Rev Port Cardiol. 2018;37(11):935---945

www.revportcardiol.org

Revista Portuguesa de

CardiologiaPortuguese Journal of Cardiology

REVIEW ARTICLE

A 2018 overview of diuretic resistance in heart failure

Sofia Isabel Jardima,∗, Luís Ramos dos Santosb, Inês Araújoc,d, Filipa Marquesc,d,Patrícia Brancoe, Augusta Gaspare, Cândida Fonsecac,d

a Unidade Funcional Medicina 1.2, Hospital de São José, Centro Hospitalar de Lisboa Central, Lisbon, Portugalb Servico de Medicina Interna, Hospital Central do Funchal, Funchal, Portugalc Unidade de Insuficiência Cardíaca, Servico de Medicina III, Hospital São Francisco Xavier, Lisbon, Portugald NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugale Servico de Nefrologia, Hospital de Santa Cruz, Centro Hospitalar de Lisboa Ocidental, Lisbon, Portugal

KEYWORDSHeart failure;Diuretic resistance;Loop diuretic;Sequential nephronblockade;Ultrafiltration

Abstract Heart failure is a disease with high direct and indirect costs. Current treatmentincludes drugs that alter disease progression and drugs that to improve symptoms. Loop diureticsare the cornerstone of congestion relief for acute management, as well as for chronic stabiliza-tion. In heart failure patients, maximal diuretic response is reduced by many individual factors.Diuretic resistance is defined as failure to achieve effective congestion relief despite appropri-ate or escalating diuretic doses. Its causes include impaired delivery of the diuretic to its luminalsite of action, neurohormonal activation, tubular compensatory adaptation and drug interac-tions. Several strategies can be employed to aid decongestion of patients with impaired diureticresponse. These include salt restriction, a higher effective single dose or higher dose frequencyof loop diuretics, continuous infusion of diuretics and/or sequential nephron blockade througha synergistic combination of two or more diuretics from different classes. Ultrafiltration hasalso been found to be another effective and safe therapeutic option and should be consideredin patients with refractory diuretic resistance. Overall, there is a lack of high-quality clinicaldata to guide the choice of treatment strategy and therapy should be tailored on a case-by-casebasis.© 2018 Sociedade Portuguesa de Cardiologia. Published by Elsevier Espana, S.L.U. This is anopen access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

PALAVRAS-CHAVE A resistência aos diuréticos na insuficiência cardíaca revisitada em 2018

ardíaca é uma doenca com custos diretos e indiretos elevados. Aacos que alteram a progressão da doenca e fármacos que melhoram

icos de ansa constituem a pedra basilar no alívio da congestão quera estabilizacão crónica. Nos doentes com insuficiência cardíaca, a

encontra-se diminuída devido a múltiplos fatores. A resistência aos

Insuficiênciacardíaca;Resistência aosdiuréticos;Diuréticos de ansa;

Resumo A insuficiência cterapêutica atual inclui fárma sintomatologia. Os diurétna abordagem aguda quer nresposta diurética máxima

∗ Corresponding author.E-mail address: sofiaisabeljardim@gmail.com (S.I. Jardim).

https://doi.org/10.1016/j.repc.2018.03.0140870-2551/© 2018 Sociedade Portuguesa de Cardiologia. Published by Elsevier Espana, S.L.U. This is an open access article under the CCBY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

936 S.I. Jardim et al.

Bloqueio sequencialdo nefrónio;Ultrafiltracão

diuréticos é definida como a ausência de alívio eficaz da congestão apesar de doses apropriadasou crescentes de diuréticos. As causas de resistência aos diuréticos incluem o compromisso daentrega de diurético no seu local de acão, a ativacão neuro-hormonal, a adaptacão compen-satória tubular e interacões medicamentosas. Podem ser implementadas várias estratégias paradiminuir a congestão em doentes com resposta diurética insuficiente. Essas estratégias incluemrestricão salina, aumento da dose ou frequência dos diuréticos de ansa, infusão contínua dediuréticos e/ou bloqueio sequencial do nefrónio através da combinacão de dois ou mais diuréti-cos de diferentes classes e com efeitos sinérgicos. A ultrafiltracão tem-se revelado uma outraestratégia segura e eficaz e deve ser considerada em doentes com resistência aos diuréticosrefratária. Verifica-se globalmente uma escassez de dados clínicos de elevada qualidade paraguiar a escolha da estratégia terapêutica pelo que a abordagem deve ser adequada caso a caso.© 2018 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier Espana, S.L.U. Este e umartigo Open Access sob uma licenca CC BY-NC-ND (http://creativecommons.org/licenses/by-nc-nd/4.0/).

