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.     

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.     

Einsatz von Diuretika bei der akut dekompensierten Herzinsuffizienz

Patients with acute heart failure usually present with dyspnea and edema secondary to elevated intracardiac filling pressure resulting from volume overload. Despite significant progress in understanding heart failure, the treatment strategy for acute heart failure did not change in the same way. Diuretics, especially loop diuretics, are the most common drugs used in this setting. Intravenous diuretics act acutely by exerting a modest vasodilatory response and chronically by reducing circulating blood volume. Despite a very common use of diuretics in patients hospitalized with acute heart failure, nearly half of these patients are discharged from the hospital without weight loss. This could be due to inadequate diuresis, overdiuresis with subsequent volume replacement and diuretic resistance. Aggressive diuresis carries a significant risk of electrolyte and volume depletion with subsequent arrhythmias, hypotension, and worsening renal function. Actually, little data from randomized clinical trials are available to guide therapeutic treatment with diuretics. Thus, the choice and dosing of diuretic therapy must be individualized based on general knowledge of potency and pharmacokinetic and pharmacodynamic considerations.     

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.     

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.     

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.     

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).     

Preliminary report of tolvaptan treatment in Japanese patients with heart failure

While diuretic drugs are commonly used in patients with congestive heart failure, the efficacy of their long-term use still remains controversial. Recently, a new class of diuretics, vasopressin receptor 2 antagonists, has been launched, and tolvaptan is one such drug. We describe our initial experience with this novel agent. Tolvaptan is potentially useful for treatment of heart failure patients with fluid overload who are refractory to conventional diuretic therapies.     

Clinical benefit of tolvaptan in patients with acute decompensated heart failure and chronic kidney disease

Tolvaptan, a vasopressin type 2 receptor antagonist, has an aquaretic effect without affecting renal function. The effects of long-term tolvaptan administration in heart failure patients with renal dysfunction have not been clarified. Here, we assessed the clinical benefit of tolvaptan during a 6-month follow-up in acute decompensated heart failure (ADHF) patients with severe chronic kidney disease (CKD; estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m²). We compared 33 patients with ADHF and severe CKD who were administered tolvaptan in addition to loop diuretics (TLV group), with 36 patients with ADHF and severe CKD who were administered high-dose loop diuretics (≥40 mg) alone (LD group). Alterations in serum creatinine and eGFR levels from the time of hospital discharge to 6-month follow-up were significantly different between the groups, with those in the TLV group being more favorable. Furthermore, Kaplan–Meier analysis revealed that rehospitalization for heart failure (HF) was significantly lower in the TLV group compared with the LD group. In ADHF patients with severe CKD, tolvaptan use for 6 months reduced worsening of renal function and rehospitalization rates for HF when compared with conventional diuretic therapy. In conclusion, tolvaptan could be a safe and effective agent for long-term management of HF and CKD.     

Loop diuretics versus others in the treatment of congestive heart failure after myocardial infarction

Summary Most frequently, diuretic therapy in congestive heart failure has as its main objective ridding the lungs of water. The work of the muscles of external respiration is thus decreased, the fraction of cardiac output that is distributed to vascular beds other than that of the respiratory muscles is consequently increased, and the functional and clinical condition of the patient improves. Diuretic therapy does not change cardiac output significantly in most cases; in some circumstances diuretic therapy may increase cardiac output in a clinically relevant fashion, and in some other cases diuretic therapy may lower cardiac output to the extent of impairing the overall functional situation. The dose of diuretics should be the minimal compatible with the prosecution of the main clinical objective (class betterment), to minimize possible increases in the afterload to the left ventricle (intravenous administration), to minimize hemodynamically detrimental decreases in the preload, and to minimize the likelihood of development or the severity of undesired changes in plasma biochemistry (hyponatremia, hypokalemia, hypomagnesemia, hyperuricemia, etc.). Loop diuretics are preferred shortly after myocardial infarction, given the ample dose-effect range of these substances and their relatively benign effect on renal blood flow. During chronic therapy, loop diuretics at low doses may be tried first, and the dose may be increased if necessary, provided higher doses do not cause symptomatic falls in cardiac output through the striking renal excretory response that these drugs elicit shortly after dosing. Thiazide-type drugs should be used if the brisk diuresis induced by loop diuretics causes a symptomatic fall in cardiac output and/or when it is necessary that once-daily (oral) diuretic therapy exert a highly potent 24-hour natriuretic action.     

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.     

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.     

