Blood Purif 2014;37(suppl 2):51–60 DOI: 10.1159/000361063
Published online: July 31, 2014
The Case for Treating Refractory Congestive Heart Failure with Ultrafiltration Bernard Canaud a, b Sudhir K. Bowry a Ciro Tetta a Emanuele Gatti a, c c
Fresenius Medical Care, Bad Homburg, Germany; b Montpellier University I, UFR Medicine, Montpellier, France; Danube University, Krems, Austria
Key Words Ultrafiltration · Slow continuous ultrafiltration · Heart failure · Cardiorenal syndrome
Abstract Extracellular fluid retention and congestion is a fundamental manifestation of heart failure (HF) and cardiorenal syndrome (CRS). Patients are normally hospitalized and treated with diuretics, but their outcomes are often poor as severe congestion and diuretics resistance is the primary cause of HF-related hospital admissions and readmissions. Isolated ultrafiltration (UF), which can be considered as a ‘mechanical diuretic and natriuretic’ tool, offers promise in achieving safe and effective fluid volume removal in HF patients with CRS who are resistant to stepwise guided diuretic therapy. This paper outlines the rationale for machine-driven isolated UF in CRS and the available clinical evidence regarding its use in patients with HF. In addition, this article summarizes some future clinical perspectives for expanding the use of UF therapy in HF patients in order to improve outcomes. © 2014 S. Karger AG, Basel
Introduction
Despite better understanding of cardiac pathology and major progress in therapy, heart failure (HF) remains a frequent and highly morbid condition with poor out© 2014 S. Karger AG, Basel 0253–5068/14/0376–0051$39.50/0 E-Mail [email protected] www.karger.com/bpu
comes [1]. HF worsens patient quality of life, leads to frequent hospitalization, and consumes significant resources of chronic illness healthcare [2, 3]. Progressive sodium and fluid retention are key features of HF leading to congestion associated with various degrees of dyspnea and edema. Significantly, extracellular fluid overload and congestion are present in almost 90% of patients admitted to hospital for HF and are indicators of the severity of HF [4, 5]. Congestive HF (CHF) results from a mechanism in which heart and renal dysfunction interact together in a self-aggravating mode (fig. 1), and is otherwise known as the cardiorenal syndrome (CRS) [6, 7]. The simplified view is that CRS results from a pathologic continuum that progresses gradually from an acute to chronic condition with distinct stages. Early on, acute cardiac dysfunction induces a functional kidney deterioration mediated by a series of neurohumoral factors [e.g. renin angiotensinaldosterone systems, vasopressin, catecholamines, endothelin, and brain natriuretic peptide (BNP)] with the aim of preserving systemic arterial blood pressure but reducing glomerular filtration (vasoconstriction, reduction of renal perfusion) and enhancing sodium retention (type 1 CRS) [8, 9]. Later on, chronic cardiac deterioration is associated with ischemic renal tissue damage (glomerular ischemia, tubular atrophy, and fibrosis) due to prolonged renal vasoconstriction and hypoperfusion leading to renal atrophy and progressive chronic renal failure (type 2 CRS) [10, 11]. Prof. Bernard Canaud Medical Board FMC-EMEALA Else-Kröner Strasse 1 DE–61352 Bad Homburg (Germany) E-Mail bernard.canaud @ fmc-ag.com
Downloaded by: Glasgow Univ.Lib. 130.209.6.50 - 10/11/2014 2:22:26 PM
a
Adrenergic stimulation
Ç Norepinephrin Ç Vasopressin, AVP Endothelial dysfunction Imbalance endothelin 1-NO
Hypotension
Ç Renin
Ç BNP È Cardiac output
CHF
Angiotensin II
Effective hypovolemia
Ç Aldosterone
AKI
Na-H2O retention Edema congestion
Fig. 1. Neurohumoral adaptation to CHF
with the ‘vicious circle’ leading to types 1 and 2 CRS.
Adrenergic stimulation
Ç Norepinephrin Ç Vasopressin, AVP Endothelial dysfunction Imbalance endothelin 1-NO
Hypotension
Ç Renin
ÇBNP
Fig. 2. Isolated UF as ‘mechanical natriuresis’ provides a means to break the ‘vicious circle’ of types 1 and 2 CRS.
