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Treatment of acute decompensated heart failure: Components of therapy
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Treatment of acute decompensated heart failure: Components of therapy
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Nov 2016. | This topic last updated: Oct 13, 2016.

INTRODUCTION — Acute decompensated heart failure (ADHF) is a common and potentially fatal cause of acute respiratory distress. The clinical syndrome is characterized by the development of dyspnea, generally associated with rapid accumulation of fluid within the lung's interstitial and alveolar spaces, which is the result of acutely elevated cardiac filling pressures (cardiogenic pulmonary edema) [1]. ADHF can also present as elevated left ventricular filling pressures and dyspnea without pulmonary edema.

ADHF is most commonly due to left ventricular systolic or diastolic dysfunction, with or without additional cardiac pathology, such as coronary artery disease or valve abnormalities. However, a variety of conditions or events can cause cardiogenic pulmonary edema due to an elevated pulmonary capillary wedge pressure in the absence of heart disease, including primary fluid overload (eg, due to blood transfusion), severe hypertension (particularly renovascular hypertension), and severe renal disease.

In the large majority of patients who present with ADHF, acute or subacute decompensation is in the context of chronic HF with reduced ejection fraction (also known as systolic HF) or HF with preserved ejection fraction (also known as diastolic HF) and in many cases, there is a prior history of episodes of decompensation. In such patients, information regarding the precipitating factors, workup for HF, and the elements of successful therapy for prior episodes (eg, types and doses of diuretics used) can be of great value in approaching the current episode.

The components of therapy of ADHF in patients without acute myocardial infarction (MI) will be reviewed here. A table to assist with emergency management of ADHF is provided (table 1). General considerations for treatment of ADHF and the pathophysiology and evaluation of patients with ADHF are presented separately. (See "Treatment of acute decompensated heart failure: General considerations" and "Evaluation of acute decompensated heart failure".)

Treatment of ADHF and cardiogenic shock in the setting of acute coronary syndrome is discussed separately. Management of right ventricular MI, which typically presents with hypotension and clear lungs, is also discussed separately. (See "Treatment of acute decompensated heart failure in acute coronary syndromes" and "Prognosis and treatment of cardiogenic shock complicating acute myocardial infarction" and "Right ventricular myocardial infarction".)

INITIAL THERAPY

Approach to general management — Patients presenting with acute dyspnea from acute decompensated heart failure (ADHF) should be rapidly assessed and stabilized. A table to assist with emergency management of ADHF is provided (table 1). The initial approach is similar in patients with ADHF whether caused by systolic or diastolic dysfunction. Initial measures include:

Airway assessment and continuous pulse oximetry to assure adequate oxygenation and ventilation

Supplemental oxygen and ventilatory support (noninvasive ventilation [NIV] or intubation) as indicated

Vital signs assessment with attention to hypotension or hypertension

Continuous cardiac monitoring

Intravenous access

Seated posture

Diuretic therapy

Early vasodilator therapy (for severe hypertension, acute mitral regurgitation, or acute aortic regurgitation); later vasodilator use for refractory cases is discussed below.

Urine output monitoring (perhaps with urethral catheter placement)

Following airway and oxygenation assessment and management, initial therapy includes the initiation of treatments aimed at rapidly correcting hemodynamic and intravascular volume abnormalities. It is important to tailor the therapy to the individual patient. The mainstay of therapy in the acute setting is diuretic for volume overload.

Early intravenous vasodilator therapy is suggested in selected patients with ADHF who require a decrease in systemic vascular resistance and left ventricular afterload (eg, those with severe hypertension, acute mitral regurgitation, or acute aortic regurgitation). The aggressiveness of diuretic and vasodilator therapy depends on the patient's hemodynamic and volume status. Patients with flash pulmonary edema due to hypertension, for instance, require aggressive vasodilatory therapy. Patients with normotension and volume overload may be treated with diuretic therapy with or without vasodilator therapy.

Venous thromboembolism prophylaxis is indicated in patients hospitalized with acute HF. Sodium restriction is suggested in all patients with HF.

Vasopressin receptor antagonists are a rarely required option for patients with volume overload with severe hyponatremia (ie, serum sodium ≤120 meq/L) despite fluid restriction. We suggest generally avoiding opiate therapy in patients with ADHF.

Supplemental oxygen and assisted ventilation — Supplemental oxygen therapy and assisted ventilation should be provided as needed to treat hypoxemia (SpO2 <90 percent). Oxygen is not recommended as routine therapy in patients without hypoxemia, as it may cause vasoconstriction and reduction in cardiac output [2].

For patients requiring supplemental oxygen, we suggest initial therapies in the following order:

Non-rebreather facemask delivering high-flow percent oxygen

If respiratory distress, respiratory acidosis, and/or hypoxia persist on oxygen therapy, we recommend a trial of noninvasive ventilation (NIV) if emergent intubation is not indicated (algorithm 1), no contraindications to NIV exist (table 2), and personnel with experience in NIV are available.

This approach is supported by evidence from meta-analyses and randomized trials in patients with cardiogenic pulmonary edema, indicating that NIV decreases the need for intubation and improves respiratory parameters, such as dyspnea, hypercapnia, acidosis, and heart rate. NIV may be particularly beneficial in patients with hypercapnia. These issues and conflicting data on a possible impact on mortality are discussed in detail separately. (See "Noninvasive ventilation in acute respiratory failure in adults", section on 'Cardiogenic pulmonary edema'.)

Patients with respiratory failure who fail to improve with NIV (within one-half to two hours) or do not tolerate or have contraindications to NIV (table 2) should be intubated for conventional mechanical ventilation. In such patients, positive end-expiratory pressure is often useful to improve oxygenation. (See "Overview of mechanical ventilation" and "Positive end-expiratory pressure (PEEP)".)

Once initial therapy has begun, oxygen supplementation can be titrated in order to keep the patient comfortable and arterial oxygen saturation consistently above 90 percent.

Diuretics — Patients with ADHF and evidence of volume overload, regardless of etiology, should be treated with intravenous diuretics as part of their initial therapy [3-5]. As noted in the 2013 American College of Cardiology Foundation/American Heart Association (ACC/AHA) HF guidelines, patients admitted with significant fluid overload should receive diuretic therapy without delay in the emergency department or outpatient clinic, as early intervention may produce better outcomes [4]. Rare exceptions include patients with severe hypotension or cardiogenic shock. In such cases, the underlying cause for hemodynamic instability should be sought and the patient may require hemodynamic and mechanical ventilatory support along with diuresis.

Patients with aortic stenosis with volume overload should be diuresed with caution.

Patients with ADHF are usually volume overloaded. Even in the less common situation in which cardiogenic pulmonary edema develops without significant volume overload (eg, with hypertensive emergency, acute aortic or mitral valvular insufficiency), fluid removal with intravenous diuretics can relieve symptoms and improve oxygenation. Intravenous rather than oral administration is recommended because of greater and more consistent drug bioavailability.

Limited clinical trial data have shown a mortality benefit from diuretic therapy in patients with chronic HF. (See "Use of diuretics in patients with heart failure", section on 'Efficacy and safety'.) Although the safety and efficacy of diuretics to treat ADHF have not been established in randomized trials, extensive observational experience has demonstrated that they effectively relieve congestive symptoms [6].

Diuretic administration

Individualized dosing — Diuretic dosing should be individualized and titrated according to patient status and response. The approach to initial diuretic therapy in patients with ADHF and fluid overload varies according to whether or not the patient has received prior loop diuretic therapy:

For patients who have not previously received loop diuretic therapy, the following are common initial intravenous doses of loop diuretics in patients with normal renal function:

Furosemide – 20 to 40 mg intravenously

Bumetanide – 1 mg intravenously

Torsemide – 10 to 20 mg intravenously

If there is little or no response to the initial dose, the dose should be doubled at two-hour intervals as needed up to the maximum recommended doses. While patients with a relatively normal glomerular filtration rate (typically estimated from the serum creatinine concentration, although this method can be used only if kidney function is stable) can usually be diuresed with intravenous doses of 40 to 80 mg of furosemide, 20 to 40 mg of torsemide, or 1 to 2 mg of bumetanide, patients with renal insufficiency or severe HF may require higher maximum bolus doses of up to 160 to 200 mg of furosemide, 100 to 200 mg of torsemide, or 4 to 8 mg of bumetanide [7]. (See "Treatment of refractory edema in adults", section on 'Basic principles of diuretic dosing' and "Treatment of refractory edema in adults", section on 'Maximum effective dose of loop diuretics'.)

