ESC GuidelinesExecutive summary of the guidelines on thediagnosis and treatment of acute heart failureThe Task Force on Acute Heart Failure of theEuropean Society of CardiologyEndorsed by the European Society of Intensive Care Medicine (ESICM)Authors/Task Force Members, Markku S. Nieminen, Chairperson* (Finland),Michael Bo hm (Germany), Martin R. Cowie (UK), Helmut Drexler (Germany),Gerasimos S. Filippatos (Greece), Guillaume Jondeau (France),Yonathan Hasin (Israel), Jose Lopez-Sendon (Spain),Alexandre Mebazaa{(France), Marco Metra (Italy),Andrew Rhodes{(UK), Karl Swedberg (Sweden)ESC Committee for Practice Guidelines (CPG), Silvia G. Priori (Chairperson) (Italy),Maria Angeles Alonso Garcia (Spain), Jean-Jacques Blanc (France), Andrzej Budaj (Poland),Martin R Cowie (UK), Veronica Dean (France), Jaap Deckers (The Netherlands),Enrique Fernandez Burgos (Spain), John Lekakis (Greece),Bertil Lindahl (Sweden),Gianfranco Mazzotta (Italy),Joa o Morais (Portugal), Ali Oto (Turkey), Otto A. Smiseth (Norway)Document Reviewers, Maria Angeles Alonso Garcia (Co-CPG Review Coordinator) (Spain),Kenneth Dickstein (Co-CPG Review Coordinator) (Norway), Anibal Albuquerque (Portugal), Pedro Conthe (Spain),Maria Crespo-Leiro (Spain), Roberto Ferrari (Italy), Ferenc Follath (Switzerland), Antonello Gavazzi (Italy),Uwe Janssens (Germany), Michel Komajda (France), Joa o Morais (Portugal), Rui Moreno (Portugal),Mervyn Singer (UK), Satish Singh (UK), Michal Tendera (Poland), Kristian Thygesen (Denmark)Online publish-ahead-of-print 28 January 2005Table of contentsPreamble......................... 3851. Introduction ................... 3852. Epidemiology, aetiology, andclinical context ................. 386I. Denitions, diagnostic steps, instrumentationand monitoring of the patient with AHF..... 3863. Denition and clinical classication of AHF . 3863.1. Denition.................. 3863.2. The clinical syndrome of AHF ...... 3884. Pathophysiology of AHF............. 3894.1. The vicious circle in the acute failingheart .................... 3894.2. Myocardial stunning............ 3894.3. Hibernation ................. 3895. Diagnosis of AHF................. 3905.1. Clinical evaluation ............. 3905.2. Electrocardiogram (ECG) ......... 3915.3. Chest X-ray and imaging techniques .. 3915.4. Laboratory tests .............. 3915.5. Echocardiography ............. 3915.6. Other investigations............ 3926. Goals of the treatment of AHF ........ 3926.1. Organization of the treatment of AHF . 3937. Instrumentation and monitoring of patients inAHF ........................ 3937.1. Non-invasive monitoring ......... 3937.2. Invasive monitoring ............ 393& The European Society of Cardiology 2005. All rights reserved. For Permissions, please e-mail: journals.permissions@oupjournals.org*Correspondingauthor.Chairperson:MarkkuS.Nieminen,DivisionofCardiology, Helsinki UniversityCentral Hospital, Haartmaninkatu4,00290 Helsinki, Finland. Tel.: 358 94717 22 00; fax: 358 9 4717 40 15.E-mail address: markku.nieminen@hus.{Members of the EuropeanSociety of Intensive Care MedicineEuropean Heart Journal (2005)26, 384416doi:10.1093/eurheartj/ehi044 by guest on December 3, 2010eurheartj.oxfordjournals.orgDownloaded from II. Treatment of AHF.................. 3948. General medical issues in thetreatment of AHF ................ 3949. Oxygen and ventilatory assistance ...... 3959.1. Rationale for using oxygen in AHF .... 3959.2. Ventilatory support withoutendotracheal intubation (non-invasiveventilation)................. 3959.3. Mechanical ventilation withendotracheal intubation in AHF ..... 39610. Medical treatment ............... 39610.1. Morphine and its analogues in AHF.. 39610.2. Anticoagulation ............. 39610.3. Vasodilators in the treatment of AHF 39610.4. Angiotensin converting enzyme(ACE)-inhibitors in AHF ......... 39710.5. Diuretics ................. 39810.6. b-blocking agents............ 39910.7. Inotropic agents ............. 40011. Underlying diseases and co-morbiditiesin AHF ...................... 40311.1. Coronary artery disease ........ 40311.2. Valvular disease............. 40511.3. Management of AHF due to prostheticvalve thrombosis (PVT) ......... 40511.4. Aortic dissection ............ 40511.5. AHF and hypertension ......... 40511.6. Renal failure ............... 40611.7. Pulmonary diseases andbronchoconstriction ........... 40611.8. Arrhythmias and AHF.......... 40611.9. Peri-operative AHF ........... 40812. Surgical treatment of AHF .......... 40812.1. AHF related to complications of AMI . 40813. Mechanical assist devices andheart transplantation ............. 40913.1. Indication ................ 40913.2. Heart transplantation ......... 41014. Summary comments .............. 411References ........................ 412PreambleGuidelines and Expert Consensus documents aimto presentall therelevant evidenceonaparticular issueinordertohelpphysicians toweighthebenets andrisks of aparticular diagnostic or therapeutic procedure. Theyshould be helpful in everyday clinical decision-making.Agreat number of Guidelines andExpert ConsensusDocuments have been issued in recent years by theEuropeanSocietyof Cardiology(ESC) andbydifferentorganizationsandotherrelatedsocieties.This profusioncan put at stake the authority and validity of guidelines,whichcanonlybeguaranteediftheyhavebeendevel-oped by an unquestionable decision-making process.ThisisoneofthereasonswhytheESCandothershaveissued recommendations for formulating and issuingGuidelines and Expert Consensus Documents.Inspiteof thefact that standards for issuing goodqualityGuidelinesandExpertConsensusDocumentsarewell dened, recent surveys of Guidelines andExpertConsensus Documents publishedinpeer-reviewedjour-nalsbetween1985and1998haveshownthatmethodo-logical standards were not complied with in the vastmajority of cases. It is thereforeof great importancethat guidelines and recommendations are presentedin formats that are easily interpreted. Subsequently,their implementation programmes must also be wellconducted. Attempts have been made to determinewhetherguidelinesimprovethequalityofclinicalprac-tice and the utilization of health resources.The ESC Committee for Practice Guidelines (CPG)supervises and coordinates the preparation of new Guide-lines and Expert Consensus Documents produced by TaskForces, expertgroupsorconsensuspanels. Thechosenexperts in these writing panels are asked to provide dis-closurestatements of all relationships they may havewhichmightbeperceivedasreal orpotential conictsof interest. Thesedisclosureforms arekept onleatthe European Heart House, headquarters of the ESC.TheCommitteeisalsoresponsiblefortheendorsementoftheseGuidelinesandExpertConsensusDocumentsorstatements.The Task Force has classied and ranked the usefulnessor efcacy of the recommended procedure and/or treat-ments and the Level of Evidence as indicated in thetables below:1. IntroductionTheaimoftheseguidelinesistodescribetherationalebehind the diagnosis and treatment of acute heartfailure (AHF) in the adult population.Classes of RecommendationsClass I Evidence and/or general agreement that a givendiagnostic procedure/treatment is benecial,useful and effective;Class II Conicting evidence and/or a divergence ofopinion about the usefulness/efcacy of thetreatment;Class IIa Weight of evidence/opinion is in favour of use-fulness/efcacy;Class IIb Usefulness/efcacy is less well established byevidence/opinion;Class IIIEvidence or general agreement that the treat-ment is not useful/effective and in some casesmay be harmful.Use of Class III is discouragedby the ESC.Levels of EvidenceLevel of Evidence A Data derived from multiple random-ized clinical trials or meta-analysesLevel of Evidence B Data derived from a single random-ized clinical trial or large non-randomized studiesLevel of Evidence C Consensus of opinion of the expertsand/or small studies; retrospectivestudies and registriesESC Guidelines 385 by guest on December 3, 2010eurheartj.oxfordjournals.orgDownloaded from TheCommitteefor PracticeGuidelines (CPG) of theEuropean Society of Cardiology nominated the TaskForcefortheAHFGuidelines. TheTaskForceincludedrepresentatives fromthe Heart Failure Association ofthe ESC and members of the European Society ofIntensiveCareMedicine(ESICM).TheTaskForcerecom-mendationswerecirculatedamongareviewboardandapproved by the CPGof the ESC and by the ESICM.Together with the Guidelines for the diagnosis and treat-ment of chronic heart failure1these Guidelines form therecommendations ondiagnosis andtreatment of heartfailure.The recommendations are also published as an un-abridged version of the document,2as a pocket guideline,and as an ESC educational product CD.2. Epidemiology, aetiology, andclinical contextThecombinationoftheagingofthepopulationinmanycountries,andimprovedsurvivalafteracutemyocardialinfarction (AMI)3has created a rapid growth in thenumber of patients currentlylivingwithchronicheartfailure (CHF),4with a concomitant increase in thenumber of hospitalizations for decompensated heartfailure. Coronaryheartdiseaseistheaetiologyof AHFin 6070% of patients,57particularly in the elderly popu-lation.Inyoungersubjects,AHFisfrequentlycausedbydilatedcadiomyopathy,arrhythmia,congenitalorvalvu-lar heart disease, or myocarditis. The causes and compli-cations of AHF are described in Table 1.Themanagement of heart failureconsumes 12%ofhealthcareexpenditureinEuropeancountries,8,9witharound75%relatingtoinpatient care. Advancedheartfailureandrelatedacutedecompensationhavebecomethe single most costly medical syndrome incardiology.10,11Patients with AHF have a very poor prognosis. Mortalityis particularly high in patients with acute myocardialinfarction (AMI) accompanied by severe heart failure,with a 30% 12 month mortality.12Likewise, in acutepulmonary oedema a 12% in-hospital and 40% 1 yearmortality have been reported.13About 45%of patients hospitalizedwithAHFwill berehospitalized at least once (and 15%at least twice)within twelve months.14,15Estimates of the risk ofdeathor rehospitalizationwithin60days of admissionvary from30 to 60%, depending on the populationstudied.5,6,1619I. Denitions, diagnostic steps,instrumentation and monitoringof the patient with AHF3. Denitionand clinical classication of AHF3.1. DenitionAcute heart failure is dened as the rapid onset of symp-toms and signs secondary to abnormal cardiac function. Itmay occur with or without previous cardiac disease. Thecardiac dysfunction can be related to systolic or diastolicdysfunction, toabnormalities incardiacrhythm, or topre-loadandafter-loadmismatch.Itisoftenlifethrea-tening and requires urgent treatment.AHF can present itself as acute de novo (new onset ofacute heart failure in a patient without previouslyknowncardiacdysfunction)oracutedecompensationofchronic heart failure.The patient with acute heart failure may present withone of several distinct clinical conditions (Table 2 ):(i) Acute decompensated heart failure (de novo oras decompensation of chronic heart failure) withsigns andsymptoms of acuteheart failure, whicharemildanddonot full criteriafor cardiogenicshock, pulmonary oedema or hypertensive crisis.