Evaluation and Management of Patients with Acute Decompensated Heart Failure

IV Vasodilators

Recommendation

12.17

In the absence of symptomatic hypotension, intravenous nitroglycerin, nitroprusside or nesiritide may be considered as an addition to diuretic therapy for rapid improvement of congestive symptoms in patients admitted with ADHF. (Strength of Evidence = B)

Frequent blood pressure monitoring is recommended with these agents. (Strength of Evidence = B)

These agents should be decreased in dosage or discontinued if symptomatic hypotension or worsening renal function develops. (Strength of Evidence = B)

Reintroduction in increasing doses may be considered once symptomatic hypotension is resolved. (Strength of Evidence = C)

Background

Nitroglycerin. Intravenous nitroglycerin acutely reduces LV filling pressure, primarily through its venodilator effects, which reduce pulmonary congestion.106 At higher doses the drug may lower systemic afterload and increase stroke volume and cardiac output, but the extent of these effects is variable. Intravenous nitroglycerin may improve coronary blood flow, making it potentially more effective in patients with ADHF from acute ischemia or MI. Nitroglycerin therapy results in neurohormonal activation; whether this has a detrimental effect in acute HF is uncertain.105,106

Data demonstrating favorable hemodynamic effects of intravenous nitroglycerin in HF are derived primarily from small, uncontrolled studies of patients who were not usually hospitalized for acute decompensation.107 These studies demonstrate beneficial hemodynamic effects, but also document a relative resistance to nitroglycerin and significant tachyphylaxis to the vascular actions of this drug, changes that can occur within hours at high doses. The strategy of a nitrate-free interval, which may be an option to reduce tolerance during chronic therapy, could result in adverse hemodynamic effects that would be unacceptable in patients with acute HF.

Approximately 20% of patients with HF are resistant to the hemodynamic effects of any dose of nitroglycerin.108,109 Patients who do not have hemodynamic benefit at doses of intravenous nitroglycerin in the range of 200 μg/kg can be considered non-responders for whom additional dosing is unwarranted.

The adverse effects of nitroglycerin therapy include headache, abdominal discontent, and symptomatic hypotension.110 Hypotension is more likely when preload is low, which may occur as filling pressures decline in response to diuretic therapy. Symptomatic hypotension and headache respond to reduction in dose, but may require discontinuation of therapy.

Nitroprusside. This potent vasodilator has balanced effects on the venous and arteriolar tone. PCWP is reduced almost immediately, and there usually is a robust increase in cardiac output. The drug is used primarily in conjunction with hemodynamic monitoring. It can be easily titrated to an appropriate dose while maintaining a systolic blood pressure >90 mm Hg or mean arterial pressure >65 mm Hg. The dose range is between 5 and 300 mcg/minute. Thiocyanate toxicity may occur gradually in patients with renal dysfunction, but is rare when nitroprusside is used by an experienced care team.111

Nesiritide. A number of cardiovascular, renal, and neurohormonal effects of BNP have been identified.112,113 Nesiritide, a peptide identical to human BNP, represents the form of BNP available for clinical use. Extensively evaluated in patients with HF from almost exclusively LV systolic dysfunction, nesiritide administration produces dose-dependent reductions in filling pressure, systemic and pulmonary vascular resistance, and an increase in cardiac output.114-117 At the currently recommended dose (0.01 μg/kg), nesiritide significantly reduces LV filling pressure but has variable effects on cardiac output.110 A reduction in circulating aldosterone levels has been observed.118

Studies of nesiritide in patients with HF from LV systolic dysfunction show no consistent effect on glomerular filtration rate and renal blood flow. Some studies have demonstrated enhanced urinary output and increased sodium excretion, while others have not.118,119 A number of explanations have been proposed for these variable effects, including the dose of nesiritide studied, degree of concomitant diuretic therapy, and hemodynamic effects, which may include a reduction in blood pressure or an augmentation of cardiac output.

The VMAC Trial. The Vasodilator in the Management of Acute Heart Failure (VMAC) study was a complex multicenter, randomized, double-blinded controlled trial of nesiritide, nitroglycerin, and standard therapy in 489 patients hospitalized for worsening HF.110 The study used a dose of nesiritide (bolus of 2 μg/kg followed by an infusion of 0.01 μg/kg/min) .The primary endpoints of the VMAC trial were change in PCWP from baseline (catheterized stratum only) and change in dyspnea score from baseline. The primary study comparison of these endpoints was between nesiritide on top of standard therapy versus standard therapy alone at 3 hours.

