Diuretic usage for protection against end‐organ damage in liver cirrhosis and heart failure

Volume overload is common in liver cirrhosis, heart failure, and chronic kidney disease, being an independent risk factor for mortality. Loop diuretics have been widely used for treating volume overload in these patients. However, there is a tendency to increase the dose of loop diuretics partly because of diuresis resistance. Neurohormonal factors are also enhanced in these patients, which play a role in volume overload and organ ischemia. Loop diuretics cannot improve neurohormonal factors and could result in end‐organ damage. The water diuretic tolvaptan has been approved for use for volume overload in heart failure and liver cirrhosis. Despite causing similar increases in urine volume, its characteristics differ from those of loop diuretics. Renal blood flow is maintained with tolvaptan but decreased with furosemide in heart failure patients. Neurohormonal factors and blood pressure are not markedly altered by tolvaptan administration. It is expected that these mechanisms of tolvaptan can protect against worsening renal function by volume overload diseases compared with loop diuretics. It has also been reported that some patients do not respond well to tolvaptan. Loop diuretics and tolvaptan share the same mechanism with regard to decreasing renal interstitial osmolality, which plays a fundamental role in water diuresis. Thus, a high dose of loop diuretics could result in resistance to tolvaptan, so tolvaptan should be administered before increasing the loop diuretic dose. Therefore, volume control without enhancing end‐organ damage can be achieved by adding tolvaptan to a tolerable dose of Na‐sparing diuretics.     

Effective Use of Loop Diuretics in Heart Failure Exacerbation: A Nephrologist's View

Unfortunately, patients with congestive heart failure suffer frequent admissions for the management of fluid overload. Loop diuretics are pivotal in the management of this common clinical problem. Although loop diuretics have been in clinical use since the 1960s, we still do not understand how to optimally administer these drugs. It is unknown why some decompensated heart failure patients exhibit improvements in renal function with diuresis, whereas others display renal function deterioration, limiting attainment of euvolemia. Here the physiologic interactions between the failing heart and kidneys are reviewed. A conceptual framework is presented that emphasizes the balance between tubuloglomerular feedback and venous congestion in determining renal function during loop diuretic use in heart failure. within this framework, guidelines are derived that seek to maximize the chance for achieving adequate volume removal while maintaining stable or improved renal function during the treatment of acute decompensated heart failure.     

Value of aldosterone receptor blockade in diuretic therapy of patients with chronic heart failure

PATHOGENESIS: All forms of chronic heart failure (high-output and low-output failure) are accompanied by an "arterial underfilling" inducing the activation of various neurohumoral systems (renin-angiotensin-aldosterone system, sympathic nervous system, non-osmotic stimulation of vasopressin). Elevated levels of those neurohormones detrimentally modulate renal function. Subsequently, renal salt and volume retention occurs leading to the main symptoms of heart failure, edema formation and dyspnea. DIURETIC THERAPY: Diuretics, which have been discovered more than 40 years ago, beneficially influence renal salt- and volume retention by their effects on tubular sodium reabsorption. While thiazides are recommended in mild forms, loop diuretics are used in severe stages of congestive heart failure. The clinician has to consider the changed pharmacokinetic and -dynamic properties during the application of diuretics in patients with chronic heart failure. In addition, increased sodium reabsorption occurs immediately after cessation of diuretic action often nullifying the preceding diuresis. Thus, salt- and volume restriction should be guaranteed, and a regular application of loop diuretics during the day should be preferred due to the short-acting nature of currently available loop diuretics. Sometimes, diuresis does not longer occur during the treatment with one substance (diuretic resistance), although the therapeutic goals of water excretion have not been achieved. After ruling out factors reducing the actions of diuretics (non-compliance, hyponatremia, etc.), a sequential nephron blockade should be initiated (combination of loop diuretics and a thiazide or an aldosterone-receptor antagonist) to increase diuresis and to elevate symptoms of volume overload. SIDE EFFECTS: Loop diuretics and thiazides often induce mild hypokalemia, which has been demonstrated to be not as benign as thought before. Chronic treatment with oral potassium supplements has several drawbacks, as urine excretion of potassium is subsequently increased and supplementation is not as effective as believed. Diuretic-induced hypokalemia seems to be aldosterone dependent. As aldosterone levels increase during diuretic therapy even during chronic treatment with an angiotensin-converting enzyme (aldosterone-escape) a combined treatment including an aldosterone-receptor antagonist has been suggested. Beneficial effects of aldosterone-receptor blockade on mortality (RALES trial) appear to be mediated be extrarenal and renal mechanisms. The suggested beneficial renal mechanisms of aldosterone receptor blockade are discussed in detail in the review. CONCLUSION: In conclusion, diuretic therapy of patients with congestive heart failure is effective to relieve symptoms and, presumably, to prolong life. As renal function and pharmacokinetics and -dynamics of diuretics are changed in heart failure, diuretic treatment has to be adapted to provide optimal treatment. Increased levels of aldosterone appear to play an important role in diuretic-induced hypokalemia, and in the progression of heart and renal failure. Thus, aldosterone receptor antagonists should be used in the treatment of heart failure more frequently.     

