The optimal treatment strategy for patients with HF depends on numerous clinical factors, particularly the presence or absence of active decompensation. In the critical care setting, management strategies for acute HF syndromes are much more relevant and will be the focus of this chapter.
Once acute decompensated HF has been confirmed or become the leading diagnosis, initial treatment should focus on decongestion and maximizing end-organ perfusion. The specific treatment regimen needed to accomplish these goals depends largely on the hemodynamic profile, which typically will fall into one of four main categories, depending on the adequacy of end-organ perfusion and degree of hypervolemia (Fig. 95.1). Early hemodynamic characterization, and therefore initial treatment strategy, can be accomplished in many patients at the bedside simply by measuring systemic blood pressure and central venous pressure (62).
The most common profile is “warm and wet,” which characterizes patients who are not overtly hypotensive and have evidence of hypervolemia, with preserved overall end-organ perfusion. In these patients, afterload reduction and volume management are the main goals of care, accomplished mostly with vasodilator and diuretic therapy. Common vasodilators with proven efficacy in the management of HF patients include nitrates, ACEIs, angiotensin receptor blockers (ARBs), and hydralazine.
Loop diuretics should be used first line for treatment of congestion related to hypervolemia. Intravenous administration, rather than oral, increases bioavailability, onset of action, and peak effect, and is therefore the preferred method in the critical care setting. Bolus dosing or continuous infusions appear to be equally safe and effective with regard to net volume loss over a given time period (63). However, in our experience continuous infusions are sometimes better tolerated in patients with marginal blood pressure, possibly due to less abrupt redistributions of intra- and extravascular volume compared to bolus dosing.
Resistance to loop diuretics, also called diuretic “braking,” can be encountered, particularly in patients who are receiving loop diuretics chronically or have impaired renal function. If patients cannot be brought to euvolemia with a loop diuretic–based strategy, several ways of intensifying the regimen for volume management exist. Providing a dose of thiazide diuretic, given orally or intravenously 30 minutes prior to loop diuretic dosing, potentiates the diuretic effect and can result in large increases in urine output (64). Frequent electrolyte monitoring and replacement is crucial in this setting as the diuretic combination can quickly cause severe deficiencies, namely hypokalemia and hypomagnesemia, which in turn precipitate atrial and ventricular dysrhythmias.
Nesiritide, a synthetic form of B-type NP, can be highly effective in patients with severe congestion and suboptimal response to diuretics. It has natriuretic, diuretic, and vasodilator effects, and reduces neurohormonal activation. It is administered by continuous infusion with an initial bolus typically not recommended due to risk of causing profound hypotension. Although no clear benefits in HF outcomes have been demonstrated with nesiritide compared to traditional loop diuretic regimens, it remains a valuable option for volume management, especially in the setting of loop diuretic resistance (65,66).
In many HF patients, the predominant hemodynamic alteration is a markedly reduced cardiac output, characterized by severe symptomatic hypotension that essentially contraindicates the use of vasodilators or diuretics by themselves, the so-called “cold and wet” profile. In these patients several inotropes and vasopressors can be used to maximize end-organ perfusion, facilitate volume management, and provide symptom relief. It is crucial to understand that the predominant hemodynamic effect of these agents varies depending on the dose. Table 95.2 outlines the mechanism of action, dose range, and special considerations for vasopressors and inotropes used in HF.
For catecholaminergic agents at low to moderate doses, positive inotropic effects will generally predominate. At high doses, all can be potentially detrimental to cardiac function due to increased afterload from excessive vasoconstrictive effect and extreme tachycardia (67). Multiple markers of cardiac output and end-organ perfusion, rather than systemic blood pressure alone, should guide titration of inotropes and vasopressors to optimal doses for HF treatment. Both dobutamine and milrinone, the most commonly utilized inotropic agents, can worsen hypotension due to vasodilation from peripheral β2-receptor stimulation. If poorly tolerated, it is reasonable to delay initiation of inotropes until risk of precipitating overt shock is lower. Low-dose dopamine or norepinephrine, used alone or started preemptively/simultaneously with low-dose inotropes, can readily offset this risk of worsening hypotension. Used at the right doses, they facilitate initial hemodynamic stabilization of severely decompensated HF patients. This is particularly true for patients with any degree of acidosis or worsening end-organ function, where rescuing them from overt shock is critical.