Ultrafiltrate Na-H2O
Symptomatic treatments of CHF aiming to prevent or correct congestion and volume overload are essential in the context of this disabling pathology. For several decades, salt and water restriction, patient education, and use of diuretics (loop diuretics and antialdosterone products) have been the primary methods to restore extracellular fluid balance, achieve fluid loss, and relieve congestion in CHF patients. However, as HF progresses, dete52
Blood Purif 2014;37(suppl 2):51–60 DOI: 10.1159/000361063
CHF
Effective hypovolemia
Edema congestion
Ç Aldosterone
AKI Isolated UF
Na-H2O retention
riorating renal function leads to progressive resistance to diuretics. This clinical situation indicates a clear worsening of the HF patient’s condition, corresponding to type 2 CRS, which leads to a complex situation in which fluid removal and decongestion with conventional therapies are more difficult to achieve or even fail. Several approaches have been proposed to overcome this critical situation with varying degrees of success: intensification Canaud /Bowry /Tetta /Gatti
Downloaded by: Glasgow Univ.Lib. 130.209.6.50 - 10/11/2014 2:22:26 PM
ÈCardiac output
Angiotensin II
of loop diuretic (intravenous use, continuous or bolus), adjunction of inotropes and/or vasoactive compounds, combination of diuretics (loop diuretic, thiazide, and antialdosterone), and adjunction of aquaretics (tolvaptan). It is in this setting of identified diuretic resistance and conventional treatment failure that an alternative means of fluid depletion needs to be considered [12, 13]. We acknowledge the fact that other modalities [peritoneal dialysis, ultrafiltration (UF) combined with hemodialysis, and hemodiafiltration] may be proposed in these conditions, but due to space limitations and recent clinical findings on UF, these renal replacement therapies will not be discussed here. This paper will instead focus on slow isolated UF, an extracorporeal method of extracellular fluid removal that could be considered as a form of ‘mechanical natriuresis’ (fig. 2).
Blood circuit
Blood
Hemofilter
Ultrafiltrate 1 liter = 150 mmol = 9g NaCl
Fig. 3. Principle of isolated UF using a venovenous circuit.
UF from a Technical Point of View: What Is Different with Slow Continuous UF?
Treating Refractory CHF with UF
can be compensated by extravascular space refilling rate. Isolated UF is clearly indicated when loss of extracellular fluid, i.e. sodium and water depletion, is the main goal of therapy [15]. As soon as HF patients have more advanced renal failure (urea, creatinine, and uric acid retention) and/or severe electrolyte abnormalities, an appropriate renal replacement therapy should be proposed (UF combined to hemodiafiltration and/or hemodialysis). Hence, in the absence of clinical indication for complete renal replacement modality, isolated slow continuous UF is the preferred form of mechanical fluid depletion in HF patients. Isolated UF requires a specific medical device (UF monitor), blood access (catheters), and expertise in the field (personnel trained in extracorporeal therapies). Although chronic hemodialysis machines or acute multipurpose monitors may be used to carry out isolated UF in experienced centers (hemodialysis or intensive care units), the clear trend now is to move towards simple and user-friendly UF monitors. Schematically, UF monitors may be classified in two categories: those dedicated to intensive care units permitting the initiation of treatment in unstable HF patients, and those dedicated to home or self-care units permitting maintenance therapy in stabilized HF patients. The development of low-flow UF systems that use small peripheral vein catheters instead of large-bore central venous catheters has facilitated the implementation of UF in nonrenal fields, thereby making this therapy more broadly applicable. Anticoagulation of the extracorporeal circuit may be easily achieved by an Blood Purif 2014;37(suppl 2):51–60 DOI: 10.1159/000361063
53
Downloaded by: Glasgow Univ.Lib. 130.209.6.50 - 10/11/2014 2:22:26 PM
For nonnephrologists, it would be useful to briefly review the underlying concepts of isolated UF. UF involves the convective transfer of water and solutes (‘solvent drag’) in response to the application of a machine-driven hydraulic membrane pressure gradient (transmembrane pressure) across a synthetic permeable membrane (fig. 3). Plasma water and solutes are then forced to pass the semipermeable membrane following exertion of transmembrane pressure between blood and ultrafiltrate compartments of the filter that houses the hollow-fiber membrane bundle. Solute particles that are smaller than the mean pore size of the membrane are ‘dragged’ across the membrane into the ultrafiltrate (plasma water bulk flow) at the same concentrations that they are in the plasma. In other words, ultrafiltrate is isotonic to plasma composition, meaning that sodium concentration in the ultrafiltrate is close to 150 mmol/l (NaCl 9 g/l), when neglecting Na membrane sieving and the Gibbs-Donnan effect. The amount of water, sodium, and electrolytes removed in isolated UF is directly proportional to the amount of ultrafiltrate formed, and can easily be managed by prescription and a UF-monitoring device. In slow continuous UF, a suitable and highly favored approach in HF patients, the amount of ultrafiltrate generated is small (1 or 2 liters based on a UF rate of 100–200 ml/h) and does not require replacement fluid infusion [14]. Higher UF rates may cause vascular volume depletion and worsen the hemodynamic stability of HF patients. In such situations, the goal is to remove extracellular volume at the same rate it