How to use diuretics in heart failure

Systemic and pulmonary congestion is a central aspect of both acute and chronic heart failure and directly leads to many of the clinical manifestations of these syndromes. Therefore, diuretic therapy to treat congestion plays a fundamental role in heart failure management. However, although diuretics are the most common drugs prescribed for heart failure, there is limited quality evidence to guide their use. Unlike other components of the heart failure armamentarium, such as β-blockers and angiotensin-converting enzyme inhibitors, diuretics (with the exception of aldosterone antagonists) have not been shown to decrease heart failure progression or improve mortality. Additionally, some observational data suggest that diuretics may actually be harmful in heart failure, contributing to neurohormonal activation, renal dysfunction, and potentially mortality. Despite these concerns, diuretics remain ubiquitous in heart failure management because of the need to address symptoms of congestion and the lack of alternative strategies. Recently, the development of a variety of potential adjuncts or alternatives to diuretic therapy has suggested the need for an active reappraisal of diuretic therapy for heart failure. The main classes of diuretics are the loop diuretics, potassium-sparing diuretics, and thiazides. Loop diuretics, the mainstay of acute and chronic therapy for heart failure, are “threshold drugs”; therefore, an adequate dose to achieve a pharmacodynamic effect (ie, to increase urine output) must be prescribed for effective therapy. The minimum dose to achieve diuresis and manage congestion should be used to minimize adverse effects. For patients refractory to initial dosing of intravenous diuretics, options include dose escalation, use of continuous infusion rather than intermittent boluses, or combination therapy with the addition of a thiazide or thiazide-like diuretic (eg, metolazone). Management of chronic heart failure often includes patient-directed titration of diuretics based on changes in symptoms or body weight in an attempt to decrease hospitalizations, although the efficacy of this strategy has not been tested in well-designed trials. Aldosterone antagonists, which are used primarily as neurohormonal agents rather than for their diuretic effects, are indicated for patients with systolic failure and moderate to severe symptoms, as long as renal function and serum potassium are stable and monitored closely. All diuretic therapy requires careful monitoring of electrolytes and renal function. Whether newer modalities for managing congestion (vasopressin antagonists, adenosine A1 antagonists, and ultrafiltration therapy) will be an improvement over diuretic therapy will be determined by the results of multiple ongoing clinical trials.     

