1. Ultrafiltration as a Therapy Option for Diuretic Resistance: Inpatient & Outpatient Case Studies
Beth Davidson DNP, ACNP, CCRN Kristi Hayes MSN, FNP St. Thomas Hospital Nashville, TN

2. Objectives
Review the epidemiology and pathophysiology of diuretic-resistant, acute heart failure
Identify volume overload treatment options
Review/discuss case studies of diuretic-resistance and use of ultrafiltration for volume removal

3. Epidemiology of Heart Failure (HF)
Section 1: Epidemiology and Demographics
Epidemiology of Heart Failure (HF)
Population Group
Prevalence
Incidence
Mortality
Hospital Discharges
Cost
Total population
5,000,000
550,000
57,218
1,093,000
$29.6 billion
Heart failure is a major public health problem resulting in substantial morbidity and mortality
Major cost-driver of HF is high incidence of hospitalizations
JCAHO has initiated quality care indicators for hospitalized HF patients
CMS reimbursement for readmission < 30 days = $ 0
Since the 1980s there has been a staggering increase in hospital discharges for heart failure (HF), and it is now the most common reason for hospitalization in the elderly.1
HF is a progressive disease associated with high rates of morbidity and mortality—indeed,
the natural history is for this disease to progress over time. Even patients with entirely
asymptomatic left ventricular dysfunction have an annual mortality rate that is not
insignificant. As patients’ symptoms progress and left ventricular dysfunction worsens, the
annual mortality rate becomes even higher. Additionally, HF patients face both progressive
HF and sudden death. By understanding the mechanisms behind the progression of HF, the therapeutic approach for this disease can be better delineated.
Some facts:
Most frequent cause of hospitalization over the age of 65, with a prevalence of 5 million people in the United States.2
1 million patients hospitalized every year with HF as a primary diagnosis, and 2 million hospitalized every year with HF as a secondary diagnosis.2
It is the single largest expense for Medicare—at about 28 billion dollars—with the major cost-driver of HF being high incidence of hospitalizations.2
In 1996, there were 4.8 million cases, with 400,000 new cases each year. There are million cases in the US alone by the year
The Joint Commission on Accreditation of Healthcare Organizations (JCAHO) has initiated
HF quality care indicators for hospitalized HF patients.
References:
Topol E, Califf RM, Isner J, et al. Textbook of Cardiovascular Medicine. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2006;
American Heart Association 2005.

4. Fluid Overload Symptoms
Decompensated
Heart Failure
Section 2: Pathophysiology of Acute Decompensated Heart Failure
Insult
Cardiac Dysfunction
LV Remodeling
Neurohormonal
Activation
 RAAS/SNS
 Catecholamine
 Endothelin
Hemodynamic
Decompensation
 Preload
 Afterload
↓ Cardiac Output
REVISED
I CHANGED THIS ONE. MAKE SURE IT LOOKS OK BEFORE DELETING THE OTHER ONE, SLIDE 4
Colucci WS, Braunwald E. Heart Disease: A Textbook of Cardiovascular Medicine. 5th ed. 1997:394.
This diagram shows the relationship between the primary myocardial insult and subsequent events that contribute to the clinical syndrome of CHF.1 The pathophysiology of HF involves hemodynamic abnormalities, neurohumoral abnormalities, and myocardial cellular alterations. Left ventricular (LV) dysfunction results from myocardial injury. Neurohumoral activation, which includes activation of the sympathetic nervous system (SNS) and the renin-angiotensin-aldosterone system (RAAS), occurs in response to acute hemodynamic alterations and myocardial injury. This neurohumoral activation is counterproductive in patients with HF. Changes occur in cardiac function and peripheral circulation that contribute to the symptoms and drive the progression of HF.
Neurohumoral activation results in an excess of vasoconstrictors—those in the SNS and the RAAS, as well as endothelin—which increase afterload and preload by retention of salt and water. Vasodilators—hormones in the endogenous natriuretic peptide system (NPS)—work to unload the left ventricle and promote natriuretic actions, but they are overwhelmed by the excess of vasoconstricting neurohomones. Vasodilators are ultimately beneficial counterregulatory hormones.2-4
Neurohumoral activation results in progressive dilation and dysfunction of the left ventricle (remodeling). There are also fundamental abnormalities at the cellular level, including myocyte dysfunction, programmed cell death (apoptosis), fetal gene expression, hypertrophy, and myocardial fibrosis.5 Other circulating proinflammatory cytokines, such as interleukin-6 and TNF-alpha, can lead to a progressive wasting of lean tissue, fat, and bone mass.4 Based on this model, hemodynamic decompensation and neurohormonal activation may give rise to either acute impairment of LV function or chronic progression of disease, or both, in a vicious cycle.
References:
Colucci WS, Braunwald E. In: Braunwald E, ed. Heart Disease: A Textbook of Cardiovascular Medicine. 5th ed. Philadelphia: Saunders; 1997:
Stevenson W. J Am Coll Cardiol. 2005;45:
Weber. J Am Coll Cardiol. 2004:44(6):
Anker et al. Am J Cardiol. 1999;83:
Shah M et al. Rev Cardiovasc Med. 2001;2(suppl 2):S2-S6.
Fluid Overload Symptoms
Morbidity
Death
Renal Vasoconstriction/
Fluid Retention

5. ACC/AHA Guidelines: Management of Fluid Status
Patients should not be discharged from the hospital until a stable and effective diuretic regimen is established, and ideally, not until euvolemia is achieved
Patients who are sent home before these goals are reached are at high risk of recurrence of fluid retention and early readmission because unresolved edema may itself attenuate the response to diuretics

6. Diuretics Current “Standard of Care” Diuretics… Still more diuretics…

7. Change in Weight During Hospitalization Outcomes with Standard Care
Evidence of Incomplete Relief From Congestion
Nearly 50% of ADHF patients discharged with weight gain or losing less than 5 lbs
27% 30 25
26% 20
Enrolled Discharges (%) 15
13%
16% 7% 6% 10
Adhere National Benchmark Report Data, January 2001 to April 2006
Despite the use of diuretics in 90% of patients, 20% gain weight on discharge
Note: n represents the number of patients who have both baseline and discharge weight, and the percentage is calculated based on the total patients in the corresponding population. Patients without baseline or discharge weight are omitted from the histogram calculations. 3% 2% 5
(<-20)
(–20 to –15)
(-15 to –10)
(–10 to –5)
(–5 to 0)
(0 to 5)
(5 to 10)
(>10)
Change in Weight (lbs)

8. Outcomes with Standard Care
Hospital Readmissions
Mortality
50%
50%
33%
37%
20%
12%
Fonarow, GC. Rev Cardiovasc Med. 2002;3(suppl 4):S Jong P et al. Arch Intern Med. 2002;162:1689
Rudiger et. al. Eur J Heart Fail 7:662– O’Connor CM. JCF 2005;11:3:
Setoguchi S et.al. Am Heart J 2007;154:
“To shorten lengths of stay, patients are discharged too early while they still have evidence of volume overload.” (O’Connor, n=908)
Setoguchi: “A potential explanation was due to the treatment a patient received during hospitalization. With each subsequent HF hospitalization, there is additional exposure to diuretics.”
O’Connor: A possible explanation… the patients’ heart failure symptoms were incompletely treated before hospital discharge.
Despite advances in care – medical Rx and devices – mortality remains high 30
Days 3
Months 6
Months 30
Days 12
Months 5
Years
Patients have persistently high event rates despite use of evidence-based therapies…

9. Effect of Loop Diuretics on RAAS in Cardiac Failure
Section 3: Diuretic Therapy in Acute Decompensated Heart Failure
Loop Diuretic Inhibition of Macula Densa
Increased Renin-Angiotensin
Increased
Aldosterone
Cardiac Remodeling and Fibrosis
Left Ventricular Dysfunction
CARDIAC FAILURE
Schrier. J Am Coll Cardiol. 2006;47:1-8.
The renin-angiotensin system is known to be activated in the ADHF patient.1 The activation of this system is due to a variety of factors, including poor renal perfusion related to cardiac pump failure and/or loop diuretic inhibition of the macula densa. The resulting upregulation may cause progression of the cardiac dysfunction by: (1) direct myocardial effects of angiotensin and aldosterone causing cardiac remodeling and fibrosis; (2) increasing proximal sodium reabsorption and impairing aldosterone escape, thereby perpetuating volume overload with the potential for cardiac dilation, left ventricular hypertrophy, and blunting beneficial atrial-renal reflexes; and (3) moreover, the resultant volume overload in chronic HF patients is most frequently treated with loop diuretics. The loop diuretics in turn block sodium chloride transport at the macula densa, with resultant further activation of renin-angiotensin-aldosterone system.2
References:
Schrier R. J Am Coll Cardiol. 2006;47:1-8.
He X-R et al. Effects of furosemide and verapamil on the NaCl dependency of macula densa-mediated secretion. Hypertension. 1995;26:

10. Current Options May Have Undesirable Clinical Impacts
Section 3: Diuretic Therapy in Acute Decompensated Heart Failure
Favorable aspects of diuretic therapy
Increases urine output; reduces total body volume
Adverse aspects of diuretic therapy
Direct activation of renin-angiotensin-aldosterone system
Enhanced myocardial aldosterone uptake
Loss of K, Mg, Ca, secondary myocyte Ca loading
Indirect reduction of cardiac output
Increased total systemic vascular resistance
Reduced natriuresis and GFR
Associated with increased morbidity and mortality
References:
1. ADHERE® Registry. 3rd Quarter National Benchmark Report.
2. Emerman. J Card Fail. 2004;10:S116:368.
3. Bayliss. Br Heart J. 1987;57:17-22.
4. Faris. Int J Cardiol. 2002;82:
5. Mehta. JAMA. 2002;288:
6. Butler. Am Heart J. 2004;147:
7. Gottlieb. J Am Coll Cardiol. 2000;35:56-59.
8. Brater DC. N Engl J Med. 1998;339:387.
9. Firth et al. Lancet. 5/7/1988.
10. Francis. Ann Intern Med. 1985;103:1-6.
11. Ribboli. Am J Physiol Sep;267(3 pt 2):H1054-H1061.
12. McCurley. J Am Coll Cardiol. 2004;44:

11. Diuretics and ADHF No consensus dosing guidelines
Section 3: Diuretic Therapy in Acute Decompensated Heart Failure
Diuretics and ADHF
No consensus dosing guidelines
No common definition of diuretic resistant
No long-term studies of diuretic therapy for the treatment of heart failure
No outcomes data regarding morbidity and mortality
Although diuretics are widely used in the treatment of ADHF, there have been few controlled studies to assess the relative safety and efficacy of these agents, especially compared with more recent additions to therapeutic options for ADHF.1,2
References:
Ravnan SL et al. Congest Heart Fail. 2002;8:80.
Kramer et al. Nephrol Dial Transplantation. 1999;14(suppl 4):39-42.
14):39-42.

12. Diuretic Resistance
Can be described as a clinical state in which the diuretic response is diminished or lost before the therapeutic goal of relief from edema has been reached
Affects 20%–30% of patients with HF

13. Diuretic Resistance: Two Types
“Braking” phenomenon
A decrease in response to a diuretic after the first dose has been administered
Long-term tolerance
Tubular hypertrophy to compensate for salt loss
Causes of diuretic resistance: renal insuff, variable diuretic absorption, RAAS/SNS, increased Na intake, noncompliance, infrequent dosing

14. Diuretic Therapeutic Dilemma
Diminished renal function and concurrent sodium and water retention in ADHF presents a therapeutic dilemma with regard to sub-maximal diuretic therapy
Fluid removal by ultrafiltration may be recommended in this clinical setting
Schrier. J Am Coll Cardiol. 2006;47:1-8.

15. What is Aquapheresis? Method to safely achieve euvolemia
Section 7: AQUADEX™ FlexFlow™ Device Overview
What is Aquapheresis?
Method to safely achieve euvolemia
Simplified form of ultrafiltration
Inpatient or outpatient settings
ICU, CCU, MICU, telemetry, step-down, observation, ED, outpatient clinics
Peripheral or central venous access
Flexible access sites and catheters
Diverse physician prescription
Highly automated operation
No clinically significant impact on electrolyte balance, blood pressure, or heart rateor heart rate*
If an appropriate rate of ultrafiltration is selected and where vascular refill rate is not exceeded. The specific clinical circumstances at the time of device use may also have an impact on patient hemodynamics.

16. Fluid Removal by Ultrafiltration
Section 4: Ultrafiltration History and Physiology
Ultrafiltration can remove fluid from the blood at the same rate that fluid can be naturally recruited from the tissue
The transient removal of blood illicits compensatory mechanisms, termed plasma or intravascular refill (PR), aimed at minimizing this reduction
Interstitial
Space (edema) Na P
H2O Na K UF K PR
The plasma refill (PR) response is a compensatory response by the circulation in response to volume loss.1 The rate of plasma refill is important, for if the ultrafiltration rate is too aggressive intravascular volume may decrease because the rate of refill from the interstitial to the intravascular space is exceeded. This in turn may lead to hemodynamic instability and renal dysfunction. There have been studies that document an increase in creatinine and hemodynamic instability when ultrafiltration rates are too aggressive in a high-risk, advanced HF subset of patients,2 and thus the clinician should be aware of this risk.
“Balanced diuresis”
References:
1. Marenzi et al. J Am Coll Cardiol. 2001;38:4.
2. Liang KV et al. J Card Fail. 2006;12: P Na
Vascular
Space
Vascular
Space Na

17. The EUPHORIA Study Single center, prospective study, 20 patients
Initial UF within 12 hours of hospitalization and before any significant administration of IV diuretics and/or vasoactive drugs
Results
Removed an average of 8.6 liters of fluid
60% of patients were discharged in ≤ 3 days
Average hospitalization was 3.7 days
Baseline Cre 2.1
Average volume removal = 9L
Sustained decrease in weight, BNP, and Cre over time (90 days)
7/20 normalized their hyponatremia

18. The EUPHORIA Study Rehospitalization
In the three months preceding ultrafiltration:
10 hospitalizations in 9 patients
After ultrafiltration:
1 readmission for ADHF within 30 days

19. The UNLOAD Study
200 patients (100 each arm) randomized, multi- center study comparing ultrafiltration versus standard care for acutely decompensated patients
Superior salt & water removal/weight loss
At 48 hours, ultrafiltration demonstrated
38% greater weight loss
28% greater net fluid loss
At 90 days, reduced readmissions
50% reduction in re-hospitalization episodes
63% reduction in total re-hospitalized days
52% reduction in emergency department or clinic visits
Costanzo, ACC.06 Smaller Trial Late-Breaking Clinical Trials II, American College of Cardiology 2006 Scientific Sessions;
March 12, 2006; Atlanta, GA. Publication in JACC expected Feb 13, 2007.
Standard care – IV lasix (bolus or continuous 2X oral dose)
No statistical diff in serum Cre b/w groups
Equal dyspnea score b/w groups
Decreased rehospitalization/unscheduled visits in UF arm

20. ACC/AHA Guidelines: Class IIa, Level of Evidence B
I IIa IIb III
Ultrafiltration is reasonable for patients with refractory congestion not responding to medical therapy
Aquapheresis is now ranked HIGHER in the
Level of Evidence than:
- salt restriction
- strict I/Os
- higher doses of loop diuretics
- addition of a second diuretic
- continuous infusion of a loop diuretic
- vasodilators – IV nitroglycerin, nesiritide
- IV inotropes
All of these are Level of Evidence: C
Class IIa: Data derived from a single randomized trial, more studies needed
Level of Evidence B: consensus opinion, standard of care, limited evidence 20

21. Case Study 68 yo WM Diastolic heart failure Ischemic heart disease
CAB 4/06
HTN
Afibrillation/flutter
Anemia
Hospitalized every
6 months for exacerbation

22. Case Study: Inpatient Therapy
Inpatient ultrafiltration – January 2010
Access issues – extended length catheter (ELC)
Creatinine after 48 hrs of treatment
Creatinine 1.6 at discharge
Therapy/ACEI discontinued
Diuresed with IV lasix continuous infusion
LOS = 5 days
Net volume loss = 7 kgs

23. Case Study: Outpatient Therapy
1st treatment- 2/22/10
ELC catheter
1850 cc ultrafiltrate over 7 hrs
Wt loss = 2 lbs
Serum Cre = 1.8 pre and at termination of therapy
Hct 29 – sent home with hemoccult cards
Positive x 3- referred to PCP – no follow-up
SPELL OUT ELC – you have room

24. Case Study: Outpatient Therapy
2nd treatment – 3/26/10
ELC catheter and 18 g peripheral IV
Access issues!
2130 ultrafiltrate over 6.5 hrs
Also treated with Lasix 240mg IV due to loss of time waiting for access
Serum Cre = 1.7 pre and post termination of therapy
Hct 26 - referred to Hematology
EP f/u 3/29- was found to be in aflutter- TEE 3/31. Started on coumadin
Hematologist appt 4/15- Hgb- 19! Admitted for transfusion of blood products, which in turn, caused decompensated HF

25. Saint Thomas Hospital: Inpatient Outcomes
54 UF treatments from 5/1/08 – 6/1/10
Average treatment time = 37 hours, 28 minutes
Average fluid removal = 6.15 liters/circuit
Minimal adverse events
9 episodes of worsening renal insufficiency
No significant electrolyte disturbances
No significant hypotension
1 asymptomatic, small apical pneumothorax
6 minor bleeding episodes – epistaxis, line insertion site, generalized “oozing”
54 treatments – 39 different patients
Average treatment time - national average = 24 hours
Average fluid removal - national average = 4.0 liters
Most issues with renal insuff occurred early after implementation – too dry, too quickly
Increased bleeding when on coumadin at baseline – standardized heparin protocol with target PTT 25

26. Saint Thomas Hospital: Inpatient Outcomes
Readmissions < 30 days
1 re-admitted with LOC changes
2 discharged to hospice
ultrafiltration for palliation
1 patient, 5 re-admissions
now on dialysis for volume control
no readmits since dialysis except for recent hip fracture
1 expired within 90 days of readmission
1 patient, 2 re-admissions
suspect non-compliance – eating Whopper at discharge!
Several readmissions, but only with a few patients

27. Saint Thomas Hospital: Outpatient Outcomes
1st outpatient treatment – January 19, 2010
13 treatments – 7 pts
avg treatment time 5.79 hrs
avg volume removal 1.49 L
1 repeated hospitalization
now on peritoneal dialysis
1 deceased
1 ARF
patient did not follow
medication discharge
instructions
Effective in keeping pts out of hospital > 30 days
Need more data
Pt satisfaction and QOL are most important!
I DID NOT CHANGE-NOT SURE OF LAYOUT, BUT LOOKS FUNNY WITH SPACE AFTER 1ST ITEM

28. Advanced Heart Failure Clinic Saint Thomas Hospital

29. Another satisfied customer…

30. Challenges and Opportunities for Improvement
Early identification of patients that could benefit from outpatient therapy to decrease readmission within 30 days
Process improvement – timely, efficient IV access to allow faster initiation of therapy
Patient education – medications, line care, follow-up appointments, etc…
Anticoagulation – preserve integrity of circuit

31. Any questions?

32. Contact Information
Beth Davidson DNP, ACNP Kristi Hayes MSN, FNP