Chapter 497. Heart Failure

Heart failure is a complex condition with many potential causes, but with the end result that the heart is unable to meet the metabolic demands of the body (including growth in children). Many believe that there must also be a component of systemic or pulmonary congestion. However, some patients with heart failure may have no significant congestion at rest, but only develop congestion with exertion or other forms of increased oxygen demand. Heart failure is generally precipitated by an insult to the cardiovascular system, either acquired or congenital. In adults, the most common insult is ischemic coronary artery disease with resultant left ventricular dysfunction. In children, heart failure is rarely ischemic, and the causes are quite varied and age dependent; refer to Chapters 483 and 484 for specific lesions associated with heart failure in children of different ages. Although infants with large left-to-right shunts and pulmonary overcirculation are commonly referred to as being in heart failure, their ventricular performance is usually normal, and their “heart failure” is usually a manifestation of pulmonary overcirculation with or without elevated ventricular filling pressures. They may have decreased systemic blood flow as well. Severe left-sided obstructive lesions (eg, hypoplastic left heart syndrome) often present with heart failure in the newborn period because the left ventricle cannot adequately eject blood to the systemic circulation. Both of these groups of lesions are generally managed by surgery or transcatheter intervention, but symptomatic therapy is often needed prior to surgical correction

Once the body has sensed a low cardiac output, a complex neurohormonal cascade is activated that includes the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (Fig. 497-1). This adaptive process causes fluid retention and stimulates release of vasopressive neurohormones such as norepinephrine in order to maintain or increase circulating blood volume and blood pressure. However, this cascade soon becomes maladaptive because it increases preload and afterload in an already overstressed system. Cellular responses are also initiated. For example, the augmentation of beta-adrenergic activity increases intracellular calcium which in turn increases myocardial inotropy and chronotropy. These adaptive mechanisms also soon become maladaptive, as prolonged beta-adrenergic stimulation of the heart leads to apoptosis and fibrosis.

The American Heart Association and the American College of Cardiology have divided heart failure into 4 stages: stage A: at risk for heart failure; stage B: structural heart disease without signs or symptoms; stage C: structural heart disease with previous or current symptoms; stage D: refractory heart disease requiring special interventions.1 The diagnosis and management of each of these stages in adults requires different modalities and approaches. Pediatric heart failure can also be considered in a similar light, although many of the proposed treatment strategies are different.2

Infants and young children present with poor feeding, failure to thrive, respiratory distress, diaphoresis, irritability or lethargy, and pallor. Older children frequently complain of poor appetite, abdominal pain, nausea, and vomiting, and occasionally present with chest pain, palpitations or syncope. Signs of heart failure include tachycardia, tachypnea, pallor, cool extremities, and peripheral edema. Young infants may have periorbital or facial edema. Jugular venous distension can be noted in older children. Cardiac examination reveals a prominent precordium with displacement of the apical impulse, frequently distant heart tones, and a gallop rhythm. Rales, particularly at the bases, and wheezing are heard in older children with pulmonary edema. Breath sounds may be diminished because of collapse of the left lower lobe as a result of compression of the left main bronchus by a dilated left atrium or as a result of pleural effusions. Tender hepatomegaly and ascites are not uncommon.

Chest radiography usually reveals cardiomegaly, pulmonary venous congestion or frank pulmonary edema (Fig. 497-2), although children with acute myocarditis may not have cardiomegaly at initial presentation. In addition there may be pleural effusions and left lower lobe atelectasis.

An electrocardiogram (EKG) may be useful. Children with fulminant myocarditis frequently have an abnormal EKG with low voltages, global ST segment elevation, or a wide complex rhythm (Fig. 497-3). It can also be diagnostic in infants with anomalous left coronary artery from the pulmonary artery (ALCAPA) where an anterolateral infarction pattern is frequently seen. EKG may also reveal arrhythmias such as supraventricular tachycardia, ventricular arrhythmias, or rarely heart block.

Heart failure is a clinical diagnosis, but echocardiography provides valuable supportive information regarding cardiac function and the details of anatomy.