UF and Clinical Consequences
UF therapy is currently implemented in a clinical setting to relieve symptoms of congestion associated with severe and resistant HF, such as dyspnea, peripheral and lung edema, and poor quality of life. Isolated UF acts on different pathways implicated in the genesis or maintenance of CRS. UF provides a ‘mechanical diuresis and natriuresis’ [16] that facilitates extracellular fluid depletion in CHF patients resistant to diuretics. UF offers a simple tool to break the vicious circle of CRS in removing isotonic filtrate without inducing marked changes in blood pressure and without creating an osmolality gradient. By correcting fluid overload, UF reduces cardiac preload and decreases heart filling pressures and pulmonary hypertension. The reduction of ventricle distension improves the cardiac output by partly restoring the stroke volume through an optimization of the Frank-Starling mechanism obtained by shifting the stroke-volume relationship up or to the left. Interestingly, natriuretic peptides (BNP, NTproBNP, ANP, etc.) are quite sensitive biomarkers of cardiac dysfunction and fluid overload [17]. UF tends to restore systemic and renal hemodynamics by acting on vascular resistance. Marenzi et al. [18] observed positive effects of UF in HF patients in an invasive hemodynamic study. Despite a 20% reduction of plasma volume and a moderate decrease in cardiac output and arterial pressure, the neurohumoral axis was partially corrected, renal perfusion pressure was restored, and glomerular filtration and tubular functions were partially improved, translating into an increase of water and sodium excretion. UF further restores physical functional capacity and lung oxygen transfer capacity in HF patients by reducing lung edema [19]. In addition to its hemodynamic beneficial effects, some have postulated that UF reduces levels of inflammatory cytokines and cardiotoxins associated with HF [20]. UF has been associated with a significant reduction of sensitive inflammatory biomarkers such as CRP, IL-1, and TNF-β [21, 22]. Reduction of these biomarkers may reflect either the extracellular fluid depletion associated with monocyte/macrophage activation, or less likely the clearing capacity of 54
Blood Purif 2014;37(suppl 2):51–60 DOI: 10.1159/000361063
these mediators by UF due to adsorption or by sieving [23]. Clinical goals, such as reduction in symptoms or congestion, preservation of renal function, and immediate improvement of quality of life, are usually easily achieved at discharge, without requiring invasive hemodynamic assessment.
Observational Clinical Studies Evaluating UF in HF Patients
Isolated UF therapy for depleting CHF patients was introduced to the clinical setting in the 1970s [15] and has been revitalized recently with the availability of dedicated stand-alone UF devices. Several observational studies have confirmed the safety and efficacy of isolated UF in the management of CHF patients [24–26]. Canaud et al. [27] observed in a group of 54 severe resistant HF patients that isolated UF therapy permitted the identification of subgroups of HF patients according to the diuretic and natriuretic response after the first course of UF. HF patients identified as ‘responders’ had a sudden dramatic diuretic response mimicking a ‘postobstructive diuresis syndrome’. Frequency and predictors of this positive diuretic and natriuretic response remain unclear, and in this investigation the average urine output increased from 605 ml in the 24 h prior to UF to 1,965 ml in the 24 h after completion of treatment in the group of responders. HF patients in the ‘responder’ group had a significantly better outcome than those not increasing diuresis. Although the mechanism underlying this diuretic response is not clear, UF was a simple tool for identifying patients with poor or much better outcome. Marenzi et al. [28] studied the effects of UF in 24 patients with refractory CHF admitted to the cardiac intensive care unit for treatment of HF. All had signs of volume overload. All patients were treated with UF via a conventional continuous renal replacement therapy machine; access was gained via a double lumen y-shaped catheter in a femoral vein. UF resulted in an average of 4.9 liters of fluid removal over a 9-hour period. Symptoms improved, and the response to subsequent diuretic therapy was enhanced, with a reduction in the mean dose of diuretic following UF therapy. All patients had continuous hemodynamic data available via a Swan-Ganz catheter as well as invasive arterial pressure via an arterial line. No changes in heart rate, mean blood pressure, or systemic vascular resistance were observed, while mean right atrial pressure, pulmonary capillary wedge pressure, and mean pulmonary artery pressure were reduced. Intravascular volCanaud /Bowry /Tetta /Gatti
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intravenous bolus injection of low-molecular-weight heparin titrated to the patient’s needs. Blood volume monitoring during UF sessions would be a useful adjunct to adapt the instantaneous UF rate to vascular refilling capacity and to prevent further worsening of hypovolemia and hypotension.