Patients treated with loop diuretics chronically may need a higher dose in the acute setting; the initial intravenous dose should be equal to or greater than (eg, 2.5 times) their maintenance oral dose and then adjusted depending upon the response (eg, an initial intravenous furosemide dose of 40 to 100 mg for a patient who had been taking 40 mg orally per day). In the DOSE trial of intravenous furosemide in patients with ADHF, there was an almost significant trend toward greater improvement in patients’ global assessment of symptoms in the high-dose (2.5 times the patients’ prior dose) group compared to the low-dose (equal the prior dose) group, as discussed below [8]. Subsequent dose escalation and maximum doses are similar to those used in patients who are not already being treated with loop diuretics.

Bolus diuretic administration two or more times per day may be necessary. A continuous intravenous infusion is an alternative to intravenous bolus therapy, although data are limited [9]. Use of a continuous intravenous infusion requires that the patient be responsive to intravenous bolus therapy, which results in higher initial plasma concentrations and therefore higher initial rates of urinary diuretic excretion than a continuous infusion. A continuous infusion should not be tried in patients who have not shown response to a maximum intravenous bolus dose. (See "Treatment of refractory edema in adults", section on 'Regimen' and "Use of diuretics in patients with heart failure".)

As an example, an initial intravenous bolus of 20 to 40 mg of furosemide administered over one to two minutes may be followed by a continuous infusion of approximately 5 mg/h in patients with relative intact renal function (estimated glomerular filtration [GFR] rate greater than 75 mL/min) and rates of up to 20 mg/h in patients with an estimated GFR less than 30 mL/min. Adding a thiazide diuretic may potentiate the effect, but hypokalemia should be avoided [7].

The onset of diuresis typically occurs within 30 minutes with peak diuresis usually at one to two hours after intravenous diuretic administration.

We suggest switching from an effective intravenous dose to an oral regimen once the patient’s acute symptoms have been stabilized to help ensure that an effective outpatient dose is identified and prescribed.

Evidence — No single intravenous dosing regimen (bolus versus continuous infusion; high versus lower dose) has been shown to be superior to others, as discussed separately. (See "Use of diuretics in patients with heart failure", section on 'Treatment of ADHF'.)

Monitoring — Volume status, evidence of congestion, oxygenation, daily weight, fluid intake, and output should be continually reassessed. Monitoring should also include watching for and guarding against side effects (including electrolyte abnormalities, symptomatic hypotension, worsening renal function and metabolic alkalosis). Diuretic therapy can also precipitate attacks of gout. The later transition from intravenous to oral diuretics should be made with careful attention to HF status, supine and upright hypotension, renal function, and electrolytes. (See "Loop diuretics: Maximum effective dose and major side effects" and "Diuretic-induced hyperuricemia and gout".)

Electrolytes — Serum potassium and magnesium levels should be monitored at least daily, and more frequent monitoring is indicated when diuresis is rapid, particularly since hypokalemia and hypomagnesemia increase the risk of arrhythmia. Severe muscle cramps may occur with overly rapid diuresis and should be treated with potassium and magnesium repletion if indicated [3].

Hemodynamic effects — Careful monitoring during diuresis is required to prevent adverse hemodynamic effects. By reducing intravascular volume, diuresis will eventually lower central venous and pulmonary capillary wedge pressures. In addition, furosemide and possibly other loop diuretics also have an initial morphine-like effect in acute pulmonary edema, causing venodilation that can decrease pulmonary congestion prior to the onset of diuresis [10]. This effect appears to be mediated by enhanced release of prostaglandins. (See "Use of diuretics in patients with heart failure", section on 'Venodilatory effect in acute pulmonary edema'.)

Reductions in right and left heart filling pressures with diuresis are frequently associated with augmented forward stroke volume and cardiac output. Improved forward stroke volume is related to decreases in functional tricuspid and mitral regurgitation and reduction in right ventricular volume with relief of interdependent left ventricular compression and improved left ventricular distensibility [3]. (See "Cardiorenal syndrome: Definition, prevalence, diagnosis, and pathophysiology", section on 'Right ventricular dilatation and dysfunction'.)

However, during diuresis, some patients experience symptomatic hypotension with decreasing cardiac output and systemic blood pressure due to a lag in re-equilibration of intravascular volume via movement of fluid from the interstitial space. Patients with HF with preserved left ventricular ejection fraction or restrictive physiology may be more sensitive to diuresis-induced reductions in preload. Diuretics may enhance the hypotensive effects of angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) therapy even when volume overload persists.

Renal function

Patterns of change — The blood urea nitrogen (BUN) and serum creatinine often rise during diuretic treatment of ADHF and careful monitoring is recommended. In the absence of other causes for an elevated BUN, a disproportionate rise in BUN relative to serum creatinine (BUN/serum creatinine ratio >20:1) suggests a prerenal state with increased passive reabsorption of urea. An initial rise in BUN may be accompanied by a stable serum creatinine, reflecting preserved GFR. Further elevations in BUN along with a rise in serum creatinine are likely if diuresis is continued in such patients. (See "Etiology and diagnosis of prerenal disease and acute tubular necrosis in acute kidney injury (acute renal failure)", section on 'Blood urea nitrogen/serum creatinine ratio'.)

An otherwise unexplained rise in serum creatinine, which reflects a reduction in GFR, may be a marker of reduced perfusion to the kidney and other organs. Patients in whom this occurs before euvolemic status is achieved have a worse prognosis. Nevertheless, fluid removal may still be required to treat signs and symptoms of congestion, particularly pulmonary edema. On the other hand, a stable serum creatinine suggests that perfusion to the kidneys (and therefore to other organs) is being well maintained and that the diuresis can be continued if the patient is still edematous. (See "Cardiorenal syndrome: Definition, prevalence, diagnosis, and pathophysiology", section on 'Reduced renal perfusion' and "Cardiorenal syndrome: Prognosis and treatment", section on 'Change in GFR during therapy for HF'.)

Changes in cardiac output and the consequent changes in renal perfusion are not the only determinant of changes in GFR in patients with HF. Among patients with an elevated central venous pressure, the associated increase in renal venous pressure can reduce the GFR, while lowering venous pressure with diuretics and other therapies might therefore increase the GFR. (See "Cardiorenal syndrome: Definition, prevalence, diagnosis, and pathophysiology".)

Management of worsening renal function — Guidelines for management of patients with ADHF with elevated or rising BUN and/or serum creatinine include the following [3]:

Other potential causes of kidney injury (eg, use of nephrotoxic medications, urinary obstruction) should be evaluated and addressed.

Patients with severe symptoms or signs of congestion, particularly pulmonary edema, require continued fluid removal independent of changes in GFR. In the presence of elevated central venous pressure, renal function may improve with diuresis. (See "Cardiorenal syndrome: Definition, prevalence, diagnosis, and pathophysiology", section on 'Increased renal venous pressure'.)

If the BUN rises and the serum creatinine is stable or increases minimally, and the patient is still fluid overloaded, the diuresis can be continued to achieve the goal of eliminating clinical evidence of fluid retention with careful monitoring of renal function. (See "Use of diuretics in patients with heart failure", section on 'Goals of therapy'.)

If increases in serum creatinine appear to reflect intravascular volume depletion, then reduction in or temporary discontinuation of diuretic and/or ACE inhibitor/ARB therapy should be considered. Adjunctive inotropic therapy may be required. (See 'Inotropic agents' below.)

If substantial congestion persists and adequate diuresis cannot be achieved, then ultrafiltration or dialysis should be considered. (See 'Ultrafiltration' below and "Renal replacement therapy (dialysis) in acute kidney injury in adults: Indications, timing, and dialysis dose", section on 'Urgent indications'.)

Vasodilator therapy

Approach to vasodilator therapy — Vasodilators may be required to correct elevated filling pressures and/or left ventricular afterload in patients with ADHF. Indications for vasodilator therapy in the setting of ADHF include the following: early vasodilator therapy (eg, nitroprusside) is recommended for patients with urgent need for afterload reduction (eg, severe hypertension); vasodilator therapy (eg, nitroglycerin) is suggested as an adjunct to diuretic therapy for patients without adequate response to diuretics; and vasodilator therapy is a component of therapy for patients with refractory HF and low cardiac output. The latter two clinical settings are discussed below. (See 'Medical management' below and 'Vasodilator therapy' below.)