A majority of children with heart failure are decompensated on initial presentation. Symptoms of decompensation include breathlessness with minimal activity, orthopnea (inability to lie flat and/or use of multiple pillows), feeling faint or lightheaded, and gastrointestinal symptoms such as poor appetite, abdominal discomfort, nausea, and vomiting. Abdominal pain and nausea are ominous symptoms and should prompt further evaluation. A variety of clinical and laboratory parameters may help estimate the adequacy of cardiac output and oxygen delivery in the child. Peripheral pulse volume, capillary refill, blood pressure, urine output, and blood gas analysis indirectly assess cardiac output and oxygen delivery. In children, cardiac output is rarely directly measured, and is usually estimated using surrogate markers of oxygen delivery such as mixed venous oxygen saturation and serum lactate concentration.

Mixed venous oxygen saturation directly correlates with systemic oxygen extraction and thus is an excellent index of the adequacy of systemic blood flow. In patients without an intracardiac left-to-right shunt, the pulmonary artery oxygen saturation is the true “mixed” venous oxygen saturation. However, it is not easily accessed in young infants and children and cannot be used in patients with left-to-right shunting. The saturation in the superior vena cava (SVC) is also well mixed and approximates mixed venous saturation, though it is usually slightly lower due to the greater oxygen extraction of the upper body compared to that of the lower body. It is a very good surrogate for the mixed venous saturation in small children or older children with left-to-right shunting. Because an elevated serum lactate level indicates anaerobic metabolism, it is another good index of the adequacy of oxygen delivery, Several studies have demonstrated the usefulness of serum lactate in predicting outcome in adults and children after cardiac surgery, trauma, and similar events.

Near infrared spectroscopy (NIRS) is a noninvasive technique which measures wavelength-specific absorption of light. It is used to measure oxyhemoglobin and deoxyhemoglobin in specific tissues. NIRS is now being used by many centers in the postoperative period to monitor cerebral and splanchnic oxygen saturations in order to assess the adequacy of oxygen delivery at the tissue level.

Biomarkers of Heart Failure

Serum B-type natriuretic peptide (BNP) is a neurohormonal peptide secreted in response to ventricular dilatation. Normal serum BNP level is less than 100 pg/mL. Rising BNP levels are usually seen with worsening heart failure. In patients with heart failure, serum BNP level is usually significantly elevated, and is frequently greater than 1000 pg/mL. On the other hand, a decline in serum BNP level can indicate clinical improvement. Thus it is useful to follow serial serum BNP levels both while escalating therapy for worsening heart failure, and during weaning from inotropic support and afterload reduction.

Treatment of Acute Decompensated Heart Failure

Factors that influence cardiac output such as preload, afterload, myocardial contractility, heart rate and rhythm must be assessed and manipulated.3

Preload versus Fluid Overload

Patients with acute decompensated heart failure and low cardiac output syndrome (LCOS) are usually fluid overloaded; thus fluid boluses should be avoided or small aliquots (5–10 mL/kg) should be used with careful monitoring of vital signs. Rapid infusion of large volume of fluid may suddenly distend the heart and cause bradycardia, hypotension, and cardiac arrest. Most of these patients require intravenous diuretics such as furosemide. In fact, many patients will have a remarkable clinical improvement with this simple therapy, and may not need additional pharmacologic support.

Pharmacologic Support

Patients presenting with decompensated heart failure frequently require agents that provide inotropy and/or afterload reduction (Table 497-1). The treatment of choice for many centers is the use of inodilators (inotropes with afterload reducing properties) such as milrinone.4 It has replaced catecholamines such as dopamine, dobutamine, and epinephrine as first line of therapy in children with low cardiac output syndrome (LCOS). Milrinone is a nonglycoside, noncatecholamine inotropic agent with additional vasodilatory and lusitropic properties. It inhibits phosphodiesterase type III, increasing intracellular cyclic adenosine monophosphate (AMP) and intracellular calcium, thus enhancing myocardial contractility. It also enhances diastolic relaxation of the myocardium by increasing the rate of reuptake of calcium after systole. It may also act synergistically with a beta-adrenergic agonist such as dopamine and has fewer side effects. Phosphodiesterase type III inhibitors have been used extensively in adults and more recently introduced to pediatric practice. Milrinone lowers filling pressures, systemic and pulmonary artery pressures, and systemic and pulmonary vascular resistances, while improving cardiac index. Milrinone is usually initiated at 0.25 μ/kg/minute and can be titrated gradually to 1 μ/kg/minute based on clinical response.5 It is prudent to avoid a bolus of milrinone in patients with LCOS, who are either normotensive or hypotensive at presentation. Milrinone has also replaced amrinone because of the relatively high incidence of thrombocytopenia associated with the latter. Catecholamines, either endogenous (eg, dopamine or epinephrine) or synthetic (eg, dobutamine) act by stimulating myocardial surface beta-adrenergic receptors, leading to increased adenylate cyclase and intracellular cyclic adenosine monophosphate (cAMP).