Rational use of diuretics in acute decompensated heart failure

Chronic heart failure poses an enormous health care burden to the United States and other developed countries. Acute decompensated heart failure (ADHF) accounts for nearly half of the morbidity and expense of treating this disease. Most patients presenting with ADHF have symptomatic vascular congestion. Diuretics, especially loop diuretics, are the primary pharmacologic intervention used in this population. Despite their widespread use, scant data from randomized clinical trials are available to guide therapeutic choices. In addition, data from several large registries examining weight loss during hospitalization for ADHF suggest that efficacy with diuretic treatment is far from universal. Aggressive diuresis carries a significant risk of electrolyte and volume depletion, with subsequent arrhythmias, hypotension, and worsening renal function. These complications often translate into worse prognosis. Diuretic regimens used to treat ADHF must be individualized based on general knowledge of potency and pharmacokinetic and pharmacodynamic considerations. This article summarizes older and more recent literature to provide a framework for making rational treatment choices in this difficult patient population.     

Diuretics in postinfarction heart failure

Summary Severe left ventricular failure, as evidenced by radiographic pulmonary edema or raised left ventricular filling pressure, accompanying acute myocardial infarction, carries a high mortality risk. In this situation, the intravenous loopdiuretic furosemide induces a rapid reduction in the raised left ventricular filling pressure due to an immediate and substantial increase in systemic venous compliance accompanied by increasing diuresis. This diuretic-induced venodilatation is probably due to the release of prostaglandins. The transient systemic arterial constriction and small increase in systemic blood pressure that follows intravenous furosemide probably results from the release of renin and subsequent activation of angiotensin. These diuretic induced hemodynamic changes are accompanied by restoration of the vasodilator reflex, which enables the heart to accommodate an acute volume load. Orally administered loop diuretics achieve slower, but similar, directional hemodynamic changes. There is no information on hemodynamic or neuroendocrine dose-response effects of loop diuretics, and there is no information pertaining to the use of other diuretic groups in this situation. The hemodynamic changes induced by furosemide summate with the changes induced by other anti-heart-failure drugs. In this subset of patients with acute myocardial infarction and severe heart failure, the influence of the diuretics on morbidity incidence and mortality risk remains to be measured.     

Rubbing Salt into Wounds: Hypertonic Saline to Assist with Volume Removal in Heart Failure

Traditionally accepted management strategies for patients with heart failure include sodium and fluid restriction, neurohormonal blockade, and the use of loop diuretics to achieve and maintain euvolemia. Despite continued advances in medical and device therapy, fluid management remains a significant problem in patients with the cardiorenal syndrome (manifested as diuretic resistance and worsening renal function with more aggressive attempts at volume removal). This article examines the counterintuitive use of hypertonic saline as a potential therapy to facilitate diuresis in patients with decompensated heart failure and diuretic resistance. Low-volume hypertonic saline administration offsets counterproductive neurohormonal upregulation, transiently improves hemodynamics, and promotes renal sodium excretion with accompanied net water loss and preservation of renal function. This “new” therapeutic tool should be explored further as an adjunct to current medical therapies in the management of patients with refractory volume overload.     

Ultrafiltration in decompensated heart failure

Fluid congestion is the hallmark of decompensated heart failure. As heart failure progresses, reduced response to diuretics is common. In these patients, ultrafiltration has been found to alleviate excess volume and improve diuretic sensitivity. Compared with diuretics, ultrafiltration provides a more predictable and safer way to achieve euvolemia with minimal electrolyte abnormalities and neurohormonal activation. The emerging familiarity and ease of use of ultrafiltration suggests that in the future this will be an important therapy for the treatment of acute and chronic volume overload associated with decompensated heart failure.     

Diuretics in therapy of "diuretic resistance" by patients with congestive heart failure

Loop diuretics are integral part of overall therapy of severe congestive heart failure. Approximately 10-20 % of patients with congestive heart failure (NYHA class III-IV) do not respond satisfactorily to diuretic treatment. Despite its frequency, the term "diuretic resistance" remains inadequately defined. In general, failure to decrease the extracellular fluid volume despite liberal use of diuretics is often termed "diuretic resistance". The combination of diuretics, particularly of loop diuretic with thiazide agents, is recommended for prevention as well as treatment of this complication. Effective management is also continuous infusion of loop diuretic. If it is impossible to achieve adequate response by combination of diuretics, increasing of its dosage or/and frequency or continuous infusion, then dialysis methods may be employed (however it is not intended to discuss this option in this article).     