(ii) Hypertensive AHF: Signs and symptoms of heartfailure are accompanied by high blood pressureand relatively preserved left ventricular functionwith a chest radiograph compatible with acutepulmonary oedema.Table 1 Causes and precipitating factors in AHF(1) Decompensation of pre-existing chronic heart failure(e.g. cardiomyopathy)(2) Acute coronary syndromes(a) myocardialinfarction/unstableanginawithlargeextent of ischaemia and ischaemic dysfunction(b) mechanical complication of acute myocardialinfarction(c) right ventricular infarction(3) Hypertensive crisis(4) Acute arrhythmia (ventricular tachycardia, ventricularbrillation, atrial brillation or utter, other supraven-tricular tachycardia)(5) Valvular regurgitation (endocarditis, rupture of chordaetendinae, worsening of pre-existing valvularregurgitation)(6) Severe aortic valve stenosis(7) Acute severe myocarditis(8) Cardiac tamponade(9) Aortic dissection(10) Post-partum cardiomyopathy(11) Non-cardiovascular precipitating factors(a) lack of compliance with medical treatment(b) volume overload(c) infections, particularly pneumonia orsepticaemia(d) severe brain insult(e) after major surgery(f) reduction in renal function(g) asthma(h) drug abuse(i) alcohol abuse(j) phaeochromocytoma(12) High output syndromes(a) septicaemia(b) thyrotoxicosis crisis(c) anaemia(d) shunt syndromes386 ESC Guidelines by guest on December 3, 2010eurheartj.oxfordjournals.orgDownloaded from (iii) Pulmonary oedema (veried by chest X-ray) accom-paniedbysevererespiratorydistress,withcracklesover thelungandorthopnoea, withO2saturationusually,90% on room air prior to treatment.(iv) Cardiogenicshock: Cardiogenicshockisdenedasevidenceof tissuehypoperfusioninducedbyheartfailure after correction of pre-load. There is noclear denition for haemodynamic parameters,which explains thedifferences in prevalence andoutcomereportedinstudies(Table2),butcardio-genic shock is usually characterized by reducedbloodpressure(systolicBP,90 mmHgoradropofmean arterial pressure .30 mmHg) and/or lowurine output (,0.5 ml/kg/h), with a pulse rate.60 b.p.m.withorwithoutevidenceoforgancon-gestion. There is a continuumfromlowcardiacoutput syndrome to cardiogenic shock.(v) Highoutputfailureischaracterizedbyhighcardiacoutput, usually with high heart rate (caused byarrhythmias, thyrotoxicosis, anaemia, Pagetsdisease, iatrogenicor byother mechanisms), withwarm peripheries, pulmonary congestion, and some-times with low BP as in septic shock.(vi) Right heart failureis characterizedbylowoutputsyndromewithincreasedjugular venous pressure,increased liver size and hypotension.Variousotherclassicationsoftheacuteheartfailuresyndrome are utilized in coronary care and intensivecareunits. TheKillipclassicationis basedonclinicalsigns and chest X-ray ndings, and the Forrester classi-cation is based on clinical signs and haemodynamiccharacteristics. These classications have been validatedin acute heart failure after AMI and thus are bestapplied to acute de novo heart failure. The third clinicalseverity classication has been validated in a cardiomyo-pathy service20and is based on clinical ndings.21It is mostapplicable to chronic decompensated heart failure.223.1.1. Killipclassication.TheKillipclassicationwasdesignedtoprovideaclinical estimateof theseverityof myocardial derangement in the treatment of AMI:23StageINoheart failure. Noclinical signs of cardiacdecompensation;StageIIHeart failure. Diagnostic criteria include rales,S3gallopandpulmonaryvenoushypertension.Pulmonary congestion with wet rales in thelower half of the lung elds;StageIIISevere heart failure. Frank pulmonary oedemawith rales throughout the lung elds;StageIVCardiogenicshock. Signs includehypotension(SBP90mmHg), andevidenceof peripheralvasoconstrictionsuchasoliguria,cyanosisanddiaphoresis.3.1.2. Forrester classication. The Forrester AHFclassicationwas alsodevelopedinAMI patients, anddescribes four groupsaccordingtoclinical andhaemo-dynamic status24(Figure 1). Patients are classiedclinically on the basis of peripheral hypoperfusion(lliformpulse, coldclammyskin, peripheral cyanosis,Table2TerminologyandcommonclinicalandhaemodynamiccharacteristicsClinicalstatusHeartrateSBPmmHgCIL/min/m2PCWPmmHgCongestionKillip/ForresterDiuresisHypoperfusionEndorganhypoperfusionIAcutedecompensatedcongestiveheartfailure/2Lownormal/HighLownormal/HighMildelevationKII/FII/22IIAcuteheartfailurewithhypertension/hyperten-sivecrisisUsuallyincreasedHigh/2.18KII-IV/FII-III/2/2,withCNSsymptomsIIIAcuteheartfailurewithpulmonaryoedemaLownormalLowElevatedKIII/FII/22IVaCardiogenicshock/lowoutputsyndromeLownormalLow,,2.2.16KIII-IV/FI-IIIlowIVbSeverecardiogenicshock.90,90,1.8.18KIV/FIVVerylowVHighoutputfailure/2/2KII/FI-II22VIRightsidedacuteheartfailureUsuallylowLowLowLowFI/2/2,acuteonset/2Thereareexceptions;theabovevaluesintableIIaregeneralrules.Thedifferentationfromlowcardiacoutputsyndromeissubjectiveandtheclinicalpresentationmayoverlaptheseclassications.SBPsystolicbloodpressure;CIcardiacindex;PCWPpulmonarycapillarywedgepressure;CNScentralnervoussystem.ESC Guidelines 387 by guest on December 3, 2010eurheartj.oxfordjournals.orgDownloaded from hypotension, tachycardia, confusion, oliguria) andpul-monary congestion (rales, abnormal chest X-ray), andhaemodynamicallyonthebasis of adepressedcardiacindex (2.2 L/min/m2) and elevated pulmonary capillarypressure(.18 mmHg). Theoriginal paper denedthetreatmentstrategy according to the clinical and haemo-dynamicstatus.Mortalitywas2.2%ingroupI,10.1%ingroup II, 22.4% in group III, and 55.5% in group IV.3.1.3. Clinical severity classication. The clinicalseverity classication is based on observation of theperipheralcirculation(perfusion)andonauscultationofthelungs(congestion).ThepatientscanbeclassiedasClass I (Group A) (warmand dry), Class II (Group B)(warmandwet),ClassIII (GroupL)(coldanddry),andClassIV (Group C)(cold andwet). Thisclassication hasbeen validated prognostically in a cardiomyopathyservice,20and is therefore applicable to patientswith chronic heart failure, whether hospitalized oroutpatients.3.2. The clinical syndrome of AHFAHF is a clinical syndrome, with reduced cardiac output,tissue hypoperfusion, increase in the pulmonary capillarywedge pressure (PCWP), and tissue congestion. Theunderlyingmechanismmaybecardiacorextra-cardiac,andmaybetransientandreversiblewithresolutionoftheacutesyndrome,ormayinducepermanentdamageleading tochronic heart failure. Thecardiac dysfunc-tioncanberelatedtosystolicor diastolicmyocardialdysfunction(mainlyinducedbyischaemiaorinfection),acute valvular dysfunction, pericardial tamponade,abnormalitiesofcardiacrhythm,orpre-load/after-loadmismatch. Multiple extra-cardiac pathologies may resultinacuteheart failurebychangingthecardiacloadingconditions for example (i) increased after-load dueto systemic or pulmonary hypertension or massivepulmonary emboli, (ii) increased pre-load due toincreased volume intake or reduced excretion due torenal failure or endocrinopathy, or (iii) high outputstateduetoinfection,thyrotoxicosis,anaemia,Pagetsdisease. Heart failure can be complicated by co-existingend-organdisease.Severeheartfailurecanalsoinducemulti-organ failure, which may be lethal.Appropriate long-termmedical therapy and, if pos-sible, anatomical correction of the underlying patho-logymayprevent further AHFsyndromeattacks andimprovethepoor long-termprognosis associatedwiththis syndrome.The clinical AHF syndrome may be classied as predo-minantly left or right forward failure, left or right back-ward failure, or a combination of these.3.2.1. Forward (left and right) AHF. Forward acuteheartfailuremaybemild-to-moderatewithonlyeffortfatigue, up to severe with manifestations of reducedtissue perfusion at rest with weakness, confusion, drowsi-ness, paleness with peripheral cyanosis, cold clammyskin, low blood pressure, lliform pulse, and oliguria, cul-minatinginthefull blownpresentationof cardiogenicshock.This syndromemaybeinducedbyalargevarietyofpathologies.Anadequatehistorymayindicatethemaindiagnosisforexample(i)acutecoronarysyndromewiththe relevant risk factors, past history, andsuggestivesymptoms; (ii) acutemyocarditis witharecent historysuggestiveof acuteviral infection; (iii) acutevalvulardysfunctionwithahistory of chronic valvediseaseorvalvesurgery,infectionwiththepossibilityofbacterialendocarditis,orchesttrauma;(iv)pulmonaryembolismwith a relevant history and suggestive symptoms; or(v) pericardial tamponade.Figure 1 Clinical classication of the mode of heart failure (Forrester classication). H I-IV refers to haemodynamic severity, with reference gures forCI and pulmonary capillary pressures shown on the vertical and horizontal axes, respectively. C I-IV refers to clinical severity.388 ESC Guidelines by guest on December 3, 2010eurheartj.oxfordjournals.orgDownloaded from Physical examination of the cardiovascular system maybeindicativeofthemaindiagnosis,forexamplebydis-tended neck veins and paradoxical pulse (pericardialtamponade), mufed heart sounds related to myocardialsystolic dysfunction, or thedisappearanceof articialvalve sounds or an appropriate murmur indicating a valv-ular problem.In forward AHF immediate management should includesupportive treatment to improve cardiac output andtissue oxygenation. This can be achieved with vasodilat-ing agents, uid replacement to achieve an optimalpre-load,short-terminotropicsupportand(sometimes)intra-aortic balloon counterpulsation.3.2.2. Left-heart backward failure. Left-heart back-ward failure may be related to left ventriculardysfunctionwithvaryingdegreesofseverity,frommild-to-moderate with only exertional dyspnoea, to pulmonaryoedemapresentingwithshortnessofbreath(drycough,sometimes with frothy sputum), pallor or even cyanosis,cold clammy skin, and normal or elevated blood pressure.Fine rales are usually audible over the lung elds. ChestX-ray shows pulmonary congestion/oedema.Pathology of the left heart may be responsible for thissyndrome, including:myocardial dysfunctionrelatedtochronic existing conditions; acute insult such as myocar-dial ischaemia or infarction; aortic and mitral valve dys-function; cardiac rhythm disturbances; or tumours of theleft heart. Extra-cardiac pathologies may include severehypertension, high output states (anaemia, thyrotoxi-cosis) and neurogenic states (brain tumours or trauma).Physical examination of the cardiovascular system,includingthe apex beat, the qualityofthe heartsounds,the presence of murmurs, and auscultation of thelungs for nerales andexpiratory wheezing (cardiacasthma) may be indicative of the main diagnosis.In left heart backward failure patients should betreated mainly with vasodilation and the addition ofdiuretics, bronchodilators and narcotics, as required.Respiratorysupport maybenecessary. This caneitherbewithcontinuous positiveairwaypressure(CPAP) ornon-invasive positive pressure ventilation, or in somecircumstances invasive ventilation may be requiredfollowing endotracheal intubation.3.2.3. Right-heartbackwardfailure.Thesyndromeofacute right heart failure is relatedto pulmonary andright heart dysfunction, including exacerbations ofchronic lung disease with pulmonary hypertension, oracutemassivelungdisease(e.g.massivepneumoniaorpulmonary embolism), acute right ventricular infarction,tricuspid valve malfunction (traumatic or infectious), andacute or sub-acute