Mental status, urine output, capillary refill, mixed venous oxygen saturation (drawn from the PA catheter or central venous access), and lactic acid levels can all be assessed, serially over time if needed, to determine if cardiac output is adequate, worsening, or improving. In refractory cases, temporary mechanical support, in the form of an intra-aortic balloon pump or percutaneous left ventricular assist device, should be considered.
|TABLE 95.2 Vasoactive Medications in Heart Failure|
Evidence-Based Therapy for Chronic Systolic Heart Failure
The mainstays of treatment for HF are medications that modulate the neurohormonal cascade. These medications include ACEIs, ARBs, β-blockers, and mineralocorticoid antagonists. It is important to use evidence-based medications approved for HF and to titrate them to evidence-based doses as much as possible to achieve maximum benefit.
ACE Inhibitors and Angiotensin Receptor Blockers
ACEIs inhibit the enzyme ACE that converts angiotensin I to angiotensin II, a potent vasoconstrictor, simulator of the release of aldosterone, and contributor to left ventricular remodeling. Bradykinin, which induces NO-mediated vasodilatation, is degraded by ACE. Angiotensin I is converted to angiotensin II by tissue chymases as well, but the main pathway is via ACE. Data supporting the use of these medications come from three landmark trials: Consensus I, VHEFT II, and the SOLVED Treatment Trial. Consensus I enrolled 253 patients with NYHA class IV HF and randomized them to either enalapril 40 mg daily versus placebo. The result was a 27% reduction in mortality in the enalapril group. The mortality benefit in the enalapril group was found to be mainly due to a reduction in death from progressive HF (68). The VHEFT II study enrolled 804 patients with NYHA class II and III HF. These patients were randomized to either enalapril 20 mg daily versus hydralazine 300 mg daily plus isosorbide dinitrate 160 mg daily. The result was a 28% reduction in mortality in the enalapril group (69). The SOLVED Treatment Trial enrolled 2,569 patients with NYHA class II and III HF. Patients were randomized to enalapril 20 mg daily versus placebo. The result was a 16% reduction in morality in the enalapril group. Analysis showed that the mortality benefit in the enalapril group was mainly due to a reduction in death from progressive HF (70). Due to these overwhelming data, use of an ACEI is a class I level of evidence A for any patient with a LVEF of 40% or lower (71). ARBs inhibit the binding of angiotensin II to the angiotensin type II receptor, thus inhibiting the deleterious effects of angiotensin II. Due to the fact they do not inhibit the breakdown of bradykinin, they are less likely to cause a cough than ACEI. They are a class I level of evidence A recommendation for any patient with a LVEF of less than or equal to 40% who are intolerant of an ACEI (71).
β-Blockers are not a homogeneous class of medications. Only three β-blockers have been shown to improve morality in patients with HF. They are metoprolol succinate, carvedilol, and bisoprolol. Data supporting the use of metoprolol succinate came from the MERIT HF trial. This trial enrolled 3,991 patients with NYHA class II through IV HF who also had a LVEF of less than or equal to 40%. These patients were randomized to metoprolol succinate 200 mg daily versus placebo. It is important to note that 95% of patients enrolled were either on an ACEI or an ARB. The results were a 41% risk reduction in sudden cardiac death, a 49% risk reduction in death from HF, a 30% risk reduction in the number of HF hospitalizations, and a 36% risk reduction in the number of days hospitalized for HF in the metoprolol succinate group (72). A substudy of the MERIT-HF trial looked at left ventricular volumes by MRI. Patients in the metoprolol succinate group had statistically significant decreases in left ventricular volumes and mass compared to placebo (73).
The CIBIS II study evaluated the efficacy of bisoprolol. This trial enrolled 2,647 patients with NYHA class III and IV HF who had a LVEF less than or equal to 35% and randomized them to bisoprolol 10 mg daily versus placebo; 96% of enrolled patients were either on an ACEI or an ARB. The results were a 42% reduction in sudden cardiac death and a 32% reduction in the combined end point of morality and admission for HF (74).
Carvedilol was evaluated in the COPERNICUS trial. This trial evaluated 2,289 patients with NYHA class III and IV HF with a LVEF of 25% or less; 97% of patients in this trial were on an ACEI or an ARB. Patients were randomized to carvedilol 25 mg twice daily versus placebo. Patients in the carvedilol group had a 35% risk reduction in mortality when compared to placebo (75). Use of a β-blocker is a class I level of evidence A recommendation for any patient with a LVEF of 40% or less (71).