Diuretic therapy in congestive heart failure

Diuretics are a mainstay of therapy in patients with congestive heart failure. A small number of patients can achieve adequate diuresis with a thiazide diuretic alone, but most require a loop diuretic. Some patients with severe disease require combinations of diuretics. Most patients with congestive heart failure manifest resistance to diuretics by having a diminished natriuresis compared with healthy counterparts. This diminished response even to potent diuretics means that dietary sodium may exceed sodium excretion, resulting in patient decompensation. The pharmacokinetics and pharmacodynamics of loop diuretics have been characterized in patients with congestive heart failure, thereby allowing rational therapeutic strategies in terms of what type of doses should be administered, how often, and when to use diuretic combinations. The purpose of this review is to show how understanding pharmacokinetics and pharmacodynamics results in logical diuretic use. (c)2000 by CHF, Inc.     

Intra‐abdominal Hypertension: An Important Consideration for Diuretic Resistance in Acute Decompensated Heart Failure

Fluid accumulation is the hallmark of heart failure decompensation. Fluid overload and congestion are associated with recurrent hospitalizations, poor quality of life, and increased mortality in heart failure. Despite the use of high‐dose intravenous loop diuretic therapy, acutely decompensated heart failure patients may develop diuretic resistance. Diuretic refractoriness can be a result of elevated intra‐abdominal pressure (IAP) in acutely decompensated heart failure. Increased renal venous and interstitial pressures in patients with elevated IAP may lead to renal impairment and diuretic resistance. Routine approaches such as sequential nephron blockade with a combination of loop and thiazide or thiazide‐like diuretics, continuous diuretic infusion, and ultrafiltration may not be sufficient. Presented here is a case illustrating the importance of recognizing intra‐abdominal hypertension in patients with diuretic resistance. Lowering IAP improves renal perfusion, renal filtration, and diuresis. When elevated, IAP is an easily reversible cause of diuretic resistance. Additionally, abdominal perfusion pressure can be used to guide therapy to reverse end‐organ damage and avoid permanent renal replacement therapy.     

Diuretic therapy in congestive heart failure

The principal goals of treatment of the patient in heart failure are the relief of their symptoms and improvement in their prognosis. Of all antiheart failure drugs currently available, the diuretics are therapeutically superior in their efficacy in relieving clinical symptoms and signs. Whether administered intravenously or orally, all diuretics result in a substantial reduction in the raised pulmonary vascular pressures in combination with a small reduction in cardiac output. Diuretics stimulate release of renin with subsequent activation of the renin-angiotensin-aldosterone system, particularly if used in large doses, although their quantitative impact on the neuroendocrine profile at different stages of heart failure remains to be defined. In patients with mild heart failure, diuretics reduce plasma catecholamine concentrations, but their sympatholytic effects in more severe cases are unknown, as are their effects on the metabolically active tissues in these patients. Diuretic resistance can be circumvented by segmental nephron blockade with a combination of low-dose diuretics that simultaneously block sodium reabsorption in the proximal tubule, the loop of Henle, the distal tubule, and the collecting duct. Diuretics improve symptoms of breathlessness and signs of peripheral edema in patients with congestive heart failure in direct relationship to the induced diuresis. These benefits are frequently associated with a substantial improvement in patients' appreciation of quality of life and economic capacity. There are few adverse reactions to chronic diuretic therapy, but the serum electrolytes should be monitored for hypokalemia and hypomagnesemia. The impact of diuretics on prognosis of patients with congestive heart failure is unknown; however, diuretics have been a major ingredient of the therapies used in all the survival trials with vasodilators, angiotensin-converting enzyme inhibitors, and beta-blocking drugs. In addition to their clinical benefits, diuretics are the most cost-effective treatment of any single drug group currently available for the treatment of patients with congestive heart failure.     

