Acute Heart Failure: Acute Cardiorenal Syndrome and Role of Aggressive Decongestion

Abstract

Congestion and acute renal dysfunction are at the center of acute heart failure (HF) syndromes. Acute cardiorenal syndrome, which refers to worsening of renal function in a patient with acute HF syndrome, is partly related to venous congestion and high renal afterload. Aggressive decongestion improves renal and myocardial flow and ventricular loading conditions, potentially resulting in reduced HF progression, rehospitalization, and mortality. High‐dose diuretic therapy remains the mainstay therapy. Ultrafiltration and inotropic therapy are useful in the subgroup of patients with a low‐output state and diuretic resistance.

Introduction

Heart failure (HF) hospitalizations have been rising steadily and constitute a major healthcare and financial burden. Patients hospitalized with acute HF have a high in‐hospital and long‐term mortality, with a 1‐year mortality rate of approximately 30%.1, 2, 3 Two interacting factors are at the center of acute HF presentations: congestion and acute renal dysfunction. Failure to achieve decongestion contributes to poor long‐term outcomes, progressive HF, and ventricular dysfunction.4, 5

Acute Cardiorenal Syndrome

Acute HF Entities

Acute HF presentation encompasses 3 syndromes.6

• (1)Deterioration of a chronic compensated HF, called acutely decompensated HF (ADHF). ADHF is the most common form of acute HF presentation (∼70%), and is sometimes the first presentation of a chronic progressive HF.
• (2)de novo acute HF, due to acute ischemia, acute valvular regurgitation, hypertensive crisis, or acute fulminant myocarditis. The left ventricle is not as dilated in these cases as it is in chronic HF and ADHF. De novo HF, but also many cases of ADHF, develop abruptly.6, 7
• (3)Acute HF presentation that is secondary to a chronic, severe systolic HF with relentless and progressive deterioration of a low‐output state (this constitutes 5% of acute HF presentations).

Although volume overload is clinically evident in most patients (clinical congestion), a subgroup of patients, particularly those with abrupt onset of symptoms, only have a mild volume overload but a severe rise in left ventricular filling pressure (hemodynamic congestion).5, 7 In general, though, even in the latter patients, the rise in left ventricular filling pressure precedes the clinical presentation by several days or weeks.5, 8

Beside congestion (wet state), acute HF is clinically characterized by 1 the following 2 hemodynamic profiles: (1) warm (no evidence of low output) or (2) cold (evidence of low output: narrow pulse pressure, borderline or low systolic blood pressure [<90–100 mm Hg], cool or clammy extremities, drowsiness).

Acute Cardiorenal Syndrome Pathophysiology

Acute cardiorenal syndrome, also called type 1 cardiorenal syndrome, refers to worsening renal function and progressive volume overload in a patient with acute HF syndrome.9 Although it may be related to a low‐output cold HF, the ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) trial suggests a poor correlation between cardiac index and baseline or worsening renal function.10 In addition, worsening renal function is not usually due to “overdiuresis” or hypovolemia. In fact, in most patients, filling pressures are high at the time of worsening of renal function.10, 11, 12

Cardiorenal syndrome is most often related to the mechanisms described below.

• One of the mechanisms is volume overload itself, which increases the renal venous afterload and, consequently, impedes forward renal flow.10, 11, 13 In fact, renal flow is driven by the gradient between mean arterial pressure and renal venous pressure; this gradient should be high enough to overcome renal arteriolar resistance. According to 1 analysis, the admission and post‐therapy right atrial pressure was the most important factor driving renal deterioration in acute HF.11

• Slow plasma refill time is another mechanism. Diuresis initially removes fluid from the intravascular component; the latter is then briskly refilled from the overhydrated interstitium, as a result of hydrostatic and oncotic pressure gradient change (reduced intravascular hydrostatic pressure and increased intravascular oncotic pressure).14, 15, 16 The plasma refill time is the time required for the extracellular edema to refill the intravascular volume that is being diuresed. At the plasma refill rate, the intravascular volume only marginally decreases with diuresis, whereas the interstitial volume drastically decreases.17 However, a patient with 20 L of volume overload may not tolerate 5 L of negative balance per day if the patient's plasma refill time is 3 L per day.

