New Insights into Decompensated Heart Failure

Emerg Med 37(6)18-25:, 2005

In the past decade a more refined understanding of the pathogenesis of heart failure has emerged to guide therapy. The authors review the science, point out the clinical pitfalls, and discuss the diagnostic use of natriuretic peptides as well as various therapeutic agents.

By Mark Sutter, MD, and Deborah B. Diercks, MD, FACEP

Heart failure is a disease that has reached epidemic proportions in the United States. There are approximately 550,000 new cases diagnosed every year in this country, bringing the prevalence of the disease to more than 4.5 million patients. The epidemiology of heart failure demonstrates a correlation with age; the incidence in persons over the age of 65 is 10 per 1000. These numbers are staggering, and they are expected to increase as the population ages.

The complexity of heart failure is challenging. Poorly controlled diabetes, hypertension, and dyslipidemias are often found in patients with heart failure. In addition, the number of patients with a previous myocardial infarction and renal disease is increasing. All of these conditions are risk factors for impaired systolic function and predispose patients to heart failure.

As the prevalence of heart failure increases, so does the financial burden associated with the treatment of patients with this disease. It should be our goal to initiate appropriate aggressive therapy for these patients and avoid unnecessary hospitalization. To improve our ability to best utilize our resources, it is necessary to better understand the pathogenesis and treatment of heart failure.
 

INCREASED UNDERSTANDING

Over the last 10 years, our understanding of heart failure at the molecular and hormonal level has greatly increased. Everyone will agree that the final outcome is the heart's inability to adequately pump blood, but our new understanding of the neurohormonal cascade will help guide therapy.

Traditionally, heart failure has been classified as systolic dysfunction (decreased contractility) and diastolic dysfunction (increased resistance to diastolic filling). The foundation to the pathophysiology of heart failure is based on numerous studies demonstrating ventricular remodeling as a result of the activation of neurohormonal pathways. These pathways include the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (SNS).

The neurohormonal model of heart failure is based on a precipitating event, which puts increased stress on the heart, activating many inflammatory cytokines and neurohormones. These mediators cause a structural change in the ventricular wall that decreases left ventricular function, leading to the clinical syndrome of heart failure (see table).

The Development of Heart Failure Precipitating event Structural change Syndrome of failure cardiac causes   -acute coronary syndrome   -valvular disease   -arrhythmias acute inflammation hypertension extracardiac illness medication noncompliance dietary noncompliance   endothelial dysfunction myocyte hypertrophy ventricular fibrosis cell necrosis   sodium retention leg edema pulmonary congestion

Heart failure leads to a drop in cardiac output, which results in decreased renal perfusion. In response, the body activates the RAAS. The kidneys release the hormone renin and trigger a downstream cascade. Renin will act on circulating angiotensinogen and convert it to angiotensin I. The vascular endothelium responds by releasing angiotensin-converting enzyme (ACE), which converts angiotensin I to angiotensin II. This protein acts as a potent vasoconstrictor, thus increasing renal blood flow.

Angiotensin II also has a direct pathologic effect in the vessel wall, inducing oxidative stress that causes injury to the vessel. These oxidative stressors and vessel injury trigger further immunologic damage. This contributes to the vascular remodeling that leads to heart failure.

In addition, angiotensin II stimulates the adrenal glands to release aldosterone. This promotes increased absorption of sodium in exchange for potassium in the renal tubules, which increases total body fluid volume. Aldosterone also reduces nitric oxide release and promotes endothelial dysfunction; it has also been implicated in increasing myocardial hypertrophy, fibrosis, and necrosis. These effects all lead to stiffness of the ventricles and vasculature, worsening left ventricular function. This pathologic sequence illustrates how activation of the RAAS as a result of decreased renal blood flow actually exacerbates heart failure by promoting salt retention and ventricular remodeling.
 

AUGMENTED EFFECTS

The effects of the RAAS are augmented by the SNS. As the heart is stressed, the SNS is activated, releasing norepinephrine and other hormones. These work in a variety of ways to exacerbate heart failure. They include direct myocardial toxicity, heightened myocardial demand, increased salt and water retention, peripheral vasoconstriction, and apoptosis. This combination of effects not only can worsen heart failure but can also lead to life-threatening arrhythmias.