In patients with heart failure, down-regulation and desensitization of beta-adrenergic receptors as a result of either antecedent congestive heart failure or sustained use of catecholamines, can decrease the efficiency of these agents. Deleterious effects of catecholamines, as a result of their nonspecific actions on adrenergic receptors include (1) excessive chronotropy, which increases myocardial oxygen consumption; (2) atrial and ventricular dysrhythmias; and (3) increase in afterload by activating peripheral alpha-adrenergic receptors, leading to increased impedance and decreased cardiac output. Additional noncardiac side effects of catecholamines include electrolyte and glucose derangements, increase in pulmonary vascular resistance, depression of ventilatory response to hypoxemia and hypercarbia, and limb ischemia.

Other Agents

Nesiritide is a synthetic intravenous form of brain natriuretic peptide (BNP) that has recently been used to treat decompensated heart failure in adults based on its beneficial effects on the renal, neurohormonal and cardiovascular systems. Exogenous administration causes natriuresis, diuresis, vasodilatation and increased renal blood flow, increased cardiac output and urine output, as well as improved symptomatology in the adult heart failure patient.6,7 The dose used in infants and children has ranged from 0.005 to 0.03 μ/kg/minute.8

Levosimendan is a recent treatment for low cardiac output syndrome (LCOS). It is a calcium-sensitizing agent with inotropic and afterload reducing effects. It binds to troponin C and improves the efficiency of the contractile apparatus. The most appealing aspect of this medication is its ability to do this without increasing intracellular calcium levels or cAMP. In adults, early studies have suggested benefit through its ability to increase cardiac output, decrease filling pressures, and allow the use of lower doses of catecholamines and thus potentially mitigate the adverse effects of high dose catecholamines.9 It is usually given as a bolus of 6 to 12 μ/kg/minute followed by an infusion of 0.05 to 0.1 μ/kg/minute over 24 to 48 hours. Pharmacokinetic studies have shown active metabolites up to 72 hours, and the dose can be repeated weekly. Levosimendan may have a role as adjunctive therapy in refractory heart failure unresponsive to the currently available inotropic and afterload reducing agents.10

Role of Mechanical Ventilation

Patients with low cardiac output syndrome (LCOS) may require mechanical ventilation for worsening cardiorespiratory failure. Positive pressure ventilation provides afterload reduction to the failing heart, and decreases respiratory effort and oxygen consumption. However, intubation can precipitate cardiopulmonary decompensation due to a transient decrease in endogenous catecholamines, decrease in preload, and decrease in functional residual capacity. These patients should be appropriately premedicated and resuscitative medications should be readily available.

Supportive Measures

In children with low cardiac output syndrome (LCOS), maintaining a hematocrit level greater than or equal to 35% increases the oxygen carrying capacity of blood. Children with heart failure are also prone to have fever, which increases oxygen consumption. High core temperature with cool extremities may be caused by peripheral vasoconstriction, but could also be of viral etiology in children with myocarditis, or due to catheter-related infections in children with central lines. These children often decompensate due to a persistent fever, so that aggressive fever control is necessary while searching for its etiology.

Mechanical Circulatory Support

Mechanical circulatory support is an essential component of pediatric cardiac intensive care. Although conventional therapy with inotropic support and afterload reduction remains the mainstay of treatment for the failing heart, mechanical circulatory support is being increasingly used in the pediatric population.11,12 When combined with an active heart transplantation program, mechanical circulatory support can significantly improve survival.13 Most of the pediatric experience is limited to the use of extracorporeal membrane oxygenation (ECMO). However, ventricular assist devices (VAD) are now being used in infants, children, and young adults as a bridge to transplantation.

