“If you have always done it that way, it is probably wrong.” Show
—Charles F. Kettering, 1876–1958 The morbidity of decompensated heart failure is due to volume overload, a consequence of increased total body sodium.1,2 Failure to adequately reduce total body sodium contributes to progressive ventricular dysfunction, worsening heart failure, and excess morbidity. Ultrafiltration is the gold standard for sodium-volume removal and is the only intervention shown to improve outcomes in a randomized controlled trial of patients hospitalized with decompensated heart failure.3 Diuretics are inherently inferior because they produce hypotonic urine4,5and undesirable hemodynamic and neurohormonal changes.6,7 Therefore, ultrafiltration is the preferred initial treatment for patients hospitalized with decompensated heart failure and sodium-volume overload. Response by Shin and Dec on p 499 Sodium is the Major Determinant of Extracellular Fluid VolumeThe earliest descriptions of heart failure date back more than 3500 years to the Egyptian civilization. Even then, symptoms were correctly attributed to volume excess.8 It was not until the early 20th century that researchers recognized the role of salt in the formation of edema. In 1901, researchers found that salt fed to patients with congestive heart failure could not be recovered as chloride in the urine.8 This represents one of the earliest descriptions of heart failure as a sodium avid state. Later, it was demonstrated that liberal salt intake increased congestive symptoms and pulmonary edema in patients with heart failure whereas patients on salt-restricted diets could tolerate large amounts of water without any further increases in congestion or edema.8 Other studies confirmed the primary role of salt, not water, in the formation of edema in heart failure. By 1948, sodium was widely recognized as the major determinant in extracellular fluid volume.1 Today, it is understood that sodium retention in heart failure is under the influence of the sympathetic and renin-angiotensin-aldosterone (RAAS) systems.7 Renin release from the kidneys leads to the production of angiotensin II. Increased angiotensin II levels activate receptors on the epithelium of the proximal tubule enhancing sodium reabsorption in the nephron. Angiotensin II also causes constriction of the efferent arterioles disturbing the usual balance of hydrostatic and osmotic forces in the peritubular capillaries such that sodium reabsorption is increased. In addition to its direct tubular and vascular effects in the kidney, angiotensin II promotes aldosterone secretion. Aldosterone increases sodium reabsorption in the distal nephron. Decreased sodium and water delivery to the distal nephron stimulates the macula densa to increase renin synthesis. Thus, sodium retention is part of a feedback loop that amplifies the sympathetic and RAAS systems. Consequences of Sodium-Volume OverloadSodium retention has a profound effect on vascular function and the pathogenesis of hypertension.9 Excess sodium inhibits the Na+ pump/Na+-K+-ATPase of arterial and arteriolar vascular smooth muscle cells stimulating the sodium-calcium exchanger. This leads to increased intracellular calcium levels and vasoconstriction.10 In addition, sodium retention decreases the synthesis of nitric oxide and increases levels of asymmetrical dimethl l-arginine, an endogenous inhibitor of nitric oxide production.11 Sodium retention also causes obligatory (passive) water accumulation that ultimately leads to increased extracellular fluid volume and increased left and right-sided pressures.1,7 Elevated left-sided pressures result in pulmonary congestion, which is recognized clinically by dyspnea on exertion, orthopnea, cough, hemoptysis, rales, and characteristic radiographic findings. High left-sided pressures also cause left ventricular chamber dilation and distortion of the mitral annulus often leading to malcoaptation of the mitral valve leaflets and significant mitral regurgitation.12 Left ventricular chamber dilation increases wall tension and myocardial oxygen demand to the extent that myocardial ischemia and/or necrosis may occur. Functional mitral regurgitation and myocardial ischemia or necrosis adversely affect cardiac output ultimately leading to worsening symptoms, further activation of the sympathetic and RAAS systems, increased sodium retention and acceleration of cardiac remodeling (Figure 1).7 
Figure 1. Renal sodium and water retention leads to expansion of the extracellular fluid volume, increased cardiac filling pressures and cardiac dilation, and remodeling, which ultimately contribute to myocardial injury and amplification of the vasopressin, RAAS, and sympathetic. Adapted with permission from Schrier.7 Elevated right-sided pressures can lead to cardiac interstitial edema, myocardial contractile dysfunction, and interventricular dependence, factors that adversely affect stroke volume and cardiac output.13,14 Elevated venous pressures also cause clinically important reductions in renal blood flow, glomerular filtration rate, and sodium excretion.15–17 Thus, congestion of the kidney perpetuates the cycle of sodium retention, venous congestion, reduced kidney function, and sympathetic and RAAS activation. Treatment of Congestion: It’s the SaltMost patients with heart failure suffer from symptoms of congestion.18 When these symptoms become severe, patients are hospitalized and treated with diuretics — an approach that has remained essentially unchanged since the 1960s. Unfortunately, the outcomes of patients hospitalized with decompensated heart failure remain poor in spite of (or due to) the nearly universal use of diuretics: 2% to 22% of patients die during the acute hospitalization,19,20 44% are readmitted within 6 months,21 and 33% are dead within 1 year.22 Given these sobering statistics, we must carefully reexamine the use of diuretics in treating decompensated heart failure if