RAPID-CHF Relief for Acutely Fluid-OverloadedPatients With Decompensated CongestiveHeart Failure

ROSE Renal Optimization Strategies EvaluationRAA Renin-angiotensin-aldosteroneREWORD-HF Reverse Worsening Renal Function in

Decompensated Heart FailureUF UltrafiltrationUNLOAD Ultrafiltration versus Intravenous Diuretics

for Patients Hospitalized for Acute Decompen-sated Congestive Heart Failure

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gatadloop diuretics.6---8 Loop diuretics are the cornerstone ofcongestion relief and are widely used for acute man-agement (up to 90% of patients) as well as for chronic

2,5,8---10

Abbreviations

ATOMIC-HF Acute Treatment with Omecamtiv Mecar-bil to Increase Contractility in Acute HeartFailure

BNP B-type natriuretic peptideBLAST-AHF Biased ligand of the angiotensin II type 1

receptor in patients with acute heart failureCARRESS-HF Cardiorenal Rescue Study in Acute

Decompensated Heart FailureCKD Chronic kidney diseaseCUORE Continuous Ultrafiltration for Congestive

Heart FailureDOSE Diuretic Optimization Strategies EvaluationDAD-HF II Dopamine in Acute Decompensated Heart

Failure IIRELAX-AHF-2 Efficacy, Safety and Tolerability of Sere-

laxin When Added to Standard Therapy inAcute Heart Failure

RELAX-AHF Efficacy and Safety of Relaxin for theTreatment of Acute Heart Failure

TRUE-AHF Efficacy and Safety of Ularitide for theTreatment of Acute Decompensated HeartFailure

EVEREST Efficacy of Vasopressin Antagonism in HeartFailure Outcome Study with Tolvaptan

EPICA Epidemiologia da Insuficiência Cardiaca eAprendizagem

HF Heart failureNT-proBNP N-terminal pro---BNPNSAID Nonsteroidal anti-inflammatory drugPROTECT Placebo-Controlled Randomized Study of

the Selective Adenosine A1 Receptor Antago-nist Rolofylline for Patients Hospitalized withAcute Decompensated Heart Failure and Vol-ume Overload to Assess Treatment Effect onCongestion and Renal Function

REVIVE Randomized Multicenter Evaluation of Intra-venous Levosimendan Efficacy

s

ULTRADISCO Ultrafiltration vs. Diuretics in Decompen-sated Heart Failure

ntroduction

he incidence of heart failure (HF) is 1% among Americanatients over 65 years of age.1,2 Portuguese figures from the002 Epidemiologia da Insuficiência Cardiaca e Aprendiza-em (EPICA) study concluded that the overall prevalencef HF is 4.4%, peaking at 16% in those over 80 years ofge.3 It continues to be the primary discharge diagnosismong elderly American patients.4 Hospitalization for HFonstitutes an ominous sign, with half of patients read-itted in the subsequent six months and a mortality rate

f 25-35% at the end of the first year.4,5 Consequently, HFs a high burden disease with elevated direct and indirectosts.1

Current treatment includes drugs that alter disease pro-ression such as angiotensin converting enzyme inhibitors,ngiotensin II receptor blockers or, more recently, sacubi-ril/valsartan, beta-blockers and mineralocorticoid receptorntagonists --- in HF with reduced ejection fraction --- andrugs used to improve symptoms such as diuretics, namely

tabilization.

A 2018 overview of diuretic resistance in heart failure 937

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Despite the fact that diuretics themselves are not linkedto increased survival,6,8 diuretic efficacy has been shown toprolong event-free survival, regardless of glomerular filtra-tion rate.5,11---13

In this review, we discuss the underlying pathophysio-logy of diuretic resistance in HF patients, while providingseveral currently available evidence-based pharmacologicaland non-pharmacological strategies to overcome this prob-lem (Figure 1). The aim of this article is to summarize theexisting data and highlight recent research on the subject,providing an up-to-date and practical approach to diureticresistance.

Diuretic resistance --- defining the problem

There is ample variation in the definition of diuretic-resistant patients.13 The general definition refers to thefailure to achieve effective congestion relief despite appro-priate or escalating doses of diuretics.14,15

Some early reports estimated the prevalence of diureticresistance to be 20-30% among HF patients.16,17 However, thelack of a formal definition makes it impossible to properlyassess the numbers.9,13,15

Recent data link furosemide-equivalent doses of loopdiuretics (for intravenous diuretics, 1 mg of bumetanide,20 mg of torsemide and 40 mg of furosemide11) to changesin several parameters such as weight loss, urine output ornatriuresis as means to diagnose diuretic resistance.13 These

studies are summarized in Table 1.

Depending on the study, poor diuretic response may bedefined as: a weight change of 0 to 2.7 kg per 40 mg offurosemide (or equivalent)18; a urinary diuretic response

idiu

pproach to diuretic resistance.

1400 ml per 40 mg of furosemide (or equivalent)18; fractional excretion of sodium at baseline <0.2%19; urinary sodium concentration and urinary furosemideoncentration ratio (both obtained from spot urine samples)2 mmol/mg12; and/or lower chloride levels at baseline (97o 103 mEq/l).20 However, the correlation between differ-nt metrics remains poor and there is no cut-off to establishctual diuretic resistance.13 Prospective trials are needed toroperly validate these metrics.21

Predictors of diuretic resistance, on the other hand, areore firmly established between studies and include: low

ystemic blood pressure, elevated blood urea nitrogen, HFf ischemic origin and diabetes.5,11,18,22 These studies alsoound that diuretic resistance is an independent predictorf worse in-hospital outcomes for HF, early post-dischargeortality and increased HF rehospitalization.

harmacokinetics & pharmacodynamicsf loop diuretics

he relationship between loop diuretic concentration andatriuresis can be illustrated through an S-shaped dose-esponse curve,14 which means that a minimal concentrationust be reached at the site of action before any response

s noted.8 A normal dose-response relationship can be dis-orted by a variety of clinical conditions. In HF patients, theurve is shifted downwards and to the right, which translates

nto a decreased maximal diuretic response.8 Furthermore,uring hospitalization, diuretic response is affected by manyndividual factors14 including, but not limited to, renal fail-re, which also shifts the curve to the right, meaning a

938 S.I. Jardim et al.

Table 1 Relationship between diuretic efficacy and clinical outcomes in heart failure.