Mineralocorticoid antagonists block the binding of aldosterone to the mineralocorticoid receptor. Aldosterone is known to cause ventricular remodeling and fibrosis in HF. There are three landmark trials supporting the use of mineralocorticoid antagonists in the HF population. The RALES study evaluated 1,663 patients with NYHA class III and IV HF and a LVEF of 35% or less. They were randomized to spironolactone 25 mg daily, with a target of 50 mg daily, added to optimal medical therapy versus optimal medical therapy alone. In this trial, 95% of patients were on an ACEI or an ARB, and 10% were on a β-blocker. The trial has been criticized due to the low number of patients receiving a β-blocker. The results showed a 30% reduction in all-cause death, a 31% reduction in death from cardiovascular causes, and a 30% reduction in HF hospitalizations in the spironolactone group. Patients in the spironolactone group also had statistically significant improvement in NYHA functional class when compared to the optimal medical therapy group (76). It is important to note that the exclusion criteria for this trial included a creatinine of 2.5 mg/dL or higher. The addition of a mineralocorticoid antagonist to an ACEI or an ARB can cause life-threatening hyperkalemia, and the patients creatinine and serum potassium levels much be watched carefully during initiation of this class of medications.
The use of a mineralocorticoid receptor antagonist post myocardial infarction was evaluated in the EPHESUS trial. This trial enrolled 6,642 patients who were post acute myocardial infarction and had a LVEF of 40% or less and either clinical symptoms of HF or the diagnosis of diabetes mellitus. Patients were randomized to eplerenone 25 mg daily, with a target of 50 mg daily, in addition to optimal medical therapy versus optimal medical therapy alone. It is important to note 87% of these patients were on an ACEI or an ARB and 75% were on a β-blocker. The results noted a 15% reduction in mortality in the Eplerenone group (77).
The EMPHASIS HF trial evaluated the use of the mineralocorticoid receptor antagonist Eplerenone in patients with NYHA class II HF and a LVEF no greater than 30%. Enrollees also had to have been hospitalized for HF within the previous 6 months of enrollment or had to have had a BNP of 250 pg/mL or more at the time of enrollment. Patients were randomized to Eplerenone 50 mg daily added to optimal medical therapy versus optimal medical therapy alone. In this trial, 97% of patients were on an ACEI or an ARB and 86% were on a β-blocker. The results were a 24% decrease in cardiovascular death, a 42% decrease in HF hospitalizations, and a 37% decrease in the combined end point of death from cardiovascular causes or HF hospitalizations in the Eplerenone group (78). Addition of a mineralocorticoid receptor antagonist to optimal medical therapy with a β-blocker and ACEI or ARB is a class I level of evidence A for any patient with a LVEF of 35% or less, and NYHA symptom class II through IV. Patients with NYHA class II HF should have a recent history of HF hospitalization or elevated BNP (71). Mineralocorticoid receptor antagonists are also a class I level of evidence B recommendation for patients who are post acute myocardial infarction who have a LVEF of 40% or less and have HF symptoms or who are diabetic (71).
Controversies in Heart Failure
Some of the most difficult decisions affecting practitioners who care for patients with advanced HF are hemodynamic monitoring in the critically ill patient and when to refer patients for advanced HF therapies (cardiac transplantation or ventricular assist device). The utility of continuous hemodynamic monitoring in the advanced HF patient was evaluated in the ESCAPE trial (79). ESCAPE enrolled 433 patients with decompensated HF and randomized them to treatment guided by a pulmonary artery catheter versus clinically guided therapy. The trials primary end point was days alive out of the hospital 6 months after randomization. The trial showed no benefit in the primary end point in patients who underwent continuous hemodynamic monitoring with a pulmonary artery catheter as compared to those who were treated based on clinical assessment, and there were more adverse events noted in the pulmonary artery catheter cohort. The ESCAPE trial was specifically designed to determine if the routine use of continuous hemodynamic monitoring was useful in decompensated HF patients. Any patient who may have benefited from or needed acute hemodynamic monitoring was not included in the trial by design. Given this, there are certain patients with acute decompensated HF who should undergo temporary continuous hemodynamic monitoring with a pulmonary artery catheter in order to guide therapy. According to the ACC/AHA guidelines (2), patients who would benefit from monitoring are those patients whose volume status is difficult to determine clinically and have either evidence of hypoperfusion, such as worsening renal function or rising serum lactic acid, or respiratory distress despite treatment. Other patients who should be considered for hemodynamic monitoring are those whose systolic blood pressure remains low, or who remain symptomatic despite initial therapy; those whose volume status, perfusion status, or systemic or pulmonary vascular resistance are uncertain; or those who require vasoactive agents (71). Ideally, hemodynamic assessment should occur prior to initiation of vasoactive agents. Assessment of hemodynamics should also be performed on any patient being considered for temporary mechanical circulatory support (71). Hemodynamic monitoring in these patients should be short term, and should be discontinued once the patient’s clinical status begins to improve, or further monitoring is not needed to guide therapy.