pericardial disease. Advanced leftheart diseaseprogressing to right-sidedfailureshouldalsobeconsidered,andsimilarlylong-standingcongeni-tal heartdiseasewithevolvingrightventricularfailureshould be taken into account. Non-cardiopulmonarypathologies include nephritic/nephrotic syndrome andend-stage liver disease. Various vasoactive peptide-secreting tumours should also be considered.Thetypical presentationiswithfatigue,pittingankleoedema,tendernessintheupperabdomen(duetolivercongestion), shortness of breath(withpleural effusion)and distension of the abdomen (with ascites). Thefull-blown syndrome includes anasarca with liver dysfunc-tion and oliguria.Historyandphysical examinationshouldconrmthesyndromeofacuterightheartfailure,indicatethesus-pecteddiagnosisandguidefurtherinvestigation,whichis likely to include ECG, blood gases, D-dimer, chestX-ray, cardiac Doppler-echocardiography, angiographyor chest CT scan.In right heart backward failure uid overload ismanagedwithdiuretics, including spironolactone, andsometimes with a short courseof lowdose (diureticdose) of dopamine. Concomitant treatment mayinclude: antibiotics for pulmonary infection and bacterialendocarditis; Cachannel blockers, nitric oxide, orprostaglandinsforprimarypulmonaryhypertension;andanticoagulants, thrombolytics, or thrombectomy foracute pulmonary embolism.4. Pathophysiologyof AHF4.1. The vicious circle in the acute failing heartThenal commondenominatorinthesyndromeofAHFis a critical inability of the myocardiumto maintainacardiacoutputsufcienttomeetthedemandsoftheperipheral circulation. Irrespective of the underlyingcauseof AHF, avicious circleis activatedthat, if notappropriately treated, leads to chronic heart failureanddeath. ThisisshowninFigure2, andisdescribedin detail elsewhere.2In order for patients with AHF to respond to treatmentthemyocardial dysfunctionmust bereversible. This isparticularly important in AHF due to ischaemia, stunningor hibernation, whereadysfunctional myocardiumcanreturn to normal when appropriately treated.4.2. Myocardial stunningMyocardial stunningis themyocardial dysfunctionthatoccurs following prolonged ischaemia, which may persistin the short-term even when normal blood ow isrestored.25,26Theintensityanddurationof stunningisdependent on the severity and duration of the precedingischaemic insult.264.3. HibernationHibernationis denedas animpairment of myocardialfunctionduetoseverely reducedcoronary bloodowalthoughmyocardial cellsarestill intact. Byimprovingblood owand oxygenation, hibernating myocardiumcan restore its normal function.27Hibernating myocardiumand stunning can co-exist.Hibernationimprovesintimewithreinstitutionofbloodow and oxygenation, whilst stunned myocardiumretains inotropicreserveandcanrespondtoinotropicstimulation.26,28Sincethesemechanismsdependonthedurationof myocardial damage, arapidrestorationofoxygenation and blood owis mandatory to reversethese pathophysiological alterations.ESC Guidelines 389 by guest on December 3, 2010eurheartj.oxfordjournals.orgDownloaded from 5. Diagnosis of AHFThe diagnosis of AHF is based on the symptoms andclinical ndings, supported by appropriate investiga-tions such as ECG, chest X-ray, biomarkers, and Doppler-echocardiography (Figure 3). The patient should beclassiedaccordingtopreviouslydescribedcriteriaforsystolicand/ordiastolicdysfunction(Figure4),andbythecharacteristicsofforwardorbackwardleftorrightheart failure.5.1. Clinical evaluationSystematicclinicalassessmentof the peripheralcircula-tion, venous lling, and peripheral temperature areimportant.Right ventricular (RV) lling in decompensatedheartfailure mayusually be evaluated from the central jugularvenous pressure. When the internal jugular veins areimpractical for evaluation (e.g. due to venous valves) theexternal jugularveinscanbeused.Cautionisnecessaryin the interpretation of high measured central venouspressure (CVP) in AHF, as this may be a reection ofdecreased venous compliance together with decreasedRV compliance even in the presence of low RV lling.Figure 3 Diagnosis of AHF.Figure 4 Assessment of LV function in AHF.Figure 2 Pathophysiology of the syndrome of acute heart failure. Following acute critical events, LV deterioration occurs rapidly and requires urgentmedicaltreatment.Thepathophysiologyofthesyndromeofheartfailureissummarized.Mechanical,haemodynamicandneurohormonalchangesaresimilarbutnotidentical tothoseobservedinCHF. Thetimecourseof development or reversal of thesechangesvaries considerablyandstronglydependsontheunderlyingcauseofLVdeteriorationaswell aspre-existingcardiovasculardisease.However,changesdeveloprapidlyandthereforeAHF is considerably different to the syndromeof CHF.390 ESC Guidelines by guest on December 3, 2010eurheartj.oxfordjournals.orgDownloaded from Left sided lling pressure is assessed by chest ausculta-tion, withthepresenceof wet rales inthelungeldsusually indicating raised pressure. The conrmation,classicationof severity, andclinical follow-upof pul-monarycongestionandpleuraleffusionsshouldbedoneusing the chest X-ray.Class I recommendation, level of evidence CAgain, inacuteconditions theclinical evaluationofleft-sidedllingpressuremaybemisleadingduetotherapidly evolving clinical situation. Cardiac palpation andauscultation for ventricular and atrial gallop rhythms(S3,S4)shouldbeperformed.Thequalityoftheheartsounds, and the presence of atrial and ventriculargallops and valvular murmurs are important for diagnosisand clinical assessment. Assessment of the extent ofarteriosclerosisbydetectingmissingpulsesandthepre-sence of carotid and abdominal bruits is often important,particularly in elderly subjects.5.2. Electrocardiogram (ECG)Anormal ECGisuncommoninacuteheartfailure.TheECG is ableto identify the rhythm,and may helpdeter-minetheaetiologyof AHFandassesstheloadingcon-ditions of theheart. It is essential intheassessmentof acute coronary syndromes.2931The ECGmay alsoindicateacuterightorleftventricular or atrial strain,perimyocarditisandpre-existingconditionssuchasleftandrightventricularhypertrophyordilatedcardiomyo-pathy. Cardiac arrhythmia should be assessed in the12-lead ECG as well as in continuous ECG monitoring.5.3. Chest X-ray and imaging techniquesChest X-ray and other imaging should be performed earlyfor all patients with AHF to evaluate pre-existing chest orcardiac conditions (cardiac size and shape) and to assesspulmonary congestion. It is used both for conrmation ofthe diagnosis, and for follow-up of improvement or unsa-tisfactory responsetotherapy. Chest X-ray allows thedifferential diagnosis of left heart failure from inamma-toryor infectious lungdiseases. ChestCT scanwithorwithout contrast angiographyandscintigraphymaybeusedtoclarify thepulmonary pathology anddiagnosemajorpulmonaryembolism.CT scanortransesophagealechocardiographyshouldbeusedincases of suspicionof aortic dissection.5.4. Laboratory testsA number of laboratory tests should be performed in AHFpatients (Table3). Arterial bloodgas analysis (Astrup)enables assessment of oxygenation (pO2), respiratoryadequacy (pCO2), acidbase balance (pH), and basedecit, and should be performed in all patients withsevere heart failure. Non-invasive measurement withpulse oximetry and end-tidal CO2can often replaceAstrup (Level of evidence C) but not in very lowoutput, vasocontricted shock states. Measurement ofvenous O2saturation(i.e. inthejugular vein) maybeuseful for an estimation of the total body oxygensupply-demand balance.Plasma B-typenatriuretic peptide(BNP) is releasedfromthe cardiac ventricles in response to increasedwallstretchandvolumeoverloadandhasbeenusedtoexcludeand/or identifycongestiveheart failure(CHF)inpatients admitted, for dyspnoea, totheemergencydepartment.1,32Decision cut points of 300 pg/mL forNT-proBNPand100 pg/mLforBNP havebeenproposed,but the older population has been poorly studied.During ash pulmonary oedema, BNP levels mayremain normal at the time of admission. Otherwise,BNPhas a good negative predictive value to excludeheart failure.33Various clinical conditions may affecttheBNPconcentrationincludingrenalfailureandsepti-caemia.Ifelevatedconcentrationsarepresent,furtherdiagnostic tests are required. If AHF is conrmed,increasedlevels of plasma BNPandNT-proBNPcarryimportant prognostic information. The exact role ofBNP remains to be fully claried.345.5. EchocardiographyEchocardiographyisanessentialtoolfortheevaluationof thefunctional andstructural changes underlyingorassociated with AHF, as well as in the assessment ofacute coronary syndromes.Class I recommendation, level of evidence CEchocardiography with Doppler imaging should be usedto evaluate and monitor regional and global left and rightventricular function, valvular structure and function,possible pericardial pathology, mechanical complicationsofacutemyocardial infarctionandonrareoccasionsspace occupying lesions. Cardiac output can be estimatedby appropriate Doppler aortic or pulmonary time velocitycontour measurements. An appropriate echo-Dopplerstudy can also estimate pulmonary artery pressures(from the tricuspid regurgitation jet) and has alsoTable 3 Laboratory tests in patients hospitalized with AHFBlood count AlwaysPlatelet count AlwaysINR If patient anticoagulated or insevere heart failureCRP AlwaysD-dimer Always (may be falsely positiveif CRP elevated or patienthas been hospitalized forprolonged period)Urea and Electrolytes(Na, K, Urea,Creatinine)AlwaysBlood glucose AlwaysCKMB, cardiac TnI/TnT AlwaysArterial blood gases In severe heart failure, orin diabetic patientsTransaminases To be consideredUrinanalysis To be consideredPlasma BNP or NTproBNP To be consideredOther specic laboratory tests should be taken for differentialdiagnostic purposes or in order to identify end-organdysfunction.INR international normalized ratio of thromboplastin time; TnI troponin I; TnT troponin T.ESC Guidelines 391 by guest on December 3, 2010eurheartj.oxfordjournals.orgDownloaded from been used for the monitoring of left ventricularpre-load.3537Echocardiographyhasnotbeenvalidatedwith right heart catheterization in patients with AHF.385.6. Other investigationsIncases of coronary-artery-relatedcomplications suchas unstable angina or myocardial infarction, angiographyis important and angiography-based revascularizationtherapy has been shown to improve prognosis.29,30Class I recommendation, level of evidence BCoronaryarteriographyisalsooftenindicatedinpro-longed AHF, unexplained by other investigations, asrecommended in the guidelines for diagnosis of CHF.1Insertionof apulmonary artery catheter (PAC) mayassistinmakingthediagnosisofAHF.SeeSection7.2.3for further details.6. Goals of the treatment of AHFThe immediate goals are to improve symptoms andto stabilize the haemodynamic condition (Table 4,Figure 5).4051An improvement in haemodynamicparameters only may be misleading, however, and a con-comitant improvement insymptoms (dyspnoea and/orfatigue)isgenerallyrequired.52Theseshort-termbene-tsmustalsobeaccompaniedbyfavourableeffectsonlonger-termoutcomes. Thisislikelytobeachievedbyavoidance, or limitation, of myocardial damage.Another objective of treatment is reduction in theclinical signsofHF.Areductioninbodyweight,and/oranincreaseindiuresis,arebenecialeffectsoftherapyFigure 5 Immediate