Author (year) Metric Findings in patients with low diuretic efficacy

Testani et al. (2014)11 Net fluid loss Higher all-cause mortality after 5 years (PennCohort)/180 days (Evaluation Study of Congestive HeartFailure and Pulmonary Artery CatheterizationEffectiveness Cohort)

Valente et al. (2014)5 Weight loss Higher heart failure readmissions after 60 daysHigher death, heart failure or renal-relatedreadmissions after 60 daysHigher all-cause mortality after 180 days

Voors et al. (2014)22 Weight loss Higher death, heart failure or renal-relatedreadmissions after 60 daysNeutral effect on all-cause mortality after 180 days

Singh et al. (2014)12 Urinary sodiumFurosemide concentration

Higher death, transplantation or heart failurereadmission after 5 months

ter Maaten et al. (2015)18 Weight lossUrine output

Higher death or heart failure readmission after 30 days

Verbrugge et al. (2015)10 Natriuresis Higher death or heart failure readmission after 188 daysKumar et al. (2015)19 Fractional sodium excretion Higher all-cause mortality after 30 daysTer Maaten et al. (2016)20 Chloride levels Higher mortality through 180 daysAronson et al. (2016)56 Net fluid loss Higher all-cause mortality after 6 months

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igher dose of diuretics is needed to achieve the sameegree of natriuresis.8

athophysiology of diuretic resistance

he pathophysiology of diuretic resistance is complex andeveral causes may be involved (Table 2).15 It stems fromultiple factors, including reduced delivery of the diuretic

o its luminal site of action, neurohormonal activation, tubu-ar compensatory adaptation and drug interactions.15

educed delivery of the diuretic to its site of action

educed delivery of the diuretic to its site of action is closelyelated to its decreased bioavailability.

In HF patients, increased peripheral and bowel walldema leads to reduced absorption of the diuretic, with aore marked effect when oral furosemide is used.21

HF itself as well as concurrent chronic kidney diseaseCKD) (urate and other competing organic acids) may leado decreased glomerular filtration rate, which in turnseads to impaired secretion of diuretics (namely furosemide)y the organic acid transporter into the proximal tubule.educed glomerular filtration rate can, therefore, reduceelivery or reduce active secretion of loop diuretics intoheir site of action.23 Moreover, CKD has been proposeds a contributing factor to the development of HF overall,egardless of left ventricular ejection fraction. CKD leads toolume retention, altered calcium---phosphate metabolism,yperparathyroidism, vitamin D deficiency, anemia, and theccumulation of uremic toxins.24 Renal dysfunction caused

y intra-abdominal hypertension and cardiorenal syndromere also plausible mechanisms of diuretic resistance throughenous congestion.9,25 Intra-abdominal hypertension reliefmproves renal perfusion, renal filtration and diuresis. It

tHa

s usually present in up to 60% of acutely decompensatedF patients.25 It is very important to emphasize the needo detect third-space overload as opposed to intravascu-ar overload because both the kidneys and diuretic therapyan only act in vascular overload. Persistent diuretic usen patients who are already suffering from intravascularolume depletion further activates the renin-angiotensin-ldosterone (RAA) axis and makes diuretic resistanceependent on renal blood flow. Urinary sodium and chlo-ide measurements may indicate when vascular volumeas been optimized because they decrease as euvolemiapproaches.13 These may serve as more reliable markersf decongestion as opposed to the clinical signs and symp-oms traditionally used to guide decongestive therapy.26

linical signs and symptoms lack sensitivity and specificityut do raise the need for further clinical evaluation. Natri-retic peptides are helpful for diagnosis and prognosis butack the power to properly monitor volume status.26 Newerpproaches point to quantitative blood volume analysis aseans to differentiate hypervolemia profiles. Appropriaterofiling of volume overload in HF, according to blood vol-me, has therapeutic implications and may aid patientsith diuretic resistance, redirecting them to other formsf decongestion.26

Another mechanism of diuretic activity impairmentnvolves increased re-absorption of sodium and chloride inhe proximal tubule, leading to decreased delivery of theseubstrates to the distal areas of the nephron where loopiuretics act. This mechanism causes diuretic resistancehrough decreased substrate availability to the sodium-otassium-chloride cotransport system.13

Albumin levels also correlate to diuretic action because

hey are high affinity albumin-binding molecules (>90%).9

ypoalbuminemia increases the drug distribution volumend prevents suitable kidney delivery. On the other hand,

A 2018 overview of diuretic resistance in heart failure

Table 2 Causes of diuretic resistance.