Indications for mechanical support are

• Inability to wean off cardiopulmonary bypass
• Severe ventricular dysfunction of all etiologies
• Cardiopulmonary arrest
• Pulmonary hypertension refractory to medical therapy
• Intractable arrhythmias with hemodynamic compromise
• Occluded systemic-to-pulmonary artery shunt
• Respiratory failure

Extracorporeal Membrane Oxygenation (ECMO)

There is a large pediatric experience with the use of extracorporeal membrane oxygenation (ECMO) for cardiopulmonary failure. Venous-arterial ECMO is necessary for cardiac dysfunction unresponsive to conventional pharmacologic therapy or in patients with coexisting pulmonary disease. Patients must be considered to have “reversible” or “correctable” cardiac or pulmonary disease to be considered candidates for ECMO support. The pediatric experience with rapid resuscitation ECMO after cardiopulmonary arrest is growing.13 Many centers now can rapidly deploy mechanical support and current survival for this indication is 40% to 50%. Rapid institution of circulatory support with modified ECMO systems can be lifesaving with excellent short-term preservation of end-organ function in these patients.

Long-Term Ventricular Assist Devices

The pediatric experience with several long-term pulsatile devices has been growing. Advantages of these devices include their ability to support the circulation for a long period of time as a bridge to transplantation, ease of use, mobility for cardiac rehabilitation, need for low-level anticoagulation, and pulsatile flow (with the pulsatile devices). Disadvantages include a propensity to have thromboembolic complications, risk of infection, increased risk of human leukocyte antigen-sensitization, and size limitation especially with biventricular support.

When low cardiac output syndrome (LCOS) persists despite escalation of inotropic support and afterload reduction, early institution of mechanical circulatory support should be considered before the child sustains irreversible end organ damage. The choice of device should be based on urgency of need for support, patient size, need for short-term versus long-term support, and institutional resources.

In adults with diffuse inoperative myocardial disease, whether ischemic or not, few agents have produced any increase in survival and there is no reason to think that they would do better in children with comparable diffuse myocyte dysfunction. This is not surprising, because most therapies do not address the intrinsic myocyte dysfunction. On the other hand, symptomatic improvement is also an important goal, particularly in children who might then go on to surgical repair.

The management of chronic heart failure can be divided into two main areas: pharmacologic and electrophysiologic. Pharmacologic therapy primarily consists of diuretics, digoxin, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), aldosterone antagonists, and beta-adrenergic receptor antagonists (beta-blockers). Electrophysiologic therapy primarily consists of cardiac resynchronization therapy (CRT) and implantable cardioverters/defibrillators (ICDs).

Diuretics

Most patients with heart failure have some fluid overload. At the time of presentation or during acute exacerbations, fluid overload may be more apparent than during the stable chronic phase of heart failure. Although diuretic therapy is intuitive for treating someone with systemic or pulmonary venous congestion, there are surprisingly little data to support its benefit. Diuretics can exacerbate the activation of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system, thus potentially perpetuating or worsening the maladaptive neurohormonal imbalance.14 This and other concerns about the effectiveness of diuretics have led investigators to explore other methods of reducing fluid overload in adults with congestive heart failure, including ultrafiltration.15 The most commonly used diuretics are loop diuretics (eg, furosemide) and thiazide diuretics (hydrochlorothiazide and metolazone). These medications, used alone or in combination, increase urinary sodium and water excretion, thus reducing the congestion associated with heart failure.

Digoxin

Digoxin is a sodium-potassium ATPase inhibitor with positive inotropy, negative chronotropy, and inhibition of neurohormonal activation.16,17 Traditional thinking was to dose digoxin to achieve relatively high serum digoxin concentrations, while avoiding toxicity. However, more recent information suggests that lower digoxin serum concentrations may actually be preferable to higher levels due to the ability of digoxin to block neurohormonal activation at lower levels while avoiding its inotropic effects and possible toxicities at higher levels.18-21 Current recommendations in adults are for using 0.125 mg to 0.25 mg daily in most patients, a much lower dose than had traditionally been recommended.1 The role of digoxin in pediatric heart failure is not defined. In patients with pulmonary overcirculation due to large left-to-right shunts at the ventricular level, there is conflicting evidence of the utility of digoxin. Some reports have demonstrated benefit, whereas others have shown either no benefit, or actually worsening hemodynamics when administered acutely in the catheterization laboratory.22-26 In adults with heart failure, digoxin has never been shown to improve survival, only symptoms. One retrospective analysis has shown a higher mortality in a group of adults who had higher serum digoxin concentrations compared with those with lower concentrations or placebo23 (Fig. 497-4). In children with heart failure due to systemic ventricular dysfunction, there is no evidence to either support or refute the role of digoxin. Thus, one can choose to use digoxin for the same indications as in adults with heart failure (eg, symptoms), but should consider using lower doses to achieve lower serum digoxin concentrations.