With respect to when to evaluate a patient for advanced HF therapies, a timely referral to a center which specializes in advanced HF therapies is critical to the outcome of the patient. Advanced HF therapies are generally reserved for patients with stage D HF. The Heart Failure Society of America’s definition of stage D HF is “the presence of progressive and/or persistent severe signs and symptoms of heart failure despite optimized medical, surgical, and device therapy. It is generally accompanied by frequent hospitalization, severely limited exertional tolerance and poor quality of life, and is associated with high morbidity and mortality. Importantly, the progressive decline should be primarily driven by the heart failure syndrome” (80). Defining stage D HF in the individual patient is often difficult. Multiple guidelines are available to aid in the diagnosis (Table 95.3), but often no one set of guidelines is adequate. Indicators that a patient is declining and should be referred for advanced HF therapies include frequent hospitalizations for HF despite optimal medical therapy; inability to tolerate evidence-based medical therapies due to hypotension or renal dysfunction; functional decline; escalation of diuretics; refractory arrhythmias; ICD firing; and cardiac cachexia (81,82). Objective measurements that indicate a patient may have progressed to stage D HF include a 6-minute walk distance of less than 300 m and peak oxygen consumption on cardiopulmonary exercise stress test of less than 12 to 14 mL/kg/min. Unfortunately, referrals are often made too late to advanced HF centers. Patient acuity and frailty are often issues with late referrals. Data from INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) (83) show that patients with an INTERMACS scores of 1 or 2 have a higher mortality compared with patients who have lower INTERMACS scores. Implant trends have mirrored this data, with less INTERMACS 1 and 2 patients receiving durable devices due to their increased mortality. Patients should be referred for evaluation for advanced HF therapies before they reach INTERMACS 1 or 2 scores. Ideally, they should be referred for initial evaluation when they are INTERMACS score 5 or 6. Frailty is a known predictor of death, HF hospitalization, and quality of life in patients with HF and those undergoing cardiac surgery. Multiple definitions of frailty exist, but most include measurements of unintentional weight loss and malnutrition (usually <10 lb in the past year, serum albumin <3.3 mg/dL, respectively), weakness as measured by hand grip strength (<30 kg for men, <20 kg for women), gait speed (5 m gait speed <0.5 m/sec), level of physical activity, and level of exhaustion. Satisfying more than 3 of 5 of the preceding criteria qualify for the diagnosis of frailty (84). Muscle wasting (sarcopenia) and cachexia are related to frailty and are also predictive of morbidity and mortality. Sarcopenia is defined as a muscle mass more than 2 standard deviations below the mean measured in young adults of the same sex and ethnic background (85). Cachexia is defined as a metabolic syndrome that is associated with an underlying illness such as HF that is characterized by loss of muscle with or without loss of fat. The prominent clinical feature is weight loss (86). Frailty has been associated with worse outcomes after destination LVAD placement. In a study evaluating frailty in destination therapy LVAD patients, frailty was associated with a hazard ratio of 1.7 for death in patients determined to be intermediately frail, and 3.08 for those who were determined to be frail (10). Rehospitalizations were also found to be increased in the intermediately frail (hazard ratio 1.7), and frail patients (hazard ratio 1.42) (87). Referral to an advanced HF center should occur prior to a patient reaching a state of frailty that would preclude intervention.
|TABLE 95.3 Definitions of Stage D Heart Failure|