Incorrect diagnosisVenous edemaLymphatic edemaThird space overload with intravascular volume depletion

Nonadherence to recommended sodium and/or fluidrestriction

Poor diuretic delivery to the nephron lumenNonadherenceDose too low or too infrequentPoor absorption (example: edematous gut)Hypoalbuminemia and nephrotic syndromeHepatic cirrhosis

Reduced diuretic secretionTubular uptake of diuretic impaired by uremic toxinsDecreased kidney blood flowDecreased functional kidney mass

Insufficient kidney response to drugLow glomerular filtration rateDecreased effective intravascular volume despite elevatedtotal extracellular fluid volumeActivation of the renin-angiotensin-aldosterone axis andrenal sympathetic nervesIncreased sodium delivery and absorption in distal tubularsegmentsCompensatory retention of sodium after the effectiveperiod of the diureticNephron adaptation (hypertrophy and hyperplasia of distaltubular cells)

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high levels of albuminuria decrease loop diuretic deliv-ery. Increased urine albumin binds to diuretics, preventingtheir ligation to the sodium-potassium-chloride receptorsand thus impairing their action.9

Neurohormonal activation

Neurohormonal activation is strongly related to RAA axisupregulation. Loop diuretics can activate the RAA axisthrough a variety of mechanisms.15 They induce renin secre-tion through the direct blockade of the macula densasodium-potassium-chloride cotransport system, thus leadingto increased renin and aldosterone in a volume-independentpathway.8 Furthermore, diuretics induce renal prostacy-clin production, which increases renin secretion. Finally,diuretics induce volume contraction, thus activating reninsecretion through vascular stimulation.8 RAA axis activationeventually leads to increased sodium reabsorption, prom-pting the onset of post-diuretic sodium retention and thebraking phenomenon.15 Post-diuretic sodium retention isone of the processes through which diuretic resistance maybe established and it arises as soon as the concentration

of diuretic in the tubular fluid drops below the therapeuticthreshold.15 A negative net sodium balance in the 24 hoursbetween natriuresis and post-diuretic sodium retention maynot be achieved in the event of dietary noncompliance,

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939

endering the diuretic effect insignificant.15 The brakinghenomenon, on the other hand, is defined as the decreasen diuresis volume after multiple same-dose administrationsf diuretic. This is linked to RAA axis activation and com-ensatory changes in the nephron.9

ubular compensatory readaptation

ubular readaptation is another mechanism that helpsxplain reduced diuretic response.21 Owing to the above-entioned activation of the RAA axis, as well as the brakinghenomenon, proximal tubular reabsorption arises, leadingo increased sodium uptake in this area of the nephron.21

imultaneously, the chronic use of loop diuretics --- whichnhibit sodium uptake in the loop of Henle --- leads toncreased sodium delivery to the distal tubular system,esulting in compensatory hyperplasia and hypertrophy.9

his means that the patient would retain more sodium andhus water than a diuretic-naïve patient.13,21 This resistanceechanism can be overcome using a sequential nephronlockade with thiazide diuretics.9

rug interactions

ome drugs, such as nonsteroidal anti-inflammatory drugsNSAIDs), can reduce the effect of diuretics.21

NSAIDs may cause diuretic resistance in a numberf ways, particularly: decreased prostaglandin synthesis,ecreased renal vasodilation, increased renal reabsorptionn areas of the nephron other than the loop of Henle andypertension.9 Evidence regarding the effect of low-dosespirin (<1 mg/kg/day) on diuretic response in particu-ar is more scarce and controversial. A previous studyeported that chronic low-dose aspirin could profoundlyffect platelet prostaglandin production without affect-ng diuretic-stimulated renal prostacyclin production orlasma renin activity.27 However, more recently, Jhund et al.emonstrated that the venodilation that occurs follow-ng furosemide administration could be inhibited by bothigh and low dose-aspirin.28 Furthermore, Hall noted anmportant reduction in the need for diuretics when dailyspirin administration was stopped.29 There is also somevidence that aspirin, even at a low dose, may neutral-ze the favorable effects of angiotensin-converting enzymenhibitors by blocking prostaglandin production and enhanc-ng the vasoconstrictor potential of endothelin.30 In patientsith HF, aspirin should be avoided wherever possible andther antithrombotic agents that respect the integrity ofrostaglandin metabolism should be considered.

reatment options for diuretic resistance

verall, there is a lack of high-quality clinical data touide the choice of treatment strategy to overcome diureticesistance.31 Several strategies can be employed to aidecongestion in patients with acute HF manifesting anmpaired diuretic response. These include diuretic andondiuretic strategies (Table 3).21

Before considering the following treatment options,ther causes of apparent diuretic resistance, such as third-pace overload with intravascular volume depletion, muste ruled out.

940 S.I. Jardim et al.

Table 3 Strategies for treating diuretic resistance.

