Extracorporeal Ultrafiltration for Fluid Overload in Heart Failure: Current Status and Prospects for Further Research

Abstract

More than 1 million heart failure hospitalizations occur annually, and congestion is the predominant cause. Rehospitalizations for recurrent congestion portend poor outcomes independently of age and renal function. Persistent congestion trumps serum creatinine increases in predicting adverse heart failure outcomes. No decongestive pharmacological therapy has reduced these harmful consequences. Simplified ultrafiltration devices permit fluid removal in lower-acuity hospital settings, but with conflicting results regarding safety and efficacy. Ultrafiltration performed at fixed rates after onset of therapy-induced increased serum creatinine was not superior to standard care and resulted in more complications. In contrast, compared with diuretic agents, some data suggest that adjustment of ultrafiltration rates to patients' vital signs and renal function may be associated with more effective decongestion and fewer heart failure events. Essential aspects of ultrafiltration remain poorly defined. Further research is urgently needed, given the burden of congestion and data suggesting sustained benefits of early and adjustable ultrafiltration.

Keywords: biomarkers; creatinine; diuretics; glomerular filtration rate; venous congestion.

FIGURE 1. UF Circuit

(A) The console controls blood removal rates and extracts ultrafiltrate at a maximum rate set by the clinician. Blood is withdrawn from a vein through the withdrawal catheter (red) connected by tubing to the blood pump. Blood passes through the withdrawal pressure sensor before entering the blood pump tubing loop. After exiting the blood pump, blood passes through the air detector and enters the hemofilter (made of a bundle of hollow fibers) through a port on the bottom, exits through the port at the top of the filter, and passes through the infusion pressure sensor before returning to the patient (blue). The ultrafiltrate passes sequentially through the ultrafiltrate’s pressure sensor, the pump, and the collecting bag suspended from the weight scale. A hematocrit sensor is located on the withdrawal line. (B) This UF system requires only a single-lumen, multihole, small (18-gauge) cannula inserted in a peripheral vein of the arm. A syringe pump drives the blood inside the extracorporeal circuit, which includes 2 check valves that allow the blood to move from the vein to the filter, and then returns it to the same vein through alternate flows that can be independent. The priming volume of 50 ml and the reduced contact surface between blood and tubing set ensure minimal blood loss if circuit clots and for reduced heparin requirements. BD = blood detector; BLD = blood leak detector; HTC = hematocrit sensor; UF = ultrafiltration.

FIGURE 2. Adjustable UF Guidelines Used by the AVOID-HF Investigators

(A) Guidelines for the adjustment of UF therapy. (B) Guidelines for the completion of ultrafiltration therapy: 40 mg of furosemide = 1 mg bumetanide or 10 mg of torsemide (52,53). b.i.d. = twice daily; GDMT = guideline-directed medical therapy; IV = intravenous; JVP = jugular venous pressure; LV = left ventricular; QD = once daily; RV = right ventricular; SBP = systolic blood pressure; sCr = serum creatinine; UO = urine output; other abbreviations as in Figure 1.

FIGURE 3. Adjustable Loop Diuretic Agent Guidelines Used by the AVOID-HF Investigators

(A) Initiation of loop diuretic agents. *Evaluation of blood pressure, heart rate, urine output, and net intake/output was performed every 6 h; evaluation of serum chemistries was performed every 12 h. Decreasing or holding the diuretic agent dose may be considered if: 1) serum creatinine rises by 30% or ≥0.4 mg/dl (whichever is less) versus previous measurement; 2) resting systolic blood pressure decreases >20 mm Hg compared to previous 6 h or drops <80 mm Hg; or 3) resting heart rate is >30 beats/min compared to previous 6 h or >120 beats/min. LVEF = left ventricular ejection fraction; NTG = nitroglycerin; other abbreviations as in Figure 2. (B) Guidelines for the completion of adjustable loop diuretic agents. (C) Guidelines for management after completion of adjustable loop diuretic agents (see also references and 53).

FIGURE 3. Adjustable Loop Diuretic Agent Guidelines Used by the AVOID-HF Investigators

(A) Initiation of loop diuretic agents. *Evaluation of blood pressure, heart rate, urine output, and net intake/output was performed every 6 h; evaluation of serum chemistries was performed every 12 h. Decreasing or holding the diuretic agent dose may be considered if: 1) serum creatinine rises by 30% or ≥0.4 mg/dl (whichever is less) versus previous measurement; 2) resting systolic blood pressure decreases >20 mm Hg compared to previous 6 h or drops <80 mm Hg; or 3) resting heart rate is >30 beats/min compared to previous 6 h or >120 beats/min. LVEF = left ventricular ejection fraction; NTG = nitroglycerin; other abbreviations as in Figure 2. (B) Guidelines for the completion of adjustable loop diuretic agents. (C) Guidelines for management after completion of adjustable loop diuretic agents (see also references and 53).

CENTRAL ILLUSTRATION. Ultrafiltration for Fluid Overload in Heart Failure

Of the >1 million heart failure hospitalizations in the United States and Europe, 90% are due to signs and symptoms of fluid overload. This enormous worldwide health care burden is aggravated by the fact that recurrent congestion worsens patients’ outcomes, regardless of age and renal function. Abnormal hemodynamics, neurohormonal activation, excessive tubular sodium reabsorption, inflammation, oxidative stress, and nephrotoxic medications drive the complex interactions between heart and kidney (cardiorenal syndrome). Loop diuretic agents are used in most congested patients. Due to their mechanism and site of action, loop diuretic agents lead to the production of hypotonic urine and may contribute to diuretic agent resistance (“braking phenomenon,” distal tubular adaptation, and increased renin secretion in the macula densa). Increased uremic anions and proteinuria also impair achievement of therapeutic concentrations at their tubular site of action. Ultrafiltration is the production of plasma water from whole blood across a hemofilter in response to a transmembrane pressure. Therefore, ultrafiltration removes isotonic fluid without direct activation of the renin-angiotensin-aldosterone system, provided that fluid removal rates do not exceed capillary refill. Any method of fluid removal may cause an increase in serum creatinine. However, in the absence of evidence of renal tubular injury (e.g., augmented urinary concentration of neutrophil gelatinase-associated lipocalin), this increase represents a physiological decrease in glomerular filtration rate due to decreased intravascular volume from fluid removal. AVP = arginine vasopressin; GFR = glomerular filtration rate; K = potassium; KIM = kidney injury molecule; Mg = magnesium; NGAL = neutrophil gelatinase-associated lipocalin; RAAS = renin-angiotensin-aldosterone system; SNS = sympathetic nervous system.