ume, as estimated by hematocrit values, remained stable throughout the entire time of treatment despite the large amount of fluid removed overall. A fall in filling pressures with stable hematocrit during UF indicated that a proportional volume of fluid was refilling the vasculature from the congested interstitium. Taken together, these uncontrolled studies showed that UF could be performed safely in HF patients, resulting in a significant volume removal and symptom relief. These studies used conventional renal dialysis equipment, which led to the development of proprietary systems that were less cumbersome, lacked the need for central venous access, and required less specialized expertise to operate. In order to gain FDA approval for such equipment, randomized trials were required, which led to more robust data regarding the safety and efficacy of UF in patients with HF. Liang et al. [29] conducted a retrospective review of their experience with UF therapy following a guided protocol. UF was attempted after failure of diuretic and/or intravenous vasoactive therapies. The case series included 11 patients with volume overload, systolic blood pressure >90 mmHg, and diuretic refractoriness (as per the discretion of treating physician). Three patients had constriction/restriction as the etiology of HF, 2 had ischemic cardiomyopathy, and none had nonischemic dilated cardiomyopathy. Average serum creatinine was 195 μmol/l and average blood urea nitrogen was 24.7 mmol/l. There were a total of 32 UF treatments each lasting 8 h in duration. Of the total UF runs, 75% removed more than 2,500 ml of fluid, and 41% removed 3,500 ml. There were no serious bleeding complications. Notably, 5 out of 11 patients required dialysis on the same or subsequent admission, and 6-month mortality was 55%. A comprehensive systematic review of the literature was performed in the NICE guidelines of the UK, providing levels of clinical evidence for UF in CHF patients [30]. All of these studies assessing UF have proven that UF could be performed safely in HF patients resulting in a significant volume removal and symptom relief. The studies were performed in the setting of intensive care units, using conventional chronic or acute dialysis equipment and requiring implantation of large-bore central venous catheters. Due to its technical requirement and in spite of its efficiency, UF therapy was not expanded to expert units which dealt with more advanced forms of HF. Today, growing interest for UF in HF patients has led to the development of proprietary systems that are very convenient to use, less care demanding operating on peripheral venous access, and not requiring specialized ex-
pertise to launch [31]. The availability of these simple and user-friendly UF-monitoring devices has opened the way to several clinical trials in HF patients.
Treating Refractory CHF with UF
Blood Purif 2014;37(suppl 2):51–60 DOI: 10.1159/000361063
Prospective Controlled Clinical Trials Evaluating UF in HF Patients
55
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Costanzo et al. [32] explored the utility and feasibility of UF in a single center with 20 patients admitted with HF, volume overload, and renal insufficiency or diuretic resistance. HF patients were enrolled within 12 h of admission. Major exclusion criteria were a hematocrit value of 40%, systolic blood pressure of 85 mm Hg, and intravenous vasoactive therapy. Improvement in volume overload after UF persisted at 30 and 90 days after discharge, and no changes in renal function, electrolytes, or systolic blood pressure were observed at hospital discharge and at 90 days after discharge. Symptom scores improved at hospital discharge and these improvements were sustained after 90 days. UF notably reduced hospitalization frequency: in the 3 months preceding UF, 10 hospitalizations occurred in 9 patients while after UF, 3 patients were admitted within 30 and 90 days for unrelated causes. Medications did not change significantly for the 20 patients [27]. This study showed promising results both in the short term (relief of symptoms) and mid-term with durability of the fluid removal by UF. The Relief for Acutely Fluid-Overloaded Patients with Decompensated Congestive Heart Failure (RAPID-CHF) trial was the first clinical trial to evaluate a less invasive UF device (CHF Solutions, Brooklyn Park, Minn., USA) using a single peripherally inserted intravenous catheter in the antecubital forearm [33]. A total of 40 patients were enrolled in 6 US centers and randomized 1:1 to usual care or UF plus usual care. Inclusion criteria were inpatient admission with primary diagnosis of CHF, lower limb extremity edema, and one other sign of congestion. Major exclusion criteria included severe stenotic valvular disease, acute coronary syndrome, poor peripheral venous access, and severe concomitant disease. All patients in the UF-treated group received a single 8-hour UF session with fluid removal rates prescribed by the physician (up to 500 ml/h). Diuretics were held during UF and titrated afterwards at the discretion of the physician. Additional UF sessions were allowed if required and indicated by the physician. The primary endpoint was weight loss assessed at 24 h after consent was obtained. There was greater volume removal at 24 h in the UF-treated group, but total weight loss at 24 h was not different between the two
56