Strategy Summary of evidence Recommendation

Initial measuresIntravenous diuretics Improved pharmacokinetics in compensated

heart failureInitial measure in hospitalizedpatients

Increase diuretic dose Doses of ≥500 mg/day of oral furosemidewere safeHigh intravenous doses were safe and weremore effective

Consider in mildly symptomaticambulatory patients

Use alternative loop diuretic(bumetanide and torsemide)

Greater enteral absorption and lessaffected by edematous states

Consider in case of poor response tooral furosemide

Continuous infusion Lower total daily doses to elicit the samedegree of natriuresis compared to bolusdoses without better symptom relief orcreatinine improvements

Consider in case of inadequateresponse to bolus doses

Combination of intravenous loopdiuretics with one or more diureticsfrom different classes

- Thiazide/Metolazone --- Increased urinesodium and/or weight loss- Acetazolamide --- increased diuresis

Consider in case of inadequateresponse to increasing doses of IVloop diuretics

- Mineralocorticoid receptor antagonist ---increased diuresis and faster symptom relief

Consider in ambulatory oroutpatients with an inadequateresponse to loop diuretics

Advanced measuresHypertonic saline infusion Improved diuresis and renal function, and

shortened hospitalizationsConsider when the above optionshave failed

Dopamine Similar urine output when added tolow-dose intravenous furosemide comparedwith high-dose intravenous furosemidealoneSubsequent trials have failed todemonstrate a benefit

Consider only when all other optionshave failed

Nesiritide No improvement in urine output, hospitalality

Should not be used in loop diuretic

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alt restriction

ietary sodium restriction is a key determinant of diureticfficacy. When dietary sodium intake is high, post-diureticodium retention compensates almost entirely for the loop-iuretic-induced sodium loss. Conversely, if sodium intakes restricted, post-diuretic sodium retention is minimized,esulting in a negative fluid and sodium balance.32 Thus,estricting sodium intake to less than 100 mEq/day mit-gates the effect of post-diuretic sodium retention andelps achieve a negative sodium balance. A 24-hour uri-ary sodium excretion of more than 100 mEq/day or aractional excretion of sodium value >2% indicates non-ompliance with sodium restriction and rules out trueiuretic resistance.15

iscontinue concomitant use of nonsteroidalnti-inflammatory drugs

oncomitant use of NSAIDs is a major cause of diureticailure and discontinuing them can significantly improveiuretic effectiveness.15

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stablish the effective single dose

iuretics have a dose-response curve and the effect onlyegins once the diuretic level reaches a therapeutic thresh-ld within the renal tubular lumen. In conditions such as CKDnd cardiorenal syndrome, the dose-response curve shiftsownwards and towards the right. This means that theseatients need higher doses of loop diuretics to achieve theherapeutic drug level at the site of action. Diuretic doseselow said threshold are ineffective, so a higher effectiveingle loop diuretic dose is needed rather than administeringn inadequate dose more frequently.15

ncrease dose frequency of loop diuretics

ecause most loop diuretics are short acting, increasinghe dose frequency can help overcome post-diuretic sodiumetention and restore diuretic response.15

iuretic substitution

astrointestinal absorption and the bioavailability of dif-erent diuretics belonging to the same class can vary

A 2018 overview of diuretic resistance in heart failure 941

Table 4 Dosage regimens for continuous intravenous diuretic administration.

Creatinine clearance (ml/min) Loading dose (mg) Infusion rate (mg/h)

All levels <25 25-75 >75

Furosemide 40 20 then 40 10 then 20 10Bumetanide 1 1 then 2 0.5 then 1 0.5Torsemide 20 10 then 20 5 then 10 5

can be an effective approach in resistant cases (Table 5).15

For edematous disorders other than liver cirrhosis andascites, the evidence for specific diuretic combinations isless clear.36 The use of a loop diuretic and a thiazide orthiazide-like diuretic with or without a potassium-sparingagent is most common in practice.15 Nevertheless, in theabsence of evidence on the comparative efficacies of thevarious diuretic combinations, choosing a strategy should bebased on patient-specific factors and the side effect profilesof the different combinations.31

Thiazide diuretics inhibit sodium reabsorption in thedistal convoluted tubule and can thus counteract com-pensatory distal tubular hypertrophy.31 Metolazone andhydrochlorothiazide are the two thiazides most commonlyused in combination with furosemide, although there isno clear evidence that one is superior to the other, nei-ther in terms of their efficacy in increasing diuresis northeir safety with regard to renal function and electrolyteabnormalities.32,37,38 When initiating combination therapy,thiazides should be administered before intravenous loopdiuretics to allow enough time for the full blockade of thedistal nephron.32 Case studies and small observational tri-als reported effective diuresis in 75-90% of patients whoreceived thiazide diuretics in addition to loop diuretictherapy.31 However, one drawback of thiazide-type diureticsis that they limit the kidneys’ capacity to produce dilutedurine and thus free water clearance and they should there-fore be avoided in hypotonic hyponatremia.13

There is a paucity of data regarding specific mineralo-corticoid receptor antagonists use in acute HF and thecombination of spironolactone and loop diuretics has notbeen shown to be synergistic. Nevertheless, said drugs

Table 5 Combination diuretic therapy.