goals in treatment of the patients with AHF. In coronary patients mean blood pressure (mBP) should be higher to ensure coronaryperfusion, mBP .70, or systolic.90 mmHg.Table 4 Goals of treatment of the patient with AHFClinical#symptoms (dyspnoea and/or fatigue)#clinical signs#body weight"diuresis"oxygenationLaboratorySerum electrolyte normalization#BUN and/or creatinine#S-bilirubin#plasma BNPBlood glucose normalizationHaemodynamic#pulmonary capillary wedge pressure to ,18 mmHg"cardiac output and/or stroke volumeOutcome#length of stay in the intensive care unit#duration of hospitalization"time to hospital re-admission#mortalityTolerabilityLow rate of withdrawal from therapeutic measuresLow incidence of adverse effectsBUN blood urea nitrogen.392 ESC Guidelines by guest on December 3, 2010eurheartj.oxfordjournals.orgDownloaded from incongestiveandoliguricpatients withAHF.44,53Simi-larly,animprovementinoxygensaturation,renal and/or hepatic function, and/or serum electrolytes are mean-ingful goals of treatment. Plasma BNP concentration canreect haemodynamic improvement and decreasedlevels are benecial.Benecial effects of therapy on outcome includereductions in the duration of intravenous vasoactivetherapy, the length of stay, and the readmissionratewithanincreaseinthetimetoreadmission.52,54,55Areductioninbothin-hospital andlong-termmortalityis also a major goal of treatment.Lastly, afavourablesafetyandtolerabilityproleisalsonecessaryforanytreatmentusedinpatientswithAHF.Anyagentusedinthisconditionshouldbeassoci-atedwithalowwithdrawal ratewitharelativelylowincidence of untoward side effects.6.1. Organization of the treatment of AHFBest results are achieved if patients with AHF are treatedpromptly by expert staff in areas reserved for heartfailure patients. An experienced cardiologist and/orother suitablytrainedstaff shouldtreat AHFpatients.Thediagnosticservices shouldprovideearlyaccess todiagnostic procedures such as echocardiography andcoronary angiography, as needed.TreatmentofpatientswithAHFrequiresatreatmentplan in the hospital system.50Class I recommendation, level of evidence BComparative studies have shown shorter hospitaliz-ationtimeinpatientstreatedbystafftrainedinheartfailuremanagement.17ThetreatmentofAHFshouldbefollowed by a subsequent HF clinic programme whenapplicable and as recommended by ESC guidelines.1The care and information needs of the acutely illpatientandhis/herfamilywill usuallybeaddressedbyexpert nurses.Heart failure staff nurses and cardiology/heart failure/intensive care specialists should be given the opportunityfor continuing professional education.Recommendationsonthestandardstructure, nursingstaff and equipment requirements in intensive cardiologycareunitsandrelevantstep-downcareunitsbasedonthe expert opinion of the Working Group of Acute CardiacCare are under preparation.7. Instrumentationand monitoring ofpatients in AHFMonitoring of the patient with AHF should be initiated assoonaspossibleafterhis/herarrival attheemergencyunit, concurrently with ongoing diagnostic measuresaddressed at determining the primary aetiology. Thetypes and level of monitoring required for any individualpatient vary widely depending ontheseverity of thecardiac decompensation and the response to initialtherapy.Local logisticissuesmayalsoberelevant.Theguidelines onmonitoring discussedhere arebasedonexpert opinion.7.1. Non-invasive monitoringIn all critically ill patients, BP measurements shouldbe made routinely; blood pressure, temperature,respiratoryrate,heartrate,theelectrocardiogramandblood pressure is mandatory. Some laboratory testsshouldbedonerepeatedlyi.e. electrolytes, creatinineandglucoseormarkersforinfectionorothermetabolicdisorders. Hypoorhyperkalaemiamustbecontrolled.Thesecanall bemonitoredeasilyandaccuratelywithmodernautomatedequipment. If thepatient becomesmoreunwell, thefrequencyof theseobservations willneed to be increased.ECG monitoring (arrhythmias and ST segment) isnecessaryduringtheacutedecompensationphase,par-ticularly if ischaemia or arrhythmia is responsible forthe acute event.Class I recommendation, level of evidence CMaintenance of normal blood pressure is critical duringtheinitiationoftherapy,andconsequentlyitshouldbemeasured regularly (e.g. every 5 minutes), until thedosageof vasodilators, diuretics or inotropes has beenstabilized. The reliability of non-invasive, automaticplethysmographic measurement of blood pressure isgood in the absence of intense vasoconstriction andvery high heart rate.Class I recommendation, level of evidence CThe pulse oximeter is a simple non-invasive device thatestimates thearterial saturation of haemoglobinwithoxygen (SaO2). The estimate of the SaO2is usuallywithin 2% of a measured value froma co-oximeter,unless the patient is in cardiogenic shock. The pulseoximeter shouldbeusedcontinuouslyonanyunstablepatientwhoisbeingtreatedwithafractionofinspiredoxygen(FiO2)thatisgreaterthaninair.Itshouldalsobeusedatregularintervals(everyhour)onanypatientreceivingoxygentherapyforanacutedecompensation.Class I recommendation, level of evidence CCardiac output and pre-load can be monitorednon-invasivelywiththeuseof Dopplertechniques(seeSection 5.5.). There is little to no evidence to helpchoose which of these to monitor and it makes no differ-enceas long as thelimitations of individual monitor-ing devices are understood and the data are usedappropriately.Class IIb recommendation, level of evidence C7.2. Invasive monitoring7.2.1. Arterial line. The indications for the insertion ofanin-dwellingarterial catheteraretheneedforeithercontinuousbeat-to-beatanalysisofarterialbloodpress-ure due to haemodynamic instability or the requirementfor multiplearterial bloodanalyses. Thecomplicationratefortheinsertionofa20-gauge2-inchradialarterycatheter is low.Class IIb recommendation, level of evidence C7.2.2. Central venous pressure lines. Central venouslines provideaccess to thecentral venous circulationESC Guidelines 393 by guest on December 3, 2010eurheartj.oxfordjournals.orgDownloaded from andarethereforeuseful for thedeliveryof uids anddrugs and can also be used to monitor the CVPandvenous oxygen saturation (SvO2) in the superior venacava(SVC)orrightatrium,whichprovidesanestimateof oxygen transport.Class II b recommendation, level of evidence CCaution has to be advised, however, to avoid theover-interpretation of right atrial pressure measure-ments, as theserarely correlatewithleft atrial pres-sures, and therefore left ventricular (LV) llingpressures,inpatientswithAHF.CVPmeasurementsarealso affected by the presence of signicant tricuspidregurgitation and positive end-expiratory pressure(PEEP) ventilation.Class I recommendation, level of evidence C7.2.3. Pulmonary artery catheter. The pulmonaryartery catheter (PAC) is a balloon otation catheterthat measures pressures in the superior vena cava(SVC), right atrium, right ventricle and pulmonaryarteryaswell ascardiacoutput.Moderncatheterscanmeasurethecardiac output semi-continuously as wellasthemixedvenousoxygensaturationandrightventri-cular end diastolic volume and ejection fraction.Although the insertion of a PAC for the diagnosis of AHFis usually unnecessary, it can be used to distinguishbetween a cardiogenic and a non-cardiogenic mechanismincomplexpatients withconcurrentcardiacand pulmo-nary disease. The PAC is also frequently used to estimatePCWP, cardiac output and other haemodynamic variablesandthereforeguidetherapyinthepresenceof severediffusepulmonarypathologyor ongoinghaemodynamiccompromisenot resolvedby initial therapy.57,58PCWPis not an accurate reection of left ventricular enddiastolic pressure (LVEDP) in patients with mitral stenosis(MS) aortic regurgitation(AR), ventricular interdepen-dence, high airway pressure, or stiff LV, due to, forexample, left ventricular hypertrophy(LVH), diabetes,brosis, inotropes, obesity, ischaemia. Severetricuspidregurgitation, frequently found in patients with AHF,can overestimate or underestimate cardiac outputmeasured by thermodilution.Several retrospectivestudiesassessingtheuseofthePAC in acute myocardial infarction demonstratedincreased mortality with the PAC. These observationswere partially explained by case-mix differencesbetweenthegroups of thestudy.5961Similar observa-tional ndings have subsequently been reported inother groups of patients.47,61,62A recent prospectiverandomized study enrolling a mixed group of critically illpatientsfailedtodemonstrateadifferenceinoutcome,although randomization to the PAC led to increaseduidresuscitationwithintherst24 h.ThePACdidnotcause harm to patients, rather it was the use of the infor-mation derived from the catheter (sometimes in an inap-propriate fashion) that was detrimental.48The use of a PAC is recommended in haemodynamicallyunstable patients who are not responding in a predictablefashiontotraditional treatments, andinpatients witha combination of congestion and hypoperfusion. Inthese cases it is inserted in order to ensure optimaluidloadingoftheventriclesandtoguide49vasoactivetherapies andinotropicagents (Table5). Becausethecomplicationsincreasewiththedurationofitsuse,itiscritical to insert thecatheter when specic data areneeded (usually regarding the uid status of thepatient)andtoremoveitassoonasitisofnofurtherhelp(i.e. whendiureticandvasodilatingtherapyhavebeen optimized).Class IIb recommendation, level of evidence CIncardiogenicshockandprolongedseverelowoutputsyndrome it is recommended that the mixed venousoxygen saturation from the pulmonary artery bemeasured as an estimation of oxygen extraction(SpO2SvO2).TheaimshouldbetomaintainSvO2above65% in patients with AHF.II. Treatment of AHF8. General medical issues in thetreatmentof AHFInfections: Patients with advanced AHF are prone toinfectious complications, commonly respiratory orTable 5 General therapeutic approach in AHF by ndings on invasive haemodynamic monitoringHaemodynamiccharacteristicSuggested therapeutic approachCI Decreased Decreased Decreased Decreased MaintainedPCWP Low High or Normal High High HighSBP mmHg .85 ,85 .85Outline oftherapyFluid loading Vasodilator(nitroprusside,NTG) uidloading maybecome necessaryConsider inotropicagents(dobutamine,dopamine) andi.v. diureticsVasodilators(nitroprusside,NTG) and i.v. diureticsand consider inotrope(dobutamine,levosimendan, PDEI)i.v. diureticsIf SBP is low,vasoconstrictiveinotropesIn AHF patients: Decreased CI: ,2.2 L/min/m2; PCWP: low if,14 mmHg, high if.1820 mmHg.394 ESC Guidelines by guest on December 3, 2010eurheartj.oxfordjournals.orgDownloaded from urinary tract infections, septicaemia, or nosocomialinfection with Grampositive bacteria. An increase inC-reactiveprotein(CRP)andadecreaseingeneralcon-ditionmaybetheonlysignsofinfectionfevermaybeabsent. Meticulous infection control and measures tomaintainskinintegrityaremandatory.Routineculturesarerecommended.Promptantibiotictherapyshouldbegiven when indicated.Diabetes: AHFis associatedwithimpairedmetaboliccontrol. Hyperglycaemia occurs commonly. Routine hypo-glycaemic drugs should be stopped and glycaemic controlshouldbeobtainedbyusingshort-actinginsulintitratedaccording to repeated blood glucose measurements.Normoglycaemiaimproves survival indiabeticpatientswho are critically ill.50Catabolic state: negative caloric