Blood Purif 2014;37(suppl 2):51–60 DOI: 10.1159/000361063
potension following randomization was similarly low in both groups. Fewer bleeding events occurred in the UF group than in the usual care group. Lengths of stay were similar despite greater fluid loss in the UF group. Oral furosemide doses at discharge were lower in the UF group. The most important findings of this study were the decrease in HF hospitalizations and rehospitalization days per patient in the UF group. Interestingly, there was a similar net fluid loss between subjects who received continuous infusion and those treated with UF, yet the hospitalization rate was still lower in the UF group [37]. The Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trial was designed to compare the effect of UF with that of stepped pharmacologic therapy and enrolled 188 patients with acute decompensated HF, worsened renal function, and persistent congestion to a strategy of stepped pharmacologic therapy (n = 94 patients) or UF (n = 94 patients) [38, 39]. The primary endpoint was a change in serum creatinine and in weight (reflecting fluid offload) at 96 h. Inclusion criteria were patients admitted to hospital with acute decompensated HF with congestion signs with at least 2 peripheral and/or pulmonary edema or pleural effusions resistant to diuretics. Exclusion criteria were intravascular volume depletion, being clinically unstable requiring intravenous vasoactive and/or inotropic drugs, blood pressure
Published online: July 31, 2014
The Case for Treating Refractory Congestive Heart Failure with Ultrafiltration Bernard Canaud a, b Sudhir K. Bowry a Ciro Tetta a Emanuele Gatti a, c c
Fresenius Medical Care, Bad Homburg, Germany; b Montpellier University I, UFR Medicine, Montpellier, France; Danube University, Krems, Austria
Key Words Ultrafiltration · Slow continuous ultrafiltration · Heart failure · Cardiorenal syndrome
Abstract Extracellular fluid retention and congestion is a fundamental manifestation of heart failure (HF) and cardiorenal syndrome (CRS). Patients are normally hospitalized and treated with diuretics, but their outcomes are often poor as severe congestion and diuretics resistance is the primary cause of HF-related hospital admissions and readmissions. Isolated ultrafiltration (UF), which can be considered as a ‘mechanical diuretic and natriuretic’ tool, offers promise in achieving safe and effective fluid volume removal in HF patients with CRS who are resistant to stepwise guided diuretic therapy. This paper outlines the rationale for machine-driven isolated UF in CRS and the available clinical evidence regarding its use in patients with HF. In addition, this article summarizes some future clinical perspectives for expanding the use of UF therapy in HF patients in order to improve outcomes. © 2014 S. Karger AG, Basel
Introduction
Despite better understanding of cardiac pathology and major progress in therapy, heart failure (HF) remains a frequent and highly morbid condition with poor out© 2014 S. Karger AG, Basel 0253–5068/14/0376–0051$39.50/0 E-Mail [email protected] www.karger.com/bpu
comes [1]. HF worsens patient quality of life, leads to frequent hospitalization, and consumes significant resources of chronic illness healthcare [2, 3]. Progressive sodium and fluid retention are key features of HF leading to congestion associated with various degrees of dyspnea and edema. Significantly, extracellular fluid overload and congestion are present in almost 90% of patients admitted to hospital for HF and are indicators of the severity of HF [4, 5]. Congestive HF (CHF) results from a mechanism in which heart and renal dysfunction interact together in a self-aggravating mode (fig. 1), and is otherwise known as the cardiorenal syndrome (CRS) [6, 7]. The simplified view is that CRS results from a pathologic continuum that progresses gradually from an acute to chronic condition with distinct stages. Early on, acute cardiac dysfunction induces a functional kidney deterioration mediated by a series of neurohumoral factors [e.g. renin angiotensinaldosterone systems, vasopressin, catecholamines, endothelin, and brain natriuretic peptide (BNP)] with the aim of preserving systemic arterial blood pressure but reducing glomerular filtration (vasoconstriction, reduction of renal perfusion) and enhancing sodium retention (type 1 CRS) [8, 9]. Later on, chronic cardiac deterioration is associated with ischemic renal tissue damage (glomerular ischemia, tubular atrophy, and fibrosis) due to prolonged renal vasoconstriction and hypoperfusion leading to renal atrophy and progressive chronic renal failure (type 2 CRS) [10, 11]. Prof. Bernard Canaud Medical Board FMC-EMEALA Else-Kröner Strasse 1 DE–61352 Bad Homburg (Germany) E-Mail bernard.canaud @ fmc-ag.com
Downloaded by: Glasgow Univ.Lib. 130.209.6.50 - 10/11/2014 2:22:26 PM
a
Adrenergic stimulation
Ç Norepinephrin Ç Vasopressin, AVP Endothelial dysfunction Imbalance endothelin 1-NO
Hypotension
Ç Renin
Ç BNP È Cardiac output
CHF
Angiotensin II
Effective hypovolemia
Ç Aldosterone
AKI
Na-H2O retention Edema congestion
Fig. 1. Neurohumoral adaptation to CHF
with the ‘vicious circle’ leading to types 1 and 2 CRS.
Adrenergic stimulation
Ç Norepinephrin Ç Vasopressin, AVP Endothelial dysfunction Imbalance endothelin 1-NO
Hypotension
Ç Renin
ÇBNP
Fig. 2. Isolated UF as ‘mechanical natriuresis’ provides a means to break the ‘vicious circle’ of types 1 and 2 CRS.
