11. :an 5ij; H48 :an der Ler;en 3. Lhat are the costs of an intensi:e care patientP 0he direct costs of a sur6ical patient per (39-ad"ission and per inpatient da7. =edisch 3ontact 1))*K 5&:1154-C. 1$. 3arter 5. 1cute pancreatitis: the :alue of life. Ar J !ur6 1))&K *%:14))-5%%. 'P=(5 *$)*)1%, 1&. Auter 18 ("rie 3L8 3arter 328 4:ans !8 =cFa7 3J. 57na"ic nature of earl7 or6an d7sfunction deter"ines outco"e in acute pancreatitis. Ar J !ur6 $%%$K *):$)*-&%$. 'P=(5 11*+$%5&, 14. Johnson 38 1#u--ilal =. Persistent or6an failure durin6 the first wee; as a "ar;er of fatal outco"e in acute pancreatitis. .ut $%%4K 5&:1&4%-4. 'P=(5 15&%C5)C, 15. /7tras 58 =anes F8 0riantopoulou 38 Paras;e:a 38 5elis !8 1:6erinos 38 5er:enis 3. Persistent earl7 or6an failure: definin6

the hi6h-ris; 6roup of patients with se:ere acute pancreatitisP Pancreas $%%*K &C:$4)-54. 'P=(5 1*&C$*&+, 1C. /e =Re J8 Pa7e H8 !au:anet 18 OU0oole 58 -a""el P8 =art7 J8 et al. (ncidence and re:ersi#ilit7 of or6an failure in the course of sterile or infected necrotiBin6 pancreatitis. 1rch !ur6 $%%1K 1&C:1&*C-)%. 'P=(5 11+&5*C5, 1+. Hlint 28 Lindsor J1. 4arl7 ph7siolo6ical response to intensi:e care as a clinicall7 rele:ant approach to predictin6 the outco"e in se:ere acute pancreatitis. 1rch !ur6 $%%4K 1&):4&*-4&. 'P=(5 15%+*+14, 1*. 4ise"an A8 Aeart 28 Norton /. =ultiple or6an failure. !ur6 .7necol O#stet 1)++K 144:&$&-C. 'P=(5 *4144), 1). Aaue 14. =OH8 =O5!8 and !(2!: what is in a na"e or an acron7"P !hoc; $%%CK $C:4&*-4). 'P=(5 1+%4+51&, $%. Visconti =8 2a#itti P.8 9o"o .8 .iannattasio H8 Varriale =8 2usso 3. 0he "ultiple-or6an failure s7ndro"e in acute pancreatitis. (ts patho6enesis and treat"ent. 2ecenti Pro6 =ed 1))5K *C:*1-5. 'P=(5 ++541+), $1. Fallinen O8 =aisnie"i F8 AVhlin6 08 0u;iainen 48 Foljonen V. =ultiple or6an failure as a cause of death in patients with se:ere #urns. J Aurn 3are 2es $%1$K &&:$%C-11. 'P=(5 $1)+)*4&, $$. Aradle7 4/ (((. 1 clinicall7 #ased classification s7ste" for acute pancreatitis. !u""ar7 of the (nternational !7"posiu" on 1cute Pancreatitis8 1tlanta8 .a8 !epte"#er 11 throu6h 1&8 1))$. 1rch !ur6 1))$K 1$*:5*C-)%. 'P=(5 *4*)&)4, $&. 0ran 558 3uesta =18 !chneider 1J8 Lesdorp 2(. Pre:alence and prediction of "ultiple or6an s7ste" failure and "ortalit7 in acute pancreatitis. J 3rit 3are 1))&K *:145-5&. 'P=(5 *$+515), $4. Petro: =!8 !han#ha6 !8 3ha;ra#ort7 =8 Phillips 128 Lindsor J1. Or6an failure and infection of pancreatic necrosis as deter"inants of "ortalit7 in patients with acute pancreatitis. .astroenterolo67 $%1%K 1&):*1&-$%. 'P=(5 $%54%)4$, $5. Lilson 38 =c1rdle 3!8 3arter 538 ("rie 3L. !ur6ical treat"ent of acute necrotiBin6 pancreatitis. Ar J !ur6 1)**K +5:111)-$&. 'P=(5 &$%*%4*, $C. =ounBer 28 /an6"ead 3J8 Lu A98 4:ans 138 Aishehsari H8 =uddana V8 et al. 3o"parison of existin6 clinical scorin6 s7ste"s to predict persistent or6an failure in patients with acute pancreatitis. .astroenterolo67 $%1$K 14$:14+C-*$. 