Trial results showed that the combination of nesiritide plus standard therapy significantly decreased PCWP (P<.001) and dyspnea score (P=.03) at 3 hours compared with standard therapy alone. Nesiritide did not improve dyspnea compared to nitroglycerin, but did lower the PCWP more than nitroglycerin (P=.03). However, the nitroglycerin doses used in VMAC were relatively small and may account for the observed differences in PCWP.

Adverse Effects. The potential side effects of nesiritide include hypotension, headache, and worsening renal function. The risk of hypotension appears to be dose dependent and was less frequent in the VMAC study than in earlier trials that used higher maintenance doses. The incidence of symptomatic hypotension in the VMAC trial was similar in patients treated with nitroglycerin versus nesiritide. Because of the longer effective half-life of nesiritide, hypotension may last longer with nesiritide than with nitroglycerin. Headache is not a common or severe side effect of nesiritide.

Worsening Renal Function. Worsening of renal function has been observed in clinical trials with nesiritide. The mechanisms for this adverse effect on renal function are unknown but physiologic considerations suggest interaction with diuretic therapy, reductions in blood pressure and inhibition of the renin angiotensin aldosterone system may play a role. Only limited data are available from clinical trials to assess the frequency and severity of this adverse effect. Analysis of available data from the VMAC study and other nesiritide trials demonstrated that nesiritide plus standard therapy was more likely than standard therapy alone to be associated with a rise in creatinine of >0.5 mg/dL during the study period.120 This analysis was retrospective and used data from studies that were not prospectively designed to assess serial changes in renal function. The cut point of serum creatinine used to indicate worsening renal function was dictated by the data available to the investigators and has been employed in other studies. Whether there is a general relationship between nesiritide and worsening renal function or whether other cut points of creatinine increase would show a similar adverse effect is unknown. Although most of the clinical trials of nesiritide were not designed to monitor effects on renal function for a 30-day period, analysis of any additional data available is needed. The dose of nesiritide may be a significant factor related to the risk of worsening renal function. In the VMAC study worsening renal function, as defined by the 0.5 mg/dL endpoint, occurred in 21% of patients randomized to standard therapy plus nitroglycerin versus 27% in the patients randomized to nesiritide.120

Whether the worsening renal function induced by nesiritide is associated with adverse outcomes in patients with ADHF is uncertain. Additional mechanistic studies are needed to better understand the effects of nesiritide on renal function, both regarding glomerular filtration rate and urinary sodium excretion, and how this may vary with diuretic use and volume status in patients with ADHF.

Outcome Data. The current guideline has specified that nesiritide may be considered for symptom relief in patients with symptomatic congestion. A recent meta-analysis has suggested that use of nesiritide in patients with ADHF is associated with increased mortality.121 However, the data overall do not provide convincing evidence of an adverse effect. Similar evaluations for intravenous nitroglycerin and nitroprusside in patients with ADHF are not available. Well designed and adequately powered prospective studies are warranted to determine the effect of this drug on outcomes in patients with ADHF.

Morphine

Morphine has been used as adjunctive therapy in acute HF for several decades. Though its beneficial mechanism of action in acute HF is unclear, it is thought to produce mild venodilation and preload reduction.122,123 Further, it may impart a beneficial effect through relief of anxiety and a diminished catecholamine response. However, prospective data supporting its use is limited. Retrospective data suggest an association between morphine use and adverse outcomes such as endotracheal intubation, intensive care unit admission and prolonged hospital length of stay.124,125 A recent Acute Decompensated Heart Failure National Registry (ADHERE) analysis suggests the use of morphine was also associated with increased in-hospital mortality.126 Much of this data is confounded by the possibility that those patients who were "sicker" received morphine. Prospective study is necessary to determine the risks and benefits of morphine use. If used at all in acute HF, it should be used with caution, especially in those patients with abnormal mental status and impaired respiratory drive.