Management and monitoring of haemodynamic complications in acute heart failure

The pathophysiology of acute heart failure syndromes (AHFS), defined as a change or worsening in heart failure symptoms and signs, is complex. The variety of adverse neurohormonal adaptations includes increased levels of plasma renin, aldosterone and angiotensin II, all responsible for cardio-renal dysfunction. In fact, such alterations result in an array of clinical changes that include abnormal haemodynamics, altered ventricular filling pressures, pathological neurohormonal responses, leading to fluid overload, congestion and ultimately heart failure symptoms. Clinical pictures can be various: in spite of a usual improvement in dyspnoea, little weight change and significant morbidity are generally observed during hospitalization. Short-term outcomes are characterized by a high 60-day re-hospitalization and high mortality rates; apparently, both can be predicted from pre-discharge characteristics. The most frequently used treatments for AHF care include diuretics, inotropic agents, and vasodilator/vasoactive agents; however, the final therapeutic strategy is often individualized. Diuretics are currently the most used agents, but resistance to diuretic therapy is common. In addition, several studies have demonstrated that aggressive diuresis can contribute to reduced renal function, and high doses of diuretics have been associated with increased morbidity and mortality. Many patients with AHFS also suffer from acute or from chronic renal dysfunction (cardio-renal syndromes type 1 and 2, respectively), which further complicate the outcomes and treatment strategies. A personalized patient evaluation of the combined heart and kidney functions is advised to implement the best possible multidisciplinary diagnostic and therapeutic approach.     

Combination of loop diuretics with thiazide-type diuretics in heart failure

Volume overload is an important clinical target in heart failure management, typically addressed using loop diuretics. An important and challenging subset of heart failure patients exhibit fluid overload despite significant doses of loop diuretics. One approach to overcome loop diuretic resistance is the addition of a thiazide-type diuretic to produce diuretic synergy via "sequential nephron blockade," first described more than 40 years ago. Although potentially able to induce diuresis in patients otherwise resistant to high doses of loop diuretics, this strategy has not been subjected to large-scale clinical trials to establish safety and clinical efficacy. We summarize the existing literature evaluating the combination of loop and thiazide diuretics in patients with heart failure in order to describe the possible benefits and hazards associated with this therapy. Combination diuretic therapy using any of several thiazide-type diuretics can more than double daily urine sodium excretion to induce weight loss and edema resolution, at the risk of inducing severe hypokalemia in addition to hyponatremia, hypotension, and worsening renal function. We provide considerations about prudent use of this therapy and review potential misconceptions about this long-used diuretic approach. Finally, we seek to highlight the need for pragmatic clinical trials for this commonly used therapy.     

Edema mechanisms in the patient with heart failure and treatment options

Volume overload is a common accompanying feature of heart failure. The mechanistic basis for volume overload in heart failure is incompletely worked out. An important component of heart failure treatment remains diuretic therapy. Diuretic dosing remains as much an art as a science with multiple environmental and disease state-related factors influencing the efficiency with which a diuretic works. In heart failure, diuretics should always be given in the lowest possible dose with careful attention to reducing dietary sodium intake.     

A 2018 overview of diuretic resistance in heart failure

Heart failure is a disease with high direct and indirect costs. Current treatment includes drugs that alter disease progression and drugs that to improve symptoms. Loop diuretics are the cornerstone of congestion relief for acute management, as well as for chronic stabilization. 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 appropriate or escalating diuretic doses. Its causes include impaired delivery of the diuretic to its luminal site of action, neurohormonal activation, tubular compensatory adaptation and drug interactions. Several strategies can be employed to aid decongestion of patients with impaired diuretic response. These include salt restriction, a higher effective single dose or higher dose frequency of loop diuretics, continuous infusion of diuretics and/or sequential nephron blockade through a synergistic combination of two or more diuretics from different classes. Ultrafiltration has also been found to be another effective and safe therapeutic option and should be considered in patients with refractory diuretic resistance. Overall, there is a lack of high-quality clinical data to guide the choice of treatment strategy and therapy should be tailored on a case-by-case basis.     