• A diuretic bolus induces a pulse diuresis (eg, 1.5 L within 2 hours) that may be faster than the plasma refill time, which creates transient effective hypovolemia, activates the renin‐angiotensin‐aldosterone system and the sympathetic system, and reduces the glomerular filtration rate, even if the central cardiac output is eventually preserved.14, 15

• Increased intra‐abdominal pressure, secondary to ascites and visceral edema, leads to an abdominal compartment syndrome with increased renal venous pressure and reduced renal perfusion, regardless of the central venous pressure.13

This pathophysiology explains why many cases of cardiorenal syndrome (up to 50%) occur in patients with a left ventricular ejection fraction >40%. This syndrome may potentially worsen with diuresis, but more often improves with diuresis. In fact, although ∼ 30% of acute HF patients have worsening renal function during therapy,10 over 50% of HF patients have an improvement in renal function with adequate diuresis, even more so when creatinine is assessed at 30 to 60 days after hospitalization.9, 18 This is related to the following:

• reduction of renal venous pressure and renal venodilatation with loop diuretics (reduced renal afterload),

• reduction of intra‐abdominal pressure,

• reduction of right and left ventricular volumes, and as a result, improvement of cardiac output (Table 1).

Table 1.

Four Mechanisms Through Which Reduction of Ventricular Volume Improves Cardiac Output

Reduction of ventricular wall tension, which is afterload (↓ afterload → ↑ cardiac output)
Reduction of functional MR and TR
Reduction of RV‐LV interdependence
Reduction of LVEDP and RVEDP, which improves myocardial perfusion

Abbreviations: LV, left ventricle; LVEDP, left ventricular end‐diastolic pressure; MR, mitral regurgitation; RV, right ventricle; RVEDP, right ventricular end‐diastolic pressure; TR, tricuspid regurgitation.

Thus, congestion is at the center of acute HF syndromes. Aggressive decongestion greatly improves renal and myocardial flow and ventricular loading conditions (Figure 1). This allows renal function to improve enough to sustain diuresis with lower diuretic doses. This also allows the patient to tolerate lower systemic pressure without compromise of myocardial or renal perfusion.

Figure 1.

Mechanisms through which diuresis initiates a benefit that is sustained over time. Left ventricular (LV) perfusion is mainly diastolic and depends on the gradient between aortic diastolic blood pressure (DBP) and left ventricular end‐diastolic pressure (LVEDP). Right ventricular (RV) perfusion is diastolic and systolic and depends on the gradient between aortic DBP and right ventricular end‐diastolic pressure (RVEDP), as well as the gradient between aortic systolic blood pressure (SBP) and RV systolic pressure. A reduction in LVEDP improves LV perfusion, whereas a reduction in RVEDP and RV systolic pressure (ie, pulmonary arterial [PA] pressure) improves RV perfusion. Abbreviations: MR, mitral regurgitation; TR, tricuspid regurgitation.

Prior underlying kidney disease, diabetes, hypertension, the use of contrast or nonsteroidal anti‐inflammatory drugs, or repeated episodes of subclinical acute kidney injury predispose to the cardiorenal syndrome.10, 19, 20

Although cardiorenal syndrome is a common form of progressive renal dysfunction encountered in acute HF, intrinsic acute renal failure may occur as well, and should be suspected in patients who are oliguric and diuretic resistant. Acute tubular necrosis may occur as a result of the sustained ischemic injury and may persist for 7 to 10 days, requiring hemodialysis in the interim. Conversely, post‐renal obstruction, renal injury from nonsteroidal anti‐inflammatory drugs, glomerulonephritis, or acute interstitial nephritis may be present and make renal failure the cause rather than the result of acute HF.

One group of patients at a particularly high risk of renal deterioration with diuretic therapy

The combination of 2 particular factors predicts a poor renal tolerance of acute diuresis: (1) nondilated left and right ventricles with a steep pressure‐volume relationship (eg, de novo acute HF, diastolic HF) and (2) no or minimal peripheral edema. Patients with severe edema usually tolerate aggressive diuresis, especially if they have good plasma refill time. Conversely, in patients without severe peripheral edema and with poorly compliant, small ventricles, the preload volume is not dramatically increased but the preload pressure (left ventricular end‐diastolic pressure) is (Figure 2). Therefore, these patients have pulmonary edema despite being preload volume dependent.21, 22 Diuresis may be poorly tolerated in the absence of peripheral edema, leading to a large change in cardiac output and, as a result, renal failure and hypotension.21, 22 However, mild and careful diuresis, in conjunction with vasodilator therapy, is usually well tolerated and may be the best option in this case (eg, negative fluid balance of 1–1.5 L per day). In fact, 1 study suggested the efficacy and safety of diuretic therapy in HF with preserved ejection fraction.23 Another study corroborated this finding, and showed that the plasma volume is actually increased in these patients, even while receiving chronic diuretic therapy with a mean furosemide dose of 95 mg.24, 25

Figure 2.

