2015 Nonvariceal Upper Gastrointestinal Hemorrhage

Guideline a1
Diagnosisandmanagementofnonvaricealupper
gastrointestinalhemorrhage:EuropeanSocietyof
GastrointestinalEndoscopy(ESGE)Guideline
Authors
IanM.Gralnek1,2,Jean-Marc Dumonceau3,ErnstJ.Kuipers4,AngelLanas5,DavidS.Sanders6,Matthew
Kurien6,
Gianluca Rotondano7,TomasHucl8,MarioDinis-Ribeiro9,Riccardo Marmo10,Istvan Racz11,Alberto Arezzo12,
Ralf-Thorsten Hoffmann13,GillesLesur14,Roberto deFranchis15,LarsAabakken16,Andrew Veitch17,FrancoRadaelli18,
PauloSalgueiro19,Ricardo Cardoso20,LusMaia19,Angelo Zullo21,LivioCipolletta22,Cesare Hassan23
Institutions
Bibliography
DOI http://dx.doi.org/
10.1055/s-0034-1393172
Published online:0.0.
Endoscopy 2015;47:146
GeorgThieme VerlagKG
Stuttgart NewYork
ISSN0013-726X
Institutions listedatendofarticle.
ThisGuideline isanofficial statement oftheEuropean Society ofGastrointestinal Endoscopy (ESGE). It

addressesthediagnosisandmanagement ofnonvaricealuppergastrointestinal hemorrhage (NVUGIH).
Corresponding author
IanM.Gralnek, MD,MSHS
Institute ofGastroenterology
andLiverDiseases, Ha'Emek
Medical Center
Rappaport FacultyofMedicine,
Technion-Israel Institute of
Technology
Afula,Israel18101
Fax:+972-4-6495314
ian_gr@clalit.org.il
MainRecommendations
MR1.ESGErecommendsimmediateassessmentof patients with clinically severe or ongoing active
hemodynamicstatusinpatientswhopresentwith UGIH. In selected patients, pre-endoscopic infuacuteuppergastrointestinalhemorrhage(UGIH), sionoferythromycinsignificantlyimprovesendowith prompt intravascular volume replacement scopicvisualization,reducestheneedforsecondinitially using crystalloid fluids if hemodynamic lookendoscopy,decreasesthenumberofunitsof
instabilityexists (strong recommendation, mod- bloodtransfused,andreducesdurationofhospital
eratequalityevidence).
stay (strong recommendation, high quality eviMR2.ESGErecommendsarestrictiveredbloodcell dence).
transfusionstrategythataimsforatargethemoMR7.Followinghemodynamicresuscitation,ESGE
globinbetween7g/dLand9g/dL.Ahighertarget
recommends early (24 hours) upper GI endoshemoglobin should be considered in patients
copy.Veryearly(<12hours)upperGIendoscopy
withsignificantco-morbidity(e.g.,ischemiccarmaybeconsideredinpatientswithhighriskclinidiovascular disease) (strong recommendation, calfeatures,namely:hemodynamicinstability(tamoderatequalityevidence).
chycardia,hypotension)thatpersistsdespiteonMR3.ESGErecommendstheuseoftheGlasgowgoingattemptsatvolumeresuscitation;in-hospiBlatchfordScore(GBS)forpre-endoscopyriskstra- talbloodyemesis/nasogastricaspirate;orcontratification. Outpatients determined to be at very indication tothe interruption of anticoagulation
lowrisk,baseduponaGBSscoreof01,donotre(strong recommendation, moderate quality eviquireearlyendoscopynorhospitaladmission.Dis- dence).
chargedpatientsshouldbeinformedoftheriskof
MR8. ESGE recommends that peptic ulcers with
recurrent bleeding and be advised to maintain spurtingoroozingbleeding(Forrestclassification
contactwiththedischarginghospital(strongreIaandIb,respectively)orwithanonbleedingvisicommendation,moderatequalityevidence).
blevessel(ForrestclassificationIIa)receiveendoMR4.ESGErecommendsinitiatinghighdoseintra- scopic hemostasis because these lesions are at
venousprotonpumpinhibitors(PPI),intravenous high risk for persistent bleeding or rebleeding
bolus followed by continuous infusion (80mg
(strongrecommendation,highqualityevidence).
then8mg/hour),inpatientspresentingwithacute MR9.ESGErecommendsthatpepticulcerswithan
UGIHawaitingupperendoscopy.However,PPIin- adherentclot(ForrestclassificationIIb)beconsidfusionshouldnotdelaytheperformanceofearly
eredforendoscopicclotremoval.Oncetheclotis
endoscopy(strongrecommendation,highquality removed,anyidentifiedunderlyingactivebleedevidence).
ing(ForrestclassificationIaorIb)ornonbleeding
MR5.ESGEdoesnotrecommendtheroutineuseof visiblevessel(ForrestclassificationIIa)shouldrenasogastricororogastricaspiration/lavageinpa- ceiveendoscopichemostasis(weakrecommendatientspresentingwithacuteUGIH(strongrecom- tion,moderatequalityevidence).
mendation,moderatequalityevidence).
MR10.Inpatientswithpepticulcershavingaflat
MR6.ESGErecommendsintravenouserythromy- pigmentedspot(ForrestclassificationIIc)orclean
cin (single dose, 250mg given 30120 minutes base(ForrestclassificationIII),ESGEdoesnotrepriortouppergastrointestinal[GI]endoscopy)in
commendendoscopichemostasisasthesestigma-
GralnekIanMetal. Nonvaricealuppergastrointestinalhemorrhage:ESGEGuideline
Endoscopy2015;47:a1a46
a2 Guideline
tapresentalowriskofrecurrentbleeding.Inselectedclinicalsetsisifindicated.Inthecaseoffailureofthissecondattemptathetings,thesepatientsmaybedischargedtohomeonstandardPPI
mostasis,transcatheterangiographicembolization (TAE)orsurtherapy,e.g.,oralPPIonce-daily(strongrecommendation,moder- geryshouldbeconsidered(strongrecommendation,highquality
atequalityevidence).
evidence).
MR11.ESGErecommendsthatepinephrineinjectiontherapynot MR14.InpatientswithNVUGIHsecondarytopepticulcer,ESGErebeusedasendoscopicmonotherapy.Ifused,itshouldbecombined commendsinvestigatingforthepresenceofHelicobacterpyloriin
with a second endoscopic hemostasis modality (strong recom-theacutesettingwithinitiationofappropriateantibiotictherapy
mendation,highqualityevidence).
whenH.pyloriisdetected.Re-testingforH.pylorishouldbeperMR12. ESGE recommends PPI therapy for patients who receiveformedinthosepatientswithanegativetestintheacutesetting.
endoscopichemostasisandforpatientswithadherentclotnotre- DocumentationofsuccessfulH.pylorieradicationisrecommended
ceivingendoscopichemostasis.PPItherapyshouldbehighdose (strongrecommendation,highqualityevidence).
andadministeredasanintravenousbolusfollowedbycontinuous MR15.Inpatientsreceivinglowdoseaspirinforsecondarycardioinfusion (80mg then 8mg/hour) for 72 hours post endoscopy vascularprophylaxiswhodeveloppepticulcerbleeding,ESGEre(strongrecommendation,highqualityevidence).
commends aspirin be resumed immediately following index
MR13.ESGEdoesnotrecommendroutinesecond-lookendoscopy endoscopyiftheriskofrebleedingislow(e.g.,FIIc,FIII).Inpatients
aspartofthemanagementofnonvaricealuppergastrointestinal withhighriskpepticulcer(FIa,FIb,FIIa,FIIb),earlyreintroduction
hemorrhage (NVUGIH). However, in patients with clinical evi- ofaspirinbyday3afterindexendoscopyisrecommended,providdenceofrebleedingfollowingsuccessfulinitialendoscopichemo- edthatadequatehemostasishasbeenestablished(strongrecomstasis,ESGErecommendsrepeatupperendoscopywithhemosta- mendation,moderatequalityevidence).
Abbreviations
Introduction
APC
argonplasmacoagulation
ASA
American SocietyofAnesthesiologists
DAPT
dualantiplatelet therapy
CHADS2 congestiveheartfailure,hypertension, age75years,
diabetesmellitus,andpreviousstrokeortransient
ischemic attack[riskscore]
CI
confidence interval
DOAC directoralanticoagulant
ESGE
European SocietyofGastrointestinal Endoscopy
FFP
freshfrozenplasma
GBS
Glasgow-Blatchford Score
GI
gastrointestinal
GRADE GradingofRecommendations Assessment,
Development andEvaluation
hazardratio
HR
INR
international normalized ratio
NBVV nonbleeding visiblevessel
NNT
number neededtotreat
NOAC non-VKAoralanticoagulant
NVUGIH nonvariceal uppergastrointestinal hemorrhage
PAR
protease-activated receptor
PCC
prothrombin complexconcentrate
PICO
patients, interventions, controls, outcomes
PPI
protonpumpinhibitor
oddsratio
OR
pepticulcerbleeding
PUB
RBC
redbloodcell
RCT
randomized controlled trial
RR
relativeriskorriskratio
TAE
transcatheter angiographic embolization
UGIH
uppergastrointestinal hemorrhage
VCE
videocapsule endoscopy
VKA
vitaminKantagonist
Acute upper gastrointestinal hemorrhage (UGIH) is a common

condition worldwide that has an estimated annual incidence of
40150 cases per 100 000 population [1, 2], frequently leads to
hospital admission, andhassignificant associated morbidity and
mortality, especially inthe elderly.The most common causes of
acuteUGIHarenonvariceal [1,2].Thisincludespepticulcers,28
%59%(duodenal ulcer 17%37%andgastric ulcer 11%24%);
mucosal erosive disease of the esophagus/stomach/duodenum,
1%47%;MalloryWeisssyndrome, 4%7%;upperGItractmalignancy, 2%4%; other diagnosis, 2%7%; or no exact cause
identified, 7%25%[1,2].Moreover,in16%20%ofacuteUGIH
cases, more than one endoscopic diagnosis maybeidentified as
thecauseofbleeding. Theaimofthisevidence-based consensus
guideline istoprovide medical caregivers withacomprehensive
review and recommendations on the clinical and endoscopic
management ofNVUGIH.
Methods
!
The ESGE commissioned thisguideline onNVUGIH and appointedaguidelineleader(I.M.G.)whoincollaborationwiththeChair