we wish to improve on these dismal outcomes. Loop Diuretics Are Inefficient and Difficult to UseLoop diuretics such as furosemide act on the luminal surface of the ascending loop of Henle to block the sodium-potassium-chloride transporter.23 This results in an increase in urinary excretion of sodium, chloride, calcium, magnesium, and potassium. Although urinary excretion of sodium is increased, urine remains hypotonic relative to extracellular fluid because only 25% of the filtered sodium load is normally reabsorbed by the thick ascending limb; the proximal and distal convoluted tubules are responsible for the rest of sodium reabsorption in the nephron thereby limiting the amount of sodium excretion that can be achieved with loop diuretics.23 The production of hypotonic urine limits the effectiveness of loop diuretics in reducing total body sodium. For example, excess fluid volume in patients with heart failure contains isotonic fluid ≈140 mEq/L of sodium. A recent study of patients hospitalized for decompensated heart failure showed that the average urine concentration of sodium after the administration of furosemide was 60 mEq/L.5 Therefore, for every liter of urine produced in response to loop diuretics, 80 mEq of excess sodium remains unresolved. If a patient is congested with 10 L of excess fluid volume, treatment with loop diuretics would lead to 800 mEq of unresolved sodium excess (18.4 g). Persistent sodium excess results in reaccumulation of water leading to congestive symptoms, progressive ventricular dysfunction, worsening heart failure, and excess morbidity.16,17,24 There are a number of other well-established limitations to loop diuretics (Table). Diuretic resistance is common and contributes to high inter- and intraindividual dose responses.4,23 Diuretics are associated with potentially life-threatening electrolyte abnormalities, photosensitivity, skin rashes, interstitial nephritis, gout, hearing loss, and bone loss.23,25 Acutely, loop diuretics adversely affect hemodynamics and stimulate the sympathetic and RAAS systems.6,7 These hemodynamic and neurohormonal changes limit the effectiveness of subsequent doses of loop diuretics by reducing glomerular filtration rate.
Table. Limitations of Loop Diuretics and Advantages of Ultrafiltration
The Evidence Base for the Use of Loop Diuretics Is WeakThe safety and efficacy of loop diuretics in patients hospitalized for heart failure has not been established by randomized controlled trials. Such studies are difficult to perform because diuretics are deemed to be necessary in patients with decompensated heart failure. In one study, patients with acute pulmonary edema and hypoxemia were randomized to escalating doses of intravenous (IV) nitrates or furosemide after receiving oxygen, morphine, and a single 40 mg dose of furosemide. Acute treatment in both groups continued until oxygen saturation increased to at least 96% or mean arterial pressure decreased by at least 30% or <90 mm Hg. During the first hour of therapy, patients in the nitrates group received a mean dose of isosorbide dinitrate of 11.4 mg and a mean dose of furosemide of 56 mg. Patients in the furosemide group received a mean dose of isosorbide dinitrate of 1.4 mg and a mean furosemide dose of 200 mg. Compared with patients in the nitrates group, patients treated with increasing doses of furosemide experienced more myocardial infarctions (36% versus 17%, P=0.047), required more mechanical ventilatory support (40% versus 13% P=0.0041) and experienced less improvement in oxygen saturation (+13% versus +18%, P=0.0063).26 Retrospective analyses of patient registries and clinical trials show a consistent dose-dependant association between loop diuretics and increased mortality and rehospitalization.27–30 This evidence base should raise concern about the ongoing use of loop diuretics in decompensated heart failure. Treating Decompensated Heart Failure Without Substantially Reducing Total Body Sodium Does Not WorkEVEREST tested the hypothesis that removal of hypotonic fluid improves outcomes in patients hospitalized for congestion and decompensated heart failure. More than 4000 patients were randomized to receive standard care plus placebo or standard care plus the arginine vasopressin antagonist tolvaptan. Tolvaptan improved dyspnea, edema, and body weight in the short term but did not reduce all-cause mortality, cardiovascular death, or rehospitalization for heart failure (the dual primary end points of the trial).31 These results are not surprising in light of sodium’s role as the major determinant of extracellular fluid volume—failure to adequately address total body sodium excess does not improve outcomes in this patient population. Ultrafiltration Is the Preferred Initial Treatment of Volume Overload in Decompensated Heart FailureUltrafiltration is the standard by which all other treatments for sodium-volume overload should be measured. Ultrafiltration is the mechanical removal of fluid from the vasculature. Hydrostatic pressure is applied to blood across a semipermeable membrane to separate isotonic plasma water from blood.32 Because solutes in blood freely cross the semipermeable membrane, large amounts of fluid can be removed at the discretion of the treating physician without affecting any change in the serum concentration of electrolytes and other solutes. Ultrafiltration has been used to relieve congestion in patients with heart failure since the 1970s.32 In contrast to the adverse physiological consequences of loop diuretics, numerous studies have demonstrated favorable responses to ultrafiltration. Such studies have shown that removal of large amounts of isotonic fluid relieves symptoms of congestion, improves exercise capacity, improves cardiac filling pressures, restores diuretic responsiveness in patients with diuretic resistance, and has a favorable effect on pulmonary function, ventilatory efficiency, and neurohormone levels.33–46 