(Top) Left ventricular (LV) Frank‐Starling curve (ie, cardiac output‐end‐diastolic volume relationship). (Bottom) LV compliance curve (ie, pressure‐volume relationship in diastole). In diastolic dysfunction, a normal 100 to 120‐mL end‐diastolic volume, which is necessary to maintain cardiac output on the Frank‐Starling curve, leads to high LV end‐diastolic pressure and pulmonary edema. Therefore, such patients are less likely to tolerate diuresis; they are more preload dependent than patients with systolic heart failure.

Treatment Strategies With a Focus on Aggressive Decongestion

Importance of Aggressive Decongestion even in the Face of Rising Creatinine

One analysis has shown that aggressive decongestion with hemoconcentration (rise in hematocrit and albumin) is associated with a profound 70% reduction in mortality at 6 months, despite a strong association with creatinine rise.26 In fact, in this and other analyses, incomplete relief of congestion during acute heart failure, rather than the worsening of creatinine levels, strongly contributed to HF progression and worsening survival.26, 27 Therefore, the increase in creatinine does not portend a negative prognosis if decongestion is achieved. Furthermore, the rise in creatinine does not necessarily imply a worsening of renal function, it may simply reflect hemoconcentration.

Other data corroborate that baseline renal function has a prognostic value but not the in‐hospital worsening of renal function.10 In addition, in the DOSE (Diuretic Optimization Strategies Evaluation) trial, a high dose of diuretic was associated with more worsening of renal function at 72 hours but better clinical outcomes. The creatinine level eventually trended down at 60 days in patients receiving the high diuretic dose, whereas it progressively trended up at 60 days in patients who did not achieve appropriate decongestion. Although creatinine may fluctuate initially, it generally becomes lower than baseline at 30 to 60 days in patients appropriately decongested.18

Recent data using radioisotope intravascular volume measurement show that high‐volume diuresis (net negative fluid balance of 8.4 ± 5.2 L) mostly reduces interstitial volume rather than intravascular volume, owing to the plasma refill phenomenon. In fact, despite this diuresis, intravascular volume remains elevated in the majority of patients at discharge, indirectly suggesting a role for more aggressive decongestion.17

Continuous Loop Diuretic Drip vs Intermittent Boluses: Role of Ultrafiltration

The bolus diuretic dose induces pulse diuresis (eg, 1 L in 1 hour) that may be faster than the plasma refill time, potentially leading to a transient effective hypovolemia with subsequent renin‐angiotensin‐aldosterone and sympathetic activation, vasoconstriction, and avid post‐diuretic sodium reabsorption.28 This is how, in theory, diuretics may increase mortality, but as shown below, this did not prove to be true. In fact, studies associating diuretic therapy with increased mortality are retrospective and flawed with selection bias.29

The use of a continuous infusion of furosemide, rather than bolus doses, may allow steady‐state fluid removal at the plasma refill rate. In the DOSE trial, a continuous diuretic infusion was associated with similar renal and clinical outcomes as bolus administration. Conversely, the use of a high diuretic dose, as opposed to a low dose, achieved more net fluid loss and weight loss, superior decongestion, more dyspnea reduction, and a trend toward lower hospitalizations despite a transient worsening of renal function.18 In a patient receiving chronic loop diuretic therapy, the high intravenous diuretic dose consists of a total daily dose that is ∼ 2.5 times the total daily oral dose, with the bolus dose being numerically equal or higher than the single oral dose. In fact, this regimen proved beneficial in 2 trials.9, 18 For a patient using 80 mg of oral furosemide every 12 hours on a chronic basis, an appropriate initial regimen in ADHF may be 80 mg intravenously every 6 hours or 120 mg intravenously every 8 hours. This dose is then tailored according to the response to the first dose and to the 24‐hour diuresis goal (eg, 3–5 L of urine output per day).9

Continuous ultrafiltration constitutes a nonpharmacological modality of fluid removal. One device, Aquadex (Gambro, Lund, Sweden), is simpler than renal replacement devices and uses a smaller central or peripheral venous catheter with a lower venous flow (10–40 mL per minute) and a smaller blood volume outside the body (40 mL) that is more tolerated hemodynamically. It removes fluid at a rate of 100 to 250 mL per hour (≤6 liters per day). In theory, the intravascular volume remains unchanged as fluid shifts from the extracellular space to the intravascular space at the plasma refill rate, with potentially less harmful neurohormonal activation.15 In addition, ultrafiltration removes isotonic fluid, as opposed to the half‐tonic diuresis induced by diuretics; thus, for a similar amount of fluid removed, ultrafiltration removes more sodium than diuretic therapy. However, in the CARRESS‐HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure) trial of patients with acute HF and cardiorenal syndrome, ultrafiltration at a rate of 200 mL per hour did not achieve superior decongestion, weight loss, or clinical improvement than high‐dose diuretic therapy, and led to significantly more creatinine rise that persisted at 60 days.9 Ultrafiltration probably failed because of catheter‐related complications and a frequent need to interrupt therapy (eg, catheter clotting). It is also possible that diuretics have protective renal effects through blocking the adenosine triphosphate pump at the loop of Henle and reducing medullary O₂ consumption.30