Ultrafiltrate Na-H2O
Symptomatic treatments of CHF aiming to prevent or correct congestion and volume overload are essential in the context of this disabling pathology. For several decades, salt and water restriction, patient education, and use of diuretics (loop diuretics and antialdosterone products) have been the primary methods to restore extracellular fluid balance, achieve fluid loss, and relieve congestion in CHF patients. However, as HF progresses, dete52
Blood Purif 2014;37(suppl 2):51–60 DOI: 10.1159/000361063
CHF
Effective hypovolemia
Edema congestion
Ç Aldosterone
AKI Isolated UF
Na-H2O retention
riorating renal function leads to progressive resistance to diuretics. This clinical situation indicates a clear worsening of the HF patient’s condition, corresponding to type 2 CRS, which leads to a complex situation in which fluid removal and decongestion with conventional therapies are more difficult to achieve or even fail. Several approaches have been proposed to overcome this critical situation with varying degrees of success: intensification Canaud /Bowry /Tetta /Gatti
Downloaded by: Glasgow Univ.Lib. 130.209.6.50 - 10/11/2014 2:22:26 PM
ÈCardiac output
Angiotensin II
of loop diuretic (intravenous use, continuous or bolus), adjunction of inotropes and/or vasoactive compounds, combination of diuretics (loop diuretic, thiazide, and antialdosterone), and adjunction of aquaretics (tolvaptan). It is in this setting of identified diuretic resistance and conventional treatment failure that an alternative means of fluid depletion needs to be considered [12, 13]. We acknowledge the fact that other modalities [peritoneal dialysis, ultrafiltration (UF) combined with hemodialysis, and hemodiafiltration] may be proposed in these conditions, but due to space limitations and recent clinical findings on UF, these renal replacement therapies will not be discussed here. This paper will instead focus on slow isolated UF, an extracorporeal method of extracellular fluid removal that could be considered as a form of ‘mechanical natriuresis’ (fig. 2).
Blood circuit
Blood
Hemofilter
Ultrafiltrate 1 liter = 150 mmol = 9g NaCl
Fig. 3. Principle of isolated UF using a venovenous circuit.
UF from a Technical Point of View: What Is Different with Slow Continuous UF?
Treating Refractory CHF with UF
can be compensated by extravascular space refilling rate. Isolated UF is clearly indicated when loss of extracellular fluid, i.e. sodium and water depletion, is the main goal of therapy [15]. As soon as HF patients have more advanced renal failure (urea, creatinine, and uric acid retention) and/or severe electrolyte abnormalities, an appropriate renal replacement therapy should be proposed (UF combined to hemodiafiltration and/or hemodialysis). Hence, in the absence of clinical indication for complete renal replacement modality, isolated slow continuous UF is the preferred form of mechanical fluid depletion in HF patients. Isolated UF requires a specific medical device (UF monitor), blood access (catheters), and expertise in the field (personnel trained in extracorporeal therapies). Although chronic hemodialysis machines or acute multipurpose monitors may be used to carry out isolated UF in experienced centers (hemodialysis or intensive care units), the clear trend now is to move towards simple and user-friendly UF monitors. Schematically, UF monitors may be classified in two categories: those dedicated to intensive care units permitting the initiation of treatment in unstable HF patients, and those dedicated to home or self-care units permitting maintenance therapy in stabilized HF patients. The development of low-flow UF systems that use small peripheral vein catheters instead of large-bore central venous catheters has facilitated the implementation of UF in nonrenal fields, thereby making this therapy more broadly applicable. Anticoagulation of the extracorporeal circuit may be easily achieved by an Blood Purif 2014;37(suppl 2):51–60 DOI: 10.1159/000361063
53
Downloaded by: Glasgow Univ.Lib. 130.209.6.50 - 10/11/2014 2:22:26 PM
For nonnephrologists, it would be useful to briefly review the underlying concepts of isolated UF. UF involves the convective transfer of water and solutes (‘solvent drag’) in response to the application of a machine-driven hydraulic membrane pressure gradient (transmembrane pressure) across a synthetic permeable membrane (fig. 3). Plasma water and solutes are then forced to pass the semipermeable membrane following exertion of transmembrane pressure between blood and ultrafiltrate compartments of the filter that houses the hollow-fiber membrane bundle. Solute particles that are smaller than the mean pore size of the membrane are ‘dragged’ across the membrane into the ultrafiltrate (plasma water bulk flow) at the same concentrations that they are in the plasma. In other words, ultrafiltrate is isotonic to plasma composition, meaning that sodium concentration in the ultrafiltrate is close to 150 mmol/l (NaCl 9 g/l), when neglecting Na membrane sieving and the Gibbs-Donnan effect. The amount of water, sodium, and electrolytes removed in isolated UF is directly proportional to the amount of ultrafiltrate formed, and can easily be managed by prescription and a UF-monitoring device. In slow continuous UF, a suitable and highly favored approach in HF patients, the amount of ultrafiltrate generated is small (1 or 2 liters based on a UF rate of 100–200 ml/h) and does not require replacement fluid infusion [14]. Higher UF rates may cause vascular volume depletion and worsen the hemodynamic stability of HF patients. In such situations, the goal is to remove extracellular volume at the same rate it