We suggest early vasodilator therapy (typically, nitroprusside) in patients with severe hypertension, acute mitral regurgitation, or acute aortic regurgitation. Reliable blood pressure monitoring is required, and careful patient assessment is needed in determining the best vasodilator for the situation. These agents should be reduced or discontinued if symptomatic hypotension develops. (See "Acute mitral regurgitation in adults" and "Acute aortic regurgitation in adults".)

Use of vasodilator therapy in patients with ADHF is largely based upon hemodynamic response and expert opinion [3,4], since evidence on efficacy and safety of vasodilatory therapy in this setting is limited [11,12].

The routine use of vasodilators does not improve outcomes, and should be avoided [13]. For example, the largest randomized trial of the routine use of nesiritide in patients with ADHF, ASCEND-HF, found that nesiritide showed a borderline significant trend toward reducing dyspnea, but increased rates of hypotension, and did not alter rates of death, rehospitalization at 30 days, or worsening renal function [14]. As such, we recommend not treating patients routinely with nesiritide. (See "Nesiritide in the treatment of acute decompensated heart failure".)

Nitroglycerin — Nitrates, the most commonly used vasodilators in ADHF, cause greater venous than arterial vasodilation. They reduce left ventricular filling pressure primarily via venodilation. At higher doses, nitrates variably lower systemic vascular resistance and LV afterload, and may thereby increase stroke volume and cardiac output.

In patients with ADHF receiving nitrate therapy, an intravenous (rather than transdermal [ointment or patch] or oral) route is used for greater speed and reliability of delivery and ease of titration. An initial dose of 5 to 10 mcg/min of intravenous nitroglycerin is recommended with the dose increased in increments of 5 to 10 mcg/min every three to five minutes as required and tolerated (dose range 10 to 200 mcg/min). Similar benefits have been described with high-dose intravenous isosorbide dinitrate, where available [11,12]. However, if hypotension occurs, the longer half-life of isosorbide dinitrate compared to intravenous nitroglycerin (four hours versus three to five minutes) is a major disadvantage.

Tachyphylaxis can occur within hours with administration of high doses of nitroglycerin and the strategy of nitrate-free interval used to reduce tolerance during chronic therapy could result in adverse hemodynamic effects in patients with ADHF. Potential adverse effects of nitroglycerin include hypotension and headache. Nitrate therapy should be avoided or used with caution in settings in which hypotension is likely or could result in serious decompensation such as right ventricular infarction or aortic stenosis. Nitrate administration is contraindicated after use of PDE-5 inhibitors such as sildenafil. (See "Sexual activity in patients with cardiovascular disease", section on 'Adverse interaction with nitrates' and "Right ventricular myocardial infarction", section on 'Optimization of right ventricular preload' and "Medical management of symptomatic aortic stenosis", section on 'Medical management'.)

As noted in a systematic review of the limited studies comparing intravenous nitroglycerin to placebo in patients with acute HF, very low-quality evidence showed a decrease in mean pulmonary capillary wedge pressure with intravenous nitroglycerin compared to placebo but evidence of clinical benefit was lacking [13].    

Nitroprusside — In contrast to nitroglycerin, nitroprusside causes balanced arterial and venous dilation. Thus, while it can be used to decrease left ventricular filling pressures, it will cause a concomitant decrease in systemic vascular resistance. In patients in whom systemic resistance is elevated, the resulting decrease in afterload can increase stroke volume without lowering blood pressure; whereas if systemic vascular resistance is not elevated, nitroprusside may cause hypotension. Likewise, arterial dilation and afterload reduction can be of value in patients with depressed stroke volume due to elevated left ventricular afterload such as acute aortic regurgitation, acute mitral regurgitation, acute ventricular septal rupture, or hypertensive emergency. (See "Drugs used for the treatment of hypertensive emergencies", section on 'Nitroprusside'.)

Because of its very potent hemodynamic effects and the potential to excessively lower blood pressure, the use of nitroprusside requires close hemodynamic monitoring, typically with an intra-arterial catheter. The initial dose of 5 to 10 mcg/min is titrated up every five minutes as tolerated to a dose range of 5 to 400 mcg/min.

The major limitation to the use of nitroprusside is its metabolism to cyanide. The accumulation of nitroprusside metabolites can lead to the development of cyanide, or rarely thiocyanate, toxicity, which may be fatal. Doses above 400 mcg/min generally do not provide greater benefit and may increase the risk of thiocyanate toxicity. Nitroprusside administration requires close and continuous blood pressure monitoring, and may cause reflex tachycardia. Another potential risk is rebound vasoconstriction upon discontinuation of nitroprusside [15]. Thus, the use of nitroprusside is limited to selected patients, usually for durations of less than 24 to 48 hours.

Use of nitroprusside in patients with ADHF is based largely upon expert opinion since available published evidence is very limited [13].

Nesiritide — Nesiritide, like nitroprusside, is a balanced arterial and venous dilator. We recommend against routine treatment of patients with ADHF with nesiritide. In carefully selected patients with appropriate hemodynamics (including absence of hypotension or cardiogenic shock) who remain symptomatic despite routine therapy, a trial of nesiritide may be helpful as an alternative to other vasodilator therapy (nitroglycerin or nitroprusside).

Nesiritide is typically given as an initial intravenous bolus of 2 mcg/kg, followed by a continuous infusion of 0.01 mcg/kg per minute, with subsequent dose adjustment as necessary. Close monitoring of hemodynamics, urine output, and renal function are necessary for effective clinical use and safety. 

Nesiritide is less potent than nitroprusside, and both the onset and offset of action are slower. Because nesiritide has a longer effective half-life than nitroglycerin or nitroprusside, side effects such as hypotension may persist longer. (See "Nesiritide in the treatment of acute decompensated heart failure", section on 'Use'.)

Sodium and fluid restriction

Sodium restriction — Sodium restriction has been commonly recommended in patients with acute or chronic HF, although there are insufficient data to support any specific level of sodium intake in patients with symptomatic HF, as noted in the 2013 ACC/AHA and 2012 European Society of Cardiology (ESC) guidelines [4,16]. Given the available evidence, we suggest sodium restriction (eg, <2 g/d) in patients with symptomatic HF. The 2013 ACC/AHA guidelines suggest some degree (eg, <3 g/d) of sodium restriction in patients with symptomatic HF [16], while the 2012 ESC guidelines note that the safety and efficacy of salt restriction require further study [16]. (See "Patient education: Low-sodium diet (Beyond the Basics)".)

Fluid restriction — Fluid restriction (eg, 1.5 to 2 L/d) may be helpful in patients with refractory HF and hyponatremia, as suggested by the 2013 ACC/AHA guidelines [4]. Stricter fluid restriction is indicated in patients with severe (serum sodium <125 meq/L) or worsening hyponatremia, although patient tolerance of strict fluid restriction may be limited. (See "Hyponatremia in patients with heart failure", section on 'Treatment' and "Overview of the treatment of hyponatremia in adults", section on 'Fluid restriction in most patients'.)

Hyponatremia is common among HF patients and the degree of reduction in serum sodium parallels the severity of the HF. As a result, a low serum sodium is an adverse prognostic indicator. Most HF patients with hyponatremia have volume overload rather than volume depletion.

Evidence — The evidence to support sodium and/or fluid restriction in patients with ADHF is inconclusive, with two small randomized trials of fluid restriction or fluid and sodium restriction in patients hospitalized with HF showing no benefit [17,18]. As an example, the second study randomly assigned 75 patients with ADHF due to systolic dysfunction treated with the usual pharmacologic interventions to a diet with a maximum dietary sodium intake of 800 mg/day and a maximum fluid intake of 800 mL/day or to a similar diet with 3 to 5 g of total sodium intake and a fluid intake of at least 2.5 L/day [18]. At three days, weight loss was similar in both groups, as were measures of clinical congestion. Perceived thirst (graded on a scale of 0 to 10), was significantly worse in the group with stricter sodium and fluid intake (between group difference, 1.66 points).

Although some studies have suggested a possible benefit from a regimen of hypertonic saline plus furosemide in patients with ADHF, this approach is controversial and is of uncertain safety and efficacy. (See "Investigational and emerging therapies for heart failure".)