'P=(5 $$4$55*), $+. =ofidi 28 5uff =58 Li6"ore !J8 =adha:an FF8 .arden OJ8 Par;s 2L. 1ssociation #etween earl7 s7ste"ic infla""ator7 response8 se:erit7 of "ultior6an d7sfunction and death in acute pancreatitis. Ar J !ur6 $%%CK )&:+&*-44. 'P=(5 1CC+1%C$, $*. =ole 5J8 Ola#i A8 2o#inson V8 .arden OJ8 Par;s 2L. (ncidence of indi:idual or6an d7sfunction in fatal acute pancreatitis: anal7sis of 1%$4 death records. -PA $%%)K 11:1CC-+%. 'P=(5 1)5)%C4&, $). Vincent J/8 =oreno 28 0a;ala J8 Lillatts !8 5e =endonWa 18 Aruinin6 -8 et al. 0he !OH1 D!epsis-related Or6an Hailure 1ssess"entE score to descri#e or6an d7sfunction/failure. (ntensi:e 3are =ed 1))CK $$:+%+-1%. 'P=(5 **44$&), &%. Vincent J/8 5e =endonca 18 3antraine H et al. 9se of the !OH1 score to assess the incidence of or6an d7sfunction/failure in intensi:e care units: results of a "ulticenter8 prospecti:e stud7. 3rit 3are =ed 1))*K $C:1+)&-*%%. 'P=(5 )*$4%C), &1. Herreira H/8 Aota 5P8 Aross 18 =Rlot 38 Vincent J/. !erial e:aluation of the !OH1 score to predict outco"e in criticall7 ill patients. J1=1 $%%1K $*C:1+54-*. 'P=(5 115)4)%1, &$. =oreno 28 Vincent J/8 =atos 28 =endonWa 18 3antraine H8 0hijs /8 et al. 0he use of "axi"u" !OH1 score to Guantif7 or6an d7sfunction/failure in intensi:e care. 2esults of a prospecti:e8 "ulticentre stud7. (ntensi:e 3are =ed 1)))K $5:C*C-)C. 'P=(5 1%4+%5+$, &&. 0enner !8 !ica .8 -u6hes =8 Noordhoe; 48 Hen6 !8 <inner =8 Aan;s P1. 2elationship of necrosis to or6an failure in se:ere

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acute pancreatitis. .astroenterolo67 1))+K 11&:*))-)%&. 'P=(5 )$*+)*$, &4. Tan6 XN8 .uo J8 /in <Y8 -uan6 /8 Jin 08 Lu L8 et al. 0he stud7 on causes of death in ful"inant pancreatitis at earl7 sta6e and late sta6e. !ichuan 5a Xue Xue Aao Ti Xue Aan $%11K 4$:C*C-)%. 'P=(5 $$%%+4)), &5. -alonen F(8 PettilZ V8 /eppZnie"i 1F8 Fe"ppainen 418 Puola;;ainen P18 -aapiainen 2F. =ultiple or6an d7sfunction associated with se:ere acute pancreatitis. 3rit 3are =ed $%%$K &%:1$+4-). 'P=(5 1$%+$C*1, &C. Petro: =!8 Ve6e !!8 Lindsor J1. .lo#al sur:e7 of contro:ersies in classif7in6 the se:erit7 of acute pancreatitis. 4ur J .astroenterol -epatol $%1$K $4:+15-$1. 'P=(5 $$&*$+%C, &+. <hu 1J8 !hi J!8 !un XJ. Or6an failure associated with se:ere acute pancreatitis. Lorld J .astroenterol $%%K ):$5+%-&. 'P=(5 14C%C%)), &*. =ole 5J8 =c3l7"ont F/8 /au !8 et al.=ole 5J8 =c3l7"ont F/8 /au !8 =ills 28 !ta"p-Vincent 38 .arden OJ8 Par;s 2L. 5iscrepanc7 #etween the extent of pancreatic necrosis and "ultiple or6an failure score in se:ere acute pancreatitis. Lorld J !ur6 $%%)K &&:$4$+-&$. 'P=(5 1)C41)51, &). <i""er"an J48 Fnaus L18 La6ner 5P8 !un X8 -a;i" 2A8 N7stro" PO. 1 co"parison of ris;s and outco"es for patients with or6an s7ste" failure: 1)*$-1))%. 3rit 3are =ed 1))CK $4:1C&&-41. 'P=(5 **+4$)*, 4%. 0ilne7 N/8 Aaile7 ./8 =or6an 1P. !eGuential s7ste" failure after rupture of 111: 1n unsol:ed pro#le" in postoperati:e care. 1nn !ur6 1)+&K 1+*:11+-$$. 'P=(5 4+$&41), 41. A[chler =L8 .loor A8 =[ller 318 Hriess -8 !eiler 318 9hl L. 1cute necrotiBin6 pancreatitis: treat"ent strate67 accordin6 to the status of infection. 1nn !ur6 $%%%K $&$:C1)-$C. 