To an effective or maximal safe dose of a loop diuretic add:

Distal convoluted tubule diureticsMetolazone 2.5-10 mg per os daily (duration or frequencyadjusted based on the target weight)Hydrochlorothiazide (or equivalent) 25-100 mg per os dailyChlorothiazide 500-1000 mg intravenously

Proximal tubule diureticsAcetazolamide 250-375 mg daily or up to 500 mgintravenously

Potassium-sparing diuretics

Adapted from Brater (2011).35

considerably and this could be a factor behind a poorresponse. Furosemide has a bioavailability of about 50%,whereas torsemide and bumetanide have almost completeabsorption (80-100%). At times, replacing furosemide withcomparable doses of bumetanide or torsemide can beenough to improve diuresis.15

Intravenous diuretics

Sometimes, administering diuretics intravenously insteadof orally is all that is needed to improve diuresis. Oralabsorption may be altered in the presence of gastroin-testinal edema, gastroparesis and delayed gastric emptying.Drug concentration at the site of diuretic action in thetubule lumen may be inadequate, due to decompensatedHF, renal hypoperfusion or impaired secretion as a result ofhypoalbuminemia.32

Compared to bolus doses, continuous diuretic infusionmay be more effective in improving diuresis. It may decreasefluctuations in intravascular volume, resulting in a moregradual and relatively constant hourly urine output andlimiting the effect of post-diuretic sodium retention. Somestudies found that furosemide administered as a contin-uous infusion was more effective than intermittent bolusdoses, since significantly less furosemide was required toproduce the same diuresis and due to the elimination of adiuretic-free interval (during which compensatory sodiumretention occurs). Said studies found no significant differ-ences in adverse effects and no change in serum creatinineor hospital mortality.33,34 Other studies reported that bothregimens were equally effective in achieving a negative fluidbalance.32 In the Diuretic Optimization Strategies Evalua-tion (DOSE) trial, there were no significant differences inpatients’ global symptom assessment or in the change inrenal function between the two strategies.2 Despite theconflicting evidence, pharmacodynamic concepts supportthe improved efficacy of continuous infusion of all loopdiuretics except ethacrynic acid. A bolus dose of a loopdiuretic should be administered before initiating a con-tinuous infusion or when the infusion rate is increased inorder to decrease the time for the drug’s onset of action(Table 4).32,35

Sequential nephron blockade

A sequential sodium uptake blockade in different nephronsegments by means of a combination of two or morediuretics from different classes may produce an additive orsynergistic mechanism of action and diuretic response, and

Spironolactone 100-200 mg dailyAmiloride 5-10 mg daily

Adapted from Ellison (2001).8

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xhibit mild but effective natriuretic effects and minimizeotassium wasting by loop diuretics.8,13 Moreover, spirono-actone or eplerenone are recommended in all symptomaticatients (despite treatment with an angiotensin-convertingnzyme inhibitor and a beta-blocker) with HF and a reducedjection fraction in order to reduce mortality and HFospitalization.31 Therefore, there may be a strong rationaleo continue and even increase dosing of these drugs whenhe glomerular filtration rate is stable and serum potassiumevels are less than 5.5 mEq/l.8,13

While the diuretic and natriuretic capacity of acetazo-amide is poor on its own, it could well be a very efficientooster of diuretic efficacy. The combination of acetazo-amide and a loop diuretic can be very effective, blockingore than 90% of sodium reabsorption in the nephron.oreover, it reduces renin release with potentially favor-ble effects on neurohormonal activation. However, therere currently no data on the benefits of acetazolamides add-on therapy and long-term use can cause metaboliccidosis.13,15

Combination therapy is associated with a significantncrease in adverse effects such as electrolyte imbalances,ehydration and renal impairment. It requires careful mon-toring and is best reserved for the occasional patient withigh resistance to loop diuretics.15,32

anagement of intra-abdominal pressure

ntra-abdominal hypertension is defined as a sustained intra-bdominal pressure of 12 mmHg or above. Splanchnic andnterstitial congestion may cause elevated intra-abdominalressure in the absence of ascites in acute decompensatedF. In such patients, a rise in intra-abdominal pressure

ncreases renal venous pressure, thereby reducing the tran-renal perfusion gradient and renal perfusion. Elevatedntra-abdominal pressure also causes increased renal inter-titial pressure that opposes net filtration pressure. Bothontribute to renal impairment and diuretic resistance.hen intravenous loop diuretic therapy fails, measuring

ntra-abdominal pressure is an inexpensive and minimallynvasive procedure that rules out a diuretic resistance cause.f intra-abdominal hypertension or abdominal compartmentyndrome (defined as a sustained intra-abdominal pressuref >20 mmHg which is associated with new organ dysfunc-ion) is identified, a reduction in intra-abdominal pressurey mobilizing third-space fluid can be achieved through

combination of diuretics, vasodilators and/or inotropes.bundant ascites can be managed with paracentesis, ultra-ound or computer tomography guidance if needed. Inertain patients, ultrafiltration (UF) may be appropriate.he therapeutic aim is to achieve an abdominal perfusionressure (calculated as the mean arterial pressure minushe intra-abdominal pressure) of over 60 mmHg (with anntra-abdominal pressure of 5 to 7 mmHg), which signifies

favorable outcome (improvement in renal perfusion, renalltration and diuresis).25

nfusion with albumin

imultaneous infusion of a diuretic and albumin couldlightly improve diuretic resistance. A meta-analysis of eight

ldof

S.I. Jardim et al.