Angiotensin-Converting Enzyme (ACE) Inhibitors

Angiotensin-converting enzyme (ACE) inhibitors have been shown to improve symptoms and survival in adults with heart failure. ACE inhibitors inhibit the conversion of angiotensin I to angiotensin II which is a potent vasoconstrictor, enhances release of norepinephrine from sympathetic nerve endings, and induces cardiac hypertrophy, apoptosis, and fibrosis.27-30 ACE inhibitors have both systemic effects of vasodilation, and intramyocardial effects that aid in reverse remodeling in heart failure. ACE is identical to kininase II, an enzyme that breaks down bradykinin. It is this inhibition of kininase II that it is thought to be responsible for the well-known side effect of cough seen with ACE inhibitors. Side effects also include angioedema, hypotension, hyperkalemia, and renal dysfunction. The medications are generally very well tolerated and are now considered a Class I recommendation for the treatment of heart failure in adults.1 The role of ACE inhibitors in pediatric heart failure is much less clear. They may be useful in children with dilated cardiomyopathy. ACE inhibitors have also been used in cardiomyopathy after anthracycline treatment for cancer in childhood, but evidence of long-term improvement from enalapril is lacking.31-39 A more recent report in adults with acute increases in troponin I levels after anthracyline administration demonstrated significantly fewer cardiac events (eg, heart failure, arrhythmias) in those treated with enalapril compared to placebo.40 In those children with large left-to-right shunts at the ventricular level who are unable to undergo surgical correction, ACE inhibitors may be beneficial.

Angiotensin Receptor Blockers (ARBs)

Angiotensin receptor blockers (ARBs) are similar to angiotensin-converting enzyme (ACE) inhibitors, but are selective and competitive, nonpeptide angiotensin II receptor antagonists. As such, they do not have any effect on bradykinin, and therefore avoid some of the side effects of ACE inhibitors. Their use in children has been limited, and published reports have been primarily in the treatment of hypertension.41 It may be reasonable to consider ARBs to treat heart failure in children.

Aldosterone Antagonists

Aldosterone antagonists have been shown to provide a survival benefit in adults in 2 separate randomized clinical trials: Low-dose spironolactone in adults with moderate to severe heart failure,42 and eplerenone in adults with heart failure after acute myocardial infarction.43 Spironolactone has long been used by pediatric cardiologists as a potassium-sparing diuretic, and it seems reasonable to continue using this medication in children with heart failure. Eplerenone, a selective blocker of the mineralocorticoid receptor, and not glucocorticoid, progesterone, or androgen receptors, may have additional benefits over spironolactone due to its lack of the side effect of gynecomastia. However, there is very little experience with this drug in children.

Beta-Adrenergic Receptor Blockers (Beta-Blockers)

The mechanism of effect of beta-adrenergic receptor blockers (beta-blockers) in heart failure is multifactorial, but is at least partially mediated through the ability of beta-blockers to decrease beta-adrenergic receptor stimulation. Although beta-adrenergic stimulation is a positive adaptive process acutely in heart failure or other types of stress, chronic stimulation ultimately becomes maladaptive and harmful in the failing heart.44-47 Other potential mechanisms of action include negative chronotropic effects, upregulation of beta-adrenergic receptors (although many beta-blockers do not upregulate beta-adrenergic receptors), coronary vasodilatory effects, and possibly antioxidant effects of beta-blockers such as carvedilol, The two large randomized clinical trials of carvedilol in adults with mild-moderate heart failure and one with severe heart failure conclusively showed a survival benefit.47,48 Subsequent to this, both metoprolol and bisoprolol were also shown to have a survival benefit over placebo in the treatment of chronic heart failure in adults.48,49

