Author + information
- Received September 9, 2011
- Revision received August 13, 2012
- Accepted August 13, 2012
- Published online November 6, 2012.
- Maria Patarroyo, MD⁎,
- Edgard Wehbe, MD†,
- Mazen Hanna, MD⁎,
- David O. Taylor, MD⁎,
- Randall C. Starling, MD, MPH⁎,
- Sevag Demirjian, MD† and
- W.H. Wilson Tang, MD⁎,⁎ ()
- ↵⁎Reprints requests and correspondence:
Dr. W.H. Wilson Tang, Kaufman Center for Heart Failure, Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, 9500 Euclid Avenue, J3-4, Cleveland, Ohio 44195
Objectives The purpose of this study was to examine the clinical outcomes of using slow continuous ultrafiltration (SCUF) in patients with acute decompensated heart failure (HF) refractory to intensive medical therapy.
Background Several studies have demonstrated the clinical usefulness of early SCUF in patients with acute decompensated HF to improve fluid overload and hemodynamics.
Methods We reviewed clinical data from 63 consecutive adult patients with acute decompensated HF admitted to the Heart Failure Intensive Care Unit from 2004 through 2009 who required SCUF because of congestion refractory to hemodynamically guided intensive medical therapy.
Results The mean creatinine level was 1.9 ± 0.8 mg/dl on admission and 2.2 ± 0.9 mg/dl at SCUF initiation. After 48 hours of SCUF, there were significant improvements in hemodynamic variables (mean pulmonary arterial pressure: 40 ± 12 mm Hg vs. 33 ± 8 mm Hg, p = 0.002, central venous pressure: 20 ± 6 mm Hg vs. 16 ± 8 mm Hg, p = 0.007, mean pulmonary wedge pressure: 27 ± 8 mm Hg vs. 20 ± 7 mm Hg, p = 0.02, Fick cardiac index: 2.2 l/min/m2 [interquartile range: 1.87 to 2.77 l/min/m2] vs. 2.6 l/min/m2 [interquartile range: 2.2 to 2.9 l/min/m2], p = 0.0008), and weight loss (102 ± 25 kg vs. 99 ± 23 kg, p < 0.0001). However, there were no significant improvements in serum creatinine levels (2.2 ± 0.9 mg/dl vs. 2.4 ± 1 mg/dl, p = 0.12) and blood urea nitrogen (60 ± 30 mg/dl vs. 60 ± 28 mg/dl, p = 0.97). Fifty-nine percent required conversion to continuous hemodialysis during their hospital course, and 14% were dependent on dialysis at hospital discharge. Thirty percent died during hospitalization, and 6 patients were discharged to hospice care.
Conclusions In our single-center experience, SCUF after admission for acute decompensated HF refractory to standard medical therapy was associated with high incidence of subsequent transition to renal replacement therapy and high in-hospital mortality, despite significant improvement in hemodynamics.
Despite aggressive diuresis during hospital admission for acute decompensated heart failure (HF), only 52% of patients derive symptomatic improvement after discharge (1). Further, almost 16% of the patients gain rather than lose weight during their hospitalizations, which may predict subsequent rehospitalizations (2). These observations imply that diuretic therapy as a mainstay of therapeutic strategy may provide inadequate relief of congestion in a subset of patients. The underlying cause(s) of such insufficient salt and volume removal is multifactorial. Underlying chronic renal insufficiency may be more prevalent than appreciated at the bedside (3) and can be exacerbated by adverse hemodynamic alterations of HF or adverse consequences related to aggressive diuretic therapy (4). Apparent diuretic resistance also can be the result of reduced bioavailability of oral loop diuretics or decreased renal tubular delivery (5). Electrolyte disturbances associated with diuresis, such as hyponatremia, hypokalemia, and hypomagnesemia, also may limit effective diuresis (6).
Recent data have suggested that the presence of significant venous congestion can affect cardiorenal physiology directly, independent of cardiac output, which can lead to ineffective natriuresis (7,8). With the notion that the kidneys are unable to relieve downstream congestion effectively, mechanical removal of salt and water became an attractive concept in improving cardiac hemodynamics to facilitate better renal perfusion. For example, the use of peritoneal dialysis in the setting of refractory HF has long been described (9–11). Recent studies also have shown the potential benefit of slow continuous ultrafiltration (SCUF) in early pre-emptive treatment of patients admitted with volume overload secondary to acute decompensated HF, with decreased hospitalization rates and improvement in weight loss, exercise capacity, and filling pressures (12–16).
In subjects with advanced HF admitted for acute decompensation, it often has been assumed that hemodynamic compromise may drive insufficient diuretic and natriuretic responses to diuretic therapy. However, whether such hemodynamic improvement with ultrafiltration can consistently translate into improvement in renal physiology and function remains unproven. Herein, we review our single-center experience with SCUF in patients with severely decompensated HF, including the changes in cardiorenal physiologic measurements during therapy and long-term adverse outcomes. We hypothesize that hemodynamic improvements resulting from SCUF in the setting of persistent congestion refractory to medical therapy may provide short-term renal improvement.
We analyzed consecutive adult patients admitted to the HF intensive care unit at the Cleveland Clinic between January 2004 and June 2009 with acute decompensated HF for hemodynamically guided therapy who were refractory to standard medical therapy and who had progressive oliguria or worsening renal function, despite persistent congestion requiring nephrology consultation for SCUF. We excluded patients who did not undergo SCUF or who already had begun other methods of renal replacement therapy at the time of admission, had a history of heart or renal transplantation, had a pre-existing glomerular filtration rate of 15 ml/min/1.73 m2 or less, or were without a history or diagnosis of HF. The Cleveland Clinic Institutional Review Board approved the study.
We documented hemodynamic information at the time of admission, SCUF initiation, and 48 hours after SCUF initiation. The systolic and diastolic blood pressures were obtained by sphygmomanometer of the brachial artery, by peripheral arterial line measurements, or both. Central venous pressure; systolic, diastolic, and mean pulmonary arterial pressures; and pulmonary capillary wedge pressure were assessed at the end of expiration with a balloon-tipped catheter at steady state with the patient in the supine position. The cardiac index was obtained by Fick equation using sampling of mixed central venous blood gas obtained from the pulmonary artery catheter. The medications administered to achieve these goals included any combination of diuretics, vasodilators, and inotropic drugs, in addition to angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, beta-adrenergic blockers, and aldosterone antagonists. Targeted optimal hemodynamic response with SCUF and medical therapy was defined as a decrease in pulmonary capillary wedge pressure to 18 mm Hg or less, a decrease in mean pulmonary arterial pressure by at least 20%, a decrease in right atrial pressure to 8 mm Hg or less, and an improvement in cardiac index to 2.2 l/min/m2 or more, all while maintaining mean arterial pressure of more than 65 mm Hg, as previously described (6).
SCUF was performed using 2 systems: either the Gambro Prisma systems with the M60 and M100 sets (Gambro, Lakewood, Colorado), or the NxStage System 1 using the Express dialyzer set (NxStage Medical, Inc., Lawrence, Massachusetts). Vascular access was gained with a central catheter in the femoral or jugular vein. The blood flow rate ranged from 100 to 180 ml/min and the ultrafiltration rate ranged from 100 to 400 ml/h. Ultrafiltration rate adjustments and duration of therapy were driven by clinical and hemodynamic goals (volume burden, respiratory status, systemic blood pressure, filling pressures, and use of vasoactive drugs) by the caring nephrologists, in close collaboration with the cardiologists. Loop diuretic therapy was continued in a subset of patients (particularly nonanuric patients), but in the large majority of patients, loop diuretic therapy was withheld.
Paper records of all patients who underwent SCUF during the study period were reviewed carefully, and data were collected for all patients who underwent ultrafiltration in the HF intensive care unit. Procedure-related data included: dates of initiation and termination of SCUF, filter type, anticoagulation used, blood flow rate, ultrafiltration rate, and conversion to another method of renal replacement therapy, such as continuous veno-venous hemodialysis or intermittent hemodialysis.
Data collection and outcome measures
Baseline data collection included demographic and clinical data, as well as serial laboratory, echocardiographic, and hemodynamic data before ultrafiltration therapy as well as at 48 hours after SCUF initiation. The primary endpoint was all-cause mortality as determined by documentation in the electronic medical record and confirmed by the social security death index. Secondary endpoints included number of readmissions for acute decompensated HF and dialysis-dependent status at the time of discharge.
Descriptive statistics were calculated for the entire study population. Continuous variables were expressed as mean ± SD if normally distributed and median and interquartile range (IQR) for those that were nonnormally distributed. Categorical variables were expressed as proportion and frequencies. All between-subjects comparisons reported p values on the basis of 2-sided tests, and a p value <0.05 was considered statistically significant. Kaplan-Meier analysis for long-term survival was performed from the time of initial SCUF date to time of death. The Cox proportional hazards model was used as a univariate analysis of the hazard ratio to determine the prognostic value according to systolic blood pressure in this cohort. The cutoff point of 110 mm Hg was selected on the basis of the median systolic blood pressure value (rounded to the nearest 10 mm Hg). All statistical analyses were performed using JMP software version 9.0 (SAS Institute, Cary, North Carolina). All authors had full access to the data and take responsibility for its integrity.
A total of 63 consecutive patients who fulfilled inclusion and exclusion criteria were identified during the study period. Baseline characteristics are presented in Table 1, whereas Table 2 lists baseline hemodynamic measurements. These values were consistent with a study population with advanced decompensated HF. The median 24-h urine output was 1,350 ml (IQR: 605 to 2,025 ml) before initiation of SCUF. Forty-eight patients (76%) were treated in the hospital with furosemide with a median daily dose of 480 mg (IQR: 240 to 480 mg), whereas 10 (16%) were taking additional metolazone and 15 (24%) were taking additional chlorothiazide. Thirty-seven patients (59%) were treated with intravenous vasoactive medications (including 24 [38%] with dobutamine or milrinone and 13 [21%] with nitroprusside, nitroglycerin, or both).
The mean time between admission and consult to transfer to the HF intensive care unit was 5 days. The mean time between admission and initiation of SCUF was 8 days, with a mean ultrafiltration rate of 200 ml/hour (IQR: 150 to 250 ml/h). The mean duration of SCUF for the total cohort was 3 ± 2 days. In the subset with retrievable data for total fluid removal by SCUF (n = 28), there were no differences between those who needed versus did not need transition to dialysis (p = 0.76), nor between those who died versus survived (p = 0.28). Forty-five (71%) patients underwent ultrafiltration more than 48 hours after admission. In this subset, there were no significant changes between admission and the date of SCUF initiation in terms of body weight (98 kg [IQR: 87 to 119 kg] vs. 101 kg [IQR: 87.6 to 122.8 kg], p = 0.75), mean arterial blood pressure (76 mm Hg [IQR: 68 to 83 mm Hg] vs. 73 mm Hg [IQR: 68 to 82 mm Hg, p = 0.76), mean pulmonary artery pressure (39 mm Hg [IQR: 33 to 46 mm Hg] vs. 37 mm Hg [IQR: 32 to 44 mm Hg], p = 0.44), and central venous pressure (23 mm Hg [IQR: 17 to 26 mm Hg] vs. 21 mm Hg [IQR: 16 to 25 mmHg], p = 0.1). This was despite improvement in cardiac index (1.8 l/min/m2 [IQR 1.39–2.35 l/min/m2] vs. 2.2 l/min/m2 [IQR: 1.9 to 2.8 l/min/m2], p = 0.0006) and systemic vascular resistance (1,010 dyn·s/cm5 [IQR: 699 to 1,377 dyn·s/cm5] vs. 855 dyn·s/cm5 [IQR: 675 to 1,028 dyn·s/cm5], p = 0.03). It was also observed that patients who began SCUF more than 48 h after admission had worsened hyponatremia (133 ± 6 mmol/dl vs. 131 ± 7 mmol/dl, p = 0.009), worsened anemia (hemoglobin: 11 ± 1.7 mg/dl vs. 9.5 ± 1.5 mg/dl, p ≤ 0.0001), and worsening renal function (serum creatinine: 1.9 ± 0.8 mg/dl vs. 2.4 ± 0.9 mg/dl, p ≤ 0.0001; blood urea nitrogen: 55 ± 25 mg/dl vs. 64 ± 29 mg/dl, p = 0.002) from admission to the time of SCUF initiation.
In the overall cohort after 48 hours of SCUF, there was a significant weight loss (from 100 kg [IQR: 89 to 120 kg] to 94 kg [IQR: 83 to 115 kg], p < 0.0001), which was associated with a significant improvement in hemodynamic variables (Fig. 1) accompanying a negative fluid balance of 5.7 ± 3.8 l after 48 h from SCUF initiation. However, there were no improvements in renal indices observed, despite evidence of hemoconcentration with a rise in total protein content (Table 3).
Figure 2 demonstrates the long-term adverse outcomes for our study cohort. At the nephrology consult's subsequent recommendation, 37 patients (59%) were switched from SCUF to continuous hemodialysis (continuous veno-venous hemodialysis). Within this subset who required continuous veno-venous hemodialysis, 16 subjects died during hospitalization, 4 were discharged to hospice care, and 9 subjects became dependent on dialysis on discharge. In this subset, 93% were readmitted to the hospital within 60 days from discharge.
In our overall study cohort, 19 subjects died during the index hospitalization, whereas 4 were discharged to hospice care. The most likely cause of in-hospital mortality was progressive pump failure (73%), whereas no deaths were attributable to complications resulting from the SCUF procedure. The overall 1-year all-cause mortality was 70%, whereas 2 of the surviving patients at 1 year underwent orthotopic heart transplantation.
We further observed lower systolic blood pressure at the time of admission in patients who died within 30 days versus those who were alive at 30 days (99 ± 25 mm Hg vs. 113 ± 15 mm Hg, p = 0.02). In univariate analysis, systolic blood pressure had a hazard ratio of 0.5 (95% confidence interval: 0.008 to 0.8), with a 30-day mortality rate of 54% observed in patients undergoing SCUF in this setting with systolic blood pressure of 110 mm Hg or less at admission (Fig. 3).
This study represents our single-center clinical experience of a large cohort of patients with advanced HF undergoing SCUF as rescue therapy. The key finding of our study was that the initiation of SCUF to relieve congestion as a result of progressive cardiorenal compromise in our cohort of patients admitted with refractory advanced HF may provide significant hemodynamic improvement. Nevertheless, we observed no significant improvement in renal function before or after SCUF, despite effective salt and water removal, and our patient cohort demonstrated high rates of adverse clinical events and the need for renal replacement therapy. Therefore, our findings refuted our original hypothesis that hemodynamic improvement with SCUF invariably can translate into direct cardiorenal improvement and cautioned the promise of potential benefit of SCUF in the setting of advanced decompensated HF refractory to medical therapy. In particular, there is a need to discuss thoroughly the relatively poor long-term prognosis with the patient especially in the setting of low systemic blood pressure, even though transient hemodynamic improvements can be achieved.
This study presents a counterpoint to the optimistic expectations of remarkable benefits of mechanical salt and water removal in previous studies (13–16), in particular to be put in the context of a very different clinical situation in which SCUF provides temporary relief in a salvage manner, despite remarkable improvement in central hemodynamics. It is important to acknowledge that this is a patient population with advanced HF admitted for acute decompensated HF refractory to standard medical therapy in which SCUF has not been tested prospectively in randomized clinical trials. There are several important differences in the use of SCUF between our series and that reported in the UNLOAD (Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Heart Failure) study (16). First and foremost, patients in our cohort had markedly impaired hemodynamic measurements at admission and required more vasoactive therapies compared with other SCUF studies (76% vs. 3% in the UNLOAD study) (16). Second, there was a delay in SCUF initiation after failed attempts to relieve congestion by medical therapy in our study compared with immediate SCUF after admission in the UNLOAD study as pre-emptive treatment (16). Whether a more upfront approach can translate into clinical benefits in an adequately powered study in an acute decompensated HF patient population with evidence of renal vulnerability, rather than refractoriness, will be tested in the upcoming CARRESS-HF (CARdiorenal REScue Study in Acute Decompensated Heart Failure) trial (NCT00608491) (17).
One of the prevailing hypotheses regarding the pathogenesis of acute cardiorenal syndrome has been attributed to altered hemodynamics, whereby a decrease in blood flow to the kidneys leads directly to renal impairment. Furthermore, we and others previously demonstrated that venous congestion is associated with cardiorenal compromise in patients with advanced decompensated HF (6,7). In our study cohort, SCUF successfully produced a significant weight loss (mean weight loss: 4.4 kg vs. 5.0 kg in the UNLOAD trial) (16), coupled with significant improvements in venous and central hemodynamics and a corresponding increase in total protein levels (a surrogate of hemoconcentration). It therefore is logical that such observed improvements may lead directly to improvement in renal function. Instead, we observed no significant changes in serum creatinine or blood urea nitrogen levels in our study cohort; 53% required in-hospital dialysis and 14% of patients were dependent on dialysis at the time of discharge. Although patients were evaluated after 48 h of SCUF, the fact that a subset of patients warranted subsequent renal replacement therapy also argued against a delayed recovery of renal function in response to decongestion. Taken together, our observations imply that intrinsic renal impairment likely is a major determinant of disease progression in advanced HF.
Our findings are consistent with recent studies that have challenged the central doctrine of hemodynamics (at least when measured at the level of the central circulation) as the primary determinant of acute cardiorenal syndrome. Specifically in the ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) trial, baseline hemodynamic parameters may not be significantly different between patients with no change in renal function and patients with worsening renal function (18). Furthermore, improvement in hemodynamic parameters may not be closely linked with improvement in renal function (19). The high event rates in our study cohort, despite significant improvements in hemodynamics, also mirrored the primary results of the ESCAPE trial showing the lack of a relationship between improvement in central hemodynamics and survival after discharge from the hospital with advanced HF (20). Hence, effective relief of venous congestion, augmentation of cardiac output, reduction in intracardiac filling pressures, or a combination thereof cannot be translated uniformly into a more favorable and sustainable renal improvement. If improving cardiac function does not occur through the kidney, and improving the kidney function does not arise as a result of cardiac manipulation, perhaps we should look for improvements in disease mechanisms that are common to both, yet dependent on neither.
Although there were very low short-term and long-term mortality rates in the UNLOAD trial, a previously reported single-center series of SCUF therapy reported an in-hospital mortality of 11% and 1-year mortality of 39% (21). In contrast, given that ultrafiltration or dialysis after a patient has demonstrated resistance to all other therapies is a treatment of desperation, the in-hospital mortality rate in our series was 30%, and the overall 1-year mortality rate was 70%. The need to proceed with SCUF in our patient population as a rescue strategy clearly represented a patient population who were refractory to the standard medical therapy of loop diuretics, similar to a previously reported series (22). Among all the baseline hemodynamic variables, we observed that systolic blood pressure at admission was an important predictor of long-term survival, which is consistent with other large datasets (23). A decrease in systemic blood pressure may represent an inability to generate sufficient forward flow that likely will affect renal perfusion, leading to worsening renal function and potentially inadequate congestion relief (24). With SCUF, a marginal blood pressure may be intolerant to fluid removal, with a probable blunted response to intravascular depletion that may be reflected by lower perfusion to vital organs including the heart and kidneys.
There are several limitations in our single-center report. The purpose of the study was not to examine the effectiveness of SCUF versus that of conventional therapy, but rather to characterize the impact of SCUF as a rescue therapy currently used in the setting of acute (type 1) cardiorenal syndrome on hemodynamic, renal, and outcome measures. Therefore, we did not have a matched control group in part because of the inherent selection bias of comparator groups. Furthermore, we have no objective and reliable determination of preadmission intrinsic renal function to determine the threshold by which SCUF therapy may not result in significant improvement in clinical outcomes, nor do we have complete data to examine the relationship between hemodynamic and renal improvement beyond 48 h of SCUF. We also acknowledge that aggressive salt and water removal may produce a hemoconcentration effect that may affect serum creatinine levels as observed in the UNLOAD study (16). In addition, we cannot account for inherent differences in the 2 machines (gravimetric vs. volumetric controls), although the rate adjustments were driven by clinical and hemodynamic parameters, rather than a predetermined specific ultrafiltration rate. Furthermore, we cannot ignore the fact that alternative approaches to relieve significant congestion beyond acute SCUF have been described. Nevertheless, our observations demonstrated that initiation of SCUF in patients with advanced HF refractory to medical therapy identifies an exceedingly high-risk patient category—with no clear therapeutic options and the high likelihood of conversion to renal replacement therapy as well as poor outcome. Yet, the question of futility of an otherwise invasive and demanding therapy is being raised on the basis of our contemporary experience of the current rescue therapy approach for SCUF. This is the first time such a series of patients has been reviewed with respect to cardiorenal outcomes—many of whom were not classic end-stage renal disease patients. As clinicians caring for these patients, our findings provided much-needed information to guide the decision-making process in initiating SCUF in the setting of refractory advanced HF, particularly regarding long-term expectations.
In our single-center experience, the use of SCUF in patients with advanced HF demonstrated significant hemodynamic improvement, despite a lack of substantial renal improvement. Particularly in those with lower systolic blood pressure at admission, the goal to relieve congestion temporarily using this invasive strategy must be balanced carefully with the persistent burden in long-term morbidity and mortality in this population. In our contemporary experience, the need for SCUF clearly marks an advanced HF status with limited treatment options and poor outcomes, which are important to convey to patients when treatment decisions are being considered.
Dr. Tang is a consultant to Medtronic, Inc. and St. Jude Medical; and previously received an investigator-initiated research grant from Abbott Laboratories. Dr. Taylor previously received a research grant from NxStage for a single-center study evaluating the use of slow continuous ultrafiltration. All other authors have reported that they have no relationships relevant to the contents of this paper disclose.
- Abbreviations and Acronyms
- heart failure
- interquartile range
- slow continuous ultrafiltration
- Received September 9, 2011.
- Revision received August 13, 2012.
- Accepted August 13, 2012.
- American College of Cardiology Foundation
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