Cardiovascular Ultrafiltration

Number: 0741

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses indications for peripheral ultrafiltration and modified ultrafiltration in cardiovascular disease.

1. Medical Necessity

   1. Peripheral Ultrafiltration for Acute Decompensated Heart Failure:

      Aetna considers peripheral ultrafiltration medically necessary for the acute management of inpatient members hospitalized with acutely decompensated congestive heart failure (CHF) who have dyspnea at rest or with minimal activity, and have confirmed diuretic resistance defined as dose escalation beyond a person's previously recognized dose ceiling or a dose approaching the maximum recommended daily dose without incremental improvement in diuresis. 

   2. Modified Ultrafiltration for Cardiopulmonary Bypass

      Aetna considers modified ultrafiltration medically necessary for cardiopulmonary bypass in pediatric (less than 18 years of age) and neonatal cardiac surgery.

2. Experimental, Investigational, or Unproven

   Aetna considers the following experimental, investigational, or unproven:

   1. Intermittent peripheral ultrafiltration in persons who are not acutely decompensated or scheduled repetitive peripheral ultrafiltration, as is use of peripheral ultrafiltration for all other indications;
   2. Peritoneal ultrafiltration as an adjunctive therapy in end-stage heart failure;
   3. Ultrafiltration for the treatment of cardio-renal syndrome, in persons who do not meet medical necessity criteria above.

3. Related Policies

   • CPB 0541 - Dialysis - for ultrafiltration in hemodialysis
   • CPB 0610 - Biventricular Pacing (Cardiac Resynchronization Therapy)/Combination Resynchronization-Defibrillation Devices for Congestive Heart Failure
   • CPB 0709 - Nesiritide (Natrecor)

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Peripheral ultrafiltration:
CPT codes covered for indications listed in the CPB:
0692T	Therapeutic ultrafiltration [not covered for intermittent peripheral ultrafiltration]
CPT codes not covered for indications listed in the CPB:
Intermittent Peripheral ultrafiltration - no specific code:
ICD-10 codes covered if selection criteria are met:
I50.20 - I50.9	Congestive heart failure
ICD-10 codes not covered for indications listed in the CPB:
I13.0 - I13.2	Hypertensive heart and chronic kidney disease [Cardio-renal syndrome]
Modified ultrafiltration:
CPT codes covered for indications listed in the CPB:
0692T	Therapeutic ultrafiltration
Other CPT codes related to the CPB:
33010 - 37790	Cardiovascular System
ICD-10 codes covered if selection criteria are met:
I50.20 – I50.9	Congestive heart failure
ICD-10 codes not covered for indications listed in the CPB:
I13.0 - I13.2	Hypertensive heart and chronic kidney disease [Cardio-renal syndrome]
Peritoneal ultrafiltration:
CPT codes not covered for indications listed in the CPB:
Peritoneal ultrafiltration - no specific code:
ICD-10 codes not covered for indications listed in the CPB:
I13.0 - I13.2	Hypertensive heart and chronic kidney disease [Cardio-renal syndrome]
I50.84	End stage heart failure

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Background

Approximately 5 million Americans are currently diagnosed with heart failure (HF), and more than 500,000 new cases are diagnosed each year.  Heart failure is the leading cause of hospitalizations in the United States (U.S.) and is associated with significant morbidity, mortality and resource utilization.  The New York Heart Association (NYHA)'s classification of HF was the first rating system developed to quantify the degree of functional limitations exhibited by patients with HF.  It is a 4-tier system that categorizes patients based on subjective impression of the degree of functional compromise.  The 4 NYHA functional classes are as follows:

Class I: 

Patients with cardiac disease but without resulting limitation of physical activity.  Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain.  Symptoms only occur on severe exertion.

Class II:

Patients with cardiac disease resulting in slight limitation of physical activity.  They are comfortable at rest.  Ordinary physical activity (e.g., moderate physical exertion such as carrying shopping bags up several flights or stairs) results in fatigue, palpitation, dyspnea, or anginal pain.

Class III:

Patients with cardiac disease resulting in marked limitation of physical activity.  They are comfortable at rest.  Less than ordinary activity (i.e., mild exertion) causes fatigue, palpitation, dyspnea, or anginal pain.

Class IV:

Patients with cardiac disease resulting in inability to carry on any physical activity without discomfort.  Symptoms of cardiac insufficiency or of the anginal syndrome may be present even at rest.  If any physical activity is undertaken, discomfort is increased.

The NYHA's functional classification of HF entails a continuum of increasing symptom severity, in which patients in Class I report no symptoms of HF, while those in Class IV exhibit severe symptomatology at rest.  Patients with acute decompensated heart failure (ADHF) are usually characterized by an acute change in their baseline NYHA status (usually NYHA Class I or II) to NYHA Class IV disease (Hunt et al, 2001).  Although no formal definition of ADHF exists, traditional signs of ADHF include pitting edema greater than 2 mm, presence of rales on pulmonary examination, pulmonary capillary wedge pressure (greater than 18 mm Hg), elevated right atrial pressure (greater than 10 mm Hg), and an increase in body weight (greater than 4.5 kg for patients below 5 feet in height or greater than 6.8 kg for patients over 5 feet in height).  The level of brain B-type natriuretic peptide is now recommended to confirm the diagnosis of ADHF, with a level greater than 80 pg/ml being indicative of decompensation.  While ADHF can occur in patients with almost any stage of HF, episodes occur frequently in those with structural heart disease and either a history or current symptoms of HF (Bleske et al, 1998; Gottlieb et al, 1998; Hunter et al, 2001).

In contrast to chronic HF, where there have been numerous advances in care and corresponding decreases in morbidity and mortality, treatment for patients with ADHF remains largely empiric, and outcomes of these patients have remained relatively unchanged with an approximate 10 % 30-day mortality and almost 40 % 1-year re-hospitalization rate (Howlett, 2005).  Acute decompensated heart failure is an important milestone in the clinical course of HF.  It is an event associated with a significant deterioration in the prognosis of HF (Onwuanyi and Taylor, 2007).

Allen and O'Connor (2007) stated that ADHF represents a heterogeneous group of disorders that typically present as dyspnea, edema and fatigue.  Despite the high prevalence of this condition and its associated major morbidity and mortality, diagnosis can be difficult, and optimal treatment remains poorly defined.  Identification of the acute triggers for the decompensation as well as non-invasive characterization of cardiac filling pressures and output is central to management.  Diuretics, vasodilators, continuous positive airway pressure and inotropes can be used to alleviate symptoms.  However, few agents currently available for the treatment of ADHF have been definitively shown in large prospective randomized clinical trials to provide meaningful improvements in intermediate-term clinical outcomes.  Multiple novel therapies are being developed, but previous treatment failures indicate that progress in the management of ADHF is likely to be slow.

The therapeutic objective in patients with ADHF is volume and sodium removal, and the restoration of diuretic sensitivity.  A number of drugs have been demonstrated to lower morbidity and mortality in patients with chronic HF.  Despite these advances, the frequency of hospitalization for HF has continued to rise, and evidence is lacking in demonstrable benefit of pharmacotherapy for patients hospitalized with ADHF.  In particular, Sackner-Bernstein and Aaronson (2007) noted that nesiritide is approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with ADHF who suffer from symptoms at rest or with minimal exertion.  Its approval was based on a clinical development program that focused on surrogates and short-term effects on symptoms rather than clinical outcomes.  Aggregate data analysis has suggested that it may be associated with a risk of excess mortality and worsening renal insufficiency.  The association between its use and subsequent risk of death raises the question of whether the endpoints assessed in the clinical development program were adequate, and provides the opportunity to evaluate the process of weighing risks with benefits.  The authors concluded that with nesiritide, the risks of therapy outweigh the benefits demonstrated to date.

Several percutaneous/peripheral devices have been developed to improve symptoms and clinical outcomes in patients hospitalized with HF.  These include devices such as continuous aortic flow augmentation and ultra-filtration (UF) devices.  Peripheral UF therapy offers the potential of greater volume and sodium removal as compared with conventional therapies in a more expeditious manner.  Ultrafiltration differs from dialysis because it acts via convection rather than diffusion, which lowers the risk for induced metabolic abnormalities.  Conventional UF devices required central venous access with a double lumen catheter, monitoring by a dialysis technician, and specialized hospital units.  More recently, devices have been developed that allow UF to be carried out via large peripheral venous catheters (CTAF, 2007).

One device for ultrafiltration is the Aquadex FlexFlow system; Aquapheresis is the trademarked term for removal of salt and water with the Aquadex system.  The Aquadex FlexFlow technology received initial 510(k) marketing clearance from the FDA in June 2002.  An updated/amended 510(k) clearance (classified as a high permeability dialysis system) was given in February 2006 following some modifications.  That Aquadex FlexFlow System is indicated for temporary (up to 8 hours) ultrafiltration treatment of patients with fluid overload who have failed diuretic therapy, and extended (longer than 8 hours) ultrafiltration treatment of patient with fluid overload who have failed diuretic therapy and require hospitalization.

Costanzo (2006) stated that 90 % of one million annual hospitalizations for HF in the U.S. are due to symptoms of volume over-load.  Hypervolemia contributes to HF progression and mortality.  Current treatment guidelines recommend that therapy for patients with HF be aimed at achieving euvolemia.  Intravenous loop diuretics induce a rapid diuresis that reduces lung congestion and dyspnea.  However, the effectiveness of loop diuretics decreases with repeated treatments.  Unresolved congestion may contribute to high re-hospitalization rates.  Furthermore, loop diuretics may be associated with increased morbidity and mortality due to deleterious effects on neuro-hormonal activation, electrolyte balance, as well as cardiac and renal function.  Peripheral UF is an alternative method of sodium and water removal that may improve hemodynamics in patients with HF.

Bart et al (2005) evaluated the safety and effectiveness of UF in patients admitted with decompensated congestive HF (CHF).  Ultrafiltration for CHF is usually reserved for patients with renal failure or those unresponsive to pharmacological management.  These researchers performed a randomized trial of UF versus usual medical care using a simple UF device that does not require special monitoring or central intravenous access.  Patients admitted for CHF with evidence of volume over-load were randomized to a single, 8-hour UF session in addition to usual care or usual care alone.  The primary end point was weight loss 24 hours after the time of enrollment.  A total of 40 patients were enrolled (20 UF, 20 usual care).  Ultrafiltration was successful in 18 of the 20 patients in the UF group.  Fluid removal after 24 hours was 4,650 ml and 2,838 ml in the UF and usual care groups, respectively (p = 0.001).  Weight loss after 24 hours, the primary end point, was 2.5 kg and 1.86 kg in the UF and usual care groups, respectively (p = 0.240).  Patients tolerated UF well.  The authors concluded that the early application of UF for patients with CHF was feasible, well-tolerated, and resulted in significant weight loss and fluid removal.  They noted that a larger trial is underway to determine the relative effectiveness of UF versus standard care in ADHF.

In a case-series study, Dahle and colleagues (2006) reported the feasibility and effectiveness of performing large volume UF via peripherally inserted standard intravenous catheters in hospitalized patients with ADHF (n = 9).  The mean length of time of peripheral UF therapy was 33.3 +/- 20.0 hours with a mean volume removed of 7.0 +/- 4.9 L.  All patients experienced a statistically significant mean weight loss of 6.2 +/- 5.0 kg (p = 0.01).  There was no statistically significant change in renal function.  The authors noted that this was the first successful implementation of UF via standard peripheral intravenous catheters to remove a large volume of fluid over an extended period of time reliably in a small group of patients.  The ability to use peripheral UF therapy via intravenous catheters will potentially allow this therapy to be implemented more easily in a variety of care settings to treat patients with refractory HF.

Costanzo and associates (2007) compared the safety and effectiveness of peripheral (veno-venous) UF and standard intravenous diuretic therapy for patients with hyper-volemic HF.  Patients hospitalized for HF with greater than or equal to 2 signs of hypervolemia were randomized to UF or intravenous diuretics.  Primary end points were weight loss and dyspnea assessment at 48 hours after randomization.  Secondary end points included net fluid loss at 48 hours, functional capacity, HF re-hospitalizations, and unscheduled visits in 90 days.  Safety end points included changes in renal function, electrolytes, and blood pressure.  A total of 200 patients (138 men and 62 women, mean age of 63 +/- 15 years, 71 % ejection fraction less than or equal to 40 %) were randomized to UF or intravenous diuretics.  At 48 hours, weight loss (5.0 +/- 3.1 kg versus 3.1 +/- 3.5 kg; p = 0.001) and net fluid loss (4.6 versus 3.3 L; p = 0.001) were greater in the UF group.  Dyspnea scores were similar.  At 90 days, the UF group had fewer patients re-hospitalized for HF (16 of 89 [18 %] versus 28 of 87 [32 %]; p = 0.037), HF re-hospitalizations (0.22 +/- 0.54 versus 0.46 +/- 0.76; p = 0.022), re-hospitalization days (1.4 +/- 4.2 versus 3.8 +/- 8.5; p = 0.022) per patient, and unscheduled visits (14 of 65 [21 %] versus 29 of 66 [44 %]; p = 0.009).  No serum creatinine differences occurred between groups.  Nine deaths occurred in the UF group and 11 in the diuretics group.  The authors concluded that in patients with decompensated HF, peripheral UF safely produces greater weight and fluid loss than intravenous diuretics, reduces 90-day resource utilization for HF, and is an effective alternative therapy.

In an editorial that accompanied the afore-mentioned study, Elkayam et al (2007) stated that "[t]he use of this therapy should be considered early in patients not responding to intravenous diuretics and vasoactive medications and in patients in whom such therapy is discontinued or reduced because of worsening of renal function or other drug-induced complications".  Furthermore, Guglin and Polavaram (2007) stated that managing volume over-load is essential for the treatment of symptomatic HF.  Traditionally, it is achieved via oral and intravenous diuretics.  Alternatively, the excess fluid can be removed via UF.  Advent in technology has made UF more feasible than before for routine clinical practice.  Zevitz (2006) stated that patients with HF who are fluid over-loaded should be treated with diuretics, or, if necessary in patients with renal failure, hemodialysis with UF.

In contrast, in an editorial regarding the efficacy of vasopressin antagonism in heart failure outcome study with tolvaptan (EVEREST) clinical trials program, Yancy (2007) noted that UF represents at best an emerging technology with intriguing preliminary data but limited applications.

There is also a lack of consensus among several specialty societies and a technology assessment agency regarding the clinical value of peripheral UF in the treatment of patients with ADHF.  The European Society of Cardiology Task Force's guidelines on the diagnosis and treatment of acute HF (Dickstein et al, 2008) stated that ultrafiltration should be considered to reduce fluid overload in selected patients, and to correct hyponatremia in symptomatic patients that are refractory to diuretics.  The guidelines noted, however, that the appropriate selection criteria for UF have not been established.  The Heart Failure Society of America's guidelines on evaluation and management of patients with ADHF (2006) stated that when congestion fails to improve in response to diuretic therapy, UF may be considered (strength of evidence = C [expert opinion, observational studies, epidemiologic findings, safety reporting from large-scale use in practice]).  Furthermore, the Institute for Clinical Systems Improvement's guidelines on HF in adults (2006) noted that patients with persistent volume over-load may be candidates for continuous intravenous diuretics, UF, or hemodialysis (all out of guideline).

On the other hand, a technology assessment on peripheral UF for the management of ADHF by the California Technology Assessment Forum (CTAF, 2007) concluded that the use of peripheral UF does not meet Technology Assessment Criterion 3, 4 and 5 for safety, effectiveness and improvement in health outcomes when used to treat ADHF.  The CTAF assessment also discussed a number of methodological issues regarding the study by Costanzo et al (2007).  These issues include a lack of blinding for patients, investigators, staff, or those evaluating and adjudicating outcomes as well as inadequate reporting of recruitment and follow-up.  Furthermore, data for the primary endpoints (weight loss at 48 hours and dyspnea scores at 48 hours) were only available on 80 % to 84 % of the patients randomized.  This high rate of incomplete data 48 hours after randomization in a hospitalized patient population was not explained by the researchers.  Also, patients studied in this trial did not meet the FDA indication for peripheral UF as they had not previously failed diuretic therapy.  The authors of the CTAF assessment noted that the benefits of peripheral UF remain to be proven; and the findings by Costanzo et al (2007) need to be replicated before they can be accepted with confidence.

The McGill University Health Center Technology Assessment Unit (Pan and Dendukuri, 2010) found that there is sufficient evidence to conclude that UF is an effective technology for the management of ADHF, and is the method of choice when patients have become resistant to diuretics or have developed secondary renal failure.  The assessment found limited evidence that UF may have long-term health benefits including improved exercise performance for up to 3, and possibly 6 months, and that these effects are associated with a reduction in re-hospitalization rates.

An assessment of UF for HF by the Veterans Health Administration Technology Assessment Program (Flynn, 2010) found no recently published evidence to materially change conclusions from a previous report by the Centre for Evidence-based Purchasing (CEP) of the UK National Health Services, which found: “CEP finds that UF has significant potential to become a routine therapy for excess fluid removal in patients with CHF.  However, further work is needed to establish the patient groups who would benefit most, the optimal rates of fluid removal, the conditions for termination of therapy, and the cost savings associated with long-term quality of life benefits.”

The VATAP report stated that these conclusions can be transferred to the United States in 2010 (Flynn, 2010).  Additional shortcomings of the available literature include those elaborated by the CEP report: lack of blinding, which may be understandably difficult in the case of a bulky bedside device; lack of explicit power calculations and correspondingly small numbers of patients in clinical trials, which may reflect the relative lack of reliable estimates of clinically significant effects for UF in available research on which such calculations would be based; lack of follow-up beyond 2 to 3 months; reliance on intermediate or surrogate outcomes such as fluid volume removed or weight lost, rather than longer term outcomes such as quality of life or HF-specific mortality.  The VATAP report noted that the device manufacturer is a significant presence in the only published (Costanzo et al, 2007; Costanzo et al, 2010) and ongoing trials.  The VATAP report found that systematic reviews and assessments do not report significant adverse events or safety concerns with ultrafiltration for HF, but studies may not have been adequately powered or followed patients for long enough to detect uncommon adverse events.  Post-marketing surveillance for a device only available since late 2006 may also be inadequate for detecting uncommon or late adverse events.  The VATAP report notes that kidney dysfunction with over-zealous volume reduction has been observed and is under investigation for UF.

The American College of Cardiology/American Heart Association's updated guidelines on the diagnosis and management of chronic HF in adults (Hunt et al, 2005) did not discuss the use of peripheral UF as a therapeutic option for patients at various stages of HF.  Similarly, the National Heart Foundation of Australia/the Cardiac Society of Australia and New Zealand's guidelines on the prevention, detection and management of chronic HF (2006) did not address the use of peripheral UF as a therapeutic option.

The potential for peripheral UF devices to normalize underlying cardiac function and thus improve long-term clinical outcomes in patients with ADHF needs to be further investigated.

Fiaccadori et al (2011) stated that fluid over-load is a key pathophysiologic mechanism underlying both the acute decompensation episodes of HF and the progression of the syndrome.  Moreover, it represents the most important factor responsible for the high re-admission rates observed in these patients and is often associated with renal function worsening, which by itself increases mortality risk.  In this clinical context, UF has been proposed as an alternative to diuretics to obtain a quicker relief of pulmonary/systemic congestion.  These researchers reviewed technical issues, mechanisms, efficacy, safety, costs, and indications of UF in HF.  The available evidence does not support the widespread use of UF as a substitute for diuretic therapy.  Owing to its operative characteristics, UF can not be expected to directly influence serum electrolyte levels, azotemia, and acid-base balance, or to remove high-molecular-weight substances (e.g., cytokines) in clinically relevant amounts.  Ultrafiltration should be used neither as a quicker way to achieve a sort of mechanical diuresis nor as a remedy for an inadequately prescribed and administered diuretic therapy.  Instead, it should be reserved to selected patients with advanced HF and true diuretic resistance, as part of a more complex strategy aiming at an adequate control of fluid retention.

Bart et al (2012) stated that UF is an alternative strategy to diuretic therapy for the treatment of patients with ADHF.  Little is known about the safety and effectiveness of UF in patients with ADHF complicated by persistent congestion and worsened renal function.  These researchers randomly assigned a total of 188 patients with ADHF, worsened renal function, and persistent congestion to a strategy of stepped pharmacologic therapy (94 patients) or UF (94 patients).  The primary end-point was the bivariate change from baseline in the serum creatinine level and body weight, as assessed 96 hours after random assignment.  Patients were followed for 60 days.  Ultrafiltration was inferior to pharmacologic therapy with respect to the bivariate end-point of the change in the serum creatinine level and body weight 96 hours after enrollment (p = 0.003), owing primarily to an increase in the creatinine level in the UF group.  At 96 hours, the mean change in the creatinine level was -0.04 ± 0.53 mg/dL (-3.5 ± 46.9 μmol/L) in the pharmacologic-therapy group, as compared with +0.23 ± 0.70 mg/dL (20.3 ± 61.9 μmol/L) in the UF group (p = 0.003).  There was no significant difference in weight loss 96 hours after enrollment between patients in the pharmacologic-therapy group and those in the ultrafiltration group (a loss of 5.5 ± 5.1 kg [12.1 ± 11.3 lb] and 5.7 ± 3.9 kg [12.6 ± 8.5 lb], respectively; p = 0.58).  A higher percentage of patients in the UF group than in the pharmacologic-therapy group had a serious adverse event (72 % versus 57 %, p = 0.03).  The authors concluded that in a randomized trial involving patients hospitalized for ADHF, worsened renal function, and persistent congestion, the use of a stepped pharmacologic-therapy algorithm was superior to a strategy of UF for the preservation of renal function at 96 hours, with a similar amount of weight loss with the two approaches.  Ultrafiltration was associated with a higher rate of adverse events.

Wen and colleagues (2013) compared the safety and effectiveness of UF and conventional intravenous diuretic therapy for patients with acute HF and volume overload.  These investigators searched the following databases through November 2012: Cochrane Library (1993-), PubMed (1988-), OVID (1984-), EBSCO (1984-), CBM (1978-), VIP (1989-), and CNKI (1979-).  In addition, they manually searched relevant references and review articles.  Randomized controlled trials comparing the effectiveness of UF and intravenous diuretics in patients diagnosed with hypervolemic acute HF were included.  Five trials were found to satisfy all the inclusion criteria.  Two reviewers independently determined study eligibility, assessed methodological quality and extracted the data.  They analyzed the data and pooled them, when appropriate, using Revman 5.0.  They assessed the risk of bias in the included studies using guidelines in the Cochrane Handbook 5.0 for Systematic Reviews of Interventions, taking into account sequence generation, allocation concealment, blinding, incomplete outcome data, and selective outcome reporting.  Data from the initial phase of five trials involving 477 participants were included.  Meta-analysis of the pooled data showed that UF was significantly better than diuretic drugs based on 48-hr weight loss (Z = 3.72; p < 0.001, weighted mean difference [WMD] = 1.25 kg, 95 % confidence interval [CI]: 0.59 to 1.91) and based on 48-hr fluid removal (Z = 4.23; p < 0.001, WMD = 1.06 L, 95 % CI: 0.57 to 1.56).  Adverse events did not differ significantly between the UF and intravenous diuretic treatment groups.  The authors concluded that the available evidence suggested that early UF is safe and effective for patients with hypervolemic acute HF.  It allows greater fluid removal and weight loss by 48 hours than do intravenous diuretics, with no significant increase in adverse effects.

De Vecchis et al (2014) compared intravenous diuretics versus isolated ultrafiltration (IUF) regarding their respective safety and effectiveness in ADHF patients through systematic review and meta-analysis of data derived from relevant randomized controlled trials.  A total of 6 studies (477 patients) were included in the systematic review.  By contrast, data from only 3 studies were pooled for the meta-analysis, because of different adopted outcomes or marked dissimilarities in the data presentation.  Weight loss at 48 hours was greater in IUF group compared to the diuretics group [weighted mean difference (WMD) = 1.77 kg; 95 % confidence interval [CI]: 1.18 to 2.36 kg; p < 0.001)].  Similarly, greater fluid loss at 48 hours was found in IUF group in comparison with diuretics group (WMD = 1.2 L; 95 % CI: 0.73 to 1.67 L; p < 0.001).  In contrast, the probability of exhibiting worsening renal function (WRF), i.e., increase in serum creatinine greater than 0.3 mg/dL at 48 hours, was similar to the one found in the diuretics group (OR = 1.33; 95 % CI: 0.81 to 2.16 p = 0.26).  The authors concluded that on the basis of this meta-analysis, IUF induced greater weight loss and larger fluid removal compared to iv diuretics in ADHF patients, whereas the probability of developing WRF was not significantly different in the comparison between intravenous diuretics and IUF.

The National Institute for Health and Care Excellence’s clinical guideline on “Acute heart failure: Diagnosing and managing acute heart failure in adults” (NICE, 2014) stated that “Do not routinely offer ultrafiltration to people with acute heart failure. Consider ultrafiltration for people with confirmed diuretic resistance. Diuretic resistance is defined as dose escalation beyond a person's previously recognized dose ceiling or a dose approaching the maximum recommended daily dose without incremental improvement in diuresis”.

Ebrahim et al (2015) noted that although diuretics are mainly used for the treatment of ADHF, inadequate responses and complications have led to the use of extracorporeal UF as an alternative strategy for reducing volume overloads in patients with ADHF. These investigators performed meta-analysis of the results obtained from studies on extracorporeal venous UF and compared them with those of standard diuretic treatment for overload volume reduction in ADHF. MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials databases were systematically searched using a pre-specified criterion. Pooled estimates of outcomes after 48 hours (weight change, serum creatinine level, and all-cause mortality) were computed using random effect models. Pooled weighted mean differences were calculated for weight loss and change in creatinine level, whereas a pooled risk ratio was used for the analysis of binary all-cause mortality outcome. A total of 9 studies, involving 613 patients, met the eligibility criteria. The mean weight loss in patients who underwent UF therapy was 1.78 kg [95 % CI: -2.65 to -0.91 kg; p < 0.001) more than those who received standard diuretic therapy. The post-intervention creatinine level, however, was not significantly different (mean change = -0.25 mg/dL; 95 % CI: -0.56 to 0.06 mg/dL; p = 0.112). The risk of all-cause mortality persisted in patients treated with UF compared with patients treated with standard diuretics (pooled RR = 1.00; 95 % CI: 0.64 to 1.56; p = 0.993). The authors concluded that compared with standard diuretic therapy, UF treatment for overload volume reduction in individuals suffering from ADHF, resulted in significant reduction of body weight within 48 hours. However, no significant decrease of serum creatinine level or reduction of all-cause mortality was observed.

Peritoneal Ultrafiltration as an Adjunctive Therapy in End-Stage Heart Failure

Heart failure (HF) is a major cause of morbidity and mortality. Extracorporeal (EC) therapy, including ultrafiltration (UF) and hemodialysis (HD), peritoneal dialysis (PD) and peritoneal ultrafiltration (PUF) are potential therapeutic options in diuretic-resistant states. Cionh et al (2020) conducted a systematic review to assess outcomes of PD and compared the effects of PD to EC. A comprehensive search of major databases from 1966 to 2017 for studies utilizing PD (or PUF) in diuretic-resistant HF was conducted, excluding studies involving patients with end-stage kidney disease. Data were extracted and combined using a random-effects model, expressed as odds ratio (OR). Thirty-one studies (n = 902) were identified from 3195 citations. None were randomized trials. Survival was variable (0 to 100%) with a wide follow-up duration (36 hours to 10 years). With follow-up greater than 1 year, the overall mortality was 48.3%. Only four studies compared PD with EC. Survival was 42.1% with PD and 45.0% with EC; the pooled effect did not favor either (OR 0.80; 95% confidence interval (CI): 0.24-2.69; p = 0.710). Studies on PD in patients with HF reported several benefits. Left ventricular ejection fraction (LVEF) improved after PD (OR 3.76, 95%CI: 2.24-5.27; p < 0.001). Seven of nine studies saw LVEF increase by greater than 10%. Twenty-one studies reported the New York Heart Association status and 40% to 100% of the patients improved by 1 or more grades. Nine of 10 studies reported reductions in hospitalization frequency and/or duration. When treated with PD, HF patients had fewer symptoms, lower hospital admissions and duration compared to diuretic therapy. However, there is inadequate evidence comparing PD versus UF or HD. Further studies comparing these modalities in diuretic-resistant HF should be conducted.

Grossekettler and colleagues (2020) noted that peritoneal ultrafiltration (pUF) in refractory HF reduces the incidence of decompensation episodes, which is of particular significance as each episode incrementally adds to mortality.  Nevertheless, there are insufficient data regarding which patient cohort benefits the most.  These researchers compared pUF in HF with reduced left ventricular ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF), focusing on functional status, hospitalizations, surrogate end-points and mortality.  This study entailed 143 patients, who could be classified as either HFpEF (n = 37, 25.9 %) or HFrEF (n = 106, 74.1 %) and who received pUF due to refractory HF.  Baseline eGFR was similar in HFrEF (23.1 ± 10.6 mg/dL) and HFpEF (27.8 ± 13.2 mg/dL).  Significant improvements in NYHA class were found in HFpEF (3.19 ± 0.61 to 2.72 ± 0.58, p < 0.001) and HFrEF (3.45 ± 0.52 to 2.71 ± 0.72, p < 0.001).  C-reactive protein (CRP) decreased in HFrEF (19.4 ± 17.6 mg/L to 13.7 ± 21.4 mg/L, p = 0.018) and HFpEF (33.7 ± 52.6 mg/L to 17.1 ± 26.3 mg/L, p = 0.004).  Body weight was significantly reduced in HFrEF (81.1 ± 14.6 kg to 77.2 ± 15.6 kg, p = 0.003) and HFpEF (86.9 ± 15.8 kg to 83.1 ± 15.9 kg, p = 0.005).  LVEF improved only in HFrEF (25.9 ± 6.82 % to 30.4 ± 12.2 %, p = 0.046).  BCR decreased significantly in HFrEF and HFpEF (55.7 ± 21.9 to 34.3 ± 17.9 p > 0.001 and 50.5 ± 68.9 to 37.6 ± 21.9, p = 0.006).  Number of hospitalization episodes as well as number of hospitalization days decreased significantly only in HFpEF (total number 2.88 ± 1.62 to 1.25 ± 1.45, p < 0.001, days 40.4 ± 31.7 to 18.3 ± 22.5 days, p = 0.005).  The authors concluded that pUF offered various benefits in HFpEF and HFrEF, however, there were also substantial differences.  In particular, hospitalization rates were found to be significantly reduced in HFpEF patients, indicating a greater medical and economical advantage.  However, LVEF was only found to be improved in HFrEF patients.  These researchers stated that the findings of this study warrant larger controlled studies to elaborate the differential effects of pUF as an adjunct palliative therapy in end-stage HF.

The authors stated that this study had several drawbacks.  This study had a relatively small patient cohort, while cardio-renal patients were included from 18 different centers.  Thus, this all-comers population may have resulted in a highly heterogeneous collective that did not allow the exclusion of potential biases.  Furthermore, the fact that pUF patients received a rather close monitoring might have resulted in an improved outcome on its own.

Modified Ultrafiltration During Pediatric Cardiac Surgery

In a systematic review, Xing et al (2010) examined the safety and effectiveness of modified UF (MUF) during pediatric cardiac surgery.  These researchers identified relevant studies via electronic searches of the Cochrane Library (Issue 2, 2009), PubMed (1991 to April 2009), Embase (1991 to April 2009), China National Knowledge Infrastructure (CNKI, 1994 to April 2009), VIP (1991 to April 2009) and China Biomedicine Database (CBM, 1991 to April 2009), with the languages limited in English and Chinese.  In strict accordance with the inclusion and exclusion criteria of the studies, 2 independent researchers examined the quality of the included studies.  Meta-analysis of the studies was carried out using RevMan5.0 software, and the studies that could not be combined was analyzed descriptively.  A total of 9 studies involving 587 patients were included.  The results showed that compared with the group without UF, the MUF group was superior in duration of post-operative mechanical ventilation [MD = -3.66, 95 % CI: -6.02 to -1.29, p = 0.002] and showed no significant differences from the conventional UF group [MD = -3.21, 95 % CI: -6.90 to 0.49, p = 0.09].  Compared with balanced UF group, the mechanical ventilation time, intensive care unit (ICU) monitoring time and the results of chest drainage in children were similar.  Compared with the group receiving conventional or balanced UF alone, the combined group of MUF had similar ventilation time [MD = -2.34, 95 % CI: -6.74 to 2.07, p = 0.30] and ICU time [MD = -0.12, 95 % CI: -0.31 to 0.06, p = 0.19].  The included studies reported no UF-related complications.  The authors concluded that MUF improved the clinical outcomes of patients undergoing cardiopulmonary bypass (CPB) during pediatric cardiac surgery; however, the current evidence has not been sufficient to support the notion that the MUF achieved better clinical results than conventional UF (CUF) or balanced UF (BUF).

In a prospective, single-center, randomized controlled trial (RCT), Zhou et al (2013) examined the effectiveness of a combined UF strategy on the surgical treatment of pediatric patients with congenital heart diseases.  A total of 65 pediatric patients who underwent open heart surgery with CPB to treat congenital heart disease were enrolled.  Subjects were randomized into 2 groups: CUF + MUF (CM group) and prime + zero-balanced + MUF (PZM group).  In the CM group (n = 33), CUF was carried out after removal of the aortic clamp, and MUF was carried out after the completion of CPB.  In the PZM group (n = 32), UF was carried out for the circuit prime solution, zero-balance UF was carried out after removal of the aortic clamp, and MUF was carried out after the completion of CPB.  The blood gas parameters and tumor necrosis factor alpha (TNF-α) content in the priming solution and peri-operative blood samples were analyzed.  In addition, post-operative parameters, including mechanical ventilation time, respiratory indices, ICU time, and hospital time, were recorded; 1 hospital death occurred in each group.  No severe complications occurred in either group.  The lactic acid, glucose, and TNF-α contents in the priming solution and peri-operative blood samples were significantly lower in the PZM group compared with the CM group.  The respiratory indices were statistically significantly better in the PZM group compared with the CM group in the early post-operative period.  No significant differences were observed between the 2 groups regarding the post-operative ventilation time, inotropic support, homologous blood transfusion, drainage, ICU time, or post-operative hospital time.  The authors concluded that the combined use of UF of prime solution, zero-balance UF, and MUF strategy was associated with a modest improvement in pulmonary function compared with the combination of CUF and MUF strategies in the early post-operative period; however, the principal clinical outcomes were similar.

In a meta-analysis, Hu et al (2021) examined the effects of the addition of MUF and CUF to CUF alone on post-operative hemoglobin (Hb), surgical, and UF data, as well as post-operative clinical outcomes in pediatric patients undergoing cardiac surgery.  These investigators carried out a systematic search to identify RCTs that compared MUF and CUF combination with CUF alone in pediatric cardiac surgery undergoing CPB in PubMed, Embase, Cochrane Library, and Web of Science without any language or date limitation in February 2020.  For each included study, the primary outcomes including post-CPB and post-operative hematocrit (Hct), surgical and UF data, post-operative clinical outcomes including volume of chest tube drainage within 48 hours after surgery and peri-operative blood requirement, ventilation support duration, and length of stay (LOS) in the ICU and hospital were collected and analyzed.  The analysis was conducted using STATA version 12.0.  A total of 8 studies totaling 405 patients were included in this meta-analysis.  The results indicated that MUF + CUF increased the post-CPB Hct (standard MD [SMD] = 1.85, 95 % CI: 0.91 to 2.79).  Meanwhile, UF volume was higher in CUF+MUF infants than CUF-alone infants (SMD = 1.46, 95 % CI: 0.51 to 2.41, p = 0.003).  The clinical outcomes, including post-operative hemodynamic changes, prime volume, blood requirement, chest tube drainage volume, mechanical ventilation duration, and LOS I the ICU, were unclear because of the unstable sensitivity analyses.  The authors reported beneficial effects of using MUF and CUF for pediatric cardiac surgery, including increase post-CPB Hct and UF volume when compared with CUF alone.  Meanwhile, MUF and CUF did not significantly influence the post-operative hospital LOS duration, CPB, and aortic occlusion duration.

Walczak et al (2021) stated that new CPB device techniques emerge and were reported in the scientific literature.  The extent to which they are actually adopted into clinical practice is unclear.  Since 1989, these investigators have periodically surveyed pediatric cardiac centers to determine practice patterns.  In December 2016, a 186-question perfusion survey was distributed to pediatric cardiac surgery centers globally using a Web-based survey tool.  Responses were received from 93 North American (NA) centers (the U.S. and Canada) and 67 non-NA (NNA) centers, representing 19,645 cumulative annual procedures in NA and 27,776 in NNA centers on patients less than 18 years of age.  Wide variation in practice was evident across geographic regions.  However, the most common pediatric circuit consisted of a hard-shell (open) venous reservoir, an arterial roller pump, and a hollow-fiber membrane oxygenator with a separate or integrated arterial filter.  Compared with previous surveys, there was increased use of all types of safety devices.  The use of an electronic perfusion record was reported by 50 % of NA centers and 31 % of NNA centers.  There was wide regional variation in cardioplegia delivery systems and cardioplegia solutions.  A total of 79 % of the centers reported the use of some form of MUF.  The authors concluded that the survey showed that there remained variation in perfusion practice for pediatric patients.

Walczak et al (2022) noted that the use of CPB in neonatal, infant, and pediatric patients continuously evolves as new devices and innovative techniques were introduced.  Since 1989, periodic pediatric perfusion surveys have been carried out to determine practice patterns involving demographics, equipment, and perfusion techniques.  The objective of this study was to provide an updated perspective on international pediatric and congenital perfusion practice since the last survey conducted in 2016.  In July 2021, a 100-question perfusion survey was distributed to 284 pediatric cardiac surgery centers using a secure Web browser-based data application.  Each center was given a unique survey hyperlink to ensure 1 response per institution and to monitor the response rate.  Centers were given 1 month to complete the survey and electronic reminders were sent weekly to non-respondents.  After the survey was closed, information from completed surveys was exported to a software program for analysis.  Responses were received from 153 of 284 pediatric centers for a response rate of 54 %.  A total of 60 respondents (39 %) were from NA centers, and 93 respondents (61 %) were from NNA centers.  The vast majority of centers use a roller head arterial pump (93 %), hollow fiber oxygenators with open reservoirs (86 %), and integrated arterial line filters (73 %).  The use of MUF was reported by 76 % of centers; and 92 % of centers reported the use of selective antegrade cerebral perfusion for aortic arch repairs.  The N + 1 staffing model was most prevalent (52 %), followed by 2 perfusionists per case (33 %).  The authors concluded that periodic surveys continue to be a useful modality in assessing regional variation in pediatric perfusion practice.  This survey marked the 1st time the majority of responses came from NNA institutions. 

Bierer et al (2022) stated that the use of CPB could be associated with significant hemodilution, coagulopathy, and a systemic inflammatory response syndrome (SIRS) for infants and children undergoing cardiac surgery.  Intra-operative UF has been employed for many years to ameliorate these harmful effects.  The authors described an advanced intra-operative UF technique, subzero balance simple MUF (SBUF-SMUF), a combination of continuous and non-continuous form of UF.  These investigators stated that the continuous SBUF component is used during the entire CPB time and precisely targets a slight negative volume balance during the CPB time as an optimal peri-operative perfusion strategy.  This approach avoids inaccurate “eye-balling” of fluid balance.  The adjustable control of SBUF volume infusion rate and UF effluent rate by Braun Infusomat Space pumps allows for individualized weight standardization; thus, could be safely applied to a range of neonatal and pediatric patients.  After separation from CPB, this UF circuit configuration allowed for efficient and effective transition from SBUF to SMUF.  Physical alterations to the CPB manifold are completely avoided.  The authors concluded that SBUF-SMUF could be safely and efficiently implemented to optimize the inflammatory, coagulation and volume parameters for infants and children undergoing open-heart surgery with CPB.

Palanzo et al (2023) stated that MUF is used at the termination of CPB in pediatric and neonatal patients undergoing congenital heart surgery to reduce the accumulation of total body water; thereby, increasing the concentration of RBCs and the other formed elements in the circulation.  MUF has been reported to remove circulating pro-inflammatory mediators that result in SIRS post-operatively.  A total of 400 patients undergoing cardiac surgery requiring CPB and weighing less than or equal to 12 kg were retrospectively examined for the effectiveness of MUF.  After the termination of CPB, blood was withdrawn via the aortic cannula and passed through a hemo-concentrator attached to the blood cardioplegia set and returned to the patient via the venous cannula.  The entire CPB circuit volume in addition to the patient's circulating blood volume were concentrated until the Hct value displayed on the CDI 500 Blood Parameter Monitor within the MUF circuit reached 45 % or there was no more volume to safely remove.  At the same time, a full unit of fresh frozen plasma (FFP) could be infused as water was being removed; thus, maintaining euvolemia.  MUF was carried out in all 400 patients with no MUF-related complications.  Following the conclusion of MUF, anecdotal observations included improved surgical hemostasis, improved hemodynamic parameters, decreased transfusion requirements, and decreased ventilator times.  The authors concluded that complete MUF allowed the clinician to safely raise the post-CPB Hct to at least 40 % while potentially removing mediators that could result in SIRS.  Furthermore, a full unit of FFP could be administered while maintaining euvolemia.

An UpToDate review on “Blood management and anticoagulation for cardiopulmonary bypass” (Ghadimi and Welsby, 2024) lists UF as one of the strategies to minimize excessive hemodilution before and during CPB.

The American Association of Thoracic Surgery’s primer on “Cardiopulmonary bypass” (Shah, 2024) stated that “Despite miniaturization of CPB circuits, the priming volume can be many times the blood volume of the patient.  This leads to an increase in total body water and subsequent peripheral, pulmonary, visceral, and cerebral edema.  Aggressive diuresis, ultrafiltration on CPB, and modified ultrafiltration (MUF) have been used to manage the increase in total body water.  In addition to removal of excess water, ultrafiltration potentially decreases the circulating levels of inflammatory mediators.  Continuous ultrafiltration can be achieved through the pump while on CPB.  MUF is performed after weaning from CPB but prior to removal of the cannulas.  A right atrial cannula (typically the previously removed vent) is placed.  Blood is removed from the venous cannula, circulated through the ultrafiltration filter (where it is hemo-concentrated), and returned to the patient through the right atrial cannula”. 

Cardio-Renal Syndrome

Xu et al (2025) stated that due to the typical exclusion of very elderly patients from clinical trials, the applicability of trial results to this population with HF remains uncertain.  Limited data exist regarding the safety and effectiveness of UF in the elderly with type 1 cardio-renal syndrome (CRS).  In a prospective, pilot study, these researchers compared the safety and effectiveness of UF versus diuretics, providing evidence-based insights into the optimal management strategy for elderly with type 1 CRS.  This trial enrolled patients aged over 70 years old with type I CRS; they were treated with either diuretics or UF.  All participants were followed-for up to 180 days post-discharge.  Effectiveness outcomes entailed both immediate measures (changes in weight and dyspnea score from baseline to 48 hours post-treatment) as well as long-term stability indicators (hospital LOS and HF-related medical visits within 180 days post-discharge).  Safety outcomes were assessed in both groups, focusing on changes in systolic blood pressure (SBP), heart rate (HR), serum creatinine, blood urea nitrogen (BUN), blood potassium, and sodium ion concentrations, bleeding or thrombo-embolic events, as well as major adverse cardiovascular events (MACE).  A total of 159 patients with type I CRS were enrolled, with 80 receiving diuretics and 79 undergoing UF.  The mean age was 82.1 ± 5.8 years.  At 48 hours, patients in the UF group showed significantly greater weight loss and improvements in dyspnea score compared to those in the diuretic group (p < 0.05).  In addition the UF group had shorter hospital LOS and fewer medical visits for HF within 180 days post-discharge (p < 0.05).  Notably, there were no statistically significant differences in safety outcomes between the 2 groups, indicating comparable safety profiles.  The authors concluded that UF showed superior effectiveness with comparable safety profiles compared to diuretics; thus, UF may be considered a preferred therapeutic option for elderly patients with type I CRS.  Moreover, these researchers stated that further investigations with larger, multi-center studies with longer follow-up durations are needed to examine the potential role of UF in the management of CRS.

The authors stated that this trial had several drawbacks, including a small sample size (n = 79 in the UF group) and the assessment of only short-term effectiveness.  Furthermore, outcomes such as ejection fraction (EF), B-type natriuretic peptide (BNP) levels, were not evaluated, limiting the study’s comparability with other literature.  Based on these promising findings, these researchers intend to examine the long-term effectiveness of UF in future studies.  In addition, as this study only included elderly patients, the safety and effectiveness results may not be generalizable to other geographic regions.  Nonetheless, UF showed superior effectiveness in patients with type 1 CRS compared to conventional therapy.

Furthermore, an UpToDate review on “Cardiorenal syndrome: Prognosis and treatment” (Kiernan et al, 2025) states that “[A]lthough ultrafiltration may be helpful for fluid removal in acute decompensated HF in patients unresponsive to diuretic therapy, the available evidence does not establish ultrafiltration as first line therapy for acute decompensated HF or as an effective therapy for CRS”.

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References