andomized clinical trials of adults with hypoalbuminemia,omparing the co-administration of loop diuretics and albu-in versus loop diuretics alone, found transient effects ofodest clinical significance with the former strategy.39 How-

ver, this intervention should only be considered in severelyypoalbuminemic patients when the approaches discussedbove have failed.15

enal-dose dopamine

ow doses of dopamine (<3 �g/kg/min) selectively work oneripheral dopaminergic receptors resulting in vasodilationn the renal, coronary, splanchnic and cerebral circulations.wo recent trials of dopamine in acute HF --- the Dopamine incute Decompensated Heart Failure II (DAD-HF II) trial andhe Renal Optimization Strategies Evaluation (ROSE) trial ---ave shown no added benefit with the addition of dopamineo standard therapy with high-dose diuretics. Thus, on theasis of current data, dopamine has no role in nonhypoten-ive patients with acute HF. In the absence of cardiogenichock, however, the role of low-dose dopamine in acute HFith hypotension merits further study.21,31

lternative pharmacological therapies

ypertonic saline works osmotically to pull free water fromhe interstitial fluid into the renal vasculature. In additiono increasing renal blood flow, it improves sodium deliveryo the loop of Henle, thus restoring some of the loop diuret-cs’ effect. Several studies have reported better diuresis,mproved renal function and shorter hospital stays whenypertonic saline is added to loop diuretic therapy.31

Nesiritide is a synthetic B-type natriuretic peptide (BNP)pproved by the Food and Drug Administration for symp-omatic relief due to its favorable effects on hemodynamics,yspnea and renal function. However, both the ROSE trialnd ter Maaten et al. (2015) found no additive effect ofsing low-dose nesiritide added to diuretic therapy in termsf decongestion or improved renal function. Experimentalesearch has shown that renal delivery of BNP had signifi-antly greater beneficial effects than systemic delivery. Itould be that a higher systemic dose is needed; however,he usage thereof would increase the incidence of adverseffects such as hypotension.18,40

Furthermore, it is worth noting that HF trials on nesiritidend dopamine have not been specific to patients exhibiting

resistance to loop diuretics.31

Vasopressin-2-receptor antagonists may promote aquare-is by blocking the effects of vasopressin on the vasopressin

receptors located in the collecting ducts, thus blockinghe re-absorption of free water. This promotes water clear-nce without affecting sodium balance. In the Efficacy ofasopressin Antagonism in Heart Failure Outcome Study witholvaptan (EVEREST) trial, tolvaptan at a dose of 30 mg onceaily for a minimum of 60 days had no effect on total mor-ality or HF hospitalization when compared to placebo.21,41

Adenosine antagonists can potentially increase glomeru-

ar filtration and enhance the diuretic effect of diureticrugs. However, the Placebo-Controlled Randomized Studyf the Selective Adenosine A1 Receptor Antagonist Rolo-ylline for Patients Hospitalized with Acute Decompensated

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A 2018 overview of diuretic resistance in heart failure

Heart Failure and Volume Overload to Assess TreatmentEffect on Congestion and Renal Function (PROTECT) trialdid not report any beneficial effects on congestion orrenal function and was associated with an increased risk ofseizures.21,42

Glucocorticoids may promote diuresis and protect renalfunction in patients with acute HF. Liu et al. reported theeffects of prednisolone in 13 congestive HF patients withsignificant volume overload and diuretic resistance whohad failed to respond to a conventional sequential nephronblockade treatment strategy. They reported an improve-ment in diuresis, clinical status and renal function.43 Thesame author later reviewed the available evidence and con-cluded that the short-term use of glucocorticoids, whenadded to maximum conventional therapy, can potentiaterenal responsiveness to diuretic therapy in patients withHF.44 However, larger randomized double-blind placebo-controlled studies are warranted to demonstrate their safetyand efficacy in such patients. The proposed mechanismof action of glucocorticoids includes increased expressionof natriuretic peptide receptor-A in the kidney and thehypothalamus, which appear to be reduced in patients withHF, also increasing renal blood flow through dilatation of therenal vasculature via increased renal prostaglandin, nitricoxide and dopamine production.21,43,44

Levosimendan was studied in patients presenting withacute HF in the Randomized Multicenter Evaluation ofIntravenous Levosimendan Efficacy (REVIVE) studies. Theseshowed that levosimendan improved renal function anddiuretic response in such patients. However, there was alsoan increased risk of arrhythmia and hypotension.21

Ularitide, a human endogenous natriuretic peptideexpressed in the kidney, which induces natriuresis and diure-sis by binding to a specific natriuretic peptide receptor, wasinvestigated in patients with acute HF in the Efficacy andSafety of Ularitide for the Treatment of Acute Decompen-sated Heart Failure (TRUE-AHF) trial. Packer et al. reportedfavorable physiological effects (greater reductions in sys-tolic blood pressure and in levels of N-terminal pro---BNP[NT-proBNP] than the placebo group, without affectingcardiac troponin levels). However, short-term treatmentneither affected the initial 48-hour clinical course norreduced long-term cardiovascular mortality.21,45

In the Efficacy and Safety of Relaxin for the Treatment ofAcute Heart Failure (RELAX-AHF) trial, serelaxin, a humanrecombinant form of the vasodilator relaxin, showed no sig-nificant effect on diuretic response, but did have beneficialeffects in preventing organ damage in patients with acuteHF who were diuretic-resistant.21,46 The Efficacy, Safety andTolerability of Serelaxin When Added to Standard Therapyin AHF (RELAX-AHF-2) trial was designed to confirm sere-laxin’s effect on these clinical outcomes but it did not meeteither of its primary endpoints. There was no difference incardiovascular mortality at 180 days and the trend for reduc-ing worsening HF through day five with serelaxin was notstatistically significant.47