The RAAS and SNS are not the only compensatory mechanisms activated when stress is placed on the heart. The ventricles will release B-type natriuretic peptides (BNPs) that cause the efferent renal arteries to constrict and the afferent arteries to dilate. This promotes diuresis and sodium excretion, which will decrease total body fluid volume and help off-load the work placed on the heart.

In addition to their effects on the renal vasculature, the natriuretic peptides have other beneficial properties. They are known to decrease circulating endothelin, a potent vasoconstrictor, and the production of renin and aldosterone.

These complex biochemical chains of events that occur when the heart is stressed seemingly counteract one another. However, the natriuretic system is not as powerful as the RAAS and SNS combined. The balance is tipped toward sodium retention, volume preservation, and increased vascular tone. This neurohormonal pathway contributes to the development of heart failure in patients with both systolic and diastolic dysfunction. In patients with diastolic dysfunction, neurohormonal activation contributes to the progression of the disease by increasing blood pressure and impairing relaxation through myocardial fibrosis and worsening left ventricular hypertrophy.
 

PATIENT EVALUATION

A definitive diagnosis of heart failure is normally made using modalities not readily available in an emergency department, such as right heart catheterization and echocardiography. This has led to the diagnosis and treatment of heart failure as a uniform entity without regard to etiology or systolic function in the emergency department. Nevertheless, the emergency physician should use the available resources to diagnose heart failure. This usually includes a history, physical examination, ECG, chest radiograph, and laboratory evaluation.

Patients often give a history of nonspecific symptoms, but most do complain of some degree of shortness of breath. Dyspnea, in fact, is the most common symptom in patients presenting with heart failure, but it is also a predominant symptom in other diseases (see box). It is important to take a thorough history to not only evaluate for other causes of heart failure, but also to evaluate for arrhythmias and acute coronary syndrome. These can often be present with heart failure and can be immediately life-threatening. Classic historical complaints such as paroxysmal nocturnal dyspnea and orthopnea are specific for heart failure but not sensitive.

Other symptoms such as fatigue, weakness, and leg swelling often indicate elevated filling pressures, but they can also be due to other causes such as venous insufficiency, right heart failure, or pelvic vein obstruction. Despite the nonspecific constellation of symptoms, perhaps the most indicative historical finding is a prior history of heart failure.

Electrocardiograms are routine in the evaluation of patients with dyspnea and a suspected diagnosis of heart failure. While an ECG may be of limited use in diagnosing heart failure, it can help to identify a precipitating event such as ischemia, infarct, or arrhythmias.

Chest radiography can be an important source of information in the evaluation of a patient for heart failure. The major findings on chest x-ray include cardiomegaly, vascular redistribution (cephalization), and interstitial edema. While these are common, they have not been shown to be sensitive. About 20% of cardiomegaly confirmed by echocardiography is missed on chest radiographs. Studies have also shown that agreement among clinicians in chest x-ray interpretation is "moderate to almost perfect" for interstitial edema, but only "moderate" for cardiomegaly and vascular redistribution. Patients with chronic heart failure are also known to have increased lymphatic drainage; in such cases, radiographs might underestimate the degree of heart failure present.
 

TOOL OF THE FUTURE

The diagnostic tool of the future for heart failure seems to be the evaluation of natriuretic peptides. Two peptides have moved into the forefront in the diagnosis of heart failure in patients presenting to the emergency department: the BNPs and the N-terminal pro-BNP (NBNP). In response to ventricular wall stretch, both of these peptides are released.

B-type natriuretic peptides have been evaluated in several studies demonstrating their usefulness in diagnosing heart failure in patients with undifferentiated dyspnea. The Breathing Not Properly study showed that BNP levels greater than 100 pg/ml were more accurate than clinical judgment and Framingham criteria in differentiating heart failure from other causes of dyspnea. The odds ratio for BNP of 29.6 was the strongest predictor of heart failure, far superior to any of the physical exam findings. Jugular venous distension had an odds ratio of 1.87; for lower extremity edema, it was 2.88.