Venous thromboembolism prophylaxis — Prophylaxis against venous thromboembolism (deep vein thrombosis and pulmonary embolism) with low-dose unfractionated heparin or low molecular weight heparin, or fondaparinux, is indicated in patients admitted with ADHF who are not already anticoagulated and have no contraindication to anticoagulation. In patients admitted with ADHF who have a contraindication to anticoagulation, venous thromboembolism prophylaxis with a mechanical device (eg, intermittent pneumatic compression device) is suggested [3]. These issues are discussed in detail separately. (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults".)

Vasopressin receptor antagonists — For patients with HF with volume overload with persistent severe hyponatremia (ie, serum sodium ≤120 meq/L) despite water restriction and maintenance of guideline-directed medical therapy, short-term use of a vasopressin receptor antagonist (either a V2 receptor selective or nonselective vasopressin antagonist) is an option to improve serum sodium concentration [4]. Cautions include hepatotoxicity (with the United States Food and Drug Administration determining that tolvaptan should be not be used in any patient for longer than 30 days and should not be used at all in patients with liver disease due to risk of liver failure or death) and overly rapid correction of hyponatremia, which can lead to irreversible neurologic injury. These issues are further discussed separately. (See "Hyponatremia in patients with heart failure", section on 'Vasopressin receptor antagonists'.)

Vasopressin receptor antagonists have been investigated as an adjunct to diuretics and other standard therapies in patients with ADHF as a means of countering arterial vasoconstriction, hyponatremia, and water retention. Tolvaptan is the most studied agent in this setting. However, such treatment is controversial since the long-term safety and benefit of this approach are unknown. (See "Hyponatremia in patients with heart failure", section on 'Efficacy'.)

Our approach is similar to the 2013 ACC/AHA guidelines, which classify as reasonable the short-term use of vasopressin antagonists in hospitalized patients with volume overload who have persistent severe hyponatremia and are at risk for cognitive symptoms despite water restriction and maximization of guideline-directed medical therapy, although the long-term safety and benefit of this approach are unknown [4]. The 2012 ESC guidelines suggest consideration of tolvaptan for HF patients with hyponatremia in an ungraded recommendation [16].

Opiate — Given the limited evidence of benefits and potential risks of opiates, we suggest generally avoiding opiate therapy in the treatment of ADHF.

Data are limited on the effects of morphine therapy in ADHF. Morphine reduces patient anxiety and decreases the work of breathing. These effects diminish central sympathetic outflow, leading to arteriolar and venous dilatation with a resultant fall in cardiac filling pressures [19,20].

A systematic review that included one prospective and four retrospective studies of opiates (morphine or diamorphine) in ADHF found that the available evidence was very low quality, with no evidence of benefit and some evidence of harm [13]. The largest of the studies found that morphine administration for ADHF was associated with increased frequency of mechanical ventilation, admission to an intensive care unit, and in-hospital mortality [21]. After risk adjustment and exclusion of ventilated patients, morphine remained an independent predictor of mortality (odds ratio 4.8, 95% confidence interval 4.52-5.18). Two smaller studies found no significant differences in mortality rates with opiate therapy. Although risk adjustment in the largest study may not have been adequate, the results raise concern about the safety of opiate therapy in this population.

The 2012 ESC guidelines include consideration of opiates such as morphine in some patients with acute pulmonary edema as an ungraded recommendation, noting that they reduce anxiety and distress associated with dyspnea but also induce nausea and depress respiratory drive [16]. Morphine therapy is not mentioned in the 2010 Heart Failure Society of America guidelines on management of ADHF or in the 2013 ACC/AHA guidelines.

The role of morphine sulfate in patients with ADHF who have an acute myocardial infarction is discussed separately. (See "Treatment of acute decompensated heart failure in acute coronary syndromes", section on 'Morphine sulfate'.)

MANAGEMENT OF INADEQUATE RESPONSE TO DIURETIC THERAPY

Approach to inadequate response to diuretics — Patients with acute decompensated heart failure (ADHF) who fail to adequately respond to diuretic therapy are initially treated by medical management (adjustment and addition of diuretic medications and diet). If these measures are not sufficient to effectively reduce volume overload, ultrafiltration is suggested.

Medical management — Some patients with ADHF do not respond adequately to initial loop diuretic therapy [3,4]. These patients should be re-evaluated for congestion. The approach to patients with refractory edema is discussed in detail elsewhere. (See "Treatment of refractory edema in adults".)

Summarized briefly, we suggest the following measures:

Doubling the diuretic dose until diuresis ensues or the maximum recommended dose is reached. (See "Loop diuretics: Maximum effective dose and major side effects", section on 'Maximum effective dose'.)

Addition of a second diuretic to potentiate the effects of the loop diuretic. For patients in whom the diuretic response is inadequate, intravenous chlorothiazide or oral metolazone or spironolactone are reasonable choices for a second diuretic.

Chlorothiazide is the only thiazide diuretic that can be given intravenously (500 to 1000 mg/day). However, the availability of this preparation may be limited. An oral thiazide, such as hydrochlorothiazide (25 to 50 mg twice daily) or metolazone (which has the advantage of once daily dosing), is an alternative for acute therapy and can be given chronically. Although it has been suggested that metolazone is the thiazide of choice in refractory patients with advanced renal failure (glomerular filtration rate below 20 mL/min), there is at present no convincing evidence that metolazone has unique efficacy among the thiazides when comparable doses are given. (See "Treatment of refractory edema in adults", section on 'Enhanced tubular sodium reabsorption'.)

Addition of a mineralocorticoid receptor antagonist (spironolactone or eplerenone) is recommended in selected patients with HF with reduced ejection fraction to improve survival. In addition, the associated reduction in collecting tubule sodium reabsorption and potassium secretion can both enhance the diuresis and minimize the degree of potassium wasting. Thus, if not already being given, it is reasonable to initiate mineralocorticoid receptor antagonist therapy prior to the addition of a thiazide diuretic in patients with a low or low-normal serum potassium on loop diuretic therapy alone. Mineralocorticoid receptor antagonist therapy should be continued following hospital discharge only in patients who can be carefully monitored for hyperkalemia. When given for diuresis or potassium-sparing effects, a higher dose (up to 100 mg daily) than the usual HF dose may be needed. (See "Treatment of refractory edema in adults", section on 'Enhanced tubular sodium reabsorption' and 'Mineralocorticoid receptor antagonist' below.)

Sodium restriction to a limit of 2 g daily, though there is limited evidence to support this approach. Fluid restriction can also be considered in patients with hyponatremia. (See 'Sodium and fluid restriction' above.)

In patients with refractory volume overload, the addition of a vasodilator (eg, nitroglycerin, nitroprusside, or nesiritide) as a temporizing measure to relieve congestion. (See 'Nitroglycerin' above and 'Nitroprusside' above and 'Nesiritide' above.)

Ultrafiltration — Ultrafiltration is an effective method of fluid removal that provides adjustable fluid removal volumes and rates and no effect on serum electrolytes. However, studies have not found a clinical benefit over diuretic therapy and it does not preserve renal function compared to diuresis. Ultrafiltration is reserved for patients with fluid overload who do not achieve an adequate response to an aggressive diuretic regimen. This recommendation is consistent with the 2013 American College of Cardiology Foundation/American Heart Association HF guidelines [4]. Consultation with a kidney specialist may be appropriate prior to opting for a mechanical strategy of fluid removal. (See "Continuous renal replacement therapies: Overview".)

Most studies have used a peripherally inserted ultrafiltration device that does not require central access, specialized nursing, or intensive care unit admission [22].

The efficacy of ultrafiltration in patients with ADHF has been evaluated in several randomized trials [23-26]:

In the UNLOAD trial, 200 patients hospitalized for ADHF were randomly assigned to ultrafiltration or to standard care, including intravenous diuretics during the admission [24]. Renal dysfunction and/or anticipated diuretic resistance were not entry criteria. The following findings were noted:

At 48 hours, patients assigned to ultrafiltration had a significantly greater fluid loss (4.6 versus 3.3 liters with standard care). This difference may in part reflect the relatively modest level of diuretic therapy used in the standard care arm.

At 90 days, patients assigned to ultrafiltration had significantly fewer HF rehospitalizations than patients assigned to standard care (0.22 versus 0.46 admissions per patient) and fewer unscheduled clinic visits (21 versus 44 percent with standard care).

The rates of adverse events were similar in the two groups, although there was a higher incidence of bleeding in the standard care arm. There was no difference in serum creatinine, as was also found in a smaller trial with detailed assessment of renal hemodynamics [25].