UF and Clinical Consequences
UF therapy is currently implemented in a clinical setting to relieve symptoms of congestion associated with severe and resistant HF, such as dyspnea, peripheral and lung edema, and poor quality of life. Isolated UF acts on different pathways implicated in the genesis or maintenance of CRS. UF provides a ‘mechanical diuresis and natriuresis’ [16] that facilitates extracellular fluid depletion in CHF patients resistant to diuretics. UF offers a simple tool to break the vicious circle of CRS in removing isotonic filtrate without inducing marked changes in blood pressure and without creating an osmolality gradient. By correcting fluid overload, UF reduces cardiac preload and decreases heart filling pressures and pulmonary hypertension. The reduction of ventricle distension improves the cardiac output by partly restoring the stroke volume through an optimization of the Frank-Starling mechanism obtained by shifting the stroke-volume relationship up or to the left. Interestingly, natriuretic peptides (BNP, NTproBNP, ANP, etc.) are quite sensitive biomarkers of cardiac dysfunction and fluid overload [17]. UF tends to restore systemic and renal hemodynamics by acting on vascular resistance. Marenzi et al. [18] observed positive effects of UF in HF patients in an invasive hemodynamic study. Despite a 20% reduction of plasma volume and a moderate decrease in cardiac output and arterial pressure, the neurohumoral axis was partially corrected, renal perfusion pressure was restored, and glomerular filtration and tubular functions were partially improved, translating into an increase of water and sodium excretion. UF further restores physical functional capacity and lung oxygen transfer capacity in HF patients by reducing lung edema [19]. In addition to its hemodynamic beneficial effects, some have postulated that UF reduces levels of inflammatory cytokines and cardiotoxins associated with HF [20]. UF has been associated with a significant reduction of sensitive inflammatory biomarkers such as CRP, IL-1, and TNF-β [21, 22]. Reduction of these biomarkers may reflect either the extracellular fluid depletion associated with monocyte/macrophage activation, or less likely the clearing capacity of 54
Blood Purif 2014;37(suppl 2):51–60 DOI: 10.1159/000361063
these mediators by UF due to adsorption or by sieving [23]. Clinical goals, such as reduction in symptoms or congestion, preservation of renal function, and immediate improvement of quality of life, are usually easily achieved at discharge, without requiring invasive hemodynamic assessment.
Observational Clinical Studies Evaluating UF in HF Patients
Isolated UF therapy for depleting CHF patients was introduced to the clinical setting in the 1970s [15] and has been revitalized recently with the availability of dedicated stand-alone UF devices. Several observational studies have confirmed the safety and efficacy of isolated UF in the management of CHF patients [24–26]. Canaud et al. [27] observed in a group of 54 severe resistant HF patients that isolated UF therapy permitted the identification of subgroups of HF patients according to the diuretic and natriuretic response after the first course of UF. HF patients identified as ‘responders’ had a sudden dramatic diuretic response mimicking a ‘postobstructive diuresis syndrome’. Frequency and predictors of this positive diuretic and natriuretic response remain unclear, and in this investigation the average urine output increased from 605 ml in the 24 h prior to UF to 1,965 ml in the 24 h after completion of treatment in the group of responders. HF patients in the ‘responder’ group had a significantly better outcome than those not increasing diuresis. Although the mechanism underlying this diuretic response is not clear, UF was a simple tool for identifying patients with poor or much better outcome. Marenzi et al. [28] studied the effects of UF in 24 patients with refractory CHF admitted to the cardiac intensive care unit for treatment of HF. All had signs of volume overload. All patients were treated with UF via a conventional continuous renal replacement therapy machine; access was gained via a double lumen y-shaped catheter in a femoral vein. UF resulted in an average of 4.9 liters of fluid removal over a 9-hour period. Symptoms improved, and the response to subsequent diuretic therapy was enhanced, with a reduction in the mean dose of diuretic following UF therapy. All patients had continuous hemodynamic data available via a Swan-Ganz catheter as well as invasive arterial pressure via an arterial line. No changes in heart rate, mean blood pressure, or systemic vascular resistance were observed, while mean right atrial pressure, pulmonary capillary wedge pressure, and mean pulmonary artery pressure were reduced. Intravascular volCanaud /Bowry /Tetta /Gatti
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intravenous bolus injection of low-molecular-weight heparin titrated to the patient’s needs. Blood volume monitoring during UF sessions would be a useful adjunct to adapt the instantaneous UF rate to vascular refilling capacity and to prevent further worsening of hypovolemia and hypotension.