and nitrogen balanceisaprobleminongoingAHF.Thisisrelatedtoreducedcaloric intake due to reduced intestinal absorption.Care should be undertaken to maintain calorie andnitrogenbalance.Serumalbuminconcentration,aswellas nitrogen balance, may help to monitor metabolicstatus.Renalfailure:acloseinterrelationshipexists betweenAHFandrenal failure.Bothmaycause,aggravate,andinuence, theoutcomeof theother. Closemonitoringof renal function is mandatory. Preservation of renalfunctionisamajorconsiderationintheselectionoftheappropriate therapeutic strategy for these patients.9. Oxygen and ventilatory assistance9.1. Rationale for using oxygen in AHFThemaintenanceof anSaO2withinthenormal range(9598%) is important in order to maximize oxygen deliv-erytothetissuesandtissueoxygenation, thushelpingto prevent end-organ dysfunction and multiple organfailure.Class I recommendation, level of evidence CThisisbestachievedrstbyensuringthatthereisapatent airway and then by administration of an increasedFiO2. Endotracheal intubation is indicated if thesemeasures fail to improve tissue oxygenation.Class IIa recommendation, level of evidence CDespite this intuitive approach to giving oxygen, thereislittletonoevidenceavailablethatgivingincreasingdoses of oxygen results in an improved outcome.Studies have demonstrated that hyperoxia can be associ-atedwithreducedcoronarybloodow,reducedcardiacoutput, increased blood pressure, increased systemicvascular resistance, and a trend to higher mortality.51The administration of increased concentrations ofoxygen to hypoxaemic patients with acute cardiacfailure is unquestionably warranted.Class IIa recommendation, level of evidence CThe use of increased concentrations of oxygen inpatients without evidence of hypoxaemia is more contro-versial and may cause harm.639.2. Ventilatory support without endotrachealintubation (non-invasive ventilation)Two techniques are used for ventilatory support:CPAP or non-invasive positive pressure ventilation(NIPPV). NIPPV is a method of providing mechanicalventilation to patients without the need for endotrachealintubation. There is a strong consensus that one ofthese two techniques should be used beforeendotracheal intubation and mechanical ventilation.Utilization of non-invasive techniques dramaticallyreduce the need for endotracheal intubation andmechanical ventilation.9.2.1. Rationale. Applicationof CPAPcancausepul-monaryrecruitmentandisassociatedwithanincreaseinthefunctional residual capacity. Theimprovedpul-monarycompliance, reducedtransdiaphragmaticpress-ure swings, anddecreaseddiaphragmatic activity canleadtoadecreaseintheoverallworkofbreathingandtherefore a decreased metabolic demand from thebody. NIPPV is a more sophisticated technique thatrequires a ventilator. Addition of a PEEP to the inspiratoryassistanceresultsina CPAP mode (alsoknownas bilevelpositive pressure support, BiPAP). The physiological ben-ets of this mode of ventilation are the same as for CPAPbut also include the inspiratory assist which furtherreduces the work of breathing and the overall metabolicdemand.9.2.2. EvidencefortheuseofCPAPandNIPPVinleftventricular failure. CPAPin patients with cardiogenicpulmonary oedema improves oxygenation, decreasessymptomsandsignsof AHF, andresultsinadecreasedneedforendotrachealintubation.6468Thestudieshavebeenrelativelysmallandthereforehavenotreportedastatistically signicant reduction in mortality. A systema-tic review69following the rst three trials suggestedthat CPAP was associated with a decreased need for intu-bationanda trendtodecreasedin-hospital mortalitycompared to standard therapy alone. Evidence waslacking,however,onthepotential forCPAPtoactuallycause harm.There have been three randomized controlled trials ofthe use of NIPPV in the setting of acute cardiogenic pul-monary oedema.7072NIPPVappears to decrease the needforendotrachealintubation,butthisdoesnottranslateinto a reduction in mortality or improvement inlong-term function.9.2.3. Conclusions. The use of CPAP and NIPPV in acutecardiogenicpulmonaryoedemaisassociatedwithasig-nicant reductionintheneedfor tracheal intubationand mechanical ventilation.Class IIa recommendation, level of evidence AThere are insufcient data to demonstrate a signicantreduction in mortality; however, the data do not trend inthat direction.ESC Guidelines 395 by guest on December 3, 2010eurheartj.oxfordjournals.orgDownloaded from 9.3. Mechanical ventilation with endotrachealintubationin AHFInvasive mechanical ventilation (with endotracheal intu-bation)shouldnotbeusedtoreversehypoxaemiathatcouldbebetter restoredby oxygentherapy, CPAP, orNIPPV, but rather to reverse AHF-induced respiratorymusclefatigue.Thelatteristhemostfrequentreasonforendotrachealintubationandmechanicalventilation.Respiratory muscle fatigue may be diagnosed by adecrease in respiratory rate, associated with hypercapniaand confused state of mind.Invasivemechanicalventilationshouldonlybeusedifacuterespiratoryfailuredoes not respondtovasodila-tors, oxygen therapy, and/or CPAP, or NIPPV. Another con-sideration should be the need for immediate interventionin a patient with pulmonary oedema secondary toST-elevation acute coronary syndrome.10. Medical treatment10.1. Morphine and its analogues in AHFMorphine is indicated in the early stage of the treatmentof a patient admitted with severe AHF, especially ifassociated with restlessness and dyspnoea.Class IIb recommendation, level of evidence BMorphine induces venodilatation and mild arterial dila-tation, and reduces heart rate.73In most studies, ivboluses of morphine3mg wereadministeredas soonastheintravenouslinewasinserted.Thisdosingcanberepeated if required.10.2. AnticoagulationAnticoagulation is well established in acute coronarysyndromewithor without heart failure.29Thesameistrue in atrial brillation.31There is less evidencefor the initiation of unfractionated heparin or lowmolecular weight heparin (LMWH) in AHF. A largeplacebo-controlledtrial of enoxaparine40 mgsubcuta-neoulsy in acutely ill and hospitalized patients, includinga major group of heart failure patients, showed no clini-cal improvement but less venous thrombosis.74Therearenolargecomparativestudies comparing LMWHtounfractionatedheparin (given as 5000 IU twice or thricedaily). Careful monitoring of the coagulation systemismandatoryinAHFasthereisoftenconcomitantliverdysfunction. LMWHis contraindicatedif thecreatinineclearanceis below30 mL/minor shouldbeusedwithextreme care with monitoring of the anti-Factor Xa level.10.3. Vasodilators in the treatment of AHFVasodilators areindicatedinmost patients withacuteheart failure as rst line therapy, if hypoperfusion isassociatedwithanadequatebloodpressureandsignsofcongestionwithlowdiuresis,toopentheperipheralcirculation and to lower pre-load (Table 6).10.3.1. Nitrates. Nitrates relieve pulmonary congestionwithoutcompromisingstrokevolumeorincreasingmyo-cardial oxygendemandinacuteleftheartfailure,par-ticularlyinpatients withacutecoronarysyndrome. Atlowdoses they only induce venodilation, but as thedose is gradually increased they cause the arteries,including the coronary arteries, to dilate. With appropri-atedoses, nitrates exert balancedvasodilationof thevenous and arterial sides of the circulation, therebyreducingLVpre-loadandafter-load, without impairingtissue perfusion. Their effect on cardiac output dependson pre-treatment pre-load and after-load and theabilityofthehearttorespondtobaroreceptor-inducedincreases in sympathetic tone.InitiallynitratesmaybegivenorallybutintravenousnitratesarealsowelltoleratedinAMI.Tworandomizedtrials in AHF have established the efcacy of intravenousnitrates in combination with furosemide and havedemonstrated that titration to the highest haemodynami-cally tolerable dose of nitrates with low dose furosemideis superior to high dose diuretic treatment alone.Class I recommendation, level of evidence BInoneof theserandomizedstudies furosemideandisosorbidedinitrateasbolusinjectionsweretestedanditwasreportedthatintravenoushighdosenitratewasmore effective than furosemide treatment in controllingsevere pulmonary oedema.75Table 6 Indications and dosing of vasodilators in AHFVasodilator Indication Dosing Main side effects OtherGlyceryl trinitrate,5-mononitrateAcute heart failure,when bloodpressure is adequateStart 20 mg/min, increaseto 200 mg/minHypotension,headacheTolerance oncontinuous useIsosorbide dinitrate Acute heart failure,when blood pressureis adequateStart with 1 mg/h,increase to 10 mg/hHypotension,headacheTolerance oncontinuous useNitroprusside Hypertensive crisis,cardiogenic shockcombined withintoropes0.35mg/kg/min Hypotension,isocyanate toxicityDrug is light sensitiveNesiritideaAcute decompensatedheart failureBolus 2 mg/kg infusion0.0150.03 mg/kg/minHypotensionaLimited sales approval in ESC countries.396 ESC Guidelines by guest on December 3, 2010eurheartj.oxfordjournals.orgDownloaded from In practical use nitrates have a U-shaped curve effect.If giveninsub-optimal doses vasodilators may havealimitedeffectinpreventingAHFrecurrences.However,administration of high doses may also reduce theireffectiveness.Onedisadvantageofnitratesistherapiddevelopment of toleranceespeciallywhengivenintra-venously inhighdoses, limiting their effectiveness to1624 honly. Nitrates shouldbegivenat doses aimedat achieving optimal vasodilation, leading to an increaseincardiacindex(CI)anddecreaseinpulmonarywedgepressure.Inappropriatevasodilationmayinduceasteepreduction in blood pressure, which may result in haemo-dynamic instability.Nitroglycerincanbeadministeredorallyorbyinhala-tion [glyceryl trinitrate (GTN) spray 400 mg (2 puffs)every510 min], or buccally(isosorbidedinitrate1or3 mg), while monitoring blood pressure. The intravenousadministration and dosing of nitrates (glycerylnitrate20 mg/minincreasingdoseto200 mg/min,orisosorbidedinitrate 110 mg/h) should be done with extremecaution, under careful blood pressure monitoring, titrat-ing the dose administered against blood pressuredecrease. One should be particularly cautious whenadministeringnitratestoapatientwithaorticstenosis,althoughthis therapymayhelpinthesecomplexsitu-ations. The dose of nitrates should be reduced if systolicbloodpressurefallsbelow90100 mmHganddiscontin-uedpermanentlyif bloodpressuredrops further. Froma practical point of viewa reduction of 10 mmHg inmean arterial pressure should be achieved.10.3.2. Sodium nitroprusside. Sodium nitroprusside(SNP)(0.3 mg/kg/minup-titratingcarefullyto1 mg/kg/min up to 5 mg/kg/min) is recommended in patientswithsevereheartfailure,andin patientswithpredomi-nantlyincreasedafter-loadsuchas hypertensiveheartfailure or mitral regurgitation.Class I recommendation, level of evidence CSNPshouldbetitratedcautiouslyandusuallyrequiresinvasivearterial monitoringandclosesupervision. Pro-longedadministrationmay beassociatedwithtoxicityfrom its metabolites, thiocyanide and cyanide, andshould be avoided especially in patients with severerenal or hepatic failure. Controlledtrials withSNPinAHF are lacking and its administration in AMI hasyielded equivocal results.76SNP should be tapereddowntoavoidreboundeffects.InAHFcausedbyacutecoronarysyndromes, nitratesarefavouredoverSNPasSNP may cause coronary steal syndrome.77,7810.3.3. Nesiritide. Recently, nesiritide, a