In CARRESS-HF, 188 patients with ADHF, worsened renal function (defined as an increase in the serum creatinine level of at least 0.3 mg/dL [26.5 micromol/L]), and persistent congestion were randomly assigned to either stepped pharmacology therapy or ultrafiltration [26]. The stepped pharmacologic care algorithm included bolus plus high doses of continuous infusion loop diuretic, the addition of metolazone, and selective use of inotrope or vasodilator therapy. The primary end point was the bivariate change in the serum creatinine level and body weight from baseline to 96 hours after enrollment. Ultrafiltration was inferior to pharmacologic therapy with respect to the primary end point due to increase in serum creatinine in the ultrafiltration group in contrast to a fall in mean serum creatinine in the pharmacologic therapy group (+0.23±0.70 mg/dL [+20.3±61.0 micromol/L] versus -0.04±0.53 mg/dL [-3.5±46.9 micromol/L]). There was no significant difference in weight loss at 96 hours between the ultrafiltration and pharmacologic therapy groups (5.7±3.9 kg [12.6±8.5 lb] and 5.5±5.1 kg [12.1±11.3] lb]). A higher percentage of patients in the ultrafiltration group had serious adverse events (eg, HF, renal failure, anemia or thrombocytopenia, electrolyte disorder, hemorrhage, pneumonia, sepsis; 72 versus 57 percent).

Thus, while ultrafiltration was an effective method for fluid volume removal, providing similar amounts of weight loss to stepped pharmacologic therapy, it was inferior to stepped pharmacologic therapy for preservation of renal function at 96 hours and was associated with a higher rate of adverse events.

TREATMENT OF REFRACTORY HEART FAILURE AND HYPOTENSION

Approach to refractory heart failure and hypotension — The approach to refractory heart failure (HF) and hypotension differs with HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF).

Treatment of patients with HFrEF and refractory volume overload unresponsive to diuretic therapy is guided by hemodynamics, which are most commonly imputed from the physical examination with more direct assessment by right heart catheterization performed when required for selected cases. Intravenous vasodilator therapy is suggested for patients with refractory HF without symptomatic hypotension. Selected patients with hypotension may benefit from vasodilator therapy guided by invasive monitoring, including pulmonary artery catheter. If the systolic blood pressure is <85 mmHg or there is evidence of shock (eg, cool extremities, narrow pulse pressure, low urine output, confusion), addition of an inotrope is suggested [16]. In patients with persistent shock, a vasopressor may be added as a temporizing measure to support perfusion to vital organs, though this is at the expense of increased left ventricular afterload. For selected patients with severe HFrEF (generally with left ventricular ejection fraction <25 percent) with acute, severe hemodynamic compromise, nondurable mechanical support (eg, intraaortic balloon pump [IABP], extracorporeal circulatory membrane oxygenator [ECMO], or extracorporeal ventricular assist devices) is an option as a “bridge to decision” or “bridge to recovery” [4,16].

Patients with HFpEF presenting with hypotension should not receive inotropes and may require a vasopressor in addition to diuretic therapy. Patients who develop hypotension with dynamic left ventricular outflow obstruction are treated with beta blocker therapy, a vasopressor (eg, phenylephrine or norepinephrine), and gentle hydration if pulmonary edema is not present. Dynamic left ventricular outflow obstruction occurs in some patients with hypertrophic cardiomyopathy but is not limited to patients with that condition. (See "Hypertrophic cardiomyopathy: Medical therapy", section on 'Acute hemodynamic collapse in the setting of LVOT obstruction'.)

Ultrafiltration is an option for patients with HFrEF or HFpEF with refractory volume overload not responding to diuretic strategies.

Management of refractory HF is discussed in detail separately. (See "Management of refractory heart failure".)

Vasodilator therapy — Intravenous vasodilator therapy is suggested in patients with refractory HF who require reduction in preload, afterload, or both. Nitrates reduce left ventricular filling pressure primarily via venodilation and at higher doses, lower systemic vascular resistance and left ventricular afterload. Nitroprusside and nesiritide both provide balanced arterial and venous dilation.

Use of vasodilator therapy in patients with acute decompensated HF (ADHF) is largely based upon hemodynamic response and clinical experience [3,4], since other evidence on efficacy and safety of vasodilatory therapy in this setting is limited [11,12]. While nitroglycerin, nitroprusside, and nesiritide exert potent hemodynamic effects that can be of value in the management of pulmonary congestion and/or reduced cardiac output, the use of these agents should be reserved for patients in whom improved hemodynamic function is likely to lead to clinically useful improvements in oxygenation and/or organ perfusion. Reliable blood pressure monitoring is required, and careful patient assessment is needed in determining the best vasodilator for the situation. If symptomatic hypotension develops, these agents should be reduced or discontinued and invasive monitoring should be used to assess hemodynamics may be helpful.

Inotropic agents

Indications — Intravenous inotropic agents such as dobutamine and/or milrinone may be required as a temporizing measure in patients with severe left ventricular systolic dysfunction and low output syndrome (diminished peripheral perfusion and end-organ dysfunction). We agree with the recommendations on inotropic agents in the 2013 American College of Cardiology Foundation/American Heart Association guideline on HF [4]. Temporary intravenous inotropic support was recommended for patients with cardiogenic shock to maintain systemic perfusion and preserve end-organ performance until definitive therapy (eg, coronary revascularization, mechanical circulatory support, or heart transplantation) is instituted or resolution of the acute precipitating problem has occurred. Continuous intravenous inotropic support was felt to be reasonable as “bridge therapy” in patients with stage D HF refractory to guideline-directed medical therapy and device therapy who are eligible for and awaiting mechanical circulatory support or cardiac transplantation. In addition, the guidelines noted that inotropic therapy “may be reasonable” (a very weak recommendation) in the following settings: short-term, continuous intravenous inotropic support in hospitalized patients presenting with documented severe systolic dysfunction who present with low blood pressure and significantly depressed cardiac output to maintain systemic perfusion and preserve end-organ performance; and long-term continuous intravenous inotropic support as palliative therapy for symptom control in select patients with stage D HF despite optimal guideline-directed medical therapy and device therapy who are not eligible for either mechanical circulatory support or cardiac transplantation. (See "Palliative care for patients with advanced heart failure".)

Similar recommendations are included in the 2010 Heart Failure Society of America [3] and 2012 European Society of Guidelines [16].

Patients receiving intravenous inotropes require continuous or frequent blood pressure monitoring and continuous monitoring of cardiac rhythm [3]. Invasive hemodynamic monitoring is indicated in patients with respiratory distress or impaired systemic perfusion with uncertain hemodynamic status [4]. If symptomatic hypotension or worsening tachyarrhythmias develop during inotrope administration, dose reduction or discontinuation is suggested.

Inotropes are not indicated for treatment of ADHF in the setting of preserved systolic function.

Patients with hypotension with dynamic left ventricular outflow tract obstruction (who may have normal or depressed left ventricular systolic function) should not receive inotropes since they can provoke or worsen the obstruction [27]. Patients with dynamic left ventricular outflow tract obstruction are treated with beta blockers and careful fluid resuscitation in the absence of significant pulmonary congestion. Vasopressor therapy may be required for severe hypotension. (See "Hypertrophic cardiomyopathy: Medical therapy", section on 'Heart failure' and "Management and prognosis of stress (takotsubo) cardiomyopathy", section on 'With left ventricular outflow tract obstruction'.)

Specific agents — Careful titration is advised when inotropes are used in patients with ADHF (table 3) [4]:

Milrinone – Milrinone is a phosphodiesterase inhibitor that increases myocardial inotropy by inhibiting degradation of cyclic adenosine monophosphate. Other direct effects of milrinone include reducing systemic and pulmonary vascular resistance (via inhibition of peripheral phosphodiesterase) and improving left ventricular diastolic compliance [28,29]. These changes lead to an increase in cardiac index and decrease in left ventricular afterload and filling pressures. Patients should receive a loading dose of 50 mcg/kg over 10 minutes, followed by a maintenance dose of 0.375 to a maximum of 0.750 mcg/kg per min. Dose adjustment is required in the presence of renal insufficiency, hypotension, or arrhythmias.

Since milrinone does not act via beta receptors, its effects are not as diminished as those of dobutamine or dopamine by concomitant beta blocker therapy.