Recommendation

12.18

Intravenous vasodilators (nitroglycerin or nitroprusside) and diuretics are recommended for rapid symptom relief in patients with acute pulmonary edema or severe hypertension. (Strength of Evidence = C)

Background

Diuretics remain an important treatment for acute pulmonary edema, although randomized controlled trial data to establish the best strategy for the use of these agents (eg, duration and dose of this therapy) are not available. Data from contemporary randomized controlled clinical trials demonstrating the benefit of vasodilator therapy plus standard therapy compared with standard therapy alone are also lacking. Support for the use of these agents comes from extensive clinical experience in patients admitted with this syndrome, which suggests benefit is common. In addition, one study has suggested that intravenous isosorbide dinitrate and low-dose diuretics might be more effective than high-dose diuretics in patients with this condition. In this trial, 110 patients were randomized to treatment with (1) repeated high-dose boluses of intravenous isosorbide dinitrate plus a single 40-mg bolus of intravenous furosemide or (2) repeated high-dose furosemide. These regimens were administered until oxygen saturation was above 96% or mean arterial blood pressure decreased by 30% or to below 90 mm Hg. Patients randomized to repeated high doses of isosorbide dinitrate and a low-dose diuretic had a significantly lower combined risk of MI, requirement for mechanical ventilation or death than those treated primarily with a more aggressive diuretic regimen.127 Similar results were also seen in an ED-based non-randomized trial of high dose nitroglycerin in the treatment of severe decompensated HF.128

Recommendations

12.19

Intravenous vasodilators (nitroprusside, nitroglycerin, or nesiritide) may be considered in patients with ADHF who have persistent severe HF despite aggressive treatment with diuretics and standard oral therapies.

  • Nitroprusside (Strength of Evidence = B)
  • Nitroglycerine, Nesiritide (Strength of Evidence = C)
12.20

Intravenous inotropes (milrinone or dobutamine) may be considered to relieve symptoms and improve end-organ function in patients with advanced HF characterized by LV dilation, reduced LVEF, and diminished peripheral perfusion or end-organ dysfunction (low output syndrome), particularly if these patients have marginal systolic blood pressure (< 90 mm Hg), have symptomatic hypotension despite adequate filling pressure, or are unresponsive to, or intolerant of, intravenous vasodilators. (Strength of Evidence = C)

These agents may be considered in similar patients with evidence of fluid overload if they respond poorly to intravenous diuretics or manifest diminished or worsening renal function. (Strength of Evidence = C)

When adjunctive therapy is needed in other patients with ADHF, administration of vasodilators should be considered instead of intravenous inotropes (milrinone or dobutamine). (Strength of Evidence = C)

Intravenous inotropes (milrinone or dobutamine) are not recommended unless left heart filling pressures are known to be elevated or cardiac index is severely impaired based on direct measurement or clear clinical signs. (Strength of Evidence = C)

It is recommended that administration of intravenous inotropes (milrinone or dobutamine) in the setting of ADHF be accompanied by continuous or frequent blood pressure monitoring and continuous monitoring of cardiac rhythm. (Strength of Evidence = C)

If symptomatic hypotension or worsening tachyarrhythmias develop during administration of these agents, discontinuation or dose reduction should be considered. (Strength of Evidence = C)

Background

Introduction. Although they account for only a small percentage of ADHF, patients with advanced HF, which may be defined by severe LV systolic dysfunction with ventricular dilation and marked chronic clinical symptoms, represent a major therapeutic challenge.129,130 Treatment options are limited and there is little evidence from randomized trials to guide management. Marked resting hemodynamic derangements, such as reduced cardiac output and increased PCWP, are characteristic in these patients. Available clinical studies have assessed the effect of treatment almost exclusively on hemodynamic endpoints. These studies provide convincing evidence that administration of vasodilators and inotropic agents, alone or in combination, usually results in significant short-term hemodynamic improvement in most patients. Many patients with advanced HF and ADHF will have moderate to severe vasoconstriction and substantially elevated filling pressures, a hemodynamic pattern that may improve with vasodilators alone.

Intravenous inotropes (milrinone or dobutamine) may be considered to relieve symptoms and improve end-organ function in patients with advanced HF and diminished peripheral perfusion or end-organ dysfunction (low output syndrome). Inotropic therapy is often used if these patients have marginal systolic blood pressure (<90 mm Hg), have symptomatic hypotension despite adequate filling pressure, or are unresponsive to, or intolerant of, intravenous vasodilators. Patients with advanced HF and reduced blood pressure and normal or low systemic vascular resistance often will not tolerate or derive sufficient hemodynamic benefit from vasodilator therapy. Inotropic agents may be necessary to maintain circulatory function in these patients. Even patients with advanced HF may present with "low cardiac output" syndrome due to volume depletion. Elevation of left heart filling pressures based on classical signs and symptoms or direct measurement should be documented prior to use of vasodilators or inotropic agents in patients with advanced HF. Vasodilators and inotropic agents may be considered in patients with advanced HF with evidence of fluid overload if they respond poorly to intravenous diuretics or manifest diminished or worsening renal function.