ume, as estimated by hematocrit values, remained stable throughout the entire time of treatment despite the large amount of fluid removed overall. A fall in filling pressures with stable hematocrit during UF indicated that a proportional volume of fluid was refilling the vasculature from the congested interstitium. Taken together, these uncontrolled studies showed that UF could be performed safely in HF patients, resulting in a significant volume removal and symptom relief. These studies used conventional renal dialysis equipment, which led to the development of proprietary systems that were less cumbersome, lacked the need for central venous access, and required less specialized expertise to operate. In order to gain FDA approval for such equipment, randomized trials were required, which led to more robust data regarding the safety and efficacy of UF in patients with HF. Liang et al. [29] conducted a retrospective review of their experience with UF therapy following a guided protocol. UF was attempted after failure of diuretic and/or intravenous vasoactive therapies. The case series included 11 patients with volume overload, systolic blood pressure >90 mmHg, and diuretic refractoriness (as per the discretion of treating physician). Three patients had constriction/restriction as the etiology of HF, 2 had ischemic cardiomyopathy, and none had nonischemic dilated cardiomyopathy. Average serum creatinine was 195 μmol/l and average blood urea nitrogen was 24.7 mmol/l. There were a total of 32 UF treatments each lasting 8 h in duration. Of the total UF runs, 75% removed more than 2,500 ml of fluid, and 41% removed 3,500 ml. There were no serious bleeding complications. Notably, 5 out of 11 patients required dialysis on the same or subsequent admission, and 6-month mortality was 55%. A comprehensive systematic review of the literature was performed in the NICE guidelines of the UK, providing levels of clinical evidence for UF in CHF patients [30]. All of these studies assessing UF have proven that UF could be performed safely in HF patients resulting in a significant volume removal and symptom relief. The studies were performed in the setting of intensive care units, using conventional chronic or acute dialysis equipment and requiring implantation of large-bore central venous catheters. Due to its technical requirement and in spite of its efficiency, UF therapy was not expanded to expert units which dealt with more advanced forms of HF. Today, growing interest for UF in HF patients has led to the development of proprietary systems that are very convenient to use, less care demanding operating on peripheral venous access, and not requiring specialized ex-
pertise to launch [31]. The availability of these simple and user-friendly UF-monitoring devices has opened the way to several clinical trials in HF patients.
Treating Refractory CHF with UF
Blood Purif 2014;37(suppl 2):51–60 DOI: 10.1159/000361063
Prospective Controlled Clinical Trials Evaluating UF in HF Patients
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Costanzo et al. [32] explored the utility and feasibility of UF in a single center with 20 patients admitted with HF, volume overload, and renal insufficiency or diuretic resistance. HF patients were enrolled within 12 h of admission. Major exclusion criteria were a hematocrit value of 40%, systolic blood pressure of 85 mm Hg, and intravenous vasoactive therapy. Improvement in volume overload after UF persisted at 30 and 90 days after discharge, and no changes in renal function, electrolytes, or systolic blood pressure were observed at hospital discharge and at 90 days after discharge. Symptom scores improved at hospital discharge and these improvements were sustained after 90 days. UF notably reduced hospitalization frequency: in the 3 months preceding UF, 10 hospitalizations occurred in 9 patients while after UF, 3 patients were admitted within 30 and 90 days for unrelated causes. Medications did not change significantly for the 20 patients [27]. This study showed promising results both in the short term (relief of symptoms) and mid-term with durability of the fluid removal by UF. The Relief for Acutely Fluid-Overloaded Patients with Decompensated Congestive Heart Failure (RAPID-CHF) trial was the first clinical trial to evaluate a less invasive UF device (CHF Solutions, Brooklyn Park, Minn., USA) using a single peripherally inserted intravenous catheter in the antecubital forearm [33]. A total of 40 patients were enrolled in 6 US centers and randomized 1:1 to usual care or UF plus usual care. Inclusion criteria were inpatient admission with primary diagnosis of CHF, lower limb extremity edema, and one other sign of congestion. Major exclusion criteria included severe stenotic valvular disease, acute coronary syndrome, poor peripheral venous access, and severe concomitant disease. All patients in the UF-treated group received a single 8-hour UF session with fluid removal rates prescribed by the physician (up to 500 ml/h). Diuretics were held during UF and titrated afterwards at the discretion of the physician. Additional UF sessions were allowed if required and indicated by the physician. The primary endpoint was weight loss assessed at 24 h after consent was obtained. There was greater volume removal at 24 h in the UF-treated group, but total weight loss at 24 h was not different between the two
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potension following randomization was similarly low in both groups. Fewer bleeding events occurred in the UF group than in the usual care group. Lengths of stay were similar despite greater fluid loss in the UF group. Oral furosemide doses at discharge were lower in the UF group. The most important findings of this study were the decrease in HF hospitalizations and rehospitalization days per patient in the UF group. Interestingly, there was a similar net fluid loss between subjects who received continuous infusion and those treated with UF, yet the hospitalization rate was still lower in the UF group [37]. The Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trial was designed to compare the effect of UF with that of stepped pharmacologic therapy and enrolled 188 patients with acute decompensated HF, worsened renal function, and persistent congestion to a strategy of stepped pharmacologic therapy (n = 94 patients) or UF (n = 94 patients) [38, 39]. The primary endpoint was a change in serum creatinine and in weight (reflecting fluid offload) at 96 h. Inclusion criteria were patients admitted to hospital with acute decompensated HF with congestion signs with at least 2 peripheral and/or pulmonary edema or pleural effusions resistant to diuretics. Exclusion criteria were intravascular volume depletion, being clinically unstable requiring intravenous vasoactive and/or inotropic drugs, blood pressure