new classofvasodilator,hasbeendevelopedforthetreatmentofAHF.40Nesiritide is a recombinant human brain orB-typenatriureticpeptide(BNP)thatisidenticaltotheendogenous hormone. Nesiritide has venous, arterial,andcoronary vasodilatory properties that reducepre-load and after-load, and increase cardiac output withoutdirect inotropic effects.Systemic infusionof nesiritideinpatients withCHFhas benecial haemodynamic actions, results in anenhanced sodium excretion, and suppression of thereninangiotensinaldosteroneandsympatheticnervoussystems.79Nesiritide was compared to intravenous nitro-glycerin and resulted in improvement in haemodynamicsmore effectively and with fewer adverse effects,although this did not translate into improvement in clini-cal outcome. Nesiritide may cause hypotension and somepatients are non-responders.10.3.4. Calciumantagonists. Calciumantagonists arenot recommendedinthetreatment of AHF. Diltiazemand verapamil, and dihydropyridines, should be con-sidered contraindicated.10.4. Angiotensin converting enzyme(ACE)-inhibitors in AHF10.4.1. Indications. ACE-inhibitors are not indicatedin the early stabilization of patients with AHF.Class IIb recommendation, level of evidence CHowever, as these patients are at high risk, ACE-inhibitors have a role in early management of AHFpatientsandAMI.Thereisstill debateontheselectionofpatientsandthetimingofinitiationofACE-inhibitortherapy.10.4.2. Effectsandmechanismofaction.Thehaemo-dynamiceffectsofACE-inhibitorsresultfromdecreasedformation of AII and increased levels of bradykinin,whichinturndecreasestotal peripheral vascularresis-tances andpromotes natriuresis. Short-termtreatmentisaccompaniedbyadecreaseinangiotensinII(AII)andaldosteroneandanincreaseinangiotensinIandplasmarenin activity.There have been no efcacy studies of ACE-inhibitors inAHFtodate.Studies withACE-inhibitorsin heartfailureafter myocardial infarctionhavefocusedonlong-termeffects.80,81A recent meta-analysis found that mortalityat30dayswasreducedfrom7.6%intheplacebogroupto 7.1% in the ACE-inhibitor group [relative risk reduction7%(95%CI 211%, P ,0.004)]. This equates toaboutve fewer deaths per 1000 patients treated for 46weeks [number neededtotreat (NNT) toprevent onedeath 200]. The trials which selected high-risk patientsfound that ACE-inhibitors led to large relative andabsolute reductions in mortality.8210.4.3. Practical use. Intravenous ACE-inhibition shouldbeavoided.TheinitialdoseoftheACE-inhibitorshouldbelowandincreasedprogressivelyafterearlystabiliz-ationwithin48 hwithmonitoringofbloodpressureandrenalfunction.Thedurationoftherapy,wheninitiated,should be at least six weeks.Class I recommendation, level of evidence AACE-inhibitorsshould be used withcaution in patientswithmarginal cardiacoutput as theymaysignicantlyreduceglomerular ltration.Theriskof intolerancetothe ACE-inhibitors is increased by the concomitantadministrationofnon-steroidanti-inammatoryagents,and in the presence of bilateral renal artery stenosis.ESC Guidelines 397 by guest on December 3, 2010eurheartj.oxfordjournals.orgDownloaded from 10.5. Diuretics10.5.1. Indications.Administrationofdiureticsisindi-cated in patients with acute and acutely decompensatedheartfailureinthepresenceofsymptomssecondarytouid retention.Class I recommendation, level of evidence BThesymptomaticbenetsandtheiruniversal clinicalacceptance have precluded a formal evaluation inlarge-scale randomized clinical trials.10.5.2. Effects and mechanisms of action. Diureticsincreasetheurinevolumebyenhancingtheexcretionof water, sodiumchlorideandother ions, leadingtoadecreaseinplasmaandextracellularuidvolume,totalbody water andsodium, areductioninright andleftventricular lling pressures and a decrease in peripheralcongestion and pulmonary oedema.83,84Intravenousadministration of loop diuretics also exerts a vasodilatingeffect, manifestedbyanearly(530 min) decreaseinright atrial and pulmonary wedge pressure as well as pul-monaryresistances.85Withhighbolusdoses(.1 mg/kg)thereisariskofreexvasoconstriction.Asopposedtochronicuse of diuretics,in severedecompensatedheartfailure the use of diuretics normalizes loading conditionsandmayreduceneurohormonal activationintheshortterm.86Especially in acute coronary syndromes diureticsshouldbeusedinlowdoses andpreferencegiventovasodilator therapy.8710.5.3. Practical use. Intravenous administration ofloop diuretics (furosemide, bumetanide, torasemide),withastrongandbriskdiureticeffectisthepreferredchoice in patients with AHF. Therapy can safely beinitiatedbeforehospital admission75,8890andthedoseshould be titrated according to the diuretic responseandreliefofcongestivesymptoms.Administrationofaloadingdosefollowedbycontinuedinfusionof furose-mide or torasemide have been shown to be moreeffective than bolus alone.87,9195Thiazides9698and spir-onolactone99canbe used in association withloop diure-tics,thecombinationinlowdosesbeingmoreeffectiveandhavingwithfewer secondaryeffects thantheuseof higher doses of a single drug.9699Combination ofloop diuretics with dobutamine, dopamine92or nitrates88is also a therapeutic approach that is more effective andproduces fewer secondary effects than increasing thedose of the diuretic.100Class IIb recommendation, level of evidence CTable 7 lists the recommendations for the practical useof diuretics. Table8gives therecommendeddoses ofcommonly used diuretics in heart failure.Table 8 Diuretic dosing and administrationSeverity of uid retention Diuretic Dose (mg) CommentsModerate Furosemide, or 2040 Oral or intravenous according toclinical symptomsBumetanide, or 0.51.0 Titrate dose according to clinicalresponseTorasemide 1020 Monitor Na, K, creatinine andblood pressureSevere Furosemide, or 40100 IntravenouslyFurosemide infusion 540 mg/h Better than very high bolusdosesBumetanide, or 14 Orally or intravenouslyTorasemide 20100 OrallyRefractory to loop diuretics Add HCTZ, or 2550 twice daily Combination with loop diuretic betterthan very high dose ofloop diuretics aloneMetolazone, or 2.510 once daily Metolazone more potent if creatinineclearance ,30 mL/minSpironolactone 2550 once daily Spironolactone best choice if patientnot in renal failure andnormal or low serum KIn case of alkalosis Acetazolamide 0.5 IntravenouslyRefractory to loopdiuretic and thiazidesAdd dopamine for renalvasodilatation, or dobutamineas an inotropic agentConsider ultraltration orhaemodialysis if co-existingrenal failureHCTZ hydrochlorothiazide.Table 7 Practical use of diuretics in AHFStart with individualized dose depending on clinical condition(see Table 8)Titrate according to clinical responseReduce dose when uid retention is controlledMonitor serum K, Na and renal function at frequentintervals (every 12 days), according to diuretic responseReplace K and Mg lossIn case of diuretic resistance follow suggestions in Table 10398 ESC Guidelines by guest on December 3, 2010eurheartj.oxfordjournals.orgDownloaded from 10.5.4. Diuretic resistance. Diuretic resistance isdenedastheclinical stateinwhichdiureticresponseis diminished or lost before the therapeutic goal ofoedemarelief hasbeenachieved.101Suchresistanceisassociatedwithapoorprognosis.102Itismorefrequentinpatients withchronic, severeheart failureonlong-term diuretic therapy, although it has also been reportedwithacutevolumedepletionafterintravenousadminis-trationof loopdiuretics.103Diureticresistancecanbeattributed to a number of factors (Table 9).101,103Anumberoftherapeuticapproachestoovercomediureticresistance have been explored (Table 10), and in clinicalpractice different strategies may be of value in a particu-lar patient. Continuous infusionof furosemideis moreeffective than individual boluses.10410.5.5. Secondaryeffects,druginteractions.Althoughdiuretics can be used safely in the majority ofpatients, secondary effects are frequent and may belife-threatening. They include neurohormonal activation,especially of the angiotensinaldosterone system and thesympathetic nervous system97, hypokalaemia, hypo-magnesaemia, and hypochloraemic alkalosis that maylead to severe arrhythmias92, and nephrotoxicity andaggravation of renal failure.100,105Excessive diuresismay reduce venous pressure, pulmonary wedge pressureanddiastolicllingexcessively, leadingtoareductionin stroke volume and cardiac output, particularly inpatients with severe heart failure and predominant dias-tolic failure or ischaemic RVdysfunction. Intravenousadministrationof acetazolamide(1or2doses) maybehelpful for the correction of alkalosis.10610.5.6. Newdiuretic agents. Some newcompoundswithdiureticandothereffectsareunderinvestigation,including vasopressin V2 receptor antagonists, brainnatriureticpeptides(seeSection10.3.3)andadenosinereceptor antagonists.10.6. b-blocking agents10.6.1. Indications and rationale for b-blocking agents.Therehasbeennostudywithb-blockertherapyinAHFtargetedtoacutelyimprovethecondition.Onthecon-trary, AHFhas beenconsideredacontraindicationforthis treatment. Patients with more than basal pulmonaryrales, or hypotension, havebeenexcludedfromtrialsearly after AMI. In patients with AMI who are not inovert heart failure or hypotensive, b-blockers limitinfarct size, reduce life-threatening arrhythmias andrelieve pain.30,107109Intravenous administration should be considered inpatientswithischaemicchestpainresistanttoopiates,recurrent ischaemia, hypertension, tachycardia, orarrhythmia. IntheGothenburgmetoprolol study, intra-venousmetoprolol orplacebowasinitiatedearlyafteranAMI andfollowedbyoral therapyforthreemonths.Fewer patients developed heart failure in the metoprololgroup.110Inpatientswithsignsofpulmonarycongestionwith basal rales and/or treatment with intravenous furo-semide, metoprolol therapy had even greater effects andreducedmortalityandmorbidity.111Thereisexperiencewiththeshort acting b-blocker esmolol mainlyinthesetting of cardiac surgery. One small study has comparedceliprololandesmololinsevereheartfailure.CeliprololreducedCI less at similar heart ratereduction, whichwas claimed to be due to differences in the vasodilationeffect.112Theclinical importanceof this differenceisunclear.InvasivehaemodynamicmonitoringwascarriedoutintheMIAMI trial onpatientswithelevatedpulmo-nary wedgepressures upto 30 mmHg. Thesepatientswhen treated with metoprolol showed a decrease inlling pressures.11310.6.2. Practical use. Inpatients withovert AHFandmorethanbasal pulmonaryrales, b-blockersshouldbeusedcautiously. Amongsuchpatientsinwhomongoingischaemia and tachycardia are present, intravenousmetoprolol can be considered.Class IIb recommendation, level of evidence CHowever,inpatientswithanAMI whostabilizeafterdeveloping AHF, b-blockers should be initiated early.Class IIa recommendation, level of evidence BIn patients with chronic heart failure, b-blockers shouldbeinitiatedwhenthepatient has stabilizedafter theacute episode (usually after 4 days).Class I recommendation, level of evidence ATable 10 Managing resistance to diureticsRestrict Na/H2O intake and follow electrolytes113Volume repletion in cases of hypovolaemia113Increase dose and/or frequency of administration ofdiuretic109,116Use intravenous administration (more effectivethan oral)113as bolus, or as intravenous infusion (moreeffective than high dose intravenous