It is important to recognize that there are confounders that can cause an elevated BNP level. These occur in conditions that are known to cause elevated right ventricular pressures. Examples of such conditions include pulmonary embolism, fluid overload states such as dialysis and cirrhosis, primary pulmonary hypertension, and possibly even hormone replacement therapy. These conditions can cause BNP levels to rise to the 100 to 500 pg/ml range. Also, in obese patients, the BNP level has been shown to be lower than in nonobese patients, which may decrease its diagnostic utility in those patients.

Recent studies suggest that BNP levels can also be used for risk stratification. One study suggests that a BNP level above 350 pg/dl at the time of hospital discharge is an independent marker of death or readmission, and it is considered more relevant than clinical or echocardiographic parameters and the percentage change in BNP levels during the patient's hospitalization.

N-terminal Pro-BNP is a biologic inert product of BNP synthesis that is believed to be a future marker in the diagnosis of heart failure. Its utility has been evaluated and shown to be useful in the dyspneic patient. Although this marker has not been as extensively evaluated as BNP, it has some useful properties. Unlike with BNP, NBNP values can be used clinically when the patient is being treated with natriuretic peptides. In patients with decompensated heart failure, NBNP levels will be more elevated than BNP and will have a longer half-life. This may alter their utility in the acute setting. Although there are many clinical studies evaluating the use of NBNP, there are no studies that compare NBNP levels with the clinical diagnosis.
 

MANAGEMENT OF HEART FAILURE

The management goal for all patients with heart failure is to decrease afterload and ventricular wall stretch in an attempt to limit the neurohormonal cascade. To meet this goal, physicians can use nonpharmacologic options such as bilevel positive airway pressure (BiPAP) and mechanical ventilation for critically ill patients in combination with pharmacologic agents. These include inotropic drugs, arterial and venous vasodilators, diuretics, morphine, and natriuretics.

Inotropic drugs. The most commonly used inotropes in heart failure are dobutamine, dopamine, and milrinone. Dobutamine is a catecholamine that acts directly on the beta-1 receptor, causing both a chronotropic and an inotropic response from the heart. Dopamine is also a catecholamine that increases both the chronotropic and inotropic responses of the heart. In addition to its beta-1 actions, dopamine also works on both alpha and dopaminergic receptors. Milrinone is a phosphodiesterase inhibitor that allows for more cyclic adenosine monophosphate to remain in the cell. This results in increased calcium levels and increased contractility.

Inotropes, while effective in increasing contractility in the short term, have been found to have their negative side effects. All of the inotropes can induce arrhythmias, tachycardias, and activate the RAAS; they are also associated with increased mortality. Dobutamine is associated with peripheral vasodilation and tachyphylaxis. Dopamine will induce alpha effects as the dose is increased, thus placing more strain on the heart. Milrinone has been shown to have increased adverse effects and is associated with prolonged hospitalizations.

Arterial and venous dilators. These drugs work to decrease the afterload and preload placed on the heart. Commonly used medications in this category for heart failure are nitroglycerin, nitroprusside, and the ACE inhibitors. Nitroglycerin works to relax smooth muscle by increasing cyclic guanosine monophosphate, which dephosphorylates myosin, leading to vascular relaxation. It has almost no effects on cardiac and skeletal muscle; it works primarily on the venous system. Nitroglycerin will cause venous dilation, resulting in increased venous capacitance and decreased preload. Nitroglycerin is associated with tachycardia, tachyphylaxis, and neurohormonal activation.

Nitroprusside has basically the same mechanism of action as nitroglycerin, but it has dramatic effects on both the arterial and venous systems. Nitroprusside can significantly decrease blood pressure by reducing afterload, but it can be effective in lowering preload as well. Prolonged use of nitroprusside can lead to an accumulation of cyanide. Data from a multicenter heart failure registry reported in the ADHERE trial suggested that patients treated with any intravenous (IV) vasodilator in the emergency department, versus later in their hospital stay or not at all, had lower mortality and shorter hospital stays.

The ACE inhibitors have also been used in the treatment of acute heart failure. They work by blocking the formation of angiotensin II, thereby stopping the effects of its vasoconstrictive properties and thus decreasing afterload. A randomized, double-blind study using IV enalapril in acute pulmonary edema found it to be both effective and well tolerated. Enalapril decreased not only systemic blood pressure but also pulmonary capillary wedge pressure.