There are several other agents under investigation, whichcould play a role in aiding decongestion of patients pre-

senting with acute HF, such as omecamtiv mecarbil andTRV027.21

Omecamtiv mecarbil is a selective cardiac myosin activa-tor that increases myocardial function in healthy volunteers

wcit

943

nd in patients with chronic HF. Its effects on patients withcute HF were evaluated in the Acute Treatment with Ome-amtiv Mecarbil to Increase Contractility in Acute Heartailure (ATOMIC-HF) trial. This study showed that omecam-iv mecarbil may improve dyspnea scores when higher dosesere used in comparison to placebo; however, it did not

ignificantly improve overall dyspnea scores --- the primaryndpoint of the study.48

TRV027 is a novel ligand of the angiotensin II type receptor, selectively antagonizing the negative effectsf angiotensin II, while preserving the potential pro-ontractility effects of angiotensin II type 1 receptortimulation. Its safety and efficacy were assessed in theiased ligand of the angiotensin II type 1 receptor in patientsith acute heart failure (BLAST-AHF) trial and, although well

olerated, TRV027 did not improve clinical status through0-day follow-up compared to placebo.49

Further studies are needed to evaluate the safety andfficacy of these drug candidates in a larger group ofatients with acute HF.

ltrafiltration

F is very effective at removing plasma fluid from bloodcross a semipermeable membrane that allows smallolecules to pass through along its pressure gradient to the

ltrafiltrate fluid.21

Small studies suggest that UF improves pulmonary anderipheral edema, lung function and hemodynamics withoutdverse effects on renal function. The fluid removal rate iseevaluated using clinical assessment and serial hematocriteasurements to ensure appropriate vascular compartment

efill.21

The recent development of veno-venous peripheral UFas positioned this technique as a potential alternative tooop diuretics in acute HF.21

The Relief for Acutely Fluid-Overloaded Patients Withecompensated Congestive Heart Failure (RAPID-CHF) trial,

multicenter randomized controlled trial involving fortyatients, found that UF was feasible, well-tolerated, andesulted in significant weight loss and fluid removal.50

Favorable outcomes were also reported in the Ultra-ltration versus Intravenous Diuretics for Patients Hospi-alized for Acute Decompensated Congestive Heart FailureUNLOAD) trial. This prospective, randomized, multicenterrial involving 200 patients, found that UF safely producesreater weight and fluid loss than intravenous diuretics,educes 90-day resource utilization for HF and is an effectivelternative therapy.51

In the Ultrafiltration vs. Diuretics in Decompensated HFULTRADISCO) study, a prospective, randomized, open-label,ingle-center study which included 30 patients, the use ofF was associated with greater hemodynamic stability andith a greater reduction in plasma levels of NT-proBNP andldosterone compared to diuretic infusion.52

In the Continuous Ultrafiltration for Congestive Heartailure (CUORE) trial, UF as a first-line treatment in patients

ith severe congestive HF was associated with prolongedlinical stabilization and greater freedom from rehospital-zation for congestive HF compared to standard medicalherapy alone.53

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The Cardiorenal Rescue Study in Acute Decompensatedeart Failure (CARRESS-HF), however, found a steppedharmacologic-therapy algorithm to be superior to UF forhe preservation of renal function at 96 hours, with a simi-ar amount of weight loss seen with the two approaches and

higher rate of adverse events observed with UF.54

Results of the Reverse Worsening Renal Function inecompensated Heart Failure (REWORD-HF) study (whichnded in April 2017) are still pending and will help deter-ine whether fluid removal by UF is superior to differentharmacological approaches in acutely relieving congestionnd preventing further deterioration in renal function andhether it results in longer admission-free survival 90 daysfter enrolment in patients with decompensated HF and car-iorenal syndrome.

Seven randomized controlled trials, including several ofhose mentioned above, were submitted for a meta-analysis.F was found to be an effective and safe therapeu-ic strategy, resulting in greater weight loss and fluidemoval without affecting renal function, mortality orehospitalization.55

The 2016 European Society of Cardiology guidelines statehat there is no evidence favoring UF over loop diureticss first-line therapy in patients with acute HF. The formerhould thus be confined to patients who fail to respond toiuretic-based strategies.

onclusion

iuretic resistance has emerged as an independent factorehind worse HF patient outcomes, namely in-hospital wors-ning, early post-discharge mortality and rehospitalizations.hile several mechanisms help to explain their reduced

esponse to diuretics, the definition of the problem itselfemains elusive. More recent evidence is leaning towardshe coupling of parameters such as weight loss and urineutput to diuretic dose, but several challenges remain. Non-harmacological measures and a few medical options, suchs continuous infusion of diuretics and sequential nephronlockade, may be used to overcome diuretic resistance. Nev-rtheless, disease progression may warrant more invasiveethods for fluid removal. Therapy must be tailored on a

ase-by-case basis.

onflicts of interest

he authors have no conflicts of interest to declare.

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