'P=(5 11%CC1&1, 4$. /utfara;h"ano: ((8 =irono: P8 0i"er#ulato: =. Pro6nostic :alue of the pattern of "ultiple or6an d7sfunctions in se:ere acute pancreatitis. 1nesteBiol 2eani"atol $%%+K $:44-+. 'P=(5 1+5C4%%%, 4&. 2ocha H.8 Aenoit 48 <inner =J8 Lhan6 448 Aan;s P18 1shle7 !L8 =ortele FJ. ("pact of radiolo6ic inter:ention on "ortalit7 in necrotiBin6 pancreatitis: the role of or6an failure. 1rch !ur6 $%%)K 144:$C1-5. 'P=(5 1)$*)CCC, 44. /an;isch P.8 Pflichthofer 58 /ehnic; 5. 1cute pancreatitis: which patient is "ost at ris;P Pancreas 1)))K 1):&$1-4. 'P=(5 1%54+1)%, 45. Petro: =!. Predictin6 the se:erit7 of acute pancreatitis: 3hoose the ri6ht horse #efore hitchin6 the cart. 5i6 5is !ci $%11K 5C:&4%$-4. 'P=(5 $1)+1)51, 4C. Van !ant:oort -38 Aa;;er OJ8 Aollen 0/ et al. 1 conser:ati:e and "ini"all7 in:asi:e approach to necrotiBin6 pancreatitis i"pro:es outco"e. .astroenterolo67 $%11K 141:1$54-C&. 'P=(5 $1+41)$$, 4+. (sen"ann 28 2au A8 Ae6er -.. 4arl7 se:ere acute pancreatitis: characteristics of a new su#6roup. Pancreas $%%1K $$:$+4-*. 'P=(5 11$)1)$), 4*. 2e"es-0roche J=8 9scan6a /H8 Pel\eB-/una =8 5uarte-2ojo 18 .onB\leB-Aal#oa P8 0eliB =18 et al. Lhen should we #e concerned a#out pancreatic necrosisP 1nal7sis fro" a sin6le institution in =exico 3it7. Lorld J !ur6 $%%CK &%:$$$+-&&. 'P=(5 1+1%&%)*, 4). /an;isch P.8 Pflichthofer 58 /ehnic; 5. No strict correlation #etween necrosis and or6an failure in acute pancreatitis. Pancreas $%%%K $%:&1)-$$. 'P=(5 1%+CC4C%, 5%. =ara:S Po"a 48 /aplaBa !antos 38 .orraiB /]peB A8 1l#eniB 1r#iBu 48 <u#ia Olascoa6a H8 Petro: =!8 et al. 3linical pathwa7s in acute pancreatitis: reco""endations for earl7 "ultidisciplinar7 "ana6e"ent. =ed (ntensi:a $%1$K &C:&51-+. 'P=(5 $$5C4+*),

51. Petro: =!8 Lindsor J1. !e:erit7 of acute pancreatitis: i"pact of local and s7ste"ic co"plications. .astroenterolo67 $%1$K 14$:e$%-1. 'P=(5 $$54$*&&, 5$. !tewart .A8 1lt"an 5.8 1s;ie /=8 5ule7 /8 !i""onds =38 !tewart /1. !tatistical anal7sis of indi:idual participant data "eta-anal7ses: a co"parison of "ethods and reco""endations for practice. Plo! One $%1$K +:e4C%4$. 'P=(5 $&%5C$&$, 5&. 3hal"ers (. 0he 3ochrane colla#oration: preparin68 "aintainin68 and disse"inatin6 s7ste"atic re:iews of the effects of health care. 1nn N T 1cad !ci 1))&K +%&:15C-C5. 'P=(5 *1)$$)&, 54. Petro: =!. 1#do"inal fat: a ;e7 pla7er in "eta#olic acute pancreatitis. 1" J .astroenterol $%1&K 1%*:14%-$. 'P=(5 $&$*+)45, 55. !i""onds =38 -i66ins JP. 3o:ariate hetero6eneit7 in "etaanal7sis: criteria for decidin6 #etween "eta-re6ression and indi:idual patient data. !tat =ed $%%+K $C:$)*$-)). 'P=(5 1+1)5)C%, 5C. !tewart /18 3lar;e =J. Practical "ethodolo67 of "etaanal7ses Do:er:iewsE usin6 updated indi:idual patient data. !tat =ed 1))5K 14:$%5+-+). 'P=(5 *55$**+, 5+. !tewart /8 Par"ar =. =eta-anal7sis of the literature or of indi:idual patient data: is there a differenceP /ancet 1))&K &41:41*-$$. 'P=(5 *%)41*&, 5*. !i""onds =38 -i66ins JP8 !tewart /18 0ierne7 JH8 3lar;e =J8 0ho"pson !.. =eta-anal7sis of indi:idual patient data fro" rando"iBed trials: a re:iew of "ethods used in practice. 