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Ultrafiltration and cardiac support

ULTRAFILTRATION IN CARDIAC INSUFFICIENCY:
Physiopathology, Clinical Indications and Results

Giancarlo Marenzi, MD, Ivana Marana, MD, Piergiuseppe Agostoni, MD, PhD.

Centro Cardiologico Monzino, I.R.C.C.S., Institute of Cardiology, University of Milan, Milan, Italy.




Corresponding author:
Giancarlo Marenzi, M.D.
Centro Cardiologico Monzino
Via Parea 4, 20138 Milan, Italy
Telephone: +39.02.580021
Fax: +39.02.58002424
E-mail address: giancarlo.marenzi@ccfm.it


Congestive heart failure (CHF) is one of the most common causes of death in developed countries, with a mortality rate comparable to that of the more malignant disease (1). Indeed, patients with advanced CHF have a very high 1-year mortality rate, reaching about 50% for patients who are in New York Heart Association (NYHA) class IV (2,3). The prevalence of heart failure is growing dramatically in parallel with the ageing of the general population, improved survival of patients with acute coronary artery disease, and advances in management of CHF (4). In addition to cardiac mortality, all cause-mortality has been shown to be increased three-fold in CHF patients compared to the general population (3). Furthermore, CHF is a major cause of hospital admission due to congestion in patients refractory to oral diuretics (5). Although patients with severe CHF (NYHA class IV) represent only 13% of the CHF patient population, they are responsible for almost 50% of the cost of CHF hospitalizations, mainly due to the more frequent need for hospital admission (4 times per patient per year, on the average) both in Intensive and non Intensive Care Units (3). Refractory CHF is usually associated with a reduction in renal function, the so-called “cardiorenal syndrome” (6), and about 25-30% of patients hospitalized with CHF have an acute worsening in renal function, caused partly by low cardiac output and partly by aggressive diuretic therapy (7-9). Both renal dysfunction and fluid congestion are important hallmarks of decompensated CHF that have been associated with the worst prognosis (10-12). As a result, despite advances in the management of CHF in the last few years, there is a need for additional treatment options to further reduce hospitalizations, to improve quality of life, to reduce demands on health service resources, and to improve the outcome of CHF patients. This is the reason why, in the last years, several non-pharmacological strategies, such as cardiac transplantation, left ventricular assist devices, implantable cardioverter-defibrillator, biventricular pacing, have been investigated and validated in clinical practice (2). All these measures have focused their action on the heart, considered the major culprit in the CHF syndrome. However, there is a lot of experimental and clinical evidence supporting a major role of the kidney in CHF. Renal insufficiency is frequently observed in CHF (13)(Figure 1).










Figure 1: Prevalence of renal insufficiency increases in parallel with the severity of the disease, reaching 60% and 70% in CHF patients with NYHA class III and IV, respectively (adapted from McAlister et al. 13).

Renal insufficiency and diuretic resistance are associated with prolonged hospitalization and even mild renal insufficiency in CHF patients independently predicts morbidity and mortality (8,14). Finally, the kidney plays a pivotal role in the development and maintenance of the vicious circle that is responsible for the progression of the disease from asymptomatic left ventricular dysfunction up to the refractory CHF. For all these reasons, non-pharmacological options aimed at supporting or replacing kidney function are fully justified, and the increasing number of patients with combined CHF and renal disease requires a closer interaction between cardiologists and nephrologists.
The concept of the extracorporeal removal of fluid with ultrafiltration (UF) has been reported for over 50 years (15). UF represents the simplest form of renal replacement therapy and several studies have demonstrated its clinical efficacy as well as its safety profile. UF has been used basically to overcome the acute situation of overhydration in oliguric CHF patients and even the international guidelines for the management of CHF state that its use can produce meaningful clinical benefits (2). Compared with dialysis that operates predominantly by diffusion, UF operates by convection in eliminating iso-osmolar extravascular fluid. During UF as shown in Figure 2, blood is driven via an extracorporeal circuit across a highly permeable hemofilter membrane by a peristaltic pump.


Figure 2: Graphic representation of the extracorporeal circuit used in ultrafiltration. The circuit originates from and terminates in the same vein (usually a femoral vein) by means of a Y-shaped double-lumen catheter. Both water and small- and medium-molecular weight solutes are removed through a semipermeable membrane under a pressure gradient, where hydrostatic pressure exceeds plasma oncotic pressure.