The evidence base supporting the use of ultrafiltration is superior to that for loop diuretics. There are 5 randomized controlled trials of ultrafiltration in patients with heart failure. In 2 small trials, patients with mild heart failure were randomized to ultrafiltration or continued medical care. Compared with ongoing medical therapy, patients treated with ultrafiltration experienced improved hemodynamics, diastolic filling parameters, neurohormonal responsiveness, and exercise capacity.34,36 A similar trial was subsequently performed with an active control arm by the same investigative team. Sixteen patients with mild heart failure were randomized to ultrafiltration (500 mL/hr) versus IV furosemide (IV bolus followed by continuous infusion-average dose 248 mg). All patients were treated until there was a 50% decrease in right atrial pressure. Exercise capacity measured by peak oxygen consumption improved significantly in patients treated with ultrafiltration and did not change in patients treated with furosemide. Body weight, right atrial, and pulmonary capillary wedge pressures fell significantly in both groups. However, these variables rapidly returned to baseline in the furosemide-treated group and were sustained in patients treated with ultrafiltration (Figure 2).33
Figure 2. Ultrafiltration results in sustained decreases in body weight and improved functional capacity compared with IV furosemide. These results are from a randomized controlled trial of ultrafiltration versus IV furosemide in heart failure patients. Treatments were continued in both treatment groups until right atrial pressure was reduced by 50%. Adapted with permission from Agostoni et al.33 There are 2 randomized controlled trials of ultrafiltration in hospitalized patients with congestion and decompensated heart failure. RAPID was a feasibility study comparing a single 8-hour course of peripheral venovenous ultrafiltration within the first 24 hours of admission to usual care with IV diuretics in 40 patients. This study was small, but demonstrated that ultrafiltration in this setting was safe and effective compared with IV diuretics.47 In UNLOAD, a larger follow-up study, 200 patients hospitalized with decompensated heart failure and congestion were randomized to undergo early ultrafiltration versus standard care with IV diuretics. Patients in the ultrafiltration group received no diuretics for the first 48 hours of hospitalization and their volume status was managed exclusively by ultrafiltration. Patients in the standard care group were treated with IV diuretics at doses not <2 times their usual outpatient diuretic dose given IV. Patients undergoing ultrafiltration had significantly greater weight loss at 48 hours compared with standard care. In addition, rehospitalizations for heart failure at 90 days (a prespecified secondary end point of the study) were significantly reduced in the ultrafiltration group compared with standard care (Figure 3).3 Even after adjusting for differences in weight loss between the ultrafiltration and standard care groups, ultrafiltration was independently associated with improved outcomes.48
Figure 3. Ultrafiltration reduces 90-day rehospitalizations for heart failure compared with standard care with IV diuretics. These results are from a randomized controlled trial of early venovenous ultrafiltration versus standard care with IV diuretics in patients hospitalized with decompensated heart failure. Adapted with permission from Costanzo et al.3 These randomized controlled trials demonstrate that the clinical benefit of ultrafiltration is not solely related to the volume of fluid removed. Greater sodium removal during ultrafiltration (isotonic plasma water) compared with furosemide (hypotonic urine) explains sustained improvements in weight, exercise capacity, filling pressures, and rehospitalization rates. SummaryThe morbidity of decompensated heart failure is due to volume overload, a consequence of increased total body sodium. Treatments that do not adequately reduce total body sodium are ineffective. As a result, using diuretics to produce hypotonic urine or other agents to achieve hemodynamic targets will not lead to improved clinical outcomes. Ultrafiltration is the gold standard for sodium-volume removal and is the only intervention shown to improve outcomes in a randomized controlled trial of patients hospitalized with decompensated heart failure. The success of any new intervention designed to improve outcomes in this patient population should be measured against ultrafiltration. FootnotesCorrespondence to Bradley A. Bart, MD, Division of Cardiology, O5 HCMC, 701 Park Ave S, Minneapolis, MN 55415. E-mail [email protected] References
Which is a major compensatory mechanism when cardiac output is insufficient?Elevated filling pressures in heart and low systolic blood pressure occur in the setting of low cardiac output; arterial constriction occurs as a compensatory mechanism.
Which intervention does the nurse perform to decrease dyspnea in a patient with acute heart failure?Once the diagnosis of acute heart failure is made, diuretics are administered to relieve dyspnoea.
Does left sided heart failure increase/decrease or not affect kidney filtration explain?Impaired kidney function: Decreased kidney function is common in patients with left-sided heart failure. If the kidneys receive less blood, kidney failure can occur, requiring dialysis treatment.
Which factor is the most common etiology of heart failure?Coronary artery disease is the most common form of heart disease and the most common cause of heart failure. The disease results from the buildup of fatty deposits in the arteries, which reduces blood flow and can lead to heart attack.
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What are the intended outcomes of ultrafiltration when performed in a patient with renal dysfunction
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