Hamilton and colleagues demonstrated in a randomized, prospective, placebo-controlled study that sublingual captopril decreased respiratory distress and produced more rapid clinical improvement when added to standard therapy with nitrates, morphine, oxygen, and furosemide compared to standard therapy alone.

Diuretics. The purpose behind using diuretics in heart failure is to decrease pulmonary congestion and leg edema. Diuretics decrease plasma volume and sodium retention, which subsequently decreases venous return to the heart. This occurs through the induction of diuresis in the kidneys, resulting in a redistribution of fluid and further reduction in fluid overload and a decrease in vascular resistance. It is the vasodilatory effect of the loop diuretics that has the greatest initial impact in symptom reduction in acute decompensation.

In heart failure, loop diuretics such as furosemide are commonly used. The starting dose for furosemide is usually 40 mg or the patient's prehospitalization daily dose, given intravenously. Peak diuretic effects occur 30 to 60 minutes after IV administration. If the patient fails to respond, the common practice is to double the initial dose. Doses higher than 160 to 320 mg should be avoided because side effects, such as electrolyte abnormalities, volume depletion, and activation of the RAAS, are more likely.

If the patient is diuretic-resistant, an alternative approach would be to use a more potent loop diuretic. Torasemide and bumetanide, for example, are reasonable options when furosemide is ineffective. Bumetanide is reportedly 40 to 50 times more potent than furosemide on a milligram-for-milligram basis. If one is still unable to achieve the desired diuresis with these more potent loop diuretics, metolazone can be added. Metolazone is a thiazide-type diuretic that is often administered in conjunction with loop diuretics. Thiazide diuretics must be used cautiously to avoid electrolyte abnormalities and overdiuresis.

There are various options for delivering loop diuretics. The most commonly used routes are oral and IV bolus doses, but continuous infusion of loop diuretics is also effective. It has been shown that a continuous infusion of a diuretic is more effective and less toxic than bolus dosing in the treatment of heart failure in patients with renal insufficiency.

Morphine. Morphine has been used for decades in the treatment of heart failure. It appears to improve symptoms by reducing anxiety and venodilation. Unfortunately, there is little clinical evidence on the effect of morphine on mortality and morbidity in patients with acute heart failure exacerbation. A pre-hospital trial of morphine in patients with acute pulmonary edema found no benefit in the use of morphine in these patients. Another trial reported that the use of morphine was associated with an increased risk of ICU admission.

Natriuretics. The newest pharmacologic agents in the treatment of heart failure are the natriuretics. In 2001, the Food and Drug Administration approved the use of nesiritide for the treatment of acutely decompensated heart failure. Nesiritide is a BNP that acts as an endogenous natriuretic, causing renal vascular changes that promote diuresis. This medication has the potential to tip the balance of power away from the RAAS and SNS and push it toward natriuresis.

Nesiritide has been shown to produce early symptomatic relief and a reduction in pulmonary capillary wedge pressures within 15 minutes. Its effects peak at 30 to 60 minutes. Another advantage is that because it has no effect on heart rate, it does not increase myocardial oxygen consumption. This can be an important advantage with a patient who is acutely decompensated.

Nesiritide does require adjustments in the use of other drugs. Loop diuretics can be used, but the dose must be decreased because nesiritide itself produces a mild to moderate diuresis. Also, ACE inhibitors and other antihypertensives should be withheld for the first hour, until nesiritide's effects have been observed. It is not recommended at this time to combine IV nitroglycerin and nesiritide because of the lack of data on this combination.

In the PROACTION study, 237 patients in an emergency department observation unit who had decompensated heart failure were randomized to standard therapy or at least 12 hours of IV nesiritide. The study results showed that in the nesiritide group there was an 11% decrease in the need for hospital admission from the observation unit, a 21% decrease in heart failure readmission, and a 29% decrease in readmission for patients with New York Heart class III and IV disease. Of note, these differences did not reach statistical significance due to the low number of patients in the study. The two major disadvantages with nesiritide are the cost and the lack of large clinical trials. Head-to-head comparison trials are not complete, and there are questions regarding the renal impact of nesiritide. As further research is conducted, we will learn if the efficacy of nesiritide will compensate for its cost.
 