Summary

DOSE and CARRESS‐HF trials illustrate that the primordial goal of acute HF therapy is aggressive decongestion, achieved through a high‐volume diuresis and a high diuretic dose if needed (urine output 3–5 L per day, negative fluid balance 2–3 L per day), even in the face of a transient/mild increase in creatinine.9, 18 Beware that patients with abrupt acute HF, non‐dilated left ventricle, and no significant peripheral edema may not tolerate this high‐volume diuresis. Ultrafiltration remains a useful second‐line therapy in patients who do not achieve appropriate diuresis with high doses of diuretics.

Diuretic Resistance

Diuretic resistance is defined as reduced diuresis and natriuresis despite intermediate or high diuretic doses, precluding the resolution of congestion (eg, net negative fluid balance <1 L per day despite a daily dose of intravenous furosemide ≥160–240 mg).31 Diuretic resistance is seen in up to 25% of ADHF cases. Several mechanisms are implicated.32, 33, 34, 35

One mechanism is reduced renal flow, partly related to a high renal afterload and a renal compartment syndrome (high outflow pressure), and partly related to low cardiac output and low systemic pressure (low inflow pressure). The reduced renal filtration reduces the capacity to eliminate sodium. It also reduces the concentration of the diuretic reaching the tubules.

Other mechanisms include renal failure (including cardiorenal syndrome), activation of the renin‐angiotensin‐aldosterone system, hyperfunction of the Henle loop with repeated loop‐diuretic administration after the first dose (braking phenomenon), post‐diuretic rebound effect (ie, tubular reabsorption of sodium in‐between doses), hypertrophy of the distal tubules after chronic loop diuretic administration, and hyperaldosteronism with exaggeration of the distal sodium retention. Hypertrophy of the distal tubules may be counteracted by a loop diuretic‐thiazide combination, whereas hyperaldosteronism may be counteracted by a loop diuretic‐spironolactone combination.

Diuretic resistance is treated by increasing loop diuretic doses and frequency of administration, by restricting fluid and sodium intake, and by combining the loop diuretic with a thiazide diuretic, if needed, and with spironolactone.35

An inotrope is considered for low‐output cold HF not achieving the pre‐established diuresis goal. Ultrafiltration may also be considered for the latter patients. After 24 to 48 hours of ultrafiltration, diuretic responsiveness is often restored, as cardiac output improves with the reduction of afterload, right and left ventricular interdependence, and functional mitral regurgitation, whereas renal perfusion improves with the reduction of renal venous afterload.

In patients with severe renal dysfunction, full hemodialysis rather than ultrafiltration should be used, as ultrafiltration is associated with a high risk of worsening renal function and a high mortality in advanced renal failure.36 In the latter patients, acute tubular necrosis secondary to HF or acute intrinsic renal failure should be suspected.

Role of Inotropic Therapy in Acute Cardiorenal Syndrome

Intravenous inotropic agents may worsen survival over the long term, even when used temporarily; therefore, they should be avoided if possible.37 In the OPTIME‐CHF (Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure) trial, the short‐term use of milrinone increased in‐hospital death and the 60‐day risk of death or rehospitalization in ischemic HF, and increased arrhythmias in all HF.38, 39, 40 Exogenous cardiac stimulation, at a time when the myocardium is significantly energy depleted, may result in further ischemic and apoptotic damage, and lead to the poor outcomes associated with these agents despite immediate short‐term hemodynamic improvement. An inotrope, typically dobutamine, is still indicated temporarily in: (1) wet and cold HF with systolic blood pressure <85 to 90 mm Hg, or (2) wet and cold HF not responding to diuretic therapy.41

Future Direction: Role of Left Ventricular Assist Device Implantation

In patients with advanced, refractory heart failure and cardiorenal syndrome, several studies have shown that the implantation of a ventricular assist device (VAD) reverses renal dysfunction, at least partially. Creatinine level largely improves within the first month of VAD therapy, then continues to improve, more gradually, over the next 12 months.42, 43, 44 However, early postoperative mortality correlates with the severity of preoperative renal dysfunction, possibly implying a role for earlier VAD implantation in patients with persistent cardiorenal syndrome, before renal dysfunction becomes advanced.42

Conclusion

Congestion and acute renal dysfunction are at the center of acute HF syndromes. Aggressive decongestion, mainly through high‐dose diuretic therapy, improves renal and myocardial flow and ventricular loading conditions, potentially resulting in reduced HF progression, rehospitalization, and mortality.