Administration of intravenous inotropes (milrinone or dobutamine) in the setting of ADHF and advanced HF should be accompanied by continuous or frequent blood pressure monitoring and continuous monitoring of cardiac rhythm. Discontinuation or dose reduction is often necessary if the use of vasodilators or inotropic agents is accompanied by symptomatic hypotension. Inotropic agents may promote or aggravate tachyarrhythmias and discontinuation or reduction in dose may be necessary when these side effects occur. The effects of dobutamine may wane with time (tachyphylaxis) or be negated by development of hypersensitivity myocarditis.

Data concerning the hemodynamic effects of intravenous nitroglycerin and nesiritide are reported elsewhere; this background section will focus on the use of sodium nitroprusside and inotropic agents in patients with advanced HF.

Sodium Nitroprusside. Sodium nitroprusside exerts a significant effect on both ventricular preload and afterload, resulting in both a decrease in LV filling pressures and typically an increase in LV stroke volume. After-load reduction may be of particular benefit in patients with acute HF complicated by significant mitral regurgitation, making sodium nitroprusside effective in these patients. This drug can be used to establish reversibility of pulmonary hypertension in patients being evaluated for cardiac transplantation. Sodium nitroprusside may prove useful in patients with ADHF associated with LV dysfunction and severe aortic stenosis.

Despite these favorable hemodynamic effects, sodium nitroprusside has not been widely adopted as a treatment modality for acute HF. There are a number of aspects related to the pharmacologic effects of the drug and its practical application that have limited its use in ADHF. In most centers, this drug is not administered without invasive monitoring of blood pressure and typically central hemodynamics. In the absence of HF, sodium nitroprusside has been noted to increase mortality rates when given within 48 hours of an acute MI.70 One explanation for this adverse effect centers on the significant effects the drug may have on coronary blood flow. Coronary artery disease may limit the vasodilatory response to nitroprusside and thus create a circumstance of coronary steal with improved perfusion through normal vessels and reduced blood flow through diseased arteries. However, when pump dysfunction persists for greater than 48 hours after acute MI, nitroprusside may improve survival.131

Sodium nitroprusside should be initiated at a rate dose of 5-10 μg/min. Doses exceeding 400 μg/min generally do not produce added benefit and may increase the risk of thiocyanate toxicity. The drug may be titrated rapidly (up to every 5 minutes) until hemodynamic goals are reached. Caution is advised when discontinuing nitroprusside and monitoring for rebound vasoconstriction is warranted.132

Milrinone and Dobutamine. Milrinone, often termed an inodilator, causes, in the short term, increased myocardial contractility and decreased systemic and pulmonary vascular tone.133 Heart rate typically is augmented to a lesser degree with milrinone than dobutamine, but both drugs may cause unwanted tachycardia. Milrinone typically produces significant vasodilation of the pulmonary arterial system, which may be important in supporting patients with marked pulmonary hypertension and poor cardiac output. Milrinone administration may demonstrate that increased pulmonary resistance is reversible,134 an important observation in patients being considered for cardiac transplantation. Because dobutamine does not act as a direct pulmonary vasodilator, it typically has little effect on pulmonary vascular resistance. There is always concern that inotropic agents may increase myocardial oxygen consumption. In a small study of 10 patients, the use of milrinone was not associated with increased myocardial oxygen consumption from baseline.135

In contrast to dobutamine, the hemodynamic effects of milrinone are not mediated by stimulation of beta receptors. Thus the pharmacologic actions of milrinone do not appear to be diminished to the same extent as those of dobutamine by concomitant administration of beta blocking drugs. To avoid discontinuation of beta blockade, some clinicians use this agent for hemodynamic support of patients who are hospitalized with worsening HF while on beta blocker therapy. In patients with advanced dilated cardiomyopathy, the positive inotropic effects of dobutamine or milrinone may be highly variable and it is critical to titrate doses to desired clinical and hemodynamic effect.