Dobutamine – Dobutamine acts primarily on beta-1 adrenergic receptors, with minimal effects on beta-2 and alpha-1 receptors. The hemodynamic effects of dobutamine include increases in stroke volume and cardiac output, and modest decreases in systemic vascular resistance and pulmonary capillary wedge pressure [30,31]. It should be started at 2.5 mcg/kg per min and, if tolerated and needed, can be gradually increased to 20 mcg/kg per min.

Dopamine – At low doses of 1 to 3 µg/kg per min, dopamine acts primarily on dopamine-1 receptors to dilate the renal and mesenteric artery beds [32]. At 3 to 10 µg/kg per min (and perhaps also at lower doses), dopamine also stimulates beta-1 adrenergic receptors and increases cardiac output, predominantly by increasing stroke volume with variable effects on heart rate. At medium-to-high doses, dopamine also stimulates alpha-adrenergic receptors, although a small study suggested that renal arterial vasodilation and improvement in cardiac output may persist as the dopamine dose is titrated up to 10 µg/kg per min [32].

Although it has been proposed that dopamine might improve renal function in patients with severe HF by increasing renal blood flow and possibly by reducing renal venous pressure, data supporting such a potential benefit are limited. Specifically, the addition of low-dose dopamine to diuretic therapy was not found to enhance decongestion or improve renal function [33]. (See "Cardiorenal syndrome: Prognosis and treatment", section on 'Inotropic drugs'.)

Evidence — A systematic review of randomized controlled trials of inotropes in ADHF found that evidence was insufficient to determine the clinical efficacy and safety of such therapy [13].

There is concern that inotropic agents may adversely impact outcomes in patients with ADHF with congestion without a low output state [34,35]. Inotropic agents may increase heart rate and myocardial oxygen consumption and thus provoke ischemia and potentially damage hibernating but viable myocardium, particularly in patients with ischemic heart disease. In addition, inotropic agents can increase atrial [34] and ventricular [36] arrhythmias. Given these concerns, careful patient selection is required for inotrope use. (See "Inotropic agents in heart failure with reduced ejection fraction", section on 'Intravenous therapy' and "Use of vasopressors and inotropes".)

Routine use of inotropes in patients hospitalized for HF was found to be harmful in the OPTIME-CHF trial [34]. In this trial, 949 patients admitted to the hospital with an acute exacerbation of chronic HF were randomly assigned to a 48- to 72-hour infusion of milrinone or placebo. Milrinone therapy was associated with significant increases in hypotension requiring intervention and atrial arrhythmias, and with nonsignificant increases in mortality in-hospital (3.8 versus 2.3 percent) and at 60 days (10.3 versus 8.9 percent). This trial did not evaluate patients whose treating physicians felt could not be randomized, but demonstrates overall adverse effects in noncritical patients despite improved symptoms.

The general role of inotropic agents in patients with HFrEF is discussed separately. (See "Inotropic agents in heart failure with reduced ejection fraction", section on 'Intravenous therapy'.)

Vasopressor therapy — In patients with ADHF and marked hypotension, vasopressor therapy can be used as a temporizing measure to preserve systemic blood pressure and end-organ perfusion, although at the cost of increasing afterload and decreasing cardiac output [16]. Vasopressor use should be limited to patients with persistent hypotension with symptoms or evidence of consequent end-organ hypoperfusion despite optimization of filling pressures and use of inotropic agents as appropriate. In this setting, invasive monitoring can be helpful to assess filling pressures and systemic vascular resistance. (See "Pulmonary artery catheterization: Indications, contraindications, and complications in adults", section on 'Indications'.)  

Vasopressors used in this setting include norepinephrine, high-dose dopamine (>5 micrograms/kg/min), and vasopressin, and these should be carefully titrated to achieve adequate perfusion of vital organs (table 3). Dopamine and norepinephrine have beta inotropic as well as vasopressor activity. (See "Use of vasopressors and inotropes".)

A systematic review found no evidence to determine the clinical efficacy and safety of vasopressor therapy in ADHF [13].

Mechanical cardiac support — For selected patients with severe HFrEF (generally with left ventricular ejection fraction <25 percent) with acute, severe hemodynamic compromise (cardiogenic pulmonary edema with cardiogenic shock), nondurable mechanical support is an option as a “bridge to decision” or “bridge to recovery” [4,16]. These patients usually have a cardiac index less than 2.0 L/min per m2, a systolic arterial pressure below 90 mmHg, and a pulmonary capillary wedge pressure above 18 mmHg, despite adequate pharmacologic therapy.

Mechanical modalities used in this setting include IABP, ECMO, or short-term left ventricular assist devices. (See "Intraaortic balloon pump counterpulsation" and "Short-term mechanical circulatory assist devices".)

INVESTIGATIONAL THERAPY FOR ACUTE HEART FAILURE — The following investigational therapies have shown some promise but further study is needed to determine safety and efficacy.

Relaxin — Relaxin therapy may be beneficial in patients with acute heart failure (HF) but additional study is required to confirm the efficacy and safety of this approach.

Relaxin is a naturally occurring human peptide vasodilator. The RELAX-AHF trial of serelaxin, recombinant human relaxin-2, in patients with acute HF found that it improved some clinical outcomes, including a measure of dyspnea [37]. This international randomized controlled trial enrolled 1161 patients with acute HF and systolic blood pressure >125 mmHg. The study was not restricted to patients with low left ventricular ejection fraction (LVEF) and 26 percent of patients had an LVEF ≥50 percent [38]. Serelaxin improved one measure of dyspnea (the visual analogue scale area under the curve) through day five and reduced average length of index hospital stay but did not improve the proportion of patients with moderate or marked improvement in dyspnea measured by Likert scale during the first 24 hours or readmission to the hospital within 60 days. The serelaxin group experienced a significantly lower rate of cardiovascular death (hazard ratio [HR] 0.63; 95% confidence interval [CI] 0.41-0.96) and all-cause mortality (HR 0.83, 95% CI 0.43-0.93) to 180 days. Similar effects were noted in patients with LVEF <50 percent and patients with LVEF ≥50 percent [38].

Hypertonic saline plus furosemide — Several studies have suggested benefits from combined intravenous hypertonic saline solution plus intravenous furosemide as compared to intravenous furosemide alone in treating acute decompensated HF. However, the safety and effectiveness of this approach is uncertain.

The rationale for using hypertonic saline solution includes an osmotic effect that might help optimize refilling of the intravascular compartment during intravenous diuretic therapy and increases in renal blood flow that might promote diuretic action [39,40].

A meta-analysis included nine randomized controlled trials comparing intravenous hypertonic saline solution plus intravenous furosemide to intravenous furosemide alone with the following results [39]:

Analysis for all-cause mortality included five trials and found a survival benefit with combined hypertonic saline solution plus furosemide compared to furosemide alone (risk ratio [RR] = 0.57, 95% confidence interval [CI] 0.44-0.74). However, there was substantial heterogeneity among the studies (I2 = 66 percent) and no significant benefit remained if either of two trials [41,42] was excluded.

Based upon pooled results from four trials, combined hypertonic saline solution plus furosemide decreased heart failure-related hospital readmission compared to furosemide alone (RR = 0.51; 95% CI 0.35-0.75). However, there was moderate heterogeneity among studies (I2 = 58 percent) and no significant benefit remained if either of two trials [41,42] was excluded.

Analyses of length of hospital stay (seven trials), weight loss (eight trials), and preservation of renal function (serum creatinine) all favored therapy with combined hypertonic saline solution plus furosemide versus furosemide alone, although there was marked heterogeneity among studies for each of these outcomes.

Continuous aortic flow augmentation — Continuous aortic flow augmentation (CAFA) appears to improve cardiac performance but a clinical benefit has not been established and risk of major bleeds is associated with the device. CAFA does not increase cardiac output directly. Instead, arterial blood is drawn from a peripheral artery and recirculated through the aorta via an extracorporeal pump that then returns blood through a second arterial access site. The system provides continuous flow through the aorta that augments pulsatile cardiac output. Increased aortic flow is postulated to stimulate favorable hemodynamic changes, primarily through cardiac unloading and peripheral vasodilation.