Diuretics in the treatment of patients who present congestive heart failure and hypertension

The main operational objective of diuretic therapy in patients who present congestive heart failure and hypertension is to reduce or to suppress excess bodily fluid. Effective diuretic therapy decreases cardiac size when the heart is dilated, and it reduces lung congestion and excess water. Consequently, external respiratory work diminishes and cardiac output would be redistributed in favour of systemic vascular beds other than that of the respiratory muscles; dyspnoea decreases markedly and there is a slight reduction in fatigue. This clinical improvement and the fall in body weight caused by diuretics entail an increase in effort capacity. Subsequent exercise training ameliorates the abnormal ventilatory response to physical effort and the skeletal muscle myopathy that occur in heart failure, and thereby it attenuates dyspnoea and decreases fatigue further. Loop and/or thiazide-type diuretics may be used to augment natriuresis in patients with congestive heart failure and hypertension. The state of renal function, the existence of certain co-morbid conditions, potential untoward drug actions, and possible interactions of diuretics with nutrients and with other drugs are some of the factors that must be considered at the time of deciding on the diuretic drug(s) and dose(s) to be prescribed. Spironolactone has been found to increase life expectancy and to reduce hospitalisation frequency when added to the conventional therapeutic regimen of patients with advanced congestive heart failure and systolic dysfunction. Therefore, spironolactone should be the drug of choice to oppose the kaliuretic effect of a loop or of a thiazide-type diuretic.     

The role of ultrafiltration in the management of heart failure

Opinion statement In the United States, 90% of one million annual hospitalizations for heart failure are due to symptoms of volume overload. Hypervolemia contributes to heart failure progression and mortality. Treatment guidelines recommend that therapy for patients with heart failure be aimed at achieving euvolemia. Intravenous loop diuretics induce a rapid diuresis that reduces lung congestion and dyspnea. However, loop diuretics’ effectiveness declines with repeated exposure. Unresolved congestion may contribute to high re-hospitalization rates. Furthermore, loop diuretics may be associated with increased morbidity and mortality due to deleterious effects on neurohormonal activation, electrolyte balance, and cardiac and renal function. Ultrafiltration is an alternative method of sodium and water removal, which safely improves hemodynamics in patients with heart failure. Application of this technology has been limited by the need for high flow rates, large extracorporeal blood volumes, and large-bore central venous catheters. A modified ultrafiltration device has overcome these limitations. Ultrafiltration may be a safe and effective alternative to intravenous diuretics in the treatment of decompensated heart failure.     

Potent diuretic effects of prednisone in heart failure patients with refractory diuretic resistance

BACKGROUND: Refractory congestive heart failure (CHF) with diuretic resistance is life-threatening and predicts a short life expectancy. Glucocorticoids have been proven to have potent diuretic effects in animal studies; however, their efficacy in CHF patients with diuretic resistance is not known. METHODS: Thirteen CHF patients with significant volume overload and diuretic resistance who failed to respond to a conventional sequential nephron blockade therapeutic strategy; that is, the coadministration of a thiazide (hydrochlorothiazide) and spironolactone, in combination with loop diuretics, were studied. Prednisone (1 mg/kg daily) was then added to standard care, with other medications unchanged, to determine diuretic efficacy in these CHF patients. Variables included body weight, urine volume, serum electrolytes and renal function. RESULTS: Adding prednisone resulted in striking diuresis with a mean (+/- SD) body weight reduction of 9.39+/-3.09 kg. Prednisone significantly decreased serum creatinine by 52.21+/-48.68 mumol/L and increased glomerular filtration rate by 33.63+/-15.87 mL/min/1.73 m(2) compared with baseline. All patients were discharged from hospital with improved clinical status and renal function, and 11 patients remained alive in the long term. The main side effect of prednisone appeared to be hyperglycemia in diabetic patients. CONCLUSIONS: The present study demonstrated that prednisone can rapidly eliminate volume overload and improve clinical status and renal function in CHF patients with diuretic resistance. Further prospective randomized clinical studies are warranted to confirm its clinical efficacy.     

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.     

Vasopressin antagonists in heart failure

The recrudescence of interest in manipulation of the arginine vasopressin system and especially of V2 vasopressin receptor blockade in heart failure stems from the limited efficacy and possible detrimental effects of loop diuretics. The ‘braking phenomenon,’ hypertrophy of the collecting duct cells, and altered pharmacodynamics contribute to loop diuretic resistance in heart failure. Selective (tolvaptan) and nonselective (conivaptan) V2 vasopressin receptor antagonists now known as ‘vaptans’ promote free-water excretion that is labeled aquaresis and correct hyponatremia in patients with severe heart failure. A large mortality study with tolvaptan in heart failure is presently ongoing.     

Diuretic use in renal disease

Diuretics are agents commonly used in diseases characterized by excess extracellular fluid, including chronic kidney disease, the nephrotic syndrome, cirrhosis and heart failure. Multiple diuretic classes, including thiazide-type diuretics, loop diuretics and K(+)-sparing diuretics, are used to treat patients with these diseases, either individually or as combination therapies. An understanding of what determines a patient's response to a diuretic is a prerequisite to the correct use of these drugs. The response of patients with these diseases to diuretics, which is related to the dose, is best described by a sigmoid curve whose contour can become distorted by any of the several sodium-retaining states that are directly or indirectly associated with renal disease. Diuretic actions are of considerable importance to patients who have renal disease, as their effective use assists in extracellular fluid volume control, reducing excretion of protein in urine and lessening the risk of developing hyperkalemia. Diuretic-related adverse events that involve the uric acid, Na(+) and K(+) axes are not uncommon; therefore the clinician must be vigilant in looking for biochemical disturbances. As a result of diuretic-related adverse events, clinicians must be resourceful in the dose amount and frequency of dosing.