Figure 3: Graphic representation of plasma refilling during ultrafiltration (UF). In the course of an UF session, fluid is withdrawn from the intravascular compartment but fluid volume reduction is prevented by intra-vascular refill process (16). Refill from the over-hydrated interstitium depends on fluid movement through the capillary walls, a result of hydrostatic and oncotic pressure gradients between the intravascular and the interstitial compartments (17).

When fluid refilling from the extravascular space is adequate to replace the removed intravascular fluid, hypovolemia is prevented and hemodynamic worsening does not take place during UF (18). Thus, the peculiar feature of UF is its capacity for removing excessive fluid from the extra-vascular space without affecting circulating volume, and most of the clinical, hemodynamic and respiratory effects obtained with UF are the result of this property (18-20). Indeed, reduction of extra-vascular lung water with UF allows the rapid improvement of respiratory symptoms (dyspnea and orthopnea), pulmonary gas exchanges, and radiological signs of pulmonary vascular congestion and of alveolar and interstitial oedema (21). On the other hand, removal of systemic extra-vascular water allows resolution of peripheral oedema, ascites, and pleural and pericardial effusions (18-23). Notably, in CHF patients, reduction of extra-vascular water in both pulmonary and systemic districts exerts a positive influence on the heart. This is mainly due to the reduction of the increased intra-thoracic pressure and, as a consequence, of its negative influence on cardiac dynamics (21,23-26). The hemodynamic pattern usually improves after UF, as a result of both reduction of the extra-cardiac constraint and optimization of circulating volume (18). Even withdrawal of several liters of fluid, over a period of a few hours, can be safely performed without detrimental hemodynamic consequences (18,19). Indeed, during treatment, heart rate, systemic arterial pressure, cardiac output, and systemic vascular resistances do not change, despite a progressive decline in ventricular filling and pulmonary vascular pressures (18-21). In more severe CHF patients, both cardiac output and stroke volume may even increase after UF and hemodynamic improvement is generally maintained for a long time. The apparent paradox of ventricular filling pressure reduction, without a parallel cardiac output decrease, suggests that in patients with severe CHF, either the heart is operating on the horizontal part of the ventricular function curve, or that a reduction of the external work of the heart is occurring. Indeed, during UF, circulating volume – the true cardiac pre-load – is preserved, or even optimized, by fluid refilling from the extravascular space, and the parallel decrease in the ventricular filling pressures of the two sides of the heart purely reflects the reduction of intra-thoracic pressure and of lung stiffness due to reabsorption of the excessive extravascular water that burdens the heart (18,23,24,27). This extra-cardiac constraint is due to increased lung water and, when present, to pleural effusion and ascites (19,20,23,26). Indeed, removal of the constraining effect on the heart by UF has been shown to reduce the ventricular filling pressures, to improve diastolic properties of the heart and cardiac performance (24).
In addition to removing oedema without negative hemodynamic impact, UF allows for other effects that are particularly useful in patients with advanced CHF, such as correction of hyponatremia, restoration of urine output and diuretic responsiveness, reduction of circulating levels of neurohormones such as norepinephrine, renin, aldosterone, and, possibly, removal of other cardiac-depressant mediators (19,20,28,29)(Table 1).

Table 1. Clinical effects of UF in CHF

Resolution of systemic and pulmonary oedema.
Hemodynamic stability
Correction of hyponatremia
Restoration of urine output and diuretic responsiveness
Reduction of circulating levels of neurohormones
Removal of cardiac depressant mediators (cytochine, TNF, ?)