APPLYING THE THERAPEUTIC OPTIONS

Having discussed the therapeutic options, we will now review their application to individual patients. If the patient is in obvious respiratory distress or imminent respiratory failure, the patient should be mechanically ventilated, either via Bi-PAP or endotracheally, along with aggressive blood pressure management. If the blood pressure is elevated, nitroglycerin or nitroprusside is an option, with hemodynamic monitoring and ICU admission. If there is cardiogenic shock or symptomatic hypotension, the use of an inotrope such as dobutamine, dopamine, or milrinone is appropriate, with hemodynamic monitoring and ICU admission. This group of patients needs immediate attention, often before the underlying cause of their symptoms is known. Once additional data are gathered from the history and laboratory results, more targeted therapy can be initiated.

If the patient does not fall into the critically ill category, a thorough workup and appropriate diagnostic tests should be performed. Once the diagnosis of heart failure is clear, an attempt should be made to classify the patient as being in high-, medium-, or low- severity heart failure. Studies indicate that approximately 10% of heart failure patients will be in the high-severity group, another 10% in the low-severity group, and the remaining 80% in the medium-severity group.

High-severity patients are usually the ones that will end up in the ICU or at least a telemetry unit. Recommendations for this group include oxygen, a loop diuretic, and nitroglycerin or nitroprusside. Nesiritide can also be used in this group.

Patients in the moderate-severity group often require a floor or telemetry bed, but an observation unit, if available, is a viable option. Treatment usually includes oxygen, a loop diuretic, and nitrates. Aggressive therapy with nesiritide may help limit hospitalizations and keep more patients on observation status. As more studies become available, this option might turn out to be more financially advantageous if lengths of stay can be shortened.

Low-severity patients should receive oxygen, nitrates, and a trial of loop diuretics. A period of observation in the emergency department will usually demonstrate diuresis and symptomatic relief. The physician should use this time for patient education; in many cases, the precipitating event will be something as simple as medication noncompliance or dietary indiscretion. These patients are usually discharged.
 

NEW REGIMENS

Improved understanding of the pathophysiology in heart failure may lead to the development of new therapeutic regimens. Currently, tezosentan, an endothelin-1 antagonist, is being investigated in the treatment of decompensated heart failure. Initial trials of this drug, however, have not been encouraging. Tolvaptan, a vasopressin antagonist, has also been evaluated in the treatment of decompensated heart failure. Initial studies have shown it to provide added value to diuretics.

Another group of medications used in the management of heart failure is the aldosterone antagonists. While they are not commonly used in the management of an acutely decompensated heart failure patient, they are often included in the outpatient regimen. Spironolactone is in this class of medications. It works by preventing sodium reabsorption, leading to retention of potassium. These drugs also have a very mild diuretic effect. Eplerenone is the newest aldosterone antagonist; it has more selectivity than spironolactone and causes less gynecomastia and progesterone stimulation. Its effects on electrolyte balance appear to be the same as spironolactone's in early studies.

A major risk with patients on aldosterone antagonists is hyperkalemia. A potential problem with spironolactone, which is recommended in severe heart failure, is that patients in that category are usually also on an ACE inhibitor. If the patient has a episode of decompensation, the combination of an ACE inhibitor and an aldosterone antagonist can lead to the deadly complications of hyperkalemia. A recent study in the New England Journal of Medicine showed that since the RALES trial demonstrated a benefit to adding spironolactone to an ACE inhibitor in patients with severe heart failure, the rates of both hospitalization and mortality due to hyperkalemia have increased significantly.
 

DISPOSITION OF PATIENTS

Depending on institutional policies, new-onset heart failure patients and patients diagnosed with heart failure for the first time usually are admitted to the hospital or undergo echocardiographic evaluation prior to discharge. Echocardiography can not only confirm the diagnosis of heart failure, but it can also help identify systolic or diastolic dysfunction and aid in future treatment plans. Depending on the suspected etiology of new-onset heart failure, additional diagnostic tests to evaluate for underlying coronary artery disease may be performed.

Possible risk-related considerations in the disposition of patients with heart failure are summarized in the table above. Appropriate discharge from the emergency department must be combined with adequate follow-up. Instruction on diet recommendations, medication schedules, and the importance of tracking body weight are important in preventing readmission.

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