In the MOMENTUM trial, 168 patients hospitalized with HF with reduced LVEF were randomly assigned to CAFA plus medical therapy or medical therapy alone [43]. Participants had elevated pulmonary capillary wedge pressure (PCWP), and renal impairment or substantial diuretic requirement despite intravenous inotropes/vasopressors. The primary composite efficacy end point included PCWP and days alive out of hospital off mechanical support over 35 days and was similar in the two treatment groups. CAFA improved cardiac index and PCWP. CAFA resulted in improved cardiac performance, as reflected in an upward-leftward shift in the stroke work versus PCWP relationship compared with the control group [44]. Major bleeds occurred in 16.5 percent in the device group and 5.1 percent in the control group.

CONTINUATION OR INITIATION OF LONG-TERM THERAPY — The approach to managing long-term therapy during hospitalization for acute heart failure (HF) differs for HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF).

Approach to long-term therapy for heart failure with preserved ejection fraction — In patients with HFpEF, long-term therapy is based largely on associated conditions (eg, hypertension or edema) since trial data are limited, with no established survival benefit from any specific therapy. The general principles for treatment of HFpEF are control of systolic and diastolic hypertension, control of heart rate (particularly in patients with atrial fibrillation), control of pulmonary congestion and peripheral edema with diuresis (with care to avoid hypotension and/or left ventricular outflow obstruction), and coronary revascularization in patients with coronary heart disease with ischemia judged to impair diastolic function. Choice of antihypertensive therapy is based largely upon efficacy. (See "Treatment and prognosis of heart failure with preserved ejection fraction" and "Choice of drug therapy in primary (essential) hypertension".)

For patients with HFpEF who are hemodynamically stable during an acute decompensated HF (ADHF) episode, chronic antihypertensive therapy may be continued with careful monitoring. However, some patients with acute HF have severe hypertension that may require parental vasodilator therapy [45]. On the other hand, some patients with small left ventricular cavities and/or left ventricular hypertrophy are volume-sensitive and at risk for developing hypotension with diuresis. After the patient is stabilized and prior to discharge, an oral medical regimen should be instituted, including antihypertensive and diuretic therapy as needed. (See "Treatment and prognosis of heart failure with preserved ejection fraction", section on 'Treatment'.)

Approach to long-term therapy for heart failure with reduced ejection fraction — Evidence-based therapy to reduce morbidity and mortality for patients with chronic HFrEF includes an angiotensin converting enzyme (ACE) inhibitor, single-agent angiotensin receptor blocker (ARB), or angiotensin receptor-neprilysin inhibitor (ARNI); a beta blocker; and a mineralocorticoid antagonist (figure 1). During an acute HF episode, management of these agents depends upon whether the patient was already receiving these medications and whether the patient has contraindications to therapy such as hemodynamic instability or acute kidney injury. Once the patient is stable, evidence-based therapies are carefully initiated, re-initiated, or titrated with arrangements for appropriate outpatient follow-up. In stable patients, ACE inhibitor (or ARB) and beta blocker therapy should be initiated prior to hospital discharge and mineralocorticoid receptor antagonist should be added prior to or soon after discharge (as needed to allow appropriate monitoring of serum potassium levels). (See "Overview of the therapy of heart failure with reduced ejection fraction".)

ACE inhibitor, ARB or ARNI — For patients with HFrEF, an ACE inhibitor (or ARB if ACE inhibitor is not tolerated) is a mainstay of chronic therapy. The ARNI sacubitril-valsartan is a newer alternative to ACE inhibitor (or single-agent ARB) therapy. (See "ACE inhibitors in heart failure with reduced ejection fraction: Therapeutic use" and "Use of angiotensin II receptor blocker and neprilysin inhibitor in heart failure with reduced ejection fraction".)

Among patients with ADHF, the role of angiotensin inhibition depends upon whether the patient is already receiving such therapy.

Continued therapy — For patients who are already taking an ACE inhibitor, single-agent ARB, or ARNI, we suggest that maintenance of oral therapy be cautiously continued. However, the dose should be decreased or the drug discontinued if hypotension, worsening renal function, or hyperkalemia is present.

With regard to hypotension, two additional points should be considered:

Some patients with chronic HF and severe left ventricular systolic dysfunction tolerate relatively low blood pressures (eg, systolic blood pressure 90 to 100 mmHg). Such patients often tolerate chronic ACE inhibitor, ARB, or ARNI therapy and may tolerate these drugs in the acute setting as well.

Patients with acute pulmonary edema may initially be hypertensive due to high catecholamine levels during the early period of distress. With initial therapy, blood pressure may fall rapidly and patients may become relatively hypotensive, particularly if they are aggressively diuresed. Thus, long-acting drugs, such as ACE inhibitors, ARBs, or ARNI should be administered with caution or avoided during the first few hours of hospitalization.

Initiation of therapy — For patients who are not already taking an ACE inhibitor, single-agent ARB, or ARNI, we suggest that such therapy not be initiated at the time of presentation with an episode of ADHF. An oral ACE inhibitor or ARB can usually be started within 24 to 48 hours, once the patient is hemodynamically stable. Initiation of these therapies known to improve outcomes is recommended prior to hospital discharge. We reserve use of the ARNI sacubitril-valsartan for selected patients with HFrEF who have tolerated high doses of ACE inhibitor (or ARB) therapy (equivalent to at least enalapril 10 mg twice daily) for at least four weeks. However, some experts recommend sacubitril-valsartan as initial oral therapy (in place of ACE inhibitor or single-agent ARB) once the patient is hemodynamically stable. (See "ACE inhibitors in heart failure with reduced ejection fraction: Therapeutic use" and "Use of angiotensin II receptor blocker and neprilysin inhibitor in heart failure with reduced ejection fraction".)

Although some have advocated early use of intravenous ACE inhibitor in patients with ADHF, we do not recommend this approach. There are limited data on the safety and efficacy of initiating new ACE inhibitor (or ARB) therapy in the early phase of therapy of ADHF (ie, the first 12 to 24 hours) [46].

Major concerns with early therapy include:

Patients with ADHF may develop hypotension and/or worsening renal function during initial therapy. Determining the pathogenesis of such complications is more difficult if an ACE inhibitor or ARB has been given. Hypotension following administration of these agents may be prolonged given the long effective half-lives of these agents.

The intravenous ACE inhibitor enalaprilat may have deleterious effects in patients with an acute myocardial infarction, especially when complicated by HF or aggressive diuresis [47,48].

Thus, intravenous enalaprilat is contraindicated in acute myocardial infarction and not generally recommended in other patients with ADHF, although it is potentially useful in certain situations [46,48]. Other agents are available, if needed, to treat refractory hypertension.

Early initiation of oral ACE inhibitor (or single agent ARB or ARNI) therapy is also not recommended (except for early ACE inhibitor use in those with acute myocardial infarction) and should be avoided in patients at high risk for hypotension (eg, low baseline blood pressure or hyponatremia, which is a marker for increased activation of the renin-angiotensin system and therefore increased dependence upon angiotensin II for blood pressure maintenance). In addition, the aggressive diuretic therapy typically given for acute pulmonary edema may increase sensitivity to ACE inhibition or angiotensin blockade, including risks of hypotension and renal dysfunction. (See "Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Recommendations for use" and "Pathophysiology of heart failure: Neurohumoral adaptations" and "Hyponatremia in patients with heart failure".)

Beta blocker — Beta blockers reduce mortality when used in the long-term management of patients with HFrEF, but must be used cautiously in patients with decompensated HFrEF because of the potential to worsen acute HF. (See "Use of beta blockers in heart failure with reduced ejection fraction".)

Thus, in patients with acute decompensated HFrEF, we approach the use of beta blockers in the following manner:

For patients who are already taking a beta blocker, management depends upon the severity of HF decompensation and hemodynamic instability:

For patients with severe decompensation (eg, severe volume overload and/or requiring inotropic support), we suggest withholding beta blockers.

For patients with moderate-to-severe decompensation or hypotension, we suggest decreasing or withholding beta blocker therapy.

For patients with mild decompensation without hypotension or evidence of hypoperfusion, we suggest continuation of beta blocker as tolerated.

Support for continuation of beta blocker therapy with mild decompensation comes from retrospective analyses of patients enrolled in randomized trials [49,50] and reports from the OPTIMIZE-HF program and the Italian Survey on Acute Heart Failure [51,52]. Withdrawal of beta blocker therapy was associated with increased mortality, as compared to continuation of such therapy. However, these retrospective analyses cannot definitively determine whether the discontinuation was the cause of the worse outcome. While the increase in mortality was only partially explained by greater clinical risk factors in the patients withdrawn from beta blocker therapy, such analyses cannot account for all factors. For more severely ill patients, halving of the dose of beta blockers or discontinuation may be necessary.