bolus)103107,116Combine diuretic therapy108furosemide HCTZ109furosemide spironolactone111metolazone furosemide (this combination is alsoactive in renal failure)110,107Combine diuretic therapy with dopamine112,or dobutamine117Reduce the dose of ACE-inhibitor118or use very low dosesof ACE-inhibitor118,119Consider ultraltration or dialysis ifresponse to above strategies ineffective120Table 9 Causes of diuretic resistanceIntravascular volume depletionNeurohormonal activationRebound Na uptake after volume lossHypertrophy of distal nephronReduced tubular secretion (renal failure, NSAIDs)Decreased renal perfusion (low output)Impaired gut absorption of an oral diureticNon-compliance with drugs or diet (high sodium intake)ESC Guidelines 399 by guest on December 3, 2010eurheartj.oxfordjournals.orgDownloaded from The initial oral dose of bisoprolol, carvedilol, or meto-prolol should be small and increased slowly and progress-ivelytothetargetdoseusedinthelargeclinicaltrials.Up-titrationshouldbeadaptedtoindividual response.b-blockers may reducebloodpressureandheart rateexcessively. As a general rule, patients on b-blockersadmitted to hospital due to worsening heart failureshould be continued on this therapy unless inotropicsupport is needed but the dose could be reduced ifsigns of excessive dosage are suspected (i.e. bradycardiaand hypotension).10.7. Inotropic agents10.7.1. Clinical indications. Inotropic agents areindicatedinthepresenceof peripheral hypoperfusion(hypotension,decreasedrenalfunction)withorwithoutcongestionorpulmonaryoedemarefractorytodiureticsand vasodilators at optimal doses (Figure 6).Class IIa recommendation, level of evidence CTheir use is potentially harmful as they increase oxygendemandandcalciumloadingandtheyshouldbeusedwith caution.114Inpatients withdecompensatedCHFthesymptoms,clinical course, and prognosis of the disease maybecome critically dependent on the haemodynamics.Thus, improvements inthehaemodynamic parametersmaybecomeagoal of treatment andinotropicagentsmaybeuseful andlife-savinginthissetting.Thebene-cial effects of animprovement inthehaemodynamicparameters is, however, partially counteractedbytherisks of arrhythmias and, in some cases, myocardialischaemiaandbythepossiblelong-termprogressionofmyocardial dysfunctioncausedbyanexcessiveincreasein energy expenditure.114,115The risk-benet ratiomay not, however, be the same for all the inotropicagents. Those acting through the stimulation of theb1-adrenergic receptors which increase cytoplasmicmyocardial cell Caconcentrationmaybeassociatedwith the greatest risk.116,117Lastly, only a few controlledtrials withinotropicagents inpatients withAHFhavebeen performed, and very few have assessed theireffectsonthesymptomsandsignsofheartfailureandtheir long-term effects on prognosis.11710.7.2. Dopamine. At lowdoses (,2 mg/kg/min i.v.)dopamineacts onlyonperipheral dopaminergicrecep-torsandlowersperipheral resistancebothdirectlyandindirectly. Vasodilation occurs predominantly in therenal,splanchnic,coronary,andcerebralvascularbeds.Atthisdosage,itsactionmaycauseanimprovementinrenal blood ow, glomerular ltration rate, diuresis,andsodiumexcretionrate, withanincreasedresponsetodiureticagents,inpatientswithrenal hypoperfusionand failure.118121Athigherdoses(.2 mg/kg/mini.v.)dopaminestimu-lates the b-adrenergic receptors both directly andindirectly with a consequent increase in myocardial con-tractility and cardiac output. At doses .5 mg/kg/mindopamine acts on a-adrenergic receptors with anincrease in the peripheral vascular resistance which,Figure 6 Rationale for inotropic drugs in AHF.400 ESC Guidelines by guest on December 3, 2010eurheartj.oxfordjournals.orgDownloaded from though potentially useful in hypotensive patients, may bedeleteriousinpatientswithAHF,asitmayaugmenttheLV after-load, pulmonary artery pressure, and pulmonaryresistance.12210.7.3. Dobutamine. Dobutamine is a positive inotropicagentactingmainlythroughstimulationofb1-receptorsand b2-receptors to produce dose-dependent positiveinotropic and chronotropic effects,123,124and a reexdecreaseinsympathetictone, andthus vascular resis-tance.125The resultant benet may therefore differfrompatient to patient. At low doses, dobutamineinduces mild arterial vasodilatation, which augmentsstroke volume by reductions in after-load. At higherdoses dobutamine causes vasoconstriction.77Heart rate is generally increased in a dose-dependentmanner toalesser extent thanwithother cathechol-amines. However, in patients with atrial brillation,heart ratemaybeincreasedtoundesirablerates, duetofacilitationof atrioventricular (AV) conduction. Sys-temic arterial pressure usually increases slightly, butmay remain stable, or decrease. Similarly pulmonaryarterial pressureandcapillary wedgepressureusuallydecrease, but may remain stable or even increase insome patients with heart failure.119,122,126The improved diuresis observed during dobutamineinfusioninpatients withheart failureis theresult ofincreased renal blood ow in response to improvedcardiac output.10.7.4. Practical use. Dopamine may be used as aninotrope(.2 mg/kg/min i.v.) inAHFwithhypotension.Infusion of lowdoses of dopamine (23 mg/kg/min)maybeusedtoimproverenal bloodowanddiuresisin decompensated heart failure with hypotension andlowurineoutput. However if noresponseis seenthetherapy should be terminated127(Table 11).Class of recommendation IIb, level of evidence CDobutamine is currently indicated when there isevidence of peripheral hypoperfusion (hypotension,decreasedrenalfunction)withorwithoutcongestionorpulmonaryoedemarefractorytodiureticsandvasodila-tors at optimal doses (Table 11).Class IIa recommendation, level of evidence CDobutamine is used to increase the cardiac output. It isusually initiated with a 23 mg/kg/min infusion ratewithoutaloadingdose.Theinfusionratemaythenbeprogressivelymodiedaccordingtosymptoms, diureticresponse, or haemodynamic monitoring. Its haemo-dynamic actions areproportional toits dosage, whichcanbeincreasedto20 mg/kg/min. Theeliminationofthedrugisrapidaftercessationofinfusion,makingitavery convenient inotropic agent.Inpatientsreceivingb-blockertherapywithmetopro-lol, dobutaminedoses havetobeincreasedas highas1520 mg/kg/mintorestoreitsinotropiceffect.128Theeffect of dobutaminediffers in patients receiving carve-dilol: it canleadtoanincreaseinpulmonaryvascularresistance during the infusion of increasing doses ofdobutamine (520 mg/kg/min).129Based on haemodynamic data alone, the inotropic effectofdobutamineisadditivetothatofphosphodieasteraseinhibitors (PDEI); thecombinationof PDEI anddobuta-mineproduces apositiveinotropiceffect greater thaneither drug alone.129,130Prolongedinfusionof dobutamine(above2448h) isassociated with tolerance and partial loss of haemo-dynamiceffects.122Weaningfromdobutaminemaybedifcultbecauseofrecurrenceofhypotension, conges-tion, or renal insufciency. This can sometimes besolvedbyveryprogressivetaperingofdobutamine(i.e.decreaseindosagebystepsof2 mg/kg/mineveryotherday) andoptimizationof oral vasodilator therapysuchas with hydralazine and/or an ACE-inhibitor.131It is some-timesnecessarytotoleratesomerenal insufciencyorhypotension during this phase.Infusion of dobutamine is accompanied by an increasedincidenceof arrhythmia originatingfrombothventriclesandatria.Thiseffectisdose-relatedandmaybemoreprominent than with PDEI132,133and should promptTable 11 Administration of positive inotropic agentsBolus Infusion rateDobutamine No 2 to 20 mg/kg/min (b)Dopamine No ,3 mg/kg/min: renal effect (d)35 mg/kg/min: inotropic (b).5 mg/kg/min: (b), vasopressor (a)Milrinone 2575 mg/kg over 1020 min 0.3750.75 mg/kg/minEnoximone 0.250.75 mg/kg 1.257.5 mg/kg/minLevosimendan 1224 mg/kgaover 10 min 0.1 mg/kg/min which can be decreasedto 0.05 or increased to0.2 mg/kg/minNorepinephrine No bolus 0.21.0 mg/kg/minEpinephrine Bolus: 1 mg can be given i.v.at resuscitation, may be repeated after35 min, endotracheal route is notfavoured0.050.5 mg/kg/minaCurrent recommended dosing. In patientswith hypotension,therapy should be started without a bolus.ESC Guidelines 401 by guest on December 3, 2010eurheartj.oxfordjournals.orgDownloaded from strictpotassiumcompensationduringintravenousdiure-ticuse. Tachycardiamayalsobealimitingparameter,and dobutamine infusion may trigger chest pain inpatients withcoronaryarterydisease. Inpatients withhibernating myocardium dobutamine appears to increasecontractility in the short term at the expense of myocytenecrosis and loss in myocardial recovery.134There are nocontrolled trials on dobutamine in AHF patients and sometrials show unfavourable effects with increased untowardcardiovascular events.42,11610.7.5. Phosphodiesterase inhibitors. Milrinone andenoximone are the two Type III phosphodiesteraseinhibitors(PDEIs)usedinclinicalpractice.InAHF,theseagents havesignicant inotropic, lusitropic, andperi-pheral vasodilatingeffects withanincreaseincardiacoutput and stroke volume, and a concomitant decline inpulmonaryarterypressure, pulmonarywedgepressure,systemicandpulmonaryvascularresistance.122,135Theirhaemodynamicproleis intermediatebetweenthat ofapurevasodilator,likenitroprusside,andthatofapre-dominant inotropicagent, likedobutamine.126Astheirsiteofactionisdistaltothebeta-adrenergicreceptors,PDEIs maintain their effects even during concomitantb-blocker therapy.128,129,136TypeIIIPDEIsareindicatedwhenthereisevidenceofperipheral hypoperfusion with or without congestionrefractory to diuretics and vasodilators at optimaldoses, and preserved systemic blood pressure.Class of recommendation IIb, level of evidence CThese agents may be preferred to dobutamine inpatientsonconcomitantb-blockertherapy,and/orwithan inadequate response to dobutamine.Class of recommendation IIa, level of evidence CIn practical use milrinone is administered as a 25 mg/kgbolusover1020 min,followedbyacontinuousinfusionat0.3750.75 mg/kg/min.Similarly,enoximoneisadmi-nistered as a bolus of 0.250.75 mg/kg followed by a con-tinuous infusion at 1.257.5 mg/kg/min (Table 11).Hypotension caused by excessive peripheral venodilationisanuntowardeffectobservedmainlyinpatientswithlowllingpressures.Itmaybeavoidedbystartingtheinfusion without any bolus. Thrombocytopaenia is uncom-mon with both milrinone (0.4%) and enoximone.ThedataregardingtheeffectsofPDEIadministrationontheoutcomeof patients withAHFareinsufcient,butraiseconcernsaboutsafety,particularlyinpatientswith ischaemic heart failure.54,117,13710.7.6. Levosimendan. Levosimendan has two mainmechanisms of action: Ca sensitization of the contrac-tileproteinsresponsibleforapositiveinotropicaction,andsmoothmuscleKchannel openingresponsibleforperipheral vasodilation. Some data suggest levosimendanmay alsohavea phosphodioesteraseinhibitioneffect.Levosimendanhasapotent acetylatedmetabolitethatis also a Ca-concentration dependent Casensitizer.Its half-life is 80 h, which probably explains theprolonged haemodynamic effects of a 24 h levosimendaninfusion.138,139Levosimendan is indicatedin patients with sympto-matic lowcardiac output heart failure secondary tocardiacsystolicdysfunctionwithoutseverehypotension(Table 11).Class of recommendation IIa, level of evidence BLevosimendan is generally administered as a conti-nuous intravenous infusion at a dose