Recovery of diuretic responsiveness is particularly important because it allows for maintenance and even improvement, in the days and months that follow, of the clinical benefit achieved at the end of a single session of UF. Thus, by restoring diuresis and diuretic responsiveness, UF is able to interrupt the progression of CHF toward refractoriness, and to revert the clinical condition to a lower functional class.
The mechanism for renal function improvement is still unclear but it can be explained by the interaction of multiple factors, such as resolution of kidney congestion, recovery of an effective trans-renal arterial-venous pressure gradient, reduction of plasma concentration of several neurohumoral factors with vasoconstrictive and water- and salt-retaining properties. The decline in neurohormonal activation after UF is mainly due to the functional recovery of the excretory organs, in particular of the kidney and the lung (20,28). Indeed, the fall in circulating levels of norepinephrine, renin, and aldosterone during UF is closely associated with the increase in urine output and urinary sodium excretion (20,28), and with a greater reduction of norepinephrine plasma concentration across the lungs (30).
Patients who have NYHA class III CHF and whose water balance is apparently in equilibrium may also have thoracic x-ray signs of congestion and accumulation of fluid. This pulmonary over-hydration significantly contributes to limit patient’s functional capacity (23,25,31). The possibility of improving patient’s functional class through normalization of abnormal lung water content has been proposed from the beginning of ’90 (23), and several studies have shown that UF is safe and allows the improvement of clinical condition, exercise capacity, ventilatory and neurohumoral pattern, also in patients with moderate CHF (32). In a controlled study (23), clinical and functional improvement in patients with moderate CHF lasted up to 6 months after UF. Only in UF-treated patients, pulmonary function tests improved and a chest x-ray score of lung water diminished. Exercise tolerance and functional capacity, as measured by expired gas analysis during exercise, also improved. Norepinephrine at rest was reduced, and the response of norepinephrine to orthostatic tilting was partially restored. Furthermore, abnormal norepinephrine kinetics during exercise was also partially restored in patients undergoing UF. In fact, during exercise, for a given oxygen uptake, norepinephrine plasma levels were lower after the procedure. The improvement in norepinephrine kinetics persisted, on the average of 6 months after treatment, indicating that withdrawal of body fluid, in particular extravascular lung water, by UF persistently ameliorates the functional class of moderate CHF patients. The positive effects of UF in patients with moderate CHF can be ascribed to a decrease in pulmonary stiffness, due to reduction in lung water content (20,25,33). This clearly results from improvement in lung mechanics, indicated by changes in both spirometric parameters at rest and lung mechanics during exercise (20,25,26,34,35). Indeed, at peak exercise, ventilation increases after UF, due to an increase of the tidal volume with a reduced dead space/tidal volume ratio. The same happens at anaerobic threshold. Furthermore, the dynamic pulmonary compliance pattern improves during exercise (15). Altogether these data indicate that not only does ventilation increase after UF but it is also more efficient. This happens when, like in CHF, pulmonary restrictive pattern is due, at least in part, to the increased extravascular lung water content (26), pulmonary blood volume (27), dead space/tidal volume ratio (36), and heart size (37). In brief, UF decreases the external work of the heart through reduction of intrathoracic pressure and removal of the constraining effect exerted by the over-hydrated lungs on the heart (25,26,35). Improvement in pulmonary mechanics favorably affects the heart with a reduction in heart size, doppler restrictivity signs (parallel lowering in peak velocities of early left and right ventricular filling and raising in peak velocities of late ventricular filling of the two ventricles) (24), and improvement in circulatory hemodynamics during exercise. In particular, UF-induced changes occurring during exercise in moderate CHF were investigated (25) and provided further evidence of the close interplay between lung and heart mechanics within the thorax. After UF, the right and left ventricular Starling curves during exercise show a definite reduction of filling pressures for a given cardiac output. The parallelism of variations in both sides of the heart supports the concept that an extra-cardiac event is responsible for the changes observed (38). Although the source of the constraint has not been completely elucidated and a pericardial constraining effect cannot be excluded, it seems likely that the overhydrated lungs exert a constraining effect on the heart and that normalization of lung water content indirectly results in a positive effect on heart dynamics. In this study we also calculated dynamic lung compliance as the ratio of changes in volume to changes in pressure over a tidal breath. The UF-induced increase in dynamic lung compliance during exercise, shown by the reduction of esophageal swing pressure (the absolute esophageal pressure difference between inspiration and expiration) for a given tidal volume, implies a reduction in the cost of breathing and may have contributed to the improved exercise. An increased dynamic lung compliance during exercise may reduce the external work of the heart, an organ that during its rhythmic action has to “pull and push” against the lungs (39). These mechanisms - reduction in lung water content, increase in dynamic lung compliance, improvement in right and left ventricular Starling curve and in exercise capacity – are all closely interrelated and are concordant in explaining why, once UF has changed the mechanical characteristics of the intrathoracic “milieu”, the heart works in a more favorable condition, and why improvement after UF can be long lasting.
The favourable hemodynamic, neurohormonal, and ventilatory responses to UF in clinically stable chronic CHF patients were not observed in matched patients who received only a diuretic intravenous infusion to achieve equivalent fluid removal (34). In the latter group, norepinephrine, plasma renin activity, and aldosterone concentrations rose and remained elevated above pre-treatment values for several days. In contrast, in patients treated with UF, plasma levels of these neurohormones showed a transient rise during therapy, likely due to short-lasting hypovolemia, followed by a significant sustained decrease beginning 48 hours after the procedure and still detectable at the end of the 3 months follow-up. These data indicate that the long-lasting clinical effects of the two treatments are quite different even if UF and furosemide are equally effective as regards acute fluid removal. The mechanisms underlying this different response to fluid withdrawn have not been completely elucidated. A reasonable explanation could be that the fluid removed by these two kinds of treatment has different sodium content (tonicity). Indeed, UF removes fluid having a sodium concentration similar to that of plasma so that approximately 140 mmol of sodium are extracted from the patient with each liter of ultrafiltrate. In contrast, urine of CHF patients is more hypotonic than plasma with approximately 50 mmol of sodium excreted in 1 liter of urine with an increase to about 100 mmol with furosemide administration (40). As a consequence, UF provides the greatest possible amount of sodium extraction per unit of fluid removed. It can be speculated that the different amount of sodium removed with the two treatments, in spite of a similar fluid volume, could be responsible for the different neurohumoral response observed, with consequent achievement of a more favourable water and salt balance after UF (less input of water without recovery in body weight) and rapid recovery in baseline condition, after furosemide. These observations emphasize the clinical and pathophysiological relevance of a more "physiological" dehydration in CHF. In this regard, it is not known whether different kinds of renal replacement therapies, such as hemofiltration or hemodiafiltration could be more effective in CHF patients, given their greater capability to dissociate removal of sodium from that of water. Actually, no comparative study between UF and other extracorporeal renal modalities has been carried out in CHF patients. Moreover, information on the application of different renal replacement therapies in the same patient, in order to achieve different goals (recovery from acutely decompensated CHF or prevention of acute clinical worsening), is lacking.
Despite these promising results, to date no study has focused on the use of UF in the chronic treatment of CHF. Indeed, when the two kinds of strategies for fluid overload removal (diuretics and UF) are compared, besides the divergent effect in the sodium content of removed fluid (ultrafiltrate and urine), and on intravascular volume (preserved with UF and reduced with diuretics), also opposite influences on sodium and potassium serum concentrations, and on the renin-angiotensin system activity (increased by diuretics and lowered by UF) can be remarked. Thus, if we consider that hyponatremia, hypokalemia, and renin-angiotensin system activation are recognized negative prognostic indicators in CHF, it is possible that chronic treatment with UF (periodic sessions) could have, in comparison with diuretic treatment, a different impact on the progression of the disease, on oedema formation and, finally, on mortality. To date, the ability of UF to prolong survival in CHF patients has not been established yet. However, when we take into account that CHF imposes a heavy burden on individuals through a reduced tolerance of physical exertion, lengthy hospital admissions, and short life expectancy, the established improvement in their quality of life and in the reduction of hospitalisations and hospital duration by UF is certainly appreciated (Table 2).
Table 2. Clinical indications to ultrafiltration in heart failure.