Similarities and distinctions between acetazolamide and sodium–glucose cotransporter 2 inhibitors in patients with acute heart failure: Key insights into ADVOR and EMPULSE

Both acetazolamide and sodium–glucose cotransporter 2 (SGLT2) inhibitors block sodium reabsorption in the proximal renal tubule primarily through inhibition of sodium–hydrogen exchanger isoform 3 (NHE3), but neither SGLT2 inhibitors nor acetazolamide produce a sustained natriuresis due to compensatory upregulation of sodium reabsorption at distal nephron sites. Nevertheless, acetazolamide and SGLT2 inhibitors have been used as adjunctive therapy to loop diuretics in states where NHE3 is upregulated, e.g. acute heart failure. Two randomized controlled trials have been carried out with acetazolamide in acute heart failure (DIURESIS-CHF and ADVOR). In ADVOR, acetazolamide improved physical signs of fluid retention, but this finding could not be explained by the modest observed diuretic effect. Acetazolamide did not produce a natriuresis in the DIURESIS-CHF trial, and in ADVOR, immediate effects on symptoms and body weight were not reported, and the drug had no effect on morbidity or mortality after 90 days. Three randomized controlled trials have been carried out with empagliflozin (EMPAG-HF, EMPA-RESPONSE-AHF and EMPULSE) in acute heart failure. The EMPULSE trial did not report effects on diuresis or in changes in physical signs of congestion during the first week of treatment, but in EMPAG-HF and EMPA-RESPONSE-AHF, empagliflozin had no effect of dyspnoea, urinary sodium excretion or body weight during the first 4 days. In the EMPULSE trial, empagliflozin improved health status at 15 days and reduced the risk of worsening heart failure events at 90 days, but these effects are similar in magnitude and time course to the early statistical significance on the risk of heart failure hospitalizations achieved within 14–30 days in the major trials of SGLT2 inhibitors in patients with chronic heart failure. Neurohormonal inhibitors produce this early effect in the absence of a diuresis. Additionally, in numerous randomized controlled trials, in-hospital diuretic intensification has not reduced the risk of major heart failure events, even when treatment is sustained. These findings, taken collectively, suggest that any immediate diuretic effects of acetazolamide and SGLT2 inhibitors in acute heart failure are not likely to influence the short- or long-term clinical course of patients.     

Diuretic Responsiveness and Its Prognostic Significance in Children With Heart Failure

BackgroundLoop diuretics are considered first-line therapy for congestion in children with heart failure, although some patients remain volume overloaded during treatment. We sought to characterize loop diuretic responsiveness (DR) in children hospitalized with acute decompensated failure and to determine whether a decreased response was associated with worse outcomes.Methods and ResultsDR was calculated for 108 consecutive children ˂21 years of age who were hospitalized with acute decompensated heart failure. DR was defined as net fluid (mL) output per 1 mg of furosemide equivalents during the first 72 hours of treatment with a loop diuretic. The primary outcome was the composite end point of inpatient death or use of mechanical circulatory support. The median DR was 6.0 mL/mg (interquartile range -2.4 to 15.7 mL/mg). Thirty-two percent of patients remained in a positive fluid balance after 72 hours of treatment with a loop diuretic. Death or use of mechanical circulatory support occurred in 29 patients (27%). Low DR was associated with the composite end point, even after adjusting for net urine output and loop diuretic dose indexed to weight (odds ratio 5.3; P = .003). Patients with low DR also experienced longer length of hospital stay than patients with greater DR (median 33 days vs 11 days; P = .002).ConclusionIn children hospitalized with acute decompensated heart failure, early diminished loop DR during decongestion therapy is common and portends a poor prognosis.