1. Managing Volume Overload in Acute Decompensated Heart Failure
Maria Rosa Costanzo, M.D., F.A.C.C.

2. Mechanisms of Sodium and Water Retention in Heart Failure
Chronic Decrease in Cardiac Output
Or Decrease in Peripheral Vascular Resistance
Decrease Fullness of
The Arterial Circulation
Increased
Cardiac Filling Pressures
Water
Retention
V2 Receptors
Stimulation
Nonosmotic
AVP Release
Increased Sodium and Water
Resistance to
Natriuretic Peptides
Failure to Escape
From Aldosterone
Reduced
Distal Delivery of Sodium
Baroreceptor
Desensitization
Decreased Renal
Perfusion Pressure
Renal
Vasoconstriction
Increased
SNS Activity
RAAS Activity
Increased Water and Sodium
Reabsorption
in the Proximal Tubule
Decreased GFR
Adapted from Schrier RW: J Am Coll Cardiol 2006; 47:1-8

3. Prevalence of Worsening Renal Function During Hospitalization
According to Categories of Admission CVP, CI, SBP, and PCWP
Mullens, W. et al. J Am Coll Cardiol 2009;53:
Copyright ©2009 American College of Cardiology Foundation. Restrictions may apply.

4. ROC Curves for CVP and CI on Admission for the Development of WRF
Mullens, W. et al. J Am Coll Cardiol 2009;53:
Copyright ©2009 American College of Cardiology Foundation. Restrictions may apply.

5. Impact of Venous Congestion on Glomerular Net Filtration Pressure
Jessup M and Costanzo MR. J Am Coll Cardiol 2009; 53:597-9

6. Causes of Diuretic Resistance
Inadequate Dose
Patient Non Compliance
Not taking drug
High NaCl Intake
Poor Absorption
Impaired Secretion
Chronic Kidney Disease
Old Age
Kidney Transplant
Chronic Heart Failure
Drugs
NSAIDs
Probenecid
Proteinuria
Hypoproteinemia
Hypotension
Drugs-Direct Inhibitors
NSAIDs
ACE/ARB **
Diuretic Tolerance (Structural/Functional Adaptation)
Neurohormonal Activation
‘Cardiorenal Limit’

7. Inadequate Dosing =0 + AM PM Ellison DH. Cardiology 2001; 96:132–143
Ineffective
Dose =0 +
Effective
Dose
Ineffective
Dose
Ellison DH. Cardiology 2001; 96:132–143

8. Pharmacokinetics of Loop Diuretics
Maximal Intravenous Dose (mg)
Moderate Renal Insufficiency
Severe Renal Insufficiency
Heart Failure
Furosemide
80-160
40-80
Bumetanide
4-8
8-10
1-2
Torsemide
20-50
50-100
10-20
Maximal Intravenous Doses of Loop Diuretics
in Patients with Diminished Responses to Oral Therapy
Diuretic
IV Loading Dose (mg)
Infusion Rate (mg/hr)
CrCl
< 25 ml/min
25-75 ml/min
> 75 ml/min
Furosemide 40
20 then 40
10 then 20 10
Bumetanide 1
1 then 2
0.5 then 1
0.5
Torsemide 20
5 then 10 5
Brater DC. New Engl J Med 1998; 339;

9. Excessive Dietary Sodium Intake=
> =0
= ECF Reduction
Urinary Na excretion, mmol/6 hours
Dietary
Na Intake
‘Post Diuretic
Na Retention’ LD LD LD LD LD LD
Wilcox CS, Mitch WE, Kelly RA, Skorecki K, Meyer TW, Friedman PA, Souney PF.
J Lab Clin Med Sep;102(3):450-8.
Time, 6 hour periods

10. IV Loop Diuretics: Bolus vs. Continuous Infusion
Rudy DW et al. Ann Intern Med 1991; 115:360
Metanalysis: Continuous Infusion Superior to Bolus Injection:
Total UO
P = 0.003
Increase in Sr. Creatinine
P <
Length of Hospitaliization
All Cause Mortality
P =
Salvador DRK et al. The Cochrane Database of Systematic Reviews 2005, Issue 3.
Art. No.: CD pub3. DOI: / CD pub3.

11. Diuretic Secretion Is Impaired in CKD
Uremic anions block diuretic secretion into the proximal tubule
Diuretics Act from the tubule lumen D
Uremic
Anions D + - D
Loop Diuretics N a K C l K Na
Diuretic D
Albumin
Ellison DH. Cardiology 2001; 96:132–143

12. Dose-Response Curves for Loop Diuretics
Dose-response curves for loop diuretics. a. Fractional Na excretion (FENa) as a function of loop diuretics concentration. Compared with normal subjects, patients with chronic renal failure (CRF) show a rightward shift in the curve, due to impaired diuretic secretion. The maximal response is preserved when expressed as FENa, but not when expressed as absolute Na secretion. Patients with congestive heart failure (CHF) demonstrate a rightward and downward shift, even when the dose response is expressed as FENa, and thus are relatively diuretic resistant. b. Comparison of the response to intravenous and oral doses of loop diuretics. In a normal individual, an oral dose may be as effective as an intravenous dose because the time above the natriuretic threshold (indicated by the “Normal” line) is approximately equal. If the natriuretic threshold increases (indicated by the “CHF” line), then the oral dose may not provide a high enough serum level to elicit natriuresis. (Reproduced with permission from reference 5: Ellison DH. Diuretic therapy and resistance in congestive heart failure. Cardiology 2001; 96:132–143).
Ellison DH. Cardiology 2001; 96:132–143

13. Heywood JT, Fonarow GC, Costanzo MR et al
Heywood JT, Fonarow GC, Costanzo MR et al. J Cardiac Fail 2007;13:422-30

14. Loop Diuretics Stimulate ReninK Na + - MD
LOOP
DIURETIC + - N a K
TAL C l K Na
Ellison DH. Cardiology 2001; 96:132–143

15. Adaptation to Loop Diuretics
Chronic Furosemide Increases