Third-generation beta-blockers (eg, carvedilol, bucindolol) are either selective or nonselective for beta-1 or beta-2 blockade, but have important ancillary properties: alpha-receptor blockade (carvedilol) and direct systemic vasodilatory properties (bucindolol) that may add to their efficacy in the treatment of congestive heart failure. Carvedilol was actually shown to have a survival benefit over metoprolol in a group of adults with heart failure followed during a 5-year period (Fig. 497-5).50,51 More recently, it has been suggested that the variable response to bucindolol (and possibly other beta-blockers) may be due to single nucleotide polymorphisms within the beta-1 adrenergic receptor.52,53

There have been many retrospective reports of the use of beta-blockers in children with heart failure that suggested possible benefit effects on left ventricular performance and symptoms.54-59 However, a recent multicenter, prospective, randomized, double-blind, placebo-controlled, parallel group trial of carvedilol in children with heart failure failed to show a benefit in the primary endpoint, which was a composite endpoint of heart failure outcomes—worse, better, or unchanged over an 8-month period (Fig. 497-6). However, the trend of improvement with carvedilol in children with a systemic left ventricle was positive, while the opposite was found in those with a systemic ventricle that was not a left ventricle (P < 0.02) (Fig. 497-7). It may be reasonable to consider the use of beta-blockers in those with a systemic left ventricle.

Electrophysiologic Therapy in Heart Failure

The two main therapies consist of cardiac resynchronization therapy (CRT) and implantable cardioverters/defibrillators (ICDs). CRT began in response to the observation that cardiac dyssynchrony is a common, but disadvantageous phenomenon in heart failure. In adults, this is usually manifested electrocardiographically as a left bundle branch block pattern, which results in late activation of the left ventricular free wall. This late activation alters regional loading conditions, myocardial blood flow and myocardial metabolism.60,61 There are also regional alterations in gene expression and protein production involved with mechanical function and stress. These alterations ultimately lead to derangement of both contractile and noncontractile elements, with the end result of ventricular remodeling, dilatation and pump failure. Early studies with the use of CRT demonstrated improvements in symptoms, quality of life, exercise capacity and ejection fraction.62 More recently, CRT has been shown to improve survival in adults with heart failure.63 The definition of dyssnchrony has been evolving since the introduction of this concept. CRT appears to have limited value in adults with heart failure and a narrow QRS, despite the presence of mechanical dyssynchrony by echocardiography.64,65 Interestingly, CRT may also benefit papillary muscle function and thus mitral valve function in patients with heart failure.66 The indications and risk/benefit balance of CRT in children with heart failure is not well defined. There have been reports of the use of CRT acutely after surgery for congenital heart disease in children.67 There have also been reports of successful use in children with congenital heart disease more chronically.68 One large multicenter retrospective report showed possible benefit in children with a variety of heart diseases, although the indications and predictors of beneficial effect are still not clear.69 Attempts at using biventricular pacing to treat right bundle branch block have been limited, but may have some benefit in selected children.70,71 The use of CRT and/or ICDs in children is complicated by the small size of children. In the very young, a thoracotomy is usually required. Even in older children, these devices can be placed transvenously, but growth can complicate the longevity of the leads, and using the only supracardiac venous access can limit future needs for transvenous access to the heart.

Death from heart failure can result from either end organ damage from heart failure or from sudden death. Sudden death due to arrhythmias is usually (but not always) due to ventricular tachycardia or fibrillation. Implantable cardioverters/defibrillators (ICDs) can be used as either secondary prevention or primary prevention. Secondary prevention is used in those with previous cardiac arrest or documented sustained ventricular tachycardia. ICDs are indicated in this group of adults with heart failure, who also have a reasonable chance of prolonged survival.

As with all other heart failure therapies, the indications for the use of ICDs in children with heart failure are not well defined. There have been descriptions of the successful use of ICDs in children, although the complication rate (including inappropriate discharges) is significant.72-74 In the very young (as stated above), transvenous placement may not be an option, and the used of complex subcutaneous arrays are being explored. Clearly, increased study and experience is needed in the use of ICDs in children in order to determine the indications and complications of this potentially life-saving therapy.