Dosing. Bolus administration of milrinone definitely produces rapid hemodynamic improvement, but is associated with increased risk of symptomatic hypotension. Symptomatic hypotension occurred in more than 10% of patients in the milrinone arm of the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF), even though the initial dose was 0.5 μg/kg/min without a bolus.50 However, recent work has shown that by 2 hours, the hemodynamic improvement from this infusion rate is similar with or without a loading dose.136 An increase of approximately 50% in cardiac index occurs during this brief period. Initial doses of 0.1 μg/kg/min and final doses of 0.2 to 0.3 μg/kg/min should be considered, as they appear to be associated with symptomatic improvement and may be better tolerated, but the recommended dose range goes up to 0.75 μg/kg/min.

Risks of Inotropic Agents. Data from at least 2 studies confirm that there is no rationale for the use of inotropic agents in the great majority of patients admitted with acute HF with congestion who are not in a low output state.2,37 No clinical benefits and evidence of adverse effects were found from the administration of milrinone in the OPTIME-CHF study. In addition, results from an observational analysis of the patients enrolled in the ADHERE registry suggest that this class of drugs is associated with an adverse effect on mortality among patients currently hospitalized with acute HF, the great majority of whom have elevated or normal blood pressure and congestion.65,137

Acute HF appears to represent a period during which the myocardium is at risk of additional damage, especially in patients with advanced HF, who are more likely to be treated with inotropic support. In this setting, there is concern that inotropic agents may: (1) increase heart rate, (2) adversely affect coronary flow to ischemic segments, (3) augment myocardial oxygen consumption, and (4) produce symptom relief with less reduction in filling pressure. These factors may all contribute to loss of additional cardiomyocytes and promote progressive HF.

Consideration of the OPTIME-CHF trial may further illustrate the limitations of inotropic therapy in broad populations of patients with ADHF. This study was a randomized, controlled, double-blind trial that tested the potential benefit of inotropic agents in patients admitted with ADHF and systolic dysfunction, but without "low-output syndrome"--a population not usually considered for inotropic therapy. A total of 949 patients were randomized to a 48-hour infusion of milrinone (0.5 μg/kg/min) or placebo within 48 hours of admission. Patients were excluded if, in the opinion of the investigator, they had an absolute requirement for inotropic therapy. Also excluded were those with a history of poor rate control of atrial fibrillation, a history of ventricular arrhythmia, or myocardial ischemia in the past 3 months. The primary end point of the study was rehospitalization for a cardiovascular cause within 60 days.

OPTIME-CHF demonstrated that the median number of days patients were hospitalized for cardiovascular causes did not differ significantly between patients given milrinone and those given placebo. Milrinone therapy showed early treatment failure and was associated with a non-significant higher number of deaths in hospital and within 60 days. The use of milrinone resulted in significantly higher incidence of new atrial arrhythmias and of sustained systolic BP of <80 for 30 minutes, requiring intervention. The study authors concluded that milrinone therapy was not indicated for routine use as an adjunct to standard therapy in patients with an exacerbation of HF.138

Potential Role for Inotropic Therapy. Careful patient selection is required to achieve a favorable risk-benefit ratio for inotropic therapy. Although ongoing clinical studies strongly suggest that inotropic therapy is not effective in broad populations of patients with ADHF, there are instances in which these drugs are necessary to maintain cardiac output and may be more effective in the short-term for this purpose than vasodilators. Inotropic drugs may be considered in the highly selected patients described in recommendation 12.20. These patients often present with hypotension and may face an increased risk of further hypotension from vasodilator agents. Clinical experience indicates that patients with "low cardiac output" syndrome and reduced renal function may respond to inotropic support with diuresis and improved renal function. Patients presenting with cardiogenic shock may need inotropes to maintain the minimal cardiac output necessary for survival. In these cases, inotropes can be a "bridge" to more definitive therapy, such as revascularization, cardiac transplantation, or mechanical circulatory support. The use of inotropic agents as palliative care in patients who are not candidates for more definitive therapy recognizes that improvement in quality of life and clinical status may be all that is possible in certain patients and may be achieved at the expense of increased mortality during therapy. However, morbidity, such as non-related infection from central venous catheters used to administer the drugs, should also be considered.