For patients who are not already taking a beta blocker, we suggest that a beta blocker not be initiated at the time of presentation with an episode of ADHF. Beta blockers are started at low doses and are generally started later than ACE inhibitors or ARBs, when the patient is euvolemic, usually shortly before discharge. Particular caution is indicated in patients who have required inotropes during their hospitalization.

A small randomized trial and a larger observational study found that initiation of therapy prior to hospital discharge in stable patients improves long-term beta blocker compliance without an increase in side effects or drug discontinuation, so initiation prior to discharge is recommended in stable patients. (See "Use of beta blockers in heart failure with reduced ejection fraction", section on 'Initiation of therapy'.)

Ivabradine — Ivabradine reduces the risk of hospitalization in patients with chronic HFrEF but has no proven role in acute HF.

For patients who are already taking ivabradine, management depends upon the severity of HF decompensation, heart rate, and hemodynamic instability. If an increased heart rate appears necessary to maintain cardiac output, then we suggest holding ivabradine in patients with severe decompensation.

For patients who are not already taking ivabradine, we suggest that this agent not be initiated at the time of presentation with an episode of ADHF or with initial oral therapy that generally includes an angiotensin inhibitor and then a beta blocker. We suggest ivabradine for patients with chronic HFrEF (with left ventricular ejection fraction [LVEF] ≤35 percent) in sinus rhythm with a resting heart rate ≥70 beats per minute (bpm) and who are either on a maximum tolerated dose of beta blocker or have contraindication to beta blocker use. Concurrent treatment should include ACE inhibitor (or ARB), and a mineralocorticoid receptor blocker (if potassium can be appropriately monitored). (See "Use of ivabradine in heart failure with reduced ejection fraction", section on 'Selection of candidates for ivabradine therapy'.)

Mineralocorticoid receptor antagonist — Randomized trials have demonstrated that mineralocorticoid receptor antagonist therapy (spironolactone or eplerenone) reduces mortality when included in long-term management of selected patients with systolic HF who can be carefully monitored for serum potassium and renal function. These include patients who have NYHA functional class II HF and an LVEF ≤30 percent; or NYHA functional class III to IV HF and an LVEF ≤35 percent; and patients post-ST elevation myocardial infarction who are already receiving therapeutic doses of ACE inhibitor, have an LVEF ≤40 percent, and have either symptomatic HF or diabetes mellitus. The serum potassium should be <5.0 meq/L and estimated glomerular filtration rate should be ≥30 mL/min per 1.73 m2. (See "Use of mineralocorticoid receptor antagonists in heart failure with reduced ejection fraction", section on 'Our approach'.)

In patients already taking an mineralocorticoid receptor antagonist, such therapy can generally be continued during an episode of acute decompensation, with appropriate monitoring of blood pressure, renal function, and electrolytes. For patients not taking a mineralocorticoid receptor antagonist who have an indication for therapy, we favor initiation prior to or soon after discharge (as needed to allow careful monitoring of serum potassium levels). In patients in whom an ACE inhibitor or ARB was started or uptitrated shortly prior to discharge, it is recommended that mineralocorticoid receptor antagonist initiation be delayed until the first outpatient visit and evaluation of potassium.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

Basics topics (see "Patient education: When your lungs fill with fluid (The Basics)")

SUMMARY AND RECOMMENDATIONS

Initial therapy includes supplemental oxygen and assisted ventilation if necessary and a loop diuretic for volume overload (table 1).

For patients with acute decompensated heart failure (ADHF) with respiratory distress, respiratory acidosis, and/or hypoxia with oxygen therapy, we recommend a trial of noninvasive ventilation (NIV) if emergent intubation is not indicated (algorithm 1), no contraindications to NIV exist (table 2), and personnel with experience in NIV are available (Grade 1A). (See 'Supplemental oxygen and assisted ventilation' above and "Noninvasive ventilation in acute respiratory failure in adults", section on 'Cardiogenic pulmonary edema'.)

Patients with respiratory failure due to ADHF who fail to improve with NIV (within one-half to two hours), do not tolerate NIV, or have contraindications to NIV (table 2) require endotracheal intubation for conventional mechanical ventilation. (See "Overview of mechanical ventilation".)

In patients with ADHF and fluid overload, we recommend that initial therapy include a loop diuretic (administered intravenously) (Grade 1B). (See 'Diuretics' above.) Dosing is individualized, determined largely by the patient's renal function and prior diuretic exposure. (See 'Diuretic administration' above and 'Renal function' above.)

Vasodilators may be required to correct elevated filling pressures and/or LV afterload in patients with ADHF. Indications for vasodilator therapy with close hemodynamic monitoring in the setting of ADHF include the following (see 'Approach to vasodilator therapy' above):

For patients with urgent need for afterload reduction (eg, severe hypertension) or as a temporizing measure in patients with acute aortic regurgitation or acute mitral regurgitation, we suggest balanced vasodilator therapy (eg, nitroprusside) (Grade 2C). (See "Acute mitral regurgitation in adults" and "Acute aortic regurgitation in adults".)

We suggest use of vasodilator therapy (eg, nitroglycerin) as an adjunct to diuretic therapy for patients without adequate response to diuretics (Grade 2C). (See 'Medical management' above.)

We suggest vasodilator therapy as a component of therapy for patients with refractory HF and low cardiac output (Grade 2C).

For most patients hospitalized with ADHF, we recommend against treating with nesiritide (Grade 1A). In carefully selected patients with appropriate hemodynamics (including absence of hypotension or cardiogenic shock) who remain symptomatic despite routine therapy, a trial of nesiritide may be helpful as an alternative to other vasodilator therapy (nitroglycerin or nitroprusside). Nesiritide has a longer effective half-life than nitroglycerin or nitroprusside, so side effects such as hypotension may persist longer. (See "Nesiritide in the treatment of acute decompensated heart failure", section on 'Use' and 'Nesiritide' above.)

Treatment of refractory HF and hypotension in patients with HF with reduced ejection fraction (HFrEF) is guided by hemodynamics, which is most commonly imputed from the physical examination with more direct assessment by right heart catheterization when required in selected cases. Patients with severe left ventricular dysfunction and cardiogenic shock may require intravenous inotropic support as a temporizing measure. A vasopressor may be added as a temporizing measure for patients with persistent shock despite optimization of filling pressures. (See 'Inotropic agents' above and "Inotropic agents in heart failure with reduced ejection fraction".)

For selected patients with severe HFrEF with acute, severe hemodynamic compromise, non-durable mechanical support is an option. (See 'Mechanical cardiac support' above.)

Patients with HF with preserved ejection fraction (HFpEF) presenting with hypotension should not receive inotropes and may require a vasopressor in addition to diuretic therapy. Patients who develop hypotension with dynamic left ventricular outflow obstruction are treated with beta blocker therapy and gentle hydration if pulmonary edema is not present. (See 'Approach to refractory heart failure and hypotension' above.)

Ultrafiltration is an option for patients with HFrEF or HFpEF with refractory volume overload not responding to appropriate diuretic strategies. (See 'Ultrafiltration' above.)

In patients with HFpEF, long-term therapy is based largely on associated conditions (eg, hypertension or edema) since trial data are limited with no established survival benefit from any specific therapy. Management of chronic medications (such an antihypertensive agents) during an ADHF episode depends upon the patient’s hemodynamic condition. (See 'Approach to long-term therapy for heart failure with preserved ejection fraction' above and "Treatment and prognosis of heart failure with preserved ejection fraction".)

In patients with chronic HFrEF, the long-term use of angiotensin inhibitor (angiotensin converting enzyme inhibitor, angiotensin II receptor blocker, or angiotensin receptor-neprilysin inhibitor), beta blockers, and mineralocorticoid receptor antagonist reduces mortality. Management of these agents during an ADHF episode depends upon whether the patient was already taking these medications and the patient’s hemodynamic condition during the acute episode. (See 'Approach to long-term therapy for heart failure with reduced ejection fraction' above and "Overview of the therapy of heart failure with reduced ejection fraction".)

The safety and effectiveness of investigational therapies such as serelaxin or combined intravenous hypertonic saline solution plus intravenous furosemide in the treatment of ADHF is uncertain. (See 'Investigational therapy for acute heart failure' above.)

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