3lin 0rials $%%5K $:$%)-1+. 'P=(5 1C$+)144, 5). =arshall J38 3oo; 5J8 3hristou NV8 Aernard .28 !prun6 3/8 !i##ald LJ. =ultiple or6an d7sfunction score: a relia#le descriptor of a co"plex clinical outco"e. 3rit 3are =ed 1))5K $&:1C&*-5$. 'P=(5 +5*+$$*, C%. Hisher 5J8 3opas 1J8 0ierne7 JH8 Par"ar =F. 1 critical re:iew of "ethods for the assess"ent of participant le:el interactions in indi:idual participant data "eta-anal7sis of rando"ised trials and 6uidance for practitioners. J 3lin 4pid $%11K C4:)4)-C+. 'P=(5 $1411$*%, C1. 0udor !38 Lillia"son P28 =arson 1.. (n:esti6atin6 hetero6eneit7 in an indi:idual participant data "eta-anal7sis of ti"e to e:ent outco"es. !tat =ed $%%5K $4:1&%+-1). 'P=(5 15C*5+1+, C$. !i""onds =38 Aowden J8 0ierne7 JH8 3opas 18 -i66in6 JP0. (ndi:idual participant data "eta-anal7sis of ti"e-to-e:ent outco"es: one-sta6e :ersus two-sta6e approaches for esti"atin6 the haBard ratio under a rando" effect "odel. 2esearch !7nthesis =ethods $%11K $:15%-C$. C&. 2 3ore 0ea". 2: 1 lan6ua6e and en:iron"ent for statistical co"putin6. 2 Houndation for !tatistical 3o"putin6: Vienna8 1ustria: $%1$. '(!AN &-)%%%51-%+-%, C4. !troup 5H8 Aerlin J18 =orton !38 Ol;in (8 Lillia"son .58 2ennie 58 et al. =eta-anal7sis of o#ser:ational studies in epide"iolo67: a proposal for reportin6. J1=1 $%%%K $*&:$%%*1$. 'P=(5 1%+*)C+%, C5. 2ile7 258 /a"#ert P38 1#o-<aid .. =eta-anal7sis of indi:idual participant data: rationale8 conduct8 and reportin6. A=J $%1%K &4%:5$1-5. 'P=(5 $%1&)$15, CC. !tewart /18 0ierne7 JH8 Aurdett !. 5o s7ste"atic re:iews #ased on indi:idual participant data offer a "eans of circu":entin6 #iases associated with trial pu#licationsP (n: 2othstein -8 !utton 18 Aorenstein =. Pu#lication Aias in =eta1nal7sis: Pre:ention8 1ssess"ent and 1djust"ents: John Lile7 ^ !ons8 1%%5:$C1-*C. '(!AN )+*-%-4+%-*+%14-&, C+. Aradle7 4/ (((. 1tlanta redux: re:isitin6 the se:erit7 stratification s7ste" for acute pancreatitis. 1nn !ur6 $%1$K $5C:**1-$. 'P=(5 $&1%*1$4,

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C*. 5e 3a"pos 08 Parreira J.8 1ssef J38 2iBoli !8 Nasci"ento A8 Hra6a .P. 3lassification of of se:erit7 of acute pancreatitis. 2e: 3ol Aras 3ir $%1&K 4%:1C4-*. C). 9o"o .8 5ellin6er 4P8 Hors"ar; 348 /a7er P8 /R:7 P8 =ara:SPo"a 48 et al. Pancreatitis 1cross Nations 3linical 2esearch and 4ducation 1lliance DP1N3241E. (nternational "ultidisciplinar7 classification of acute pancreatitis se:erit7: 0he $%1& (talian edition. =iner:a =edica $%1& Din printE.

+%. =ara:S-Po"a 48 5ellin6er 4P8 Hors"ar; 348 /a7er P8 /R:7 P8 !hi"ose6awa 08 et al. (nternational "ultidisciplinar7 classification of acute pancreatitis se:erit7: 0he $%1& !panish edition. =ed (ntensi:a $%1&. 'P=(5 $&+4+1*), +1. /a7er P8 5ellin6er 4P8 Hors"ar; 348 /R:7 P8 =ara:S-Po"a 48 !hi"ose6awa 08 et al. (nternational "ultidisciplinar7 classification of acute pancreatitis se:erit7: 0he $%1& .er"an edition. < .astroenterol $%1&K 51:544-5%. 'P=(5 $&+4%&5&,

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