Severe congestive heart failure resistant to conventional medical therapy
Long-term maintenance treatment (intermittent ultrafiltration)
Patients contraindicated for heart transplantation
Temporary treatment for patients awaiting heart transplantation or other surgical intervention
Emergency procedure in cases of acute cardiac decompensation
Moderate congestive heart failure with clinical signs of increased lung water and reduced exercise capacity.

Recently, simplified new ultrafiltration devices have been introduced for the treatment of CHF outside the intensive care unit. They utilize less invasive catheters placed in peripheral arm veins, and require minimal operator intervention and clinical monitoring by a trained nurse. In three preliminary studies, the safety and efficacy of this “peripheral UF” was demonstrated in fluid-overloaded patients, and its clinical applicability tested (41-43). Early UF treatment in 20 patients with acute decompensated CHF, hospitalized for fluid overload and diuretic resistance, permitted the discharge of 60% of patients within 3 days, and aggressive fluid removal (>8 L) with UF was not associated with worsening renal failure, electrolyte abnormalities, or symptomatic hypotension. Furthermore, UF was associated with a sustained drop in plasma BNP levels. Only 1 patient was rehospitalized within 30 days (42). In another study, 40 CHF and fluid overload were randomized to usual care (n=20) or UF plus usual care (n=20). Also in this study, UF treatment was well-tolerated, and resulted in significant weight loss and fluid removal (43). To date several observational and randomized trials are underway in order to define the long-term efficacy of UF in both acute and chronic CHF.
In conclusion, use of UF represents an important advance in the therapy of CHF that allows improvement of clinical and hemodynamic conditions without interfering with cardiac performance, re-establishes neurohumoral imbalances, and restores diuresis and diuretic responsiveness. Ongoing studies should definitely characterize the clinical impact of UF in this setting, in terms of morbidity, (frequency of hospitalizations and number of days of hospitalization), overall cost of treatment, and mortality. Further investigation, however, is needed to better elucidate the mechanisms through which UF exerts its positive effects, and to identify patients in which the greatest benefit can be obtained.



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