of0.050.1 mg/kg/min preceded by a loading dose of1224 mg/kg, administered over 10 min.42,140142Itshaemodynamic effects are dose-dependent and the infu-sion rate may be up-titrated to a maximal rate of0.2 mg/kg/min.165Most of theclinical datahavebeenobtained with intravenous infusions lasting from 6 h142to24 h,42,141but the haemodynamic effects persist for.48 h after the end of the infusion.138,143Levosimendan infusion in patients with acutely decom-pensated heart failure caused by left ventricular systolicdysfunctionhasbeenassociatedwithadose-dependentincrease in the cardiac output and stroke volume, adecline in the pulmonary wedge pressure, systemicvascularresistance,andpulmonaryvascularresistance,andaslightincreaseintheheartrate,anddecreaseinthebloodpressure.42,143Animprovement insymptomsofdyspnoeaandfatigueandafavourableoutcomehasbeen shown in randomized trials comparing levosimendanwith dobutamine.42Differently fromdobutamine, thehaemodynamicresponsetolevosimendanismaintained,orevenof greatermagnitude,inthepatientsonconco-mitantb-blocker therapy.42Tachycardia and hypotension are described withhigh-dose levosimendan infusion42and it is not currentlyrecommendedinpatientswithasystolicbloodpressure,85 mmHg.143Levosimendan has not been associatedwithanincreasedfrequencyof malignant arrhythmiasin comparative trials with either placebo,141,142ordobutamine.42Reductions inthehaematocrit, haemo-globin, and plasma potassium, likely secondary to vasodi-lation and secondary neurohumoral activation, have beendescribed42,143and seem to be dose-dependent.14310.7.7. Vasopressor therapy in cardiogenic shock. Whenthecombinationof inotropicagent anduidchallengefails torestoreadequatearterial andorganperfusiondespite an improvement in cardiac output, therapy withvasopressorsmayberequired.Vasopressorsmayalsobeused,inemergencies,tosustainlifeandmaintainper-fusioninthefaceoflife-threateninghypotension.Sincecardiogenic shock is associated with high vascular resist-ances,anyvasopressorshouldbeusedwithcautionandonlytransiently,becauseitmayincreasetheafter-loadofafailingheartandfurtherdecreaseend-organbloodow.10.7.7.1. Epinephrine.Epinephrineisacatecholaminewith high afnity for b1, b2, and a receptors. Epinephrineis used generally as an infusion at doses of 0.05 to 0.5 mg/kg/minwhendobutaminerefractoriness ispresent andthebloodpressureremainslow.Directarterialpressure402 ESC Guidelines by guest on December 3, 2010eurheartj.oxfordjournals.orgDownloaded from monitoring and monitoring of haemodynamic response byPAC is recommended (Table 11).10.7.7.2. Norepinephrine. Norepinehrine is a catechol-aminewithhighafnityfora-receptorsandisgenerallyusedtoincreasesystemic vascular resistance. Norepi-nephrine-inducedincreases inheart rateareless thanwithepinephrine.Thedosingissimilartoepinephrine.Norepinephrine(0.2 to 1 mg/kg/min) isfavoured insitu-ationswithlowbloodpressurerelatedtoreducedsys-temic vascular resistance such as septic shock.Norepinephrineis oftencombinedwithdobutaminetoimprovehaemodynamics.144Norepinehrinemayreduceend-organ perfusion.10.7.8. Cardiac glycosides. Cardiac glycosides inhibitmyocardial Na/KATPase, thereby increasing Ca/Naexchangemechanisms,producingapositiveinotro-piceffect.Inheartfailurethepositiveinotropiceffectfollowing b-adrenergic stimulation is attenuated andthe positive forcefrequency relationshipis impaired. Incontrast tob-adrenoceptor agonists, the positive inotro-piceffect of cardiacglycosides is unchangedinfailinghearts144andtheforcefrequency relationshipis par-tially restored.145In chronic heart failure, cardiac glyco-sides reduce symptoms and improve clinical status,therebydecreasingtheriskofhospitalizationforheartfailurewithouteffectsonsurvival.146,147InAHF,cardiacglycosidesproduceasmallincreaseincardiacoutput148and a reduction of lling pressures.149In patientswith severe heart failure following episodes of acutedecompensation, cardiac glycosides have been shownto be efcacious in reducing the re-occurrence ofacute decompensation.150Predictors for these bene-cial effects are a third heart sound, extensive LVdilatationanddistendedjugular veins during theAHFepisode.However, inpatients followingmyocardial infarctionwithheartfailure,asubstudyoftheAIRE-Investigationhas shown adverse effects on outcome after AMIaccompanied by heart failure.151Furthermore, followingAMI an increase of creatinine kinase was more pro-nouncedinpatients receivingcardiacglycosides.152Inaddition, for patients with myocardial infarction andAHF, the use of digitalis was a predictor forlife-threatening pro-arrhythmic events.153Therefore,inotropicsupportwithcardiacglycosidescannotberec-ommended in AHF, in particular following myocardialinfarction.Anindication for cardiac glycosides in AHF may betachycardia-inducedheart failuree.g. inatrial brilla-tionwithinsufcientrate-control byotheragentssuchasb-blockers.Rigorouscontrolofheartrateintachyar-rhythmia during the course of AHF can control heartfailure symptoms.154Contraindications to the use ofcardiac glycosides include bradycardia, second andthird degree AV-block, sick sinus syndrome, carotidsinus syndrome, WolffParkinsonWhite syndrome,hypertrophic obstructive cardiomyopathy, hypokalaemia,and hypercalcaemia.11. Underlying diseases and co-morbiditiesin AHFThere are several acute morbidities, which can cause denovoAHFor trigger decompensationinCHF. Coronaryheart disease and acute coronary syndromes arethe most frequent causes for AHF. Non-cardiacco-morbidities may also signicantly complicate thetherapy of AHF.11.1. Coronary artery diseaseIn acute coronary syndromes (unstable angina or myocar-dial infarction) complicated by AHF, coronary angio-graphyisindicated(Figure7).InAMI,reperfusionmaysignicantly improve or prevent AHF.29,30Emergency per-cutaneous coronary intervention(PCI), or onoccasionsurgery, should be considered at an earlystage and per-formed as indicated. If neither PCI nor surgery arereadilyavailableor canonlybeprovidedafter alongdelay, early brinolytic therapy is recommended.29,30All patients with AMI and signs and symptoms of heartfailure should undergo an echocardiographic study toassess regional and global ventricular function, asso-ciated valve dysfunction (mainly mitral regurgitation)and to rule out other disease states (e.g. perimyocarditis,cardiomyopathy, and pulmonary embolism).Class of recommendation I, level of evidence CSpecial tests to provide evidence of reversible myocar-dial ischaemia are sometimes necessary.Incardiogenic shock causedby acutecoronary syn-dromes coronary angiography and revascularizationshould be performed as soon as possible.155Class I recommendation, level of evidence ATemporary stabilization of the patient can be achievedby adequate uid replacement, intra-aortic ballooncounter-pulsation, pharmacological inotropic support,nitrates and articial ventilation. Repeated bloodsamples for monitoring of electrolytes, glucose, renalfunction,andarterialbloodgasesshouldbetaken,par-ticularly in diabetic patients.Metabolic support with high-dose glucose, insulin, andpotassiumcannotberecommended(exceptindiabeticpatients) until theresults fromlarger-scalestudies inAMI become available.156Class II recommendation, level of evidence AWhen the haemodynamic state continues to beunstable for several hours, the introduction of anin-dwellingPACmaybeconsidered.Repeatedmeasure-ments of mixed venous bloodoxygen saturation fromthe PAC can be helpful.Class II recommendation, level of evidence BWhen all these measures fail to achieve stabilization ofthe haemodynamic status,mechanicalsupport with a LVassistdeviceshouldbeconsidered,particularlyifhearttransplantation is contemplated.In left heart failure/pulmonary oedema the acutemanagement is similar to that for other causes ofESC Guidelines 403 by guest on December 3, 2010eurheartj.oxfordjournals.orgDownloaded from Figure7 Algorithm:AHFinAMI.IABP intra-aorticballoonpump;VSR ventricularseptalrupture;PAC pulmonaryarterycatheterization;TEE trans-esophageal echocardiography; EF ejection fraction; MR mitral regurgitation; IVS intraventricular septum; SAM systolic anterior movement;RA right atrium; RV right ventricle; PCI percutaneous coronary intervention; Qp:Qs pulmonary circulation volume:systemic circulation volume.404 ESC Guidelines by guest on December 3, 2010eurheartj.oxfordjournals.orgDownloaded from pulmonary oedema. Inotropic agents may be deleterious.Intra-aorticballooncounter-pulsation(IABC) shouldbeconsidered.155,157,158The long-termmanagement strategy should includeadequatecoronary revascularizationand, wherethereis evidence of reduced LV function, long-termtreat-ment with renin angiotensin aldosterone system(RAAS)-inhibition andb-blockade should follow.Acuteright heart failureis usuallyrelatedtoacuteRVischaemiainacutecoronarysyndromes,particularlyRV infarction with a characteristic electro- andecho-cardiogram. Early revascularization of the rightcoronary artery and its ventricular branches is rec-ommended. Supportive treatment should focus onuid-loading and inotropic support.11.2. Valvular diseaseAHF can be caused by valvular conditions unrelatedtoacutecoronarysyndromes, suchas acutemitral oraortic valve incompetence, acutevalve incompetencefromendocarditis,aorticormitral stenosis,thrombosisof a prosthetic valve, or aortic dissection.In patients with endocarditis, treatment is initiallyconservativewithantibiotics andother medical meansoftreatmentofAHF.Cardiacdysfunctionmaybeaggra-vatedby myocarditis. However, acute valve incompe-tence is the most common cause of AHF in patientswith infective endocarditis. Heart failure should bepromptly treated. Rapid diagnosis and therapeuticdecisions require expert consultation. Surgical consul-tations arewarranted. Surgical interventionshouldbeperformed early in severe acute aortic or mitral regurgi-tation (ML).Urgent surgery is indicated in patients with endocardi-tis and severe acute aortic regurgitation.15916311.3. Management of AHF due to prosthetic valvethrombosis (PVT)AHF from prosthetic valve thrombosis is associated with ahigh mortality.164167All patients with heart failure symp-toms and suspected PVTshould undergo chest uoroscopyand an echocardiographic study (transthoracic and/ortransoesophagealifvisualizationoftheprostheticvalvearea is inadequate).Class I recommendation, level of evidence BThemanagementremainscontroversial.Thrombolysisis used for right-sided prosthetic valves, and forhigh-risk surgical candidates. Surgery is preferred forleft-sided PVT.Class IIa recommendation, level of evidence BThrombolytic therapy is not effective when broustissue ingrowth (pannus) is implicated in the obstructionwith minor secondary thrombosis.In patients with very large and/or mobile thrombi,thrombolytictherapyis associatedwithamuchhigherrisk for major embolism and stroke. In all these patientssurgical intervention should be considered as an alterna-tive. Before deciding therapy, pannus formation orstructural defects of the prosthetic valve should beruled out by transoesophageal echocardiography.168Echocardiographyshouldbeperformedinallpatientsafterthrombolytictherapy.Surgicalinterventionshouldbe considered in all cases if thrombolysis fails toresolvetheobstructionalthoughrepeatedinfusions ofthrombolytic thera