of the ESGE Guidelines Committee (C.H.), invited the listed authors to participate in the guideline development and review.
Key questions were prepared by the coordinating team (I.M.G.
andC.H.)andreviewed andapproved byalltaskforcemembers.
The coordinating team formed four task force subgroups, each
with its own coordinator, and divided the key topics/questions
amongst these four task force subgroups (see Appendix e1 , online-only).Taskforcemembers includedgastroenterologists/gastrointestinal endoscopists, an interventional radiologist, and a
surgeon. Clinical questions wereformulated using thePICO(patients,interventions, controls, outcomes) methodology.
Each task force subgroup performed a systematic literature
search to identify the relevant literature that was subsequently
used to prepare evidence-based, well-balanced statements on
each of their assigned key questions. The Ovid MEDLINE, EMBASE, Google/Google Scholar,andtheCochrane Database ofSys-
Guideline a3
tematic Reviews weresearched forEnglish-language articles in- intheobservation group(P=0.04forbothcomparisons). Howcluding ataminimum thefollowing keywords: nonvariceal up- ever, there is no evidence from randomized controlled trials
per gastrointestinal (GI) hemorrhage/bleeding, peptic ulcer he- (RCTs),fororagainstearlyorlarge-volume intravenous fluid admorrhage/bleeding, fluid resuscitation, fluid therapy, critical ill- ministration inuncontrolled hemorrhage[6,7].Moreover,theseness,crystalloid solutions, colloidsolutions, plasmatransfusions, lectionofresuscitation fluid typeincritically illpatientsrequires
red blood cell transfusion, platelet transfusion, hemoglobin, re- careful consideration based on safety, effects on patient outstrictive transfusion strategy, liberal transfusion strategy, risk comes,andcosts.Todate,thereisongoinguncertainty
regarding
stratification, mortality, rebleeding, anti-thrombotic agent, anti-the ideal fluid administration strategy inthis clinical setting [8,
plateletagent,aspirin,dualanti-platelet therapy(DAPT),anti-co- 9].
agulation/anti-coagulant, direct/new oral anticoagulants
(DOACs),coagulopathy,vitaminKinhibitor/antagonist, prokinetESGErecommendsarestrictiveredbloodcelltransfusionstrategythataims
icagent,erythromycin, freshfrozenplasma,nasogastric tube,or- foratargethemoglobinbetween7g/dLand9g/dL.Ahighertargethemoogastric tube, proton pump inhibitor, prokinetic agent, erythro- globinshouldbeconsideredinpatientswithsignificantco-morbidity(e.g.,
ischemiccardiovasculardisease)(strongrecommendation,moderatequality
mycin, endoscopic hemostasis, injection therapy, thermal therevidence).
apy(contact, non-contact), mechanical therapy/endoscopic clipping,topicalhemostasis therapy,second-look endoscopy,helico- Theuseofredbloodcell(RBC)transfusions maybelifesavingfolbacter pylori, H.pylori,transcatheter angiographic embolization lowing massive UGIH. However, the role of RBC transfusion in
(TAE), and surgery. The hierarchy of studies included as part of lesstorrentialGIbleedingremainscontroversial, withuncertainthis evidence-based guideline was, in decreasing order of evi- tyexisting regarding thehemoglobin levelatwhichbloodtransdence level, published systematic reviews/meta-analyses, ran- fusion should be initiated. This uncertainty reflects concerns
domized controlled trials (RCTs), prospective and retrospective from both the critical care and gastroenterology literature sugobservational studies. Allselectedarticles weregradedusingthe gesting poorer outcomes inpatients managed withaliberal RBC
Grading of Recommendations Assessment, Development and transfusion strategy [2,10,11].InarecentRCTthatincluded 921
patients presenting with all causes of acute UGIH, a restrictive
Evaluation(GRADE) system[3,4].
Each task force subgroup proposed statements for each of theirRBC transfusion strategy (target hemoglobin, 7 to 9g/dL) was
assigned keyquestions which werediscussed andvotedondur- comparedwithamoreliberaltransfusion strategy (targethemoglobin, 9 to 11g/dL) [12]. The restrictive RBC transfusion group
ingtheNVUGIH taskforceguideline meeting heldinBerlin,GermanyinNovember2014.InAugust2015,amanuscript draftpre- hadsignificantly improved6-weeksurvival(95%vs.91%;hazard
pared byI.M.G. wassent toall task forcemembers. After agree- ratio [HR] 0.55, 95%confidence interval [CI] 0.330.92) and rement on a final version, the manuscript was reviewed by two duced rebleeding (10%vs.16%;HR 0.68, 95%CI 0.470.98) [12].
members oftheESGEGoverningBoardandsentforfurther com- In the subgroup of patients with NVUGIH (n=699), there was a
ments to the National Societies and ESGE individual members. statistical trendtowardslowermortality intherestrictive vs.libAfter agreement onafinal version, the manuscript wassubmit- eral RBC transfusion strategy (3.7% vs. 6.9%, P=0.065). Because
ted tothe journal Endoscopy for publication. All authors agreed the study was not powered to specifically evaluate NVUGIH,
thesefindings should beinterpreted with caution. Other limitaonthefinalrevisedmanuscript.
tionsofthisstudyincludetheexclusionofpatients
withmassive
ThisNVUGIH guideline willbeconsidered forreviewandupdating in 2020, or sooner if new relevant evidence becomes avail- exsanguinating bleeding and defined co-morbidities. Furtherable. Any updates to this guideline in the interim will be noted more, all patients underwent endoscopy within 6hours of preon the ESGE website: http://www.esge.com/esge-guidelines. sentation,whichmaynotbefeasibleineverydayclinicalpractice.
html.
Coagulopathy atthetimeofNVUGIH presentation isanotherfrequent andadverse prognostic factor [13]. Published dataforthe
management ofcoagulopathy arelimited and inconclusive. One
Statementsandrecommendations
smallcohortstudyusinganhistorical comparison groupshowed
!
thataggressivevolumeresuscitation, includingcorrection ofcoa"
gulopathy (international normalized ratio [INR]<1.8), led to an
See
Table1.
improvement in mortality outcomes [5]. In a systematic review
Initialpatientevaluationandhemodynamic
thatevaluatedtherelevanceofinitialINRbeforecorrection inparesuscitation
tientswithNVUGIH,INRdidnotappeartopredictrebleeding,yet
afteradjusting forpotential confounders, aninitialINR>1.5predicted mortality (odds ratio [OR] 1.96, 95%CI 1.133.41) [14].
ESGErecommendsimmediateassessmentofhemodynamicstatusinpatients
Thismayinpart reflect thepresence ofunderlying liverdisease.
whopresentwithacuteuppergastrointestinalhemorrhage(UGIH),with
promptintravascularvolumereplacementinitiallyusingcrystalloidfluidsif Thereishowevernoavailableevidencetohelpguidecoagulopahemodynamicinstabilityexists(strongrecommendation,moderatequality
thycorrection incritically illpatientsandwidevariationinmanevidence).
agement exists in this area, indicating clinical uncertainty reThegoals ofhemodynamic resuscitation aretocorrect intravas- gardingoptimal practice [15].Plateletcounthasnotbeenshown
cular hypovolemia, restore adequate tissue perfusion, and pre- to be a predictor of either rebleeding or mortality. Currently,
ventmulti-organ failure.Earlyintensivehemodynamic resuscita- there is no high quality evidence to guide platelet transfusion
thresholds, although aplatelet transfusion threshold of50109/
tionofpatients withacuteUGIHhasbeenshowntosignificantly
decreasemortality [5].Inanobservational studyofpatientswith Lhasbeenproposed formostpatients, withatargetof1010 9/L
acuteUGIHandhemodynamic instability, patients whoreceived forpatients inwhomplateletdysfunction issuspected [16].
intensive hemodynamic resuscitation had significantly fewer
myocardialinfarctions andlowermortality comparedwiththose
a4 Guideline
Table1 Summary ofGuideline statements andrecommendations. Diagnosis andmanagement ofnonvariceal upper gastrointestinal hemorrhage: European
Society ofGastrointestinal Endoscopy (ESGE) Guideline.
Initialpatient evaluation andhemodynamic resuscitation
1 ESGErecommends immediate assessment ofhemodynamic status inpatients whopresent withacuteupper gastrointestinal hemorrhage (UGIH), with
prompt intravascular volume replacement initially using crystalloid fluids ifhemodynamic instability exists (strong recommendation, moderate quality
evidence).
2 ESGErecommends arestrictive redblood celltransfusion strategy thataimsforatarget hemoglobin between 7g/dLand9g/dL. Ahigher target hemoglobin should beconsidered inpatients withsignificant co-morbidity (e.g.,ischemic cardiovascular disease) (strong recommendation, moderate
quality evidence).
Riskstratification
3ESGErecommends theuseofavalidated riskstratification tooltostratify patients intohighandlowriskgroups. Riskstratification canaidclinical decisionmaking regarding timing ofendoscopy andhospital discharge (strong recommendation, moderate quality evidence).
4ESGErecommends theuseoftheGlasgow-Blatchford Score (GBS) forpre-endoscopy riskstratification. Outpatients determined tobeatverylowrisk,
based uponaGBSscore of01,donotrequire earlyendoscopy norhospital admission. Discharged patients should beinformed oftheriskofrecurrent
bleeding andbeadvised tomaintain contact withthedischarging hospital (strong recommendation, moderate quality evidence).
Pre-endoscopy management
5 Forpatients taking vitamin Kantagonists (VKAs), ESGErecommends withholding theVKAandcorrecting coagulopathy whiletaking intoaccount the
patient's cardiovascular riskinconsultation withacardiologist. Inpatients withhemodynamic instability, administration ofvitamin K,supplemented with
intravenous prothrombin complex concentrate (PCC)orfresh frozen plasma (FFP) ifPCCisunavailable, isrecommended (strong recommendation, low
quality evidence).
6Iftheclinical situation allows, ESGEsuggests aninternational normalized ratio (INR) value<2.5before performing endoscopy withorwithout endoscopic hemostasis (weakrecommendation, moderate quality evidence).
7ESGErecommends temporarily withholding newdirect oralanticoagulants (DOACs) inpatients withsuspected acute NVUGIH incoordination/consultation withthelocal hematologist/cardiologist (strong recommendation, verylowquality evidence).
8
evidence).
Forpatients using antiplatelet agents, ESGErecommends themanagement algorithm detailed in " Fig.2(strong recommendation, moderate quality
9 ESGErecommends initiating highdoseintravenous proton pumpinhibitors (PPI), intravenous bolusfollowed bycontinuous infusion (80mgthen8mg/
hour), inpatients presenting withacute UGIHawaiting upper endoscopy. However, PPIinfusion should notdelaytheperformance ofearlyendoscopy
(strong recommendation, highquality evidence).
10 ESGEdoesnotrecommend theuseoftranexamic acidinpatients withNVUGIH (strong recommendation, lowquality evidence).

11 ESGEdoesnotrecommend theuseofsomatostatin, oritsanalogue octreotide, inpatients withNVUGIH (strong recommendation, lowquality evidence).
12 ESGErecommends intravenous erythromycin (single dose,250mggiven30120minutes prior toupper GIendoscopy) inpatients withclinically severeorongoing active UGIH. Inselected patients, pre-endoscopic infusion oferythromycin significantly improves endoscopic visualization, reduces the
needforsecond-look endoscopy, decreases thenumber ofunits ofbloodtransfused, andreduces duration ofhospital stay(strong recommendation, high
quality evidence).
13ESGEdoesnotrecommend theroutine useofnasogastric ororogastric aspiration/lavage inpatients presenting withacute UGIH(strong recommendation, moderate quality evidence).
14Inaneffort toprotect thepatient's airway frompotential aspiration ofgastric contents, ESGEsuggests endotracheal intubation prior toendoscopy in
patients withongoing active hematemesis, encephalopathy, oragitation (weakrecommendation, lowquality evidence).
15ESGErecommends adopting thefollowing definitions regarding thetiming ofupperGIendoscopy inacuteovertUGIHrelative topatient presentation:
veryearly<12hours, early24hours, anddelayed>24hours (strong recommendation, moderate quality evidence).
16Following hemodynamic resuscitation, ESGErecommends early(24hours) upper GIendoscopy. Veryearly(<12hours) upper GIendoscopy maybe
considered inpatients withhighriskclinical features, namely: hemodynamic instability (tachycardia, hypotension) thatpersists despite ongoing attempts
atvolume resuscitation; in-hospital bloody emesis/nasogastric aspirate; orcontraindication totheinterruption ofanticoagulation (strong recommendation, moderate quality evidence).
17 ESGErecommends theavailability ofbothanon-call GIendoscopist proficient inendoscopic hemostasis andon-call nursing staff withtechnical expertise intheuseofendoscopic devices toallow performance ofendoscopy ona24/7basis (strong recommendation, moderate quality evidence).
Endoscopic therapy (peptic ulcer bleeding)
18ESGErecommends theForrest (F)classification beusedinallpatients withpeptic ulcerhemorrhage inorder todifferentiate lowandhighriskendoscopic stigmata (strong recommendation, highquality evidence).
19ESGErecommends thatpepticulcers withspurting oroozingbleeding (Forrest classification IaandIbrespectively), orwithanonbleeding visible vessel
(Forrest classification IIa)receive endoscopic hemostasis because these lesions areathighriskforpersistent bleeding orrebleeding (strong recommendation, highquality evidence).
20 ESGErecommends thatpeptic ulcers withanadherent clot(Forrest classification IIb)beconsidered forendoscopic clotremoval. Oncetheclotisremoved, anyidentified underlying active bleeding (Forrest classification IaorIb)ornonbleeding visible vessel (Forrest classification IIa)should receive
endoscopic hemostasis (weakrecommendation, moderate quality evidence).
21 Inpatients withpepticulcers havingaflatpigmented spot(Forrest classification IIc)orcleanbase(Forrest classification III),ESGEdoesnotrecommend
endoscopic hemostasis asthesestigmata present alowriskofrecurrent bleeding. Inselected clinical settings, thesepatients maybedischarged tohomeon
standard PPItherapy, e.g.,oralPPIonce-daily (strong recommendation, moderate quality evidence).
22ESGEdoesnotrecommend theroutine useofDoppler ultrasound ormagnification endoscopy intheevaluation ofendoscopic stigmata ofpeptic ulcer
bleeding (strong recommendation, lowquality evidence).
23Forpatients withactively bleeding ulcers (FIa, FIb), ESGErecommends combining epinephrine injection withasecond hemostasis modality (contact
thermal, mechanical therapy, orinjection ofasclerosing agent). ESGErecommends thatepinephrine injection therapy notbeusedasendoscopic monotherapy (strong recommendation, highquality evidence).
Guideline a5
Table1
(Continuation)
Initialpatient evaluation andhemodynamic resuscitation

24 Forpatients withnonbleeding visible vessel (FIIa), ESGErecommends mechanical therapy, thermal therapy, orinjection ofasclerosing agent as
monotherapy orincombination withepinephrine injection. ESGErecommends thatepinephrine injection therapy notbeusedasendoscopic monotherapy
(strong recommendation, highquality evidence).
Forpatients
25
withactive NVUGIH bleeding notcontrolled bystandard endoscopic hemostasis therapies, ESGEsuggests theuseofatopical hemostatic
sprayorover-the-scope clipassalvage endoscopic therapy (weak recommendation, lowquality evidence).
Endoscopic therapy (other causes ofNVUGIH)
26 Forpatients withacid-related causes ofNVUGIH different frompeptic ulcers (e.g.,erosive esophagitis, gastritis, duodenitis), ESGErecommends
treatment withhighdosePPI.Endoscopic hemostasis isusually notrequired andselected patients maybedischarged early(strong recommendation, low
quality evidence).
27
ESGErecommends thatpatients withaMallory Weisslesion thatisactively bleeding receive endoscopic hemostasis. There iscurrently inadequate
evidence torecommend aspecific endoscopic hemostasis modality. Patients withaMallory Weisslesion andnoactive bleeding canreceive highdosePPI
therapy alone (strong recommendation, moderate quality evidence).
28 ESGErecommends thataDieulafoy lesion receive endoscopic hemostasis using thermal, mechanical (hemoclip orbandligation), orcombination
therapy (dilute epinephrine injection combined withcontact thermal ormechanical therapy) (strong recommendation, moderate quality evidence).
Transcatheter angiographic embolization (TAE) orsurgery should beconsidered ifendoscopic treatment fails orisnottechnically feasible (strong recommendation, lowquality evidence).
Inpatients
29
bleeding fromupperGIangioectasias, ESGErecommends endoscopic hemostasis therapy. However, thereiscurrently inadequate evidence
torecommend aspecific endoscopic hemostasis modality (strong recommendation, lowquality evidence).
Inpatients
bleeding fromupperGIneoplasia, ESGErecommends considering endoscopic hemostasis inordertoaverturgent surgery andreduceblood
30
transfusion requirements. However, nocurrently available endoscopic treatment appears tohavelong-term efficacy (weakrecommendation, lowquality
evidence).
Postendoscopy/endoscopic hemostasis management
31
ESGErecommends PPItherapy forpatients whoreceive endoscopic hemostasis andforpatients withadherent clotnotreceiving endoscopic hemostasis. PPItherapy should behighdoseandadministered asanintravenous bolusfollowed bycontinuous infusion (80mgthen8mg/hour) for72hourspost
endoscopy (strong recommendation, highquality evidence).
32
ESGEsuggests considering PPItherapy asintermittent intravenous bolus dosing (atleast twice-daily) for72hours postendoscopy forpatients who
receive endoscopic hemostasis andforpatients withadherent clotnotreceiving endoscopic hemostasis. Ifthepatientscondition permits, highdoseoral
PPImayalsobeanoption inthoseabletotolerate oralmedications (weak recommendation, moderate quality evidence).
33
Inpatients withclinical evidence ofrebleeding following successful initial endoscopic hemostasis, ESGErecommends repeat upper endoscopy with
hemostasis ifindicated. Inthecaseoffailure ofthissecond attempt athemostasis, transcatheter angiographic embolization (TAE)orsurgery should be
considered (strong recommendation, highquality evidence).
ESGEdoesnotrecommend
34
routine second-look endoscopy aspartofthemanagement ofNVUGIH. However, second-look endoscopy maybeconsideredinselected patients athighriskforrebleeding (strong recommendation, highquality evidence).
Inpatients
withNVUGIH secondary topeptic ulcer,ESGErecommends investigating forthepresence ofHelicobacter pylori intheacute setting with
35
initiation ofappropriate antibiotic therapy whenH.pylori isdetected. Re-testing forH.pylori should beperformed inthose patients withanegative testin
theacute setting. Documentation ofsuccessful H.pylori eradication isrecommended (strong recommendation, highquality evidence).
36
ESGErecommends restarting anticoagulant therapy following NVUGIH inpatients withanindication forlong-term anticoagulation. Thetiming for
resumption ofanticoagulation should beassessed onapatient bypatient basis. Resuming warfarin between 7and15daysfollowing thebleeding event
appears safeandeffective inpreventing thromboembolic complications formostpatients. Earlier resumption, within thefirst 7days,maybeindicated for
patients athighthrombotic risk(strong recommendation, moderate quality evidence).
37
Inpatients receiving lowdoseaspirin forprimary cardiovascular prophylaxis whodevelop peptic ulcer bleeding, ESGErecommends withholding aspirin, re-evaluating therisks/benefits ofongoing aspirin useinconsultation withacardiologist, andresuming lowdoseaspirin following ulcerhealing or
earlier ifclinically indicated (strong recommendation, lowquality evidence).
38
Inpatients receiving lowdoseaspirin forsecondary cardiovascular prophylaxis whodevelop peptic ulcerbleeding, ESGErecommends aspirin beresumedimmediately following indexendoscopy iftheriskofrebleeding islow(e.g.,FIIc,FIII). Inpatients withhighriskpeptic ulcer(FIa,FIb,FIIa,FIIb), early
reintroduction ofaspirin byday3after indexendoscopy isrecommended, provided thatadequate hemostasis hasbeenestablished (strong recommendation, moderate quality evidence).
Inpatients
39
receiving dualantiplatelet therapy (DAPT)whodevelop pepticulcerbleeding, ESGErecommends continuing lowdoseaspirin therapy. Early
cardiology consultation should beobtained regarding thetiming ofresuming thesecond antiplatelet agent (strong recommendation, lowquality evidence).
40Inpatients requiring dualantiplatelet therapy (DAPT) andwhohavehadNVUGIH, ESGErecommends theuseofaPPIasco-therapy
mendation, moderate quality evidence).
Riskstratification
(strong recom-
admission.Dischargedpatientsshouldbeinformedoftheriskofrecurrent
bleedingandbeadvisedtomaintaincontactwiththedischarginghospital
(strongrecommendation,moderatequalityevidence).
Riskstratification ofpatientspresenting withacuteUGIHcanas-
ESGErecommendstheuseofavalidatedriskstratificationtooltostratifypatientsintohighandlowriskgroups.Riskstratificationcanaidclinicaldecision sistinidentifying thosewhomayrequiremoreurgentintervenmakingregardingtimingofendoscopyandhospitaldischarge(strongretion and help triage patients to in-hospital vs. out-of-hospital
commendation,moderatequalityevidence).
management. A number of scoring tools have been created for

predicting outcomes following acute UGIH, with the Glasgow-
Blatchford Score (GBS) "( Table2) and Rockall score being the
ESGErecommendstheuseoftheGlasgow-BlatchfordScore(GBS)forpreendoscopyriskstratification.Outpatientsdeterminedtobeatverylowrisk, mostwidelyevaluatedandadopted[1719].However,nosingle
baseduponaGBSscoreof01,donotrequireearlyendoscopynorhospital
scoring tool has been shown to excel at predicting all relevant
a6 Guideline
Table2 Glasgow-Blatchford Score(GBS).

Points
Systolic blood pressure, mmHg
100109
90 99
<90
Blood ureanitrogen, mmol/L
6.57.9
1
2
3
8.09.9
2
3
10.024.9
25.0
4
6
Hemoglobinformen,g/dL
12.012.9
10.011.9
<10.0
Hemoglobin forwomen, g/dL
10.011.9
1
3
6
Pre-endoscopymanagement
Initialmanagementofantithromboticagents
(anticoagulantsandantiplateletagents)
ForpatientstakingvitaminKantagonists(VKAs),ESGErecommendswithholdingtheVKAandcorrectingcoagulopathywhiletakingintoaccountthe
patientscardiovascularriskinconsultationwithacardiologist.Inpatients
withhemodynamicinstability,administrationofvitaminK,supplemented
withintravenousprothrombincomplexconcentrate(PCC)orfreshfrozen
plasma(FFP)ifPCCisunavailable,isrecommended(strongrecommendation,
lowqualityevidence).
Iftheclinicalsituationallows,ESGEsuggestsaninternationalnormalizedratio
(INR)value<2.5beforeperformingendoscopywithorwithoutendoscopic
hemostasis(weakrecommendation,moderatequalityevidence).
GI bleeding represents a serious complication of VKA therapy,

with an incidence of 1%4% per year [29,30]. Discontinuation
of anticoagulants and correction of coagulopathy before endos<10.0
copyisthe standard ofpracticeinpatients with clinically sigOtherriskvariables
Pulse100
1
nificant GI bleeding [3133]. Because data are limited, specific
1
Melena
strategies to reverse VKAs in a patient with acute overt UGIH
2
Syncope
vary [34]. Practice guidelines recommend urgent reversal in all
2
Hepatic disease
patients presenting with serious, life-threatening bleeding (i.e.,
Cardiac failure
2
hemodynamic instability or shock), either in the case of theraTOTALGBS__________________
peutic or supratherapeutic INR elevations [32,35]. For patients
GBSrestrictedforuseonlyinnonhospitalized,ambulatorypatients
who are not actively bleeding and are hemodynamically stable,
Riskvariablesmeasuredattimeofpatientpresentation
intravenous vitamin K administration may be an option. When
GBS=01denoteslow-risk
moreurgent reversalisrequired, administration ofprothrombin
complexconcentrates (PCCs)orfreshfrozenplasma(FFP)isnecoutcomes inacute UGIH (e.g.,rebleeding, need forintervention, essary,withconcomitant intravenousadministration of510mg
mortality) [19]. This isnot surprising asthe most validated risk vitamin K to prevent rebound coagulopathy once the transscores were derived to assess aspecific UGIH outcome: that for fused factors have been cleared. Prothrombin complex concentheRockallscorebeingmortality andfortheGBSbeingtheneed
tratescontainclottingfactorsprepared frompooledandconcenforintervention [17,18].
tratedhuman plasma andarepreferred overFFPbecause ofsevArecent systematic review evaluating theaccuracy ofthe avail- eral advantages, including no need to check the patient s blood
ableUGIHriskstratification toolsdemonstrated substantial het- group, lessrisk for volume overload because ofsmaller transfuerogeneity inpredictedoutcomesandhighlightedthatmethodo- sion volume, faster onset ofaction, similar thrombotic risk prologicalqualityoftheprediction scoreswaslessthanoptimal[19].
file,andminimalriskofinfectioustransmission, albeitatahigher
Regarding theneed forintervention, retrospective and prospec- cost[3640].Arecentprospective,nonrandomized, comparative
tivestudieshaveassessedtheprognostic valueoftheGBSvs.the studyof40warfarinuserswhopresented withUGIHandanINR
Rockallscore.Thesestudies showedthattheGBScorrectly iden- >2.1reportedthatpatientswhoreceivedPCChadanearnormaltified 98%(95%CI89%100%)ofthose patients whodidnotre- izedINRat2hoursfollowinginfusion(INR=1.5)whilethosewho
quireanysubsequent intervention while83%(95%CI71%91%) receivedFFPhadanINRof2.4at6hoursfollowinginfusion
[38].
of those patients were identified using the Rockall score. Ran- No patient in the PCC group had active bleeding at endoscopy
domized controlled trials andobservational studies consistently compared with 7inthe FFP group (0 vs. 35%, P<0.01). The risk
indicate thatclinical, endoscopic, andsocialfactors mayidentify of thrombosis following PCC administration approximates 1%,
patients who may be safely discharged for outpatient manage- andissimilar tothatreported withFFP[39,40].
ment [2028]. The most frequent adverse event reported isrebleedingrangingbetween0.5%and4%,withnodeathsorhospiESGErecommendstemporarilywithholdingnewdirectoralanticoagulants
talreadmissions forsurgery reported. Moreover,studies consis- (DOACs)inpatientswithsuspectedacuteNVUGIHincoordination/consultatently indicate thatoutpatient management ofappropriately se- tionwiththelocalhematologist/cardiologist(strongrecommendation,very
lowqualityevidence).
lectedpatientswithacuteUGIHreducesresourceutilization [20,
21,27]. Emergency department discharge without inpatient AsanalternativetoheparinandVKAs,thenewnon-VKAoralanendoscopy (i.e., outpatient management) should be considered ticoagulants(NOACs;alsoreferredtoasdirectoralanticoagulants
for patients if: systolic blood pressure 110mmHg, pulse <100 [DOACs]) are being rapidly adopted worldwide, primarily for
beats/minute, hemoglobin 13.0g/dL for men or 12.0g/dL for thromboembolic prevention in patients with nonvalvular atrial
fibrillation and for prophylaxis or treatment of venous thromwomen,bloodureanitrogen<18.2mg/dL,alongwiththeabsence
ofmelena,syncope,hepaticdisease,andcardiacfailure[18].(See boembolism [41]. These pharmacological agents do however,
presentariskofsignificant GIbleeding similar toorgreaterthan
Appendix e2 ,online-only.)
that reported with warfarin [42,43]. Moreover, DOACs differ in
comparison with heparin and VKA. Specifically, in the absence
of renal or hepatic failure, DOAC clearance and the subsequent
1
6
Guideline a7
Acute upper GI hemorrhage in a patient using antiplatelet agent(s)

(APA)
Upper GI endoscopy demonstrates a nonvariceal source of bleeding (e.g. peptic ulcer
bleed)
High risk endoscopic stigmata identified
(FIa, FIb, FIIa, FIIb)
APA used for primary prophylaxis

Withhold low dose acetylsalicylic acid
(ASA)
Re-evaluate risks and benefits of
ongoing low dose ASA use
Resume low dose ASA after ulcer
healing or earlier if clinically
indicated
Fig.1 Algorithm forthemanagement ofpatients

withacuteuppergastrointestinal hemorrhage who
areusingantiplatelet agent(s): European Society of
Gastrointestinal Endoscopy (ESGE)Guideline.
Low risk endoscopic stigmata identified

(FIIc, FIII)
APA used for primary prophylaxis

Withhold low dose ASA
Re-evaluate risks and benefits of
ongoing low dose ASA use
Resume low dose ASA at hospital
discharge if clinically indicated
APA used for secondary prophylaxis

APA used for secondary prophylaxis
(known cardiovascular disease)
(known cardiovascular disease)
1 Patients on low dose ASA alone
1 Patients on low dose ASA alone
Resume low dose ASA by day 3 following
Continue low dose ASA without interruption
index endoscopy
2 Patients on dual antiplatelet therapy (DAPT)
Second-look endoscopy at the discretion of Continue DAPT without interruption
the endoscopist may be considered
2 Patients on dual antiplatelet therapy (DAPT)
For patients using a non-ASA APA as
Continue low dose ASA without interruption
monotherapy
Early cardiology consultation for
(e.g., thienopyridine alone), low-dose ASA may
recommendation on resumption/
be
continuation of second APA
given as substitute for interval period in patients
Second-look endoscopy at the discretion of
with no contraindication or allergy to ASA.
the endoscopist may be considered
Early cardiology consultation should be obtained
for further APA recommendations.
lossofanticoagulation effect israpid and predictable (occurring antagonist thatinhibits thrombin. Theminimum duration ofangradually over 1224 hours), routine laboratory tests are not tiplateletagentdiscontinuation thatallowsforrestorationofnorsensitive for the quantitative assessment of their anticoagulant malplateletaggregation is57days[52].
activity,andthereiscurrentlynospecificreversalagent/antidote
Studies haveshown that inpatients taking low dose aspirin for
foremergency usewithanyDOAC,although potentialagentsare secondary cardiovascular prophylaxis, all-cause mortality was
in development and may be commercially available in the next lower if aspirin was not discontinued following peptic ulcer
12years [4446]. As there are no published clinical trials ad- bleeding [53,54]. In an RCT, 156 recipients of low dose aspirin
dressingthemanagement ofGIbleeding inpatients usingDOAC, for secondary prophylaxis who had peptic ulcer bleeding were
currentrecommendations arebasedonexpertopinionorlaborarandomized toreceive continuous aspirin or placebo [53]. At8toryend-points [4749].
week follow up, all-cause mortality was lower in the patients
At the time of patient presentation with acute UGIH, DOACs
randomized to aspirin compared with placebo (1.3% vs. 12.9%,
should be temporarily withheld. Given their relatively short
95%CI 3.7%19.5%; hazard ratio [HR] 0.20), with the difference
half-life, time is the most important antidote against DOACs.
being attributable tocardiovascular, cerebrovascular, orGIcomStrategies to accelerate anticoagulation reversal are supported plications. The30-dayulcerrebleeding ratewasnotsignificantly
only by data collected from healthy human volunteers, animal greater intheaspirin group.Patients who required dualantiplamodels, andinvitrostudies [50].Basedonthosedata,vitamin K telettherapy (DAPT) were excluded from this study. InasubseorFFP haveno place asreversal agents forDOACs. Prothrombin quent retrospective analysis that included 118 low dose aspirin
complexconcentrates oractivated PCCmaybeconsidered inpa- recipientswhohadbeentreatedforpepticulcerbleedingandfoltientswithsevereorlife-threatening bleeding, andhemodialysis lowed-up foramedian of2years,47(40%)patients stopped ascanbeusedtoreducethebloodconcentration ofdabigatran, but pirin[54].Patientswhodiscontinued aspirinandthosewhoconnot that of rivaroxaban and apixaban which are more tightly
tinued aspirin had similar mortality rates (31%). However, in a
boundtoplasmaproteins[48,49,51].Additionaldataontheclinsubgroup analysis limited to patients with cardiovascular coical effectiveness ofthese strategies inacutely bleeding patientsmorbidities, those patients who discontinued aspirin had analareurgentlyneeded.
mostfourfoldincreaseintheriskofdeathoracutecardiovascular
event (P<0.01) [54]. Randomized controlled trials have shown
that neither aspirin nor clopidogrel use impede ulcer healing
Forpatientsusingantiplateletagents,ESGErecommendsthemanagement
promoted byprotonpumpinhibitors (PPI)[55,56].
evidence).
algorithmdetailedin
"
Fig.1(strongrecommendation,moderatequality
Pharmacologicaltherapy
Antiplatelet agentsincludelowdoseaspirin andthienopyridines

(e.g., clopidogrel, prasugrel, ticlopidine) that irreversibly inhibit
ESGErecommendsinitiatinghighdoseintravenousprotonpumpinhibitors
platelet aggregation, ticagrelor a reversible P2Y12 receptor an- (PPI),intravenousbolusfollowedbycontinuousinfusion(80mgthen8mg/
tagonist, and vorapaxar, a protease-activated receptor (PAR-1) hour),inpatientspresentingwithacuteUGIHawaitingupperendoscopy.
a8 Guideline
However,PPIinfusionshouldnotdelaytheperformanceofearlyendoscopy mucosa visualization (OR 3.43, 95%CI 1.816.50; P<0.01), and
(strongrecommendation,highqualityevidence).
decreased the need for second-look endoscopy (OR 0.47, 95%CI

A Cochrane meta-analysis of 6 RCTs (n=2223 patients) showed 0.260.83,P=0.01),RBCunitstransfused (weightedmeandifferthatadministering PPIsbeforeendoscopy significantly decreasesence0.41,95%CI0.82to0.01,P=0.04),anddurationofhospitheincidence ofhighriskstigmata ofhemorrhage atthetime of tal stay (weighted mean difference 1.51 days, 95%CI 2.45 to
index endoscopy (37.2% vs. 46.5%; OR 0.67, 95%CI 0.540.84) 0.56,P<0.01)[68].
and the need for endoscopic hemostasis (8.6% vs. 11.7%; OR A single intravenous dose oferythromycin issafe and generally
0.68,95%CI0.500.93),buthasnoeffectonrebleeding,
needfor welltolerated,withnoadverseeventsreported inthemeta-anasurgery,ormortality [57].
lyses.Studiesthatfoundasignificant improvementinendoscopic
Costeffectiveness studies suggest that high dose PPI infusion visualization withpre-endoscopic erythromycin infusion includprior toendoscopy forpatients with UGIH ismore effective and edpatients admitted tothe intensive care unit because ofUGIH
lesscostlythanplacebo[58,59].(SeeAppendix e3 ,online-only.) withclinicalevidenceofactivebleedingorhematemesis orblood
seenonnasogastric lavage.Thesepatientsaremostlikelytobenefit from erythromycin infusion prior toendoscopy. Thedose of
ESGEdoesnotrecommendtheuseoftranexamicacidinpatientswithNVUerythromycin most commonly used is250mgand isinfused 30
GIH(strongrecommendation,lowqualityevidence).
to120minutespriortoupperGIendoscopy.Acosteffectiveness
Tranexamic acid reduces clotbreakdown byinhibiting thefibri- study found that pre-endoscopy erythromycin infusion inUGIH
nolytic action of plasmin. A recent RCT demonstrated that tra- was cost-effective, primarily due to a reduction in the need for
nexamicacidsignificantly reducesbleeding-related andall-cause second-look endoscopies [69]. Contraindications to erythromymortality intraumapatientswithsignificant hemorrhage [60].A cin administration include sensitivity to macrolide antibiotics
Cochrane meta-analysis evaluating theuseoftranexamic acidin andprolonged QTinterval.
1654UGIHpatientsshowedabeneficialeffectoftranexamic
acid Metoclopramide has been less studied, it has been assigned a
blackboxwarningbytheUnitedStatesFoodandDrugAdminon mortality when compared with placebo (relative risk [RR]
0.61, 95%CI 0.420.89), but not on other patient outcomes in- istration because of the riskof neurologic side effects, and caution should therefore be advised with the use of this prokinetic
cluding bleeding, surgery, or transfusion requirements [61].
However,thebeneficialeffectonmortality didnotpersistinsub- agent.
group analysis. The studies included in this meta-analysis have (SeeAppendixe6 ,online-only.)
important limitations that affect their generalizability including
theirmethodological qualityandthefactthatthemajority were Roleofgastriclavageandprophylacticendotracheal
conducted before the widespread use of therapeutic endoscopyintubation
andPPIs.Todate,nocontrolled trialassessingtheroleofalternativeantifibrinolytic agents(e.g.,aminocaproic acid,aprotinin) in
ESGEdoesnotrecommendtheroutineuseofnasogastricororogastricaspatients with acute UGIH has been reported. (See Appendix e4, piration/lavageinpatientspresentingwithacuteUGIH(strongrecommendation,moderatequalityevidence).
online-only.)
A number of studies, including a meta-analysis, have evaluated
the role of nasogastric aspiration/lavage in patients presenting
withacuteUGIH[7073].Indistinguishing upperfromlowerGI
bleeding, nasogastric aspiration has low sensitivity 44% (95%CI
Somatostatin, and its analogue octreotide, inhibit both acid and39%48%)yethighspecificity 95%(95%CI90%98%).Inidentipepsin secretion while also reducing gastroduodenal mucosal fying severe UGIH, itssensitivity and specificity are 77%(95%CI
blood flow [62]. However,theyare not routinely recommended 57%90%) and 76% (95%CI 32%95%), respectively [70]. This
inNVUGIH (e.g.,peptic ulcerbleeding), either pre-endoscopy or meta-analysis alsofoundthatascompared tonasogastric aspiraas an adjunctive therapy post endoscopy, since published data tion/lavage, clinical signsandlaboratory findings (e.g.,hemodyshow little or no benefit attributable to these pharmacological namicshockandhemoglobin <8g/dL)hadsimilarabilitytoidenagents.(SeeAppendix e5 ,online-only.)
tify severe UGIH [70]. Others havereported that nasogastric aspiration/lavage failed to assist clinicians in correctly predicting
the need for endoscopic hemostasis, did not improve visualizaESGErecommendsintravenouserythromycin(singledose,250mggiven30
120minutespriortoupperGIendoscopy)inpatientswithclinicallysevereor tion of thestomach atendoscopy, or improve clinically relevant
ongoingactiveUGIH.Inselectedpatients,pre-endoscopicinfusionoferyoutcomes such as rebleeding, need for second-look endoscopy,
thromycinsignificantlyimprovesendoscopicvisualization,reducestheneed
orbloodtransfusion requirements [7173].Italsoshouldbenoforsecond-lookendoscopy,decreasesthenumberofunitsofbloodtransfused,andreducesdurationofhospitalstay(strongrecommendation,high ted that nasogastric aspiration/lavage is a very uncomfortable
qualityevidence).
procedure thatisnotwelltoleratedordesiredbypatients [74].
ESGEdoesnotrecommendtheuseofsomatostatin,oritsanalogueoctreotide,inpatientswithNVUGIH(strongrecommendation,lowqualityevidence).
Ithasbeenreported thatin3%to19%ofUGIHcases,noobvious
causeofbleedingisidentified [63,64].Thismayinpartberelated
tothepresence ofblood andclotsimpairing endoscopic visualization. There are four published meta-analyses evaluating the
role ofprokinetic agent infusion prior toupper GIendoscopy in
patientspresenting withacuteUGIH[6568].Themostrecently
published meta-analysis (n=558patients) showedthaterythromycininfusion prior toendoscopy significantly improvedgastric
Inanefforttoprotectthepatientsairwayfrompotentialaspirationofgastric
contents,ESGEsuggestsendotrachealintubationpriortoendoscopyinpatientswithongoingactivehematemesis,encephalopathy,oragitation(weak
recommendation,lowqualityevidence).
Ithasbeenhypothesized thatpre-endoscopic endotracheal intubation mayprevent cardiorespiratory adverse eventsinpatients

with acute UGIH. However, between those patients who were
prophylactically intubated prior toupper GIendoscopy ascom-
Guideline a9
pared to those patients not intubated, published data show no

significant difference in patient outcomes (e.g., pulmonary aspiration, in-hospital mortality) [7577]. One study suggested
that aspiration was actually more frequent in those patients
who had undergone endotracheal intubation prior to upper GI
endoscopy [75]. At this time, endotracheal intubation prior to
upper GI endoscopy in patients with UGIH does not seem to
makeadifferenceinpatientoutcomebutpublished dataarelimited with small numbers of subjects and low methodological
quality.
without hospital admission facilitates discharge inupto46%of

patients andreduces costs/resource utilization [20,85].Discharginglowrisksuspected NVUGIH patients (GBS=0)directly from
theemergency department withoutundergoing upperGIendoscopyhasbeenproposedasasafeandcost-savingoptioninmultiplestudiesinvariousclinicalsettings [18,8689].Someinvesti-
"
gators havesuggested that using aGBS1(see
Table2 )could
double the number of patients eligible for ambulatory managementwhilemaintaining safety[89].
There arefourpublished studies, oneRCTandthree prospective
caseseries,thathaveevaluatedthetestcharacteristics andaccuracyparametersofvideocapsuleendoscopy(VCE)inriskstratifiTimingofendoscopy
cationofpatientspresenting withacuteUGIH[9093].Theoverallsensitivity, specificity, positive predictive value,andnegative
ESGErecommendsadoptingthefollowingdefinitionsregardingthetimingof
upperGIendoscopyinacuteovertUGIHrelativetopatientpresentation:very predictive valueofVCEfordetecting blood intheupper GItract
early<12hours,early24hours,anddelayed>24hours(strongrecommen- inpatients suspected ofacuteUGIHare75%,76%,67%,and82%
dation,moderatequalityevidence).
respectively.Becausethedataarelimited,atthistimethereisno
role forVCEinthe emergency department setting inevaluating
Followinghemodynamicresuscitation,ESGErecommendsearly(24hours)acuteupper GIH.However,additional studies areneeded tofurupperGIendoscopy.Veryearly(<12hours)upperGIendoscopymaybe
therassessVCEinthispatient population since,forlowtomodconsideredinpatientswithhighriskclinicalfeatures,namely:hemodynamic
erateriskUGIHpatients, VCEmaybeacost-effective modality if
instability(tachycardia,hypotension)thatpersistsdespiteongoingattempts
atvolumeresuscitation;in-hospitalbloodyemesis/nasogastricaspirate;or post-VCElowriskpatientsaredischargeddirectlyhomefromthe
contraindicationtotheinterruptionofanticoagulation(strongrecommenda-emergency department and hospital admission is avoided
tion,moderatequalityevidence).
[94,95].
ESGErecommendstheavailabilityofbothanon-callGIendoscopistproficientEndoscopicmanagement
inendoscopichemostasisandon-callnursingstaffwithtechnicalexpertisein Endoscopicdiagnosis
theuseofendoscopicdevicestoallowperformanceofendoscopyona24/7
basis(strongrecommendation,moderatequalityevidence).
ESGErecommendstheForrest(F)classificationbeusedinallpatientswith
Performance of upper GI endoscopy within 24 hours of patient pepticulcerhemorrhageinordertodifferentiatelowandhighriskendoscopic
stigmata(strongrecommendation,highqualityevidence).
presentation withsuspected NVUGIH andnocontraindication to
endoscopy has been proposed as a key quality indicator in the

management ofupper GIbleeding [78]. Inalarge European obESGErecommendsthatpepticulcerswithspurtingoroozingbleeding(Forrservational study thatincluded 123centers in7countries, there
estclassificationIaandIb,respectively)orwithanonbleedingvisiblevessel
(ForrestclassificationIIa)receiveendoscopichemostasisbecausetheselewaswidevariationinpracticewhereanywherefrom70%to93%
sionsareathighriskforpersistentbleedingorrebleeding(strongrecomof2660unselected patients withUGIHunderwent upperendosmendation,highqualityevidence).
copywithin24hoursofhospitaladmission [79].
TwosystematicreviewsevaluatingthetimingofupperGIendoscopy demonstrated improved risk assessment and reduction in ESGErecommendsthatpepticulcerswithanadherentclot(ForrestclassificationIIb)beconsideredforendoscopicclotremoval.Oncetheclotisremoved,
hospital length of stay if endoscopy was performed within 24
anyidentifiedunderlyingactivebleeding(ForrestclassificationIaorIb)or
hoursofpatientpresentation, yettheimpactonneedforsurgery
nonbleedingvisiblevessel(ForrestclassificationIIa)shouldreceiveendoandin-hospital mortality wasvariable [80,81].More recently,a
scopichemostasis(weakrecommendation,moderatequalityevidence).
retrospective analysis of risk factors for mortality in more than
400 000 patients with NVUGIH found an increased mortality in
Inpatientswithpepticulcershavingaflatpigmentedspot(Forrestclassificapatients who failed toreceive upper endoscopy within 1dayof
tionIIc)orcleanbase(ForrestclassificationIII),ESGEdoesnotrecommend
hospitaladmission (OR1.32,95%CI1.261.38)[82].(SeeAppenendoscopichemostasisasthesestigmatapresentalowriskofrecurrent
bleeding.Inselectedclinicalsettings,thesepatientsmaybedischargedto
dixe7 ,online-only.)
homeonstandardPPItherapy,e.g.,oralPPIonce-daily(strongrecommenWith respect tovery early upper GI endoscopy, an RCT that indation,moderatequalityevidence).
cluded 325 patients with peptic ulcer bleeding showed that upper GI endoscopy performed within 12 hours of admission (as The Forrest (F) classification wasdeveloped more than 40years
compared with1224hours) resulted inasignificant reduction ago in an attempt to standardize the characterization of peptic
intransfusion requirements inpatients with bloody nasogastric ulcers [96]. The Forrest classification is defined as follows: FIa
lavage (P<0.001). No such reduction was observed in patients spurting hemorrhage, FIb oozing hemorrhage, FIIa nonbleeding
withcoffeegroundsorclearlavage[83].Aretrospective
analy- visiblevessel,FIIbanadherent clot,FIIcflat pigmented spot,and
FIIIcleanbaseulcer[9799].Thisclassification hasbeenusedin
sisthatincluded 934UGIHpatients showedthatinthesubsetof
patientshavingaGBS12(n=97,10.4%),thetimelapsebetween numerous studies that aimed toidentify patients atriskof perpresentation toendoscopy wasthelone independent riskfactor sistent ulcer bleeding, rebleeding and mortality. Most of these
associatedwithall-causein-hospital mortality [84].Inthisstudy, studies haveshownthatthepresence ofanulcerendoscopically
acutoff time of13hours indelaytoendoscopy bestdiscrimina- classified asFIaorFIbisanindependent riskfactorforpersistent
bleeding or rebleeding [100107]. A potential limitation of the
tedbetweenpatientsurvival andnonsurvival.
Inpatientswhoarehemodynamically stableandwithoutserious Forrest classification isthat stigmata recognition and identificaco-morbidities, RCTs have shown that performing endoscopy
a10 Guideline
Performance of upper GI endoscopy

1
High risk stigmata

FIa (active
spurting)
FIIa (nonbleeding
visible
FIb (active oozing)
vessel)
Perform endoscopic
hemostasis
For FIa and FIb stigmata

Combination endoscopic therapy
using
dilute epinephrine injection plus
a second hemostasis modality
(contact
thermal , mechanical, or sclerosant )
FIIb (adherent clot)
Low risk stigmata

FIIc (flat pigmented
spot)
FIII (clean base)
Consider performing clot removal

followed
2
high risk
stigmata
by endoscopic
hemostasis
of underlying
OR
Medical management with high
dose
intravenous PPI
For FIIa stigmata
4
Contact thermal
, mechanical, or
injection of a sclerosant can be used
alone as monotherapy or in
combination
with dilute epinephrine injection
High dose intravenous PPI given as bolus + continuous

4
infusion;
twice-daily)
72 5
can considerfor
intermittent
intravenous bolus dosing (minimum
May
start clear liquids soon after
hours
endoscopy
Test for H. pylori, treat if positive
Document H. pylori eradication
No endoscopic hemostasis required

In select clinical settings, these patients
may
have expedited hospital discharge
Once daily oral PPI

Start regular diet
Test for Helicobacter pylori, treat if
positive
Document H. pylori eradication
If endoscopic hemostasis performed:

Dilute epinephrine injection circumferential to base of clot
followed by clot removal using cold polyp snare guillotine
technique
If underlying high risk stigmata identified after clot removal,
apply endoscopic hemostasis as described for FIa, FIb, FIIa
stigmata
If clinical evidence of ulcer rebleeding, repeat upper endoscopy with endoscopic hemostasis where
indicated
If hemostasis not achieved or recurrent rebleeding following second attempt at endoscopic
hemostasis,
Consider endoscopic salvage therapy with topical hemostatic spray/over-the-scope clip
Or refer for transcatheter angiographic embolization (TAE) or surgery
Fig.2 Algorithm fortheendoscopic management ofpatients withnonvariceal uppergastrointestinal hemorrhage (NVUGIH) secondary topepticulcer,stratifiedbyendoscopic stigmata: European Society ofGastrointestinal Endoscopy (ESGE)Guideline. GI,gastrointestinal; PPI,protonpumpinhibitor.
1Useofalargesingle-channel ordouble-channel therapeutic upperGIendoscope isrecommended.
2Thebenefitofendoscopic hemostasis maybegreaterinpatients athigherriskforrebleeding, e.g.,olderage,co-morbidities, in-hospital UGIH.
3Largesize10-Frproberecommended.
4Absolute alcohol,polidocanol, orethanolamine injected inlimitedvolumes.
5HighdoseoralPPImaybeanoptioninthoseabletotolerateoralmedications.
tion, aswellasinterobserver agreement, maybelessthan opti- recurrent ulcer bleeding and need for surgery in patients with
mal,althoughthedataareconflicting [108,109].
FIIaandFIIbulcers[113,114].
In addition to the Forrest classification, there are other endo- Theindication forendoscopic treatment ofFIIbulcers (adherent
scopicfeaturesofpepticulcersthatcanpredictadverseoutcomes clot)remainscontroversialbecauseofconflicting data.Inevaluaand/orendoscopic treatment failure.Theseincludelarge-size ul- tion of the natural history of FIIb ulcers (that did not receive
cer (>2cm), large-size nonbleeding visible vessel, presence of endoscopic hemostasis), it was found that 25% of patients reblood in the gastric lumen, and ulcer location on the posterior bled within 30daysof follow-up [115]. Inpatients with FIIb ulduodenal wall or the proximal lesser curvature of the stomach cers,RCTsandameta-analysis comparing medical therapyalone
[100,101,103,105,110,111].
with endoscopic hemostasis demonstrated a significant advanAmeta-analysis ofRCTsthatevaluatedendoscopichemostasis vs.tage for endoscopic hemostasis in reducing ulcer rebleeding
noendoscopic hemostasis demonstrated thatendoscopic hemo- (8.2%vs.24.7%,P<0.01, yetthere wasnodifference inneed for
stasiswaseffectiveinpreventingpersistentorrecurrentbleeding surgery or mortality [116118]. In contrast, in a separate RCT,
in actively bleeding ulcers (FIa, FIb: RR 0.29, 95%CI 0.200.43; Sung and colleagues reported no ulcer rebleeding in those panumber needed totreat[NNT] 2,95%CI22)aswellasinulcers
tients with adherent clots who received medical therapy alone;
with a nonbleeding visible vessel (FIIa: RR 0.49, 95%CI 0.40 however the numbers of such patients in the trial were quite
0.59;NNT5,95%CI46)[112].
limited (n=24) [113]. Moreover, ameta-analysis restricted only
" Fig.2presentsanalgorithmfortheendoscopicmanagement of toRCTsshowednobenefit forendoscopic hemostasis inpatients
bleeding pepticulcer,stratified byendoscopic stigmata.
with anadherent clot(RR 0.31, 95%CI0.061.77) [112].
With respect to the incremental benefit of acid suppression in Inpatients withpeptic ulcershavingaflat pigmented spot(FIIc)
addition to endoscopic hemostasis, an RCT and a subsequent or clean base (FIII), rebleeding is rare and therefore endoscopic
meta-analysis foundaclearadvantageforendoscopichemostasis hemostasis doesnotprovideasignificant advantage[9799].
combined withPPItherapyoverPPItherapyalone inpreventing
Guideline a11
tivethannoendoscopic hemostasis inachieving primary hemostasis(RR11.7,95%CI5.226.6),reducingrecurrentbleeding(RR

0.44, 95%CI 0.360.54; NNT=4), need for urgent surgery (RR
0.39, 95%CI 0.270.55; NNT=8) and mortality (RR 0.58, 95%CI
Thepersistence ofapositiveDopplersignalfollowingendoscopic 0.340.98) [112]. With respect to noncontact thermal therapy
hemostasis hasbeen shown topredict recurrent bleeding [119]. (e.g., argon plasma coagulation), limited data from three small
The results ofavailable studies havebeen disparate and limited RCTs suggest it is similar in efficacy to injection of a sclerosing
bytheirmethodology, olderendoscopic treatments applied, and agent (polidocanol) or contact thermal therapy (heater probe)
small numbers of subjects included; thus there is currently no [112].
consensus astotheadvantagefortheroutine useofDoppler ul- Mechanical therapy using through-the-scope clips wasfound to
trasound inpatents with NVUGIH [120123]. Acost-minimizabesuperior toinjection monotherapy infouroffivemeta-analytion analysis did however demonstrate per-patient cost savings ses[112,126,137,139,142].Mechanical therapysignificantly rewith use of Doppler ultrasound in patients with peptic ulcer
duced the risk of recurrent bleeding by 78% (RR 0.22, 95%CI
0.090.55)[112].Compared withthermal coagulation, mechanbleeding [124].
With respect to magnification endoscopy, one study suggested ical therapy provided no significant improvement in definitive
hemostasis (RR 1.00, 95%CI 0.771.31) [137]. However,a sepathatFIIaulcers canbeclassified aslowriskorhighriskandthat
some visible vessels classified as low risk using conventional ratemeta-analysis [126]foundthrough-the-scope clipstobesigendoscopy can be reclassified as high risk using magnification nificantly more effective than thermal therapy in reducing the
endoscopy [125]. However,the classification used has not been riskofrecurrent bleeding (OR0.24,95%CI0.060.95).Twosmall
validated andnoclinical benefit ofthisapproach hasbeendem- studies from Japan compared the efficacy ofclips versus hemoonstrated.
staticforceps[143,144].ThefirstwasanRCTconductedin96patientswithhighriskbleeding gastric ulcersandshowedthatuse
Endoscopictherapy
of monopolar, soft coagulation hemostatic forceps was as effectiveasclipping [143].Thesecondwasanobservational prospective cohort study on 50 patients inwhich use of bipolar hemoForpatientswithactivelybleedingulcers(FIa,FIb),ESGErecommendscomstatic forceps was more effective than endoscopic clipping for
biningepinephrineinjectionwithasecondhemostasismodality(contact
thermal,mechanicaltherapy,orinjectionofasclerosingagent).ESGEreboth initial hemostasis (100% vs. 78.2%) and preventing recurcommendsthatepinephrineinjectiontherapynotbeusedasendoscopic
rent bleeding (3.7% vs. 22.2%) [144]. Unlike thermal therapies
monotherapy(strongrecommendation,highqualityevidence).
and sclerosing agents, mechanical therapy using clips has the
theoretical benefit of inducing only limited tissue injury, and
Forpatientswithnonbleedingvisiblevessel(FIIa),ESGErecommendsme- thereforemaybepreferredinpatientsonantithrombotic therapy
chanicaltherapy,thermaltherapy,orinjectionofasclerosingagentas
andthosepatients undergoing repeatendoscopic hemostasis for
monotherapyorincombinationwithepinephrineinjection.ESGErecommendsthatepinephrineinjectiontherapynotbeusedasendoscopicmono- rebleeding. Amultidisciplinary expert paneldevelopedanexplitherapy(strongrecommendation,highqualityevidence).
cit set of evidence-based quality indicators for NVUGIH [78].
Amongthem,itwasfeltthatpatientswithulcer-relatedbleeding
with highrisk stigmata and elevatedINR (>1.52.0), should reForpatientswithactiveNVUGIHbleedingnotcontrolledbystandardendoscopichemostasistherapies,ESGEsuggeststheuseofatopicalhemostatic ceiveendoscopic hemostasis using endoscopic clips oracombisprayorover-the-scopeclipassalvageendoscopictherapy(weakrecomnationofepinephrine injectionplusclips.
mendation,lowqualityevidence).
Meta-analyses haveshown that combination endoscopic hemoEndoscopic hemostasis canbeachievedusinginjection, thermal, stasistherapy(diluteepinephrine injectioncombinedwithasecandmechanical modalities (seeBox1),andanyendoscopic ther- ond hemostasis modality including injectable, thermal contact
apyissuperior topharmacotherapy inpatients withFIa,FIband
probe, orclips) issuperior toinjection therapy alone, but notto
FIIa ulcers [112,126]. Meta-analyses show that thermal devices clips orcontact thermal therapy alone [126,139]. There may be
(contact and noncontact), injectable agents other than epine- practical reasons to pre-inject dilute epinephrine before other
phrine (i.e., sclerosing agents, thrombin/fibrin glue), and clips therapies for high risk endoscopic stigmata. Injection of epinearealleffectivemethodsforachievinghemostasis, withnosingle phrine may slow or stop bleeding allowing improved visualizamodality beingsuperior [112,126,137141].
tion forapplication ofsubsequent therapy.Adverse eventsassoEpinephrine injection therapy is effective at achieving primary ciatedwith combination endoscopic hemostasis arelowand inhemostasis, but inferior to other endoscopic hemostasis mono- clude induction ofbleeding (1.7%)and perforation (0.6%)[139].
therapies orcombination therapyinpreventing ulcerrebleeding Recent international consensus guidelines endorse combination
[112,126,139].Inthemostrecentlypublished meta-analysis (19 therapy (dilute epinephrine injection combined with contact
RCTs, 2033 patients), epinephrine plus any second hemostasis thermal therapy,clips,orinjection ofasclerosant [e.g.,absolute
ethanol]) asappropriate treatment inpatients with peptic ulcer
modality significantly reduced rebleeding (OR 0.53, 95%CI
0.350.81) and emergency surgery (OR 0.68, 95%CI 0.500.93) bleeding withhighriskendoscopic stigmata[98,99,145].
butnotmortalityascomparedwithepinephrine injectionmono- New endoscopic hemostasis modalities (topical hemostatic
therapy forhigh risk peptic ulcers [140]. Therefore, it is recom- sprays and over-the-scope clips) are emerging aspossible altermended thatifepinephrine isusedtotreatpepticulcerbleeding
native endotherapies for primary hemostasis when bleeding is
with high risk stigmata, it should only be used in combination refractory or not amenable to standard endoscopic hemostasis
withasecondendoscopic hemostasis modality [9799,141].
therapies [136,146].Moreover,several small retrospective studWithrespecttocontactthermaltherapy(e.g.,bipolarelectrocoaies have reported that an over-the-scope clip (OVESCO), may
gulation, heater probe), a meta-analysis restricted only to RCTs have a role as rescue hemostasis therapy for severe NVUGIH
foundthatcontact thermal therapywassignificantly moreeffec- when conventional endoscopic treatment modalities fail [133,
ESGEdoesnotrecommendtheroutineuseofDopplerultrasoundormagnificationendoscopyintheevaluationofendoscopicstigmataofpepticulcer
bleeding(strongrecommendation,lowqualityevidence).
a12 Guideline
134,147]. An inert nanopowder (Hemospray) that causes im- studies[164,167,168].Mechanicaltherapyappearstobesafe,yet
mediate hemostasis when sprayed onto active bleeding [136, dataareinsufficient tomakeaclearrecommendation ofonehe148]hasrecently beenusedasaprimary hemostasis agentoras mostasis modality overanother[164,167,169,170].
a second-line salvage therapy. Several prospective uncontrolledTheproximal stomach andduodenum arethemostcommon locationsforDieulafoylesions[171].Endoscopichemostasisiswarstudies,alargeEuropeanregistry[149154]andasystematicreviewofthecurrent limited datasuggests thatHemospray issafe rantediftechnicallyfeasible.Observational studieshavereported
the superiority of combined, thermal and mechanical methods
andeffectiveandmaybebestusedinhighriskcasesasatemporizing measure or a bridge toward more definitive treatment
over injection monotherapy, in achieving primary hemostasis,
[136]. Other topical agents, such as the starch-derived polysac-preventing rebleeding, andinreducing theneedforrescuethercharide hemostatic system (EndoClot) and the Ankaferd blood apy,yet with no proven mortality benefit [172180]. All endostopperarealsoemerging [136].However,RCTsdirectlycompar- scopic hemostasis modalities (e.g., band ligation, through-theing topical agents with traditional hemostasis methods are re- scope clips, over-the-scope clips, contact thermal coagulation,
and argon plasma coagulation) appear safeand havesimilar requiredtobetterdefinetheiroptimal roleandsafetyintheendoscopicmanagement ofNVUGIH.
ported outcomes [171180]. Selective TAE has been described
as an effective rescue therapy if endoscopic hemostasis fails or
in patients who are poor surgical candidates [181, 182]. If both
Forpatientswithacid-relatedcausesofNVUGIHdifferentfrompepticulcers
endoscopic and angiographic therapies fail, surgery should be
(e.g.,erosiveesophagitis,gastritis,duodenitis),ESGErecommendstreatment
withhighdosePPI.Endoscopichemostasisisusuallynotrequiredandselect- considered.
edpatientsmaybedischargedearly(strongrecommendation,lowquality
Studiesonendoscopic hemostasis therapyofangioectasias ofthe
evidence).
upperGItractareobservational andincludeonlyalimitednumber ofsubjects. Intwo recent meta-analyses, endoscopic hemoESGErecommendsthatpatientswithaMalloryWeisslesionthatisactively stasis therapy (e.g., argon plasma coagulation, heater probe, bibleedingreceiveendoscopichemostasis.Thereiscurrentlyinadequateevipolarcoagulation, monopolar coagulation, bandligation, YAGladencetorecommendaspecificendoscopichemostasismodality.Patients
withaMalloryWeisslesionandnoactivebleedingcanreceivehighdosePPI ser)isreported tobeinitiallyeffective andsafe,yetbleeding retherapyalone(strongrecommendation,moderatequalityevidence).
currence ratesaresignificant [183,184].Giventhelowqualityof
evidenceandscarcityofcomparativedata,arecommendation on
a specific endoscopic hemostasis treatment is not permitted at
ESGErecommendsthataDieulafoylesionreceiveendoscopichemostasis
usingthermal,mechanical(hemocliporbandligation),orcombinationther- thistime.
apy(diluteepinephrineinjectioncombinedwithcontactthermalormechan- Therearelimitedpublisheddataontheroleofendoscopichemoicaltherapy)(strongrecommendation,moderatequalityevidence).Trans- stasisinbleedingduetoupperGItractneoplasiaandevidenceto
catheterangiographicembolization(TAE)orsurgeryshouldbeconsideredif
endoscopictreatmentfailsorisnottechnicallyfeasible(strongrecommen- support a specific modality is scarce [185188]. Numerous
dation,lowqualityevidence).
endoscopic hemostasis modalities (e.g., injection, thermal, mechanical, topical spray/powder) have been reported, generally
with limited impact on primary hemostasis, prevention of reInpatientsbleedingfromupperGIangioectasias,ESGErecommendsendoscopichemostasistherapy.However,thereiscurrentlyinadequateevidencebleeding,ormortality.However,endoscopic treatment mayavert
urgent surgery, reduce transfusion requirements, and may protorecommendaspecificendoscopichemostasismodality(strongrecommendation,lowqualityevidence).
vide a temporary bridge to oncologic therapy and/or selective
embolization [185188].
InpatientsbleedingfromupperGIneoplasia,ESGErecommendsconsidering
Managementfollowingendoscopy/
endoscopichemostasisinordertoaverturgentsurgeryandreduceblood
transfusionrequirements.However,nocurrentlyavailableendoscopictreat-endoscopichemostasis
mentappearstohavelong-termefficacy(weakrecommendation,lowquality
evidence).
ESGErecommendsPPItherapyforpatientswhoreceiveendoscopichemo-
Erosiveesophagitis, gastritis andduodenitis arecommon causes stasisandforpatientswithadherentclotnotreceivingendoscopichemostasis.PPItherapyshouldbehighdoseandadministeredasanintravenousbolus

of NVUGIH and generally have a benign course and excellent
followedbycontinuousinfusion(80mgthen8mg/hour)for72hourspost
prognosis [2,64,155158]. Meta-analyses show that acid supendoscopy(strongrecommendation,highqualityevidence)
pression therapy is effective, with high dose PPI therapy being
significantly moreeffectivethanH2-receptor antagonists andno
observed differences in effectiveness amongst PPIs [159,160]. ESGEsuggestsconsideringPPItherapyasintermittentintravenousbolus
dosing(atleasttwice-daily)for72hourspostendoscopyforpatientswhoreEndoscopic hemostasis is usually not required in this patient
ceiveendoscopichemostasisandforpatientswithadherentclotnotreceiving
population andselectedpatientsarecandidatesforearlyhospital
endoscopichemostasis.Ifthepatientsconditionpermits,highdoseoralPPI
mayalsobeanoptioninthoseabletotolerateoralmedications(weakredischarge.
Although spontaneous resolution ofbleeding isfrequent, obser- commendation,moderatequalityevidence).
vational studies have demonstrated that acute UGIH secondary Based upon previously published meta-analytic data, evidencebased guidelines on NVUGIH have recommended that PPI therto MalloryWeiss syndrome has a mortality similar to that of
peptic ulcer bleeding [161,162]. Risk factors for adverse out- apy be given as an 80mg intravenous bolus followed by 8mg/
comes include older age, medical co-morbidities, and active hourcontinuousinfusiontoreducerebleeding,surgery,andmortality in patients with high risk ulcers that had undergone sucbleeding at the time of endoscopy. The latter supports early
endoscopy tostratify riskandtoperform endoscopic hemostasis cessful endoscopic hemostasis [98,99,189,190]. More recently
if active bleeding is identified [162166]. Despite suggestions however, a meta-analysis of RCTs of high risk bleeding ulcers
that mechanical methods (clips and band ligation) are more ef- treated with endoscopic hemostasis compared intermittent PPI
dosing (oral or intravenous) with the currently recommended
fectivethanepinephrine injection, thishasnotbeenfoundinall
Guideline a13
posthemostasisPPIregimenof80mgintravenousbolusfollowed
and over-the-scope clips may also be considered as rescue/salby 8mg/hour continuous infusion [191]. In that meta-analysis, vage therapy. Although limited, emerging data suggest that heSachar etalreported thattheriskratioofrecurrent ulcerbleed- mostaticpowdermaybesuccessfullyemployedassalvagehemoing within 7 days for intermittent infusion of PPI vs. bolus plus stasistherapy[154,198].Theover-the-scope clip(OTSC)hasalso
continuous infusion ofPPIwas0.72 (upper boundary ofone-siproven aneffective and safetherapeutic option forsevere acute
ded95%CI0.97), withanabsolute riskdifference of2.64%.Risk GIbleeding whenconventional endoscopic treatment modalities
ratiosforotheroutcomes,includingradiologic/surgical interven- fail[134,147].
tionandmortality,showednodifferencesbetweeninfusionregi(SeeAppendixe9 ,online-only.)
mens. These meta-analytic data indicate that intermittent PPI
therapyappearscomparabletothecurrentlyrecommended regiESGEdoesnotrecommendroutinesecond-lookendoscopyaspartofthe
men of intravenous bolus plus continuous PPI infusion post
managementofNVUGIH.However,second-lookendoscopymaybeconsidendoscopic hemostasis. It should be noted however, that inter- eredinselectedpatientsathighriskforrebleeding(strongrecommendation,
highqualityevidence).
mittent PPI bolus dosing is associated with a somewhat higher
riskofrebleedingthatingeneralcanbemanagedendoscopically.
Routine second-look endoscopy isdefined asascheduled repeat
Giventhepharmacodynamic profileofPPIs,consideration should endoscopic assessment ofthe previously diagnosed bleeding lesion usually performed within 24 hours following the index
begiventouseofhighdosePPIinfusion givenatleasttwice-daily,and using highdose oral PPIsinpatients able totolerate oral endoscopy [98].Thisstrategy employsrepeatendoscopy regardmedications [191]. The concept ofhighdose PPIvaries between less of the type of bleeding lesion, perceived rebleeding risk, or
thedifferent studies usedinthemeta-analysis conducted bySa- clinicalsignsofrebleeding.Ameta-analysis thatevaluatedtheefchar et al. However, it appears that an 80mg oral PPI dose fol- fectivenessofroutinesecond-look endoscopyinNVUGIH reported a significant reduction in rebleeding (OR 0.55, 95%CI 0.37
lowedby4080mgorallyevery 12hoursfor72hours yieldsan
intragastric pHsimilar tothatreported withcontinuous intrave- 0.81) and need for emergency surgery (OR 0.43, 95%CI 0.19
nous PPIinfusion following successful endoscopic hemostasis of 0.96), butnotmortality (OR0.65,95%CI0.261.62)[199].However,onlyoneincluded study inthatmeta-analysis utilized high
highriskpepticulcers[192].Thisisbutonestudy,andtherefore
dose intravenous PPI, and in that study no benefit for secondweneedmoredatatoconfirmthesefindingsbeforedrawingfirm
practical conclusions forthepost-endoscopy management ofpa- look endoscopy was observed, while any protective effect was
tients with NVUGIH. These data are in agreement with an RCT limitedonlytohighriskpatients(e.g.,thosewithactivebleeding
that randomized patients to high dose continuous infusion of atindexendoscopy).Similarly,scheduledsecond-lookendoscopy
esomeprazole vs.40mgoforal esomeprazole twice-daily for72 doesnotappear tobecost-effective outside thesubgroup ofpahours(118vs.126patients respectively) [193].Recurrent bleed- tients thought to be at high risk for recurrent ulcer bleeding
ingat30dayswasreported in7.7%and6.4%ofpatients, respec- [200].Thus,theclinicalutilityandcostefficiency ofroutinesectively(difference 1.3 percentage points, 95%CI 7.7 to5.1 per-ond-lookendoscopyinunselectedpatientsremainstobeproven.
centage points). However,thisstudy wasconducted inanAsian
population (e.g.,PPIslowmetabolizers) anditsfindings maynot
InpatientswithNVUGIHsecondarytopepticulcer,ESGErecommendsinvesbegeneralizable toWesternNVUGIH populations. Moreover,this tigatingforthepresenceofHelicobacterpyloriintheacutesettingwithinitiastudy was stopped prematurely since it was not designed as an tionofappropriateantibiotictherapywhenH.pyloriisdetected.Re-testingfor
H.pylorishouldbeperformedinthosepatientswithanegativetestinthe
equivalency trial, and based onthe preliminary data, thousands acutesetting.DocumentationofsuccessfulH.pylorieradicationisrecomof patients would have been required in order to complete the mended(strongrecommendation,highqualityevidence).
study.(SeeAppendix e8 ,online-only.)
Peptic ulcer remains the most frequent cause of acute NVUGIH
withH.pyloriinfectionremaining theprimarycauseofpepticulInpatientswithclinicalevidenceofrebleedingfollowingsuccessfulinitial
endoscopichemostasis,ESGErecommendsrepeatupperendoscopywithhe-cer disease [201,202]. Indeed, when H. pylori is eradicated, the
mostasisifindicated.Inthecaseoffailureofthissecondattemptathemorisk of ulcer rebleeding is reported to be extremely low [203,
stasis,transcatheterangiographicembolization(TAE)orsurgeryshouldbe
204].However,thefalse-negative rateofH.pyloridiagnostictestconsidered(strongrecommendation,highqualityevidence).
ing is higher if the test is performed at the time of the acute
bleeding episode ascompared tolater follow-up [205]. AmetaAnRCTcomparingendoscopictherapywithsurgeryforrecurrent
pepticulcerbleedingaftersuccessfulinitialendoscopiccontrolof
regression analysisincluding8496bleeding pepticulcerpatients
bleeding showed that 35/48 (73%) of patients randomized to found an H. pylori prevalence of 72%, with the infection rate
endoscopic re-treatment had long-term control of their peptic being significantly higher when diagnostic testing was delayed
ulcerbleeding, avoided surgery, andhadalowerrateofadverse
untilatleast4weeksfollowingthebleedingevent(OR2.08,95%
eventsascomparedtothesurgery-treated patients[194].There- CI1.103.93;P=0.024)[206].Therefore,itisadvisable
tore-test
maining13patientsunderwent salvagesurgerybecauseoffailed atalatertimethosepatients whohadanegativeH.pyloritestin
repeatendoscopic hemostasis (n=11)orperforation duetocon- theacutesetting.
tactthermal therapy(n=2).
When H.pylori infection isfound,eradication therapyshould be
If further bleeding occurs following a second endoscopic treat- initiated and guided by patient and local factors [98,99]. Document, surgery for low risk patients or interventional radiology mentation of successful H. pylori eradication is strongly recomforhigh risk patients should be considered [195]. In recent sys- mended given the high risk of recurrent ulcer bleeding in the
tematic reviewsandmeta-analyses comparing TAEwithsurgery presence ofpersistent H.pylori infection [98,99]. (See Appendix
for peptic ulcer bleeding after failed endoscopic hemostasis, a e10 ,online-only.)
higher rebleeding rate was observed following TAE. No significantdifference inmortality orneed foradditional interventions
ESGErecommendsrestartinganticoagulanttherapyfollowingNVUGIHin
was shown between treatments [196,197]. Hemostatic powder patientswithanindicationforlong-termanticoagulation.Thetimingfor
a14 Guideline
resumptionofanticoagulationshouldbeassessedonapatientbypatientba- HR 1.9, 95%CI 0.66.0), yet a 10-fold reduced risk of all-cause
sis.Resumingwarfarinbetween7and15daysfollowingthebleedingevent
appearssafeandeffectiveinpreventingthromboemboliccomplicationsfor mortality at8weeks(1.3%vs.12.9%;difference 11.6percentage
mostpatients.Earlierresumption,withinthefirst7days,maybeindicatedfor points, 95%CI 3.719.5 percentage points; HR 0.2 95%CI 0.06
patientsathighthromboticrisk(strongrecommendation,moderatequality 0.60) and alower mortality rate related tocardiovascular, cereevidence).
brovascular,orgastrointestinal events(1.3%vs.10.3%;difference
Retrospective, observational datahaveshownthatresuming an- 9percentage points, 95%CI 1.716.3 percentage points; HR 0.2,
ticoagulation in patients with GI bleeding is associated with a 95%CI0.050.70),comparedwiththosepatientsinwhomaspirlower riskof thrombosis and death [207209]. Restarting war- inwaswithheld[53].PatientswhorequiredDAPTwereexcluded
farintherapywithin7daysoftheindexbleedingeventwasassofromthisstudy.Theantiplateleteffectofaspirinlastsforapproxiciatedwith anapproximately twofold increased riskofrebleedmately5days(although newactiveplateletsincrease innumber
ing[207,209]. Conversely,ascompared with resuming warfarin each day),and the riskofearly recurrent bleeding ishighinthe
beyond 30 days, resuming warfarin between 7 and 30 days did first3days[53].Therefore,restarting aspirinonday3inpatients
notincrease theriskofrebleeding, butdidsignificantly decrease with highriskendoscopic stigmata isareasonable trade-off betheriskofthromboembolism andimprovedsurvival[209].These tween the risks of rebleeding and thrombosis. In patients with
dataappeartosupportthatresumptionofanticoagulation after7 peptic ulcer bleeding with nohighriskendoscopic stigmata, asdays of interruption is safe and effective in preventing throm- pirin canberesumed immediately asRCTshaveshown thatneiboembolic complications formostpatients. However,inpatients ther aspirin norclopidogrel use impede ulcer healing promoted
athighthrombotic risk(e.g.,chronic atrial fibrillation with pre- byPPIs[53,55,56].Nohighlevelevidencehelpsguidethetiming
vious embolic event, CHADS2 score 3, mechanical prosthetic forresumptionofP2Y12plateletreceptorinhibitors(e.g.,clopidoheartvalve,recent[withinpast3months]deepvenousthrombogrel)followingNVUGIH. However,inviewofitssimilarantiplatesisorpulmonary embolism, andpatients withknownseverehy- let activity, it seems reasonable to apply a similar management
percoagulable state),forwhom earlyresumption ofanticoagula- strategy. Moreover,there isnoevidence intheliterature tohelp
tion within the first week following an acute bleeding event
guide themanagement ofpatients receiving DAPT inthesetting
might be appropriate, bridging therapy using unfractionated or of NVUGIH. The overriding principle of balancing bleeding and
lowmolecular weightheparin maybeconsidered [210].Nodata thrombotic event risks requires close collaboration between the
are currently available to guide the management of DOACs fol- gastroenterology andcardiology teams.
lowingNVUGIH. Yetcaution intheearlyresumption ofDOACsis
required because of their rapid onset of action and the current
Inpatientsrequiringdualantiplatelettherapy(DAPT)andwhohavehad
lackofreversalagents.(SeeAppendix 11 ,online-only.)
NVUGIH,ESGErecommendstheuseofaPPIasco-therapy(strongrecommendation,moderatequalityevidence.
Inpatientsreceivinglowdoseaspirinforprimarycardiovascularprophylaxis
whodeveloppepticulcerbleeding,ESGErecommendswithholdingaspirin, Dual antiplatelet therapy, combining low dose aspirin and a
re-evaluatingtherisks/benefitsofongoingaspirinuseinconsultationwitha P2Y12plateletreceptorinhibitor (e.g.,clopidogrel), isthecornercardiologist,andresuminglowdoseaspirinfollowingulcerhealingorearlierif
stoneofmanagement ofpatientswithacutecoronarysyndromes
clinicallyindicated(strongrecommendation,lowqualityevidence).See
andfollowingcoronarystentplacement,butisassociatedwithan
"
Fig.1.
increased riskofGIbleeding [215217].Protonpumpinhibitors

substantially reduce this risk and their use is recommended in
Inpatientsreceivinglowdoseaspirinforsecondarycardiovascularprophylaxis
patients with aprevious GIbleeding event [218220]. Pharmawhodeveloppepticulcerbleeding,ESGErecommendsaspirinberesumed
immediatelyfollowingindexendoscopyiftheriskofrebleedingislow(e.g., codynamic studies have shown that the co-administration of
FIIc,FIII).Inpatientswithhighriskpepticulcer(FIa,FIb,FIIa,FIIb),earlyrein- PPIswith clopidogrel reduces platelet inhibition, but theclinical
troductionofaspirinbyday3afterindexendoscopyisrecommended,
significance of this interaction has been extensively debated
providedthatadequatehemostasishasbeenestablished(strongrecommen[221225]. Previous meta-analyses suggest that concomitant
clopidogrelandPPIusemaybeassociatedwithincreasedadverse
dation,moderatequalityevidence).See " Fig.1.
cardiovascular eventsandmyocardialinfarction, butnoeffecton
Inpatientsreceivingdualantiplatelettherapy(DAPT)whodeveloppeptic
mortality [226,227].However,thepresenceofsignificant heteroulcerbleeding,ESGErecommendscontinuinglowdoseaspirintherapy.Early
cardiologyconsultationshouldbeobtainedregardingthetimingofresuming geneity inthe included studies indicates that this evidence isat
thesecondantiplateletagent(strongrecommendation,lowqualityevibest, inconsistent, and at worst, potentially biased or confoun"
dence).See
Fig.1.
ded. A recent meta-analysis included a subanalysis limited to

Discontinuing lowdoseaspirin therapy inthesetting ofsecond- RCTsandpropensity-matched studies evaluating theinteraction
ary cardiovascular prophylaxis significantly increases theriskof between PPIandclopidogrel; thesubanalysis showednosignifian adverse cardiovascular event, usually occurring within the cant differences between patients using clopidogrel alone and
first week of discontinuation [211214]. In a retrospective co- patients receiving the combination ofclopidogrel and aPPI(n=
hort study, patients with cardiovascular disease who discontin- 11 770) for all-cause mortality (OR 0.91, 95%CI 0.581.40; P=
ued low dose aspirin following peptic ulcer bleeding had an al- 0.66), acute coronary syndrome (OR 0.96, 95%CI 0.881.05; P=
mosttwofoldincreaseinriskfordeathoranacutecardiovascular
0.35), myocardial infarction (OR 1.05, 95%CI 0.861.28; P=
eventinthefirst6months afterhospital discharge, ascompared 0.65),andcerebrovascular accident (OR1.47,95%CI0.6603.25;
withpatientswhocontinuedaspirintherapy[54].InanRCTevalP=0.34)[228].Theincidence ofGIbleeding wassignificantly deuating continuous vs. interrupted aspirin treatment in patients creasedinthegroupofpatientswhoreceivedaPPI(OR0.24,95%
withhighriskpepticulcersandathighcardiovascular
risk,those CI 0.090.62; P=0.003). Current evidence does not support a
receivingcontinuous aspirinhadatwofoldincreasedriskofearly,
clinically relevantinteraction between PPIsandclopidogrel. (See
nonfatal, recurrent bleeding (10.3% vs. 5.4% at 4 weeks; differ- Appendices e12ande13 ,online-only.)
ence4.9percentagepoints,95%CI3.6to13.4percentagepoints;
Guideline a15
Box1Endoscopichemostasismodalities:aprimer
Injection therapy
Theprimary mechanism ofaction ofinjection therapyislocal
tamponade resulting from a volume effect. Diluted epinephrine (1:10 000 or 1:20 000 with normal saline injected in
0.52-ml aliquots in and around the ulcer base) may also
have a secondary effect that produces local vasoconstriction
[126]. Sclerosing agents such as absolute ethanol, ethanolamine, and polidocanol produce hemostasis bycausing direct
tissue injury and thrombosis. It should be noted that when
usingasclerosing agentinnonvariceal upper gastrointestinal
hemorrhage (NVUGIH), thevolumeinjectedshouldbelimited
becauseofconcernsabouttissuenecrosis,perforation, orpancreatitis. Anotherclassofinjectable agentsistissueadhesives
includingthrombin,fibrin,andcyanoacrylate glues,whichare
usedtocreateaprimary sealatthesiteofbleeding.
Endoscopic injection is performed using needles which consistofanoutersheath andaninnerhollow-core needle (19
25gauge).Theendoscopistornursingassistantcanretractthe
needle into the sheath for safe passage through the working
channeloftheendoscope. When thecatheter ispassed outof
theworkingchannelandplacednear thesiteofbleeding, the
needleisextendedoutofthesheathandthesolution
injected
into the submucosa using a syringe attached to the catheter
handle[126].
Thermal therapy
Thermal devicesusedinthetreatment ofuppergastrointestinal (UGI) bleeding are divided into contact and noncontact
modalities. Contact thermal devices include heater probes
which generate heat directly and bipolar electrocautery
probeswhichgenerateheatindirectlybypassageofanelectricalcurrentthroughthetissue.Noncontact thermaldevicesinclude argon plasma coagulation (APC) tools. Heat generated
fromthesedevices leadstoedema, coagulation oftissue proteins,contraction ofvessels,andindirect activation ofthecoagulation cascade,resulting inahemostatic bond[126,127].
Contact thermal probes use local tamponade (mechanical
pressureoftheprobetipdirectlyontothebleedingsite)combined with heat or electrical current to coagulate blood vessels,aprocessknownascoaptivecoagulation.Heaterprobes
(available in 7-Fr and 10-Fr sizes) consist of a Teflon-coated
hollow aluminum cylinder with an inner heating coil combinedwithathermocoupling deviceatthetipoftheprobeto
maintain aconstant energy output (measured injoules,commonly 1530 joules of thermal energy are delivered). An
endoscopist-controlled foot pedal activates the heater probe
and provides waterjet irrigation. Multipolar/bipolar electrocautery contact probes (7-Frand10-Fr sizes) deliver thermal
energybycompletion ofanelectrical localcircuit(nogrounding pad required) between two electrodes on the tip of the
probe as current flows through nondesiccated tissue. As the
targetedtissuedesiccates,thereisadecreaseinelectricalconductivity, limiting the maximum temperature, depth, and
area of tissue injury. An endoscopist-controlled foot pedal
controlsthedeliveryoftheenergy[127].Thestandardsetting
foruseinachievinghemostasis inpepticulcerbleedingis15
20 watts, which is delivered in 810-second applications
(commonly referredtoastamponade stations) [96].
APC, a noncontact thermal modality, uses high frequency,
monopolar alternating current conducted tothetarget tissue
through astream ofionized gas,without mechanical contact,

resulting incoagulation ofsuperficial tissue [128]. Asthetissuesurface loses itselectrical conductivity, theargon plasma
stream shifts to adjacent nondesiccated (conductive) tissue,
whichagainlimitsthedepthoftissue injury [126].IftheAPC
catheterisnotnearthetargettissue,thereisnoignitionofthe
gasanddepression ofthefootpedalresultsonlyinflowofinertargongas(flowratesof0.50.7L/min).Coagulation
depth
isdependent onthegenerator powersetting, duration ofapplication, anddistance fromtheprobe tiptothetarget tissue
(optimal distance,28mm)[129,130].
Mechanical therapy
Endoscopic mechanical therapies include clips (through-thescope and over-the-scope) and band ligation devices. Endoscopicclipsaredeployed directly ontoableeding siteandtypicallysloughoffwithindaystoweeksafterplacement
[131].
Hemostasis is achieved by mechanical compression of the
bleeding site.
Clips are available in a variety of jaw lengths and opening
widths. Thedeliverycatheterconsists ofametalcablewithin
asheath enclosed within aTeflon catheter.After insertion of
the catheter through the working channel of the endoscope,
theclipisextendedoutofthesheath,positioned
overthetarget area and opened with the plunger handle. A rotation
mechanism onthehandle isavailable onsome commercially
available clips and this allows the endoscopist tochange the
orientation ofthe clipatthesiteofbleeding. Thejawsofthe
clipare applied with pressure and closed ontothetarget tissue by using the device handle. Some clips may be opened,
closed,andrepositioned, whereasothersarepermanently deployedandreleased uponclipclosure. Someclipsareprovidedwithareusable delivery sheath, greatlyreducing costs.Similarly,someclipsareautomatically releasedondeployment,
whileothersrequirerepositioning oftheplungerhandletoreleasethedeployedclipfromthecatheter[131].
The over-the-scope clip device includes an applicator cap, a
nitinol clip, and ahand wheel [132,133]. The applicator cap,
withthemountednitinolclip,isaffixedtothetipoftheendoscope in a manner similar to that of a variceal band ligation
device.Caps areavailable inthree sizestoaccommodate various endoscope diameters: 11mm, 12mm, and 14mm. Caps
are also available in two lengths (3mm and 6mm) to allow
variationintheamountoftissuegrasped. Clipscomeinthree
different shapesofteeth:rounded, pointed andlong-pointed.
Clips with rounded teeth are used where the goal is tissue
compression toachievehemostasis. Theapplicator capincorporates a clip release thread, which is pulled retrogradely
through the working channel of the endoscope and fixed
onto a hand wheel mounted on the working-channel access
port of the endoscope. The clip is released by turning the
hand wheel, inamanner similar todeploying avariceal ligationband[134].
Last, endoscopic band ligation devices, commonly used in
esophageal variceal bleeding, have also been reported for
treatment of NVUGIH (e.g., for Dieulafoy lesion) and involve
theplacementofelasticbandsovertissuetoproducemechanicalcompression andtamponade.
a16 Guideline
Topicaltherapy
Topical hemostatic sprays have been used in acute NVUGIH
withpromisingresults,butthusfarinalimitednumberofpatients and without anycomparative data regarding standard
endoscopic hemostasis therapies [135,136]. Advantages of
noncontact, spray catheter delivery of hemostatic agents includeeaseofuse,lackofneedforpreciselesiontargeting,
accesstolesions indifficult locations, and the ability totreat a
largesurfacearea.
Topicalhemostatic sprays include TC-325, (Hemospray, Cook
Medical Inc,Winston-Salem, North Carolina, USA),whichisa
proprietary, inorganic,absorbentpowderthatrapidlyconcentratesclottingfactorsatthebleedingsite,formingacoagulum.
Hemospray comesinahand-held deviceconsisting ofapressurized CO2 canister, a through-the-scope delivery catheter,
andareservoir forthepowdercartridge. Thepowderisdeliveredviapushbutton in12-secondburstsuntilhemostasis is
achieved. Themaximum amount ofTC-325 thatcanbesafely
administered during a single treatment session has not yet
been established [135,136]. The coagulum typically sloughs
within 3daysandisnaturally eliminated. Hemospray hasreceivedregulatory clearanceinsomecountries.
Additionaltopicalhemostatic spraysincludeEndoClotandthe
Ankaferd Blood Stopper [135,136]. EndoClot (EndoClot Plus
Inc,SantaClara,California,USA)isastarch-derived compound
that rapidly absorbs waterfrom serum andconcentrates platelets,redbloodcells,andcoagulationproteinsatthebleeding
site toaccelerate the clotting cascade. Hemostatic sprays derived from plant products/extracts havealso been evaluated.
Clinicalexperiencewiththeseagentsforendoscopichemostasis is currently limited to the off-label use of the Ankaferd
Blood Stopper (Ankaferd Health Products Ltd, Istanbul, Turkey). This topical agent promotes formation of a protein
meshthatactsasananchorforerythrocyte aggregation withoutsignificantly alteringcoagulationfactorsorplateletsandis
deliveredontothebleeding siteviaanendoscopic spraycatheter until an adherent coagulum isformed. The particles are
subsequently cleared from the bleeding site within hours to
days later. The overall efficacy of these topical agents is unknown inbrisk arterial bleeding and maybelimited because
oftherapidwash-awayeffectofthehemostaticagentbyongoingbloodflow.
16Department
ofMedicalGastroenterology, Rikshospitalet University Hospital,
ESGEguidelines represent aconsensus ofbestpractice based on

Oslo,Norway
the available evidence atthe time ofpreparation. They maynot 17Department ofGastroenterology, RoyalWolverhampton Hospitals NHS
apply in all situations and should be interpreted in the light of
Trust,Wolverhampton, UnitedKingdom
18Department ofGastroenterology, ValduceHospital, Como,Italy
specific clinical situations andresource availability. Further con- 19Department ofGastroenterology, CentroHospitalar doPorto,Portugal
trolled clinical studies maybeneeded toclarify aspects ofthese 20Department ofGastroenterology, CentroHospitalar eUniversitrio de
statements, and revision may be necessary as new data appear. Coimbra, Portugal
Endoscopy Unit,NuovoReginaMargherita Hospital, Rome,Italy
Clinical consideration may justify a course of action at variance 21
22Gastroenterology andEndoscopy Department, Antonio Cardarelli Hospital,
to these recommendations. ESGE guidelines are intended to be Naples,Italy
an educational device to provide information that may assist 23Digestive Endoscopy Unit,Catholic University, Rome,Italy
endoscopists in providing care to patients. They are not rules
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a22 Guideline
Appendix e1 Nonvariceal upper gastrointestinal hemorrhage (NVUGIH): taskforces andkeyquestions.

Topicsandkeyquestions
Taskforces
(leader inbold)
Taskforce 1:Initial patient evaluation/hemodynamic resuscitation/risk stratification

Howshouldthepatientbeinitiallyhemodynamicallyresuscitated?
Whoshouldreceivebloodproducttransfusion?Whattargetforhemoglobin?
Howshould patient riskstratification beused?
Whatriskstratification score(s) arereliable andvalid? Pre-endoscopy riskscore?Post-endoscopy riskscore?
Howshould riskstratification toolsbeapplied?
David S.Sanders
Jean-Marc Dumonceau
Matthew Kurien
Gilles Lesur
Riccardo Marmo
Taskforce 2:Pre-endoscopic management
Jean-Marc Dumonceau
Howtomanagethepatientusingantiplateletandanticoagulantdrugs(knowncollectivelyasantithromboticagents)atthe IanGralnek
Cesare Hassan
timeofacuteuppergastrointestinal(UGI)bleeding?
Needtoalsoconsiderthecurrentdataonpotentialadverseeventsrelatedtoantiplatelet/anticoagulantdruginterruption Angel Lanas
Gilles Lesur
(i.e.atrialfibrillation,cardiacstentthrombosis,cardiacischemicevent,neurovascularevent)
Istvan Racz
Whatistheroleofpre-endoscopy proton pumpinhibitor (PPI) therapy?
Franco Radaelli
Whatistheroleofpre-endoscopy somatostatin therapy?
Gianluca Rotondano
Whatistheroleofnaso-/orogastric tubeaspiration/lavage?
Whatistheroleofendotracheal intubation before upper endoscopy?
Isthere aroleforantifibrinolytic medications?
Whatistheroleofprokinetic agents prior toupper endoscopy?
Isthere aroleforcapsule endoscopy intheemergency department inevaluating acute UGIbleeding?
Whatisappropriate timing forupper endoscopy?
Taskforce 3:Endoscopic management
Whichendoscopicclassificationshouldbeusedfordescribinghighandlowriskendoscopicstigmataofrecenthemorrhage
inpepticulcerbleeding?Whatarehighriskvs.lowriskendoscopicstigmataandtheirimportanceinriskstratification?
Istherearolefordopplerultrasonography,magnificationendoscopy,chromoendoscopyinhelpingtobetterevaluate
endoscopicstigmataofrecenthemorrhageforpepticulcerbleeding?
Which ulcer stigmata require endoscopic hemostasis? Which donot?
Which endoscopic hemostasis modality should beused(with focusonpeptic ulcer bleeding)?
Injection therapy?
Ernst J.Kuipers
Ricardo Cardoso
Livio Cipolletta
Mrio Dinis-Ribeiro
LusMaia
Gianluca Rotondano
Paulo Salgueiro
Thermal contact therapy?

Thermal noncontact therapy?
Mechanical therapy?
Combination therapy?
Topical spray/powder therapy
Whattodoinsituations ofnonvariceal, nonulcer bleeding lesions?
Taskforce 4:Post-endoscopic management
Angel Lanas
LarsAabakken
Alberto Arezzo
Roberto deFranchis
Isthere aroleforscheduled second-look endoscopy?
Rebleeding/failed endoscopic hemostasis: Whenshould theinterventional radiologist beinvolved/when should the Cesare Hassan
Ralf-Thorsten Hoffmann
surgeon beinvolved?
Diagnosis andtreatment ofHelicobacter pylori? When? Inwhom? Whatiftesting forH.pylori intheacute setting of TomasHucl
Gilles Lesur
bleeding isnegative? Documentation oferadication?
Franco Radaelli
Howtomanage theNVUGIH patient using antiplatelet andanticoagulant drugs (collectively known asantithrombotics
Andrew Veitch
agents) postendoscopy? Howandwhentoreinstitute these medications?
Angelo Zullo
Whentodischarge patients home?
Whatisthemedicalmanagementpostendoscopichemostasis?
Whattodowhenrebleedingoccurs?Whatistheroleofrepeatupperendoscopy?
Guideline a23
a24 Guideline
Guideline a25
a26 Guideline
Guideline a27
a28 Guideline
Guideline a29
a30 Guideline
Guideline a31
a32 Guideline
Guideline a33
a34 Guideline
Guideline a35
Appendix e7 Summary oftheevidence regarding impact ofearlyendoscopy (24h)ontheoutcome ofpatients withnonvariceal upper gastrointestinal
hemorrhage (NVUGIH).
Firstauthor,
Country
year[ref.]
Studytype,
Patients, n
Major findings
Studyperiod
Spiegel,
2001[269]
Systematic review
19802000
23studies
6controlled in
lowriskpatients
7uncontrolled in
lowriskpatients
6controlled in
highriskpatients
4comparing resource
utilization
12625
Earlyendoscopy (24h)safeandeffective inallriskgroups.

Lowrisk: allows safeandprompt discharge.
Highrisk: significantly reduces recurrent bleeding, transfusion requirements, needforsurgery andlength ofhospital stay.
Tsoi,2009
[270]
Systematic review
19962007
8studies
3RCT
5retrospective
5677
Earlyendoscopy aidsriskstratification andreduces theneedforhospitalization; however itmayincrease theuseofunnecessary therapeutic

procedures.
Endoscopy performed 8hofpresentation hasnoadvantage over
endoscopy performed within 1224hofpresentation inreducing
recurrent bleeding orimproving survival.
Sarin, 2009
[271]
Canada
Retrospective
20042006
502
Noadvantage forearlyendoscopy (<6h)compared withendoscopy

within 24hinterms ofmortality, needforsurgery, ortransfusion
requirements.
Lim,2011
[272]
Singapore
Retrospective
Endoscopy within 13hofpresentation isassociated withlower mortality

inhighriskbutnotlow-risk patients withNVUGIH.
Marmo,
2011[273]
Italy
Multicenter, prospective
cohort studies (3databases)
20042009
837lowrisk
97highrisk
3207
Wysocki,
2012[274]
US
Jairath,
2012[275]
UK
Retrospective
Administrative data
NIS20022007
Multicenter, prospective
cohort study
2007
Significant increase ofmortality inhighriskpatients whenendoscopy is

performed 12hcompared withendoscopy performed 1324hafter
presentation (14.3%16.6%vs.5.2%,P =0.001).
435765
Increased mortality riskinpatients whodonotreceive endoscopy within

1dayofadmission: OR1.32, 95%CI1.261.38.
4478
Compared withlater endoscopy (>24to48h),endoscopy performed

12hdidnotaffect mortality (OR0.98, 95%CI0.881.09), butledto
adecreased risk-adjusted length ofhospital stay(1.7days,
95%CI1.391.99).
CI,confidenceinterval;OR,oddsratio;RCT,randomizedcontrolledtrial.
a36 Guideline
Guideline a37
a38 Guideline
Guideline a39
a40 Guideline
Appendix e10 Helicobacter pylori andnonvariceal upper gastrointestinal hemorrhage (NVUGIH).

Firstauthor,year
Studydesign,
[ref.]
studyobjective
Participants
Outcomes
Results
Snchez-Delgado,
2011[291]
Meta-regression
analysis
NVUGIB patients
H.pylori infection
rateafter theevent
Delayed testing forH.pylori increases Moderate

thedetection rate(OR2.08, 95%CI
1.103.93)
Gisbert, 2006[292] Meta-analysis
NVUGIB patients
Barkun, 2010[240]
NVUGIB patients
H.pylori infection
rateafter theevent
Re-bleeding
Lowsensitivity ofhistology, RUT,

culture, UBT,andserology
H.pylori therapy anderadication
confirmation needed
International
consensus recommendations
Levelofevidence,
conclusions
Gisbert, 2012[293] Prospective study NVUGIB patients

on1000patients
Moderate
High
Gisbert, 2004[294] Meta-analysis
NVUGIB patients
Re-bleeding after
Rebleeding was0.15%perpatientModerate
H.pylori eradication yearoffollow-up anditwasassociated
witheither re-infection orNSAIDs use.
Rebleeding wassignificantly lower in High
Re-bleeding after
eradication
theH.pylori eradication groupthanin
antisecretory therapy group (1.6%vs.
5.6%)
Dixon, 1996[295]
Gastritis
NA
International
workshop
Presence ofneutrophil histology

Moderate
strongly suggests H.pylori infection
CI,confidenceinterval;NA,notavailable;NVUGIB,nonvaricealuppergastrointestinalbleeding;OR,oddsratio;RUT,rapidureasetest;UBT,ureabreathtest.
Guideline a41
a42 Guideline
Guideline a43
Appendix e12 Observational studies assessing theeffect ofproton pumpinhibitors (PPIs) onclinical cardiovascular outcomes inpatients prescribed clopidogrel.
Firstauthor,year[ref.]
Design
Population
Studies withevidence ofaclinically significant interaction

Goodman, 2012[299] Retrospective cohort
Acute coronary synwithin RCT(PLATO)
drome (ACS)
Stockl, 2010[300]
Patients, n
Endpoint
Results
PPI
NoPPI
3255
6021
Cardiovascular death, myocar- Clopidogrel cohort:

dialinfarction, cerebrovascular HR1.20(95%CI
accident
1.041.38)
Ticagrelor cohort:
HR1.24(95%CI,
1.071.45)
1033
Myocardial infarction
Myocardial infarction or
revascularization
Retrospective
Propensity matching
Postmyocardial infarc- 1033

tionorpostpercutaneous coronary intervention
Retrospective cohort
Postpercutaneous cor- 6828

onary intervention
Ho,2009[302]
Postmyocardial infarc- 5244

tion
2961
Deaths, acutecoronary syndrome
HR1.25(95 %CI,
1.111.41)
Huang, 2010[303]
Registry
Postpercutaneous cor- 572

onary intervention
2706
Death
HR1.65(95 %CI,
1.352.01)
Zou,2014[304]
Postpercutaneous cor- 61288 1465

onary intervention
Myocardial infarction, stent

thrombosis, cardiovascular
deaths
HR1.33(95%CI
1.121.57)
VanBoxel, 2010[305]
Clopidogrel users
5734
Munoz-Torrero, 2011
[306]
Registry
Vascular disease
519
Kreutz, 2010[301]
Schmidt, 2012[313]
Retrospective
Propensity matching
Retrospective
Propensity matching
Registry
Propensity matching
Registry
Propensity matching
Registry
Propensity matching
Rassen, 2009[314]
Banerjee, 2011[309]
Harjai, 2011[310]
Aihara, 2012[311]
Tentzeris, 2010[312]
Ray,
2010[315]
Postmyocardial
infarction
Postpercutaneous
coronary intervention
Postpercutaneous
Postpercutaneous
Postpercutaneous
Postpercutaneous
Cardiovascular deaths, acute HR1.51(95%CI,

coronary syndrome, cerebro- 1.391.64)
vascular accident revascularization
12405 Deaths, acute coronary

syndrome, cerebrovascular
accident
HR1.75(95%CI,
1.581.94)
703
Deaths, myocardial infarction, HR1.8(95%CI,

acute coronary syndrome, cer- 1.12.7)
ebrovascular accident, chronic
limbischemia
4538
Cardiovascular death, myocar- Noeffect

dialinfarction, cerebrovascular
accident
622
9131
Acute coronary syndrome
867
3678
751
1900
Death, myocardial infarction, Noeffect

revascularization
Death, myocardial infarction, Noeffect
819
1068
Death, myocardial infarction
Noeffect
691
519
Death, acute coronary

syndrome
Noeffect
2742
10259 Cardiovascular deaths, acute Noeffect

coronary syndrome, cerebrovascular accident, revascularization
Studies without evidence ofaclinically significant interaction

ODonoghue, 2009
Acute coronary
2257
within RCT
[307]
syndrome andpost
percutaneous coronary
(TRITON-TIMI 38)
intervention
Hsiao, 2011[308]
9862
HR1.93(95%CI,
1.053.54)
HR1.91(95%CI
1.193.06)
Noeffect
revascularization
Postpercutaneous
3996
orpostacute coronary
syndrome
7593
Postpercutaneous
orpostacute coronary
syndrome
14569 Death, myocardial infarction,

revascularization
13003 Death, myocardial infarction,

revascularization
Noeffect
Noeffect
CI,confidenceinterval;HR,hazardratio;PLATO,PlateletInhibitionandPatientOutcomes;RCT,randomizedcontrolledtrial.
a44 Guideline
Appendix e13 Meta-analyses evaluating theeffect ofproton pumpinhibitors (PPIs) onclinical outcomes inpatients treated withclopidogrel.
Firstauthor,
Included studies
Patients, n
Endpoint
Results
1nested case-control
20retrospective
(3studies usedapropensity
scoring method fortheanalysis)
3post.hoc analyses ofRCT
1prospective RCT
93278
Myocardial infarction oracute

coronary syndrome (12studies)
RR1.43(95%CI1.151.77)
RR1.15(0.891.48): analysis from
propensity matched ortrial
participants
Overall mortality (13studies)
RR1.09(95%CI0.941.53)
participants
year[ref.]
Kwok,2010
[316]
Major adverse cardiovascular event RR1.25(95%CI1.091.42)

(MACE)
(19studies)
participants
Siller-Matula,
2010[317]
2nested case-control
20retrospective cohort
(3studies usedapropensity
scoring method fortheanalysis)
2post.hoc analyses ofRCT
1prospective RCT
159138
Myocardial infarction
(13studies)
Death
(13studies)
MACE
(19studies)
RR1.31(95%CI1.121.53)
RR1.04(95%CI0.931.24)
RR1.29(95%CI1.151.44)
CI,confidenceinterval;RCT,randomizedcontrolledtrial;RR,riskratio
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Guideline a1

ThisGuideline isanofficial statement oftheEuropean Society ofGastrointestinal Endoscopy (ESGE). It

Acute upper gastrointestinal hemorrhage (UGIH) is a common

The ESGE commissioned thisguideline onNVUGIH and appointedaguidelineleader(I.M.G.)whoincollaborationwiththeChair

10 ESGEdoesnotrecommend theuseoftranexamic acidinpatients withNVUGIH (strong recommendation, lowquality evidence).

Initialpatient evaluation andhemodynamic resuscitation

Riskstratification ofpatientspresenting withacuteUGIHcanas-

management. A number of scoring tools have been created for

Table2 Glasgow-Blatchford Score(GBS).

GI bleeding represents a serious complication of VKA therapy,

Acute upper GI hemorrhage in a patient using antiplatelet agent(s)

APA used for primary prophylaxis

Fig.1 Algorithm forthemanagement ofpatients

Low risk endoscopic stigmata identified

APA used for primary prophylaxis

APA used for secondary prophylaxis

Antiplatelet agentsincludelowdoseaspirin andthienopyridines

decreased the need for second-look endoscopy (OR 0.47, 95%CI

Ithasbeenhypothesized thatpre-endoscopic endotracheal intubation mayprevent cardiorespiratory adverse eventsinpatients

pared to those patients not intubated, published data show no

without hospital admission facilitates discharge inupto46%of

endoscopy has been proposed as a key quality indicator in the

Performance of upper GI endoscopy

High risk stigmata

For FIa and FIb stigmata

FIIb (adherent clot)

Low risk stigmata

Consider performing clot removal

High dose intravenous PPI given as bolus + continuous

No endoscopic hemostasis required

Once daily oral PPI

If endoscopic hemostasis performed:

tivethannoendoscopic hemostasis inachieving primary hemostasis(RR11.7,95%CI5.226.6),reducingrecurrentbleeding(RR

Erosiveesophagitis, gastritis andduodenitis arecommon causes stasisandforpatientswithadherentclotnotreceivingendoscopichemostasis.PPItherapyshouldbehighdoseandadministeredasanintravenousbolus

increased riskofGIbleeding [215217].Protonpumpinhibitors

ded. A recent meta-analysis included a subanalysis limited to

through astream ofionized gas,without mechanical contact,

ofMedicalGastroenterology, Rikshospitalet University Hospital,

ESGEguidelines represent aconsensus ofbestpractice based on

11 Restellini S,Kherad O,JairathVetal.Redbloodcelltransfusion isasso- 34

RadaelliF,PaggiS,Terruzzi Vetal.Management ofwarfarin-associated

Chuttani R, Barkun A, Carpenter S et al. Endoscopic clip application

Iacopini F,Petruzziello L,Marchese Metal.Hemostasis ofDieulafoys

201 HolsterIL,KuipersEJ.Management ofacutenonvariceal uppergastro- 216

Appendix e1 Nonvariceal upper gastrointestinal hemorrhage (NVUGIH): taskforces andkeyquestions.

Taskforce 1:Initial patient evaluation/hemodynamic resuscitation/risk stratification

Taskforce 2:Pre-endoscopic management

Thermal contact therapy?

Earlyendoscopy (24h)safeandeffective inallriskgroups.

Earlyendoscopy aidsriskstratification andreduces theneedforhospitalization; however itmayincrease theuseofunnecessary therapeutic

Noadvantage forearlyendoscopy (<6h)compared withendoscopy

Endoscopy within 13hofpresentation isassociated withlower mortality

Significant increase ofmortality inhighriskpatients whenendoscopy is

Increased mortality riskinpatients whodonotreceive endoscopy within

Compared withlater endoscopy (>24to48h),endoscopy performed

Appendix e10 Helicobacter pylori andnonvariceal upper gastrointestinal hemorrhage (NVUGIH).

Delayed testing forH.pylori increases Moderate

Gisbert, 2006[292] Meta-analysis

Lowsensitivity ofhistology, RUT,

Gisbert, 2012[293] Prospective study NVUGIB patients

Gisbert, 2004[294] Meta-analysis

Presence ofneutrophil histology

Studies withevidence ofaclinically significant interaction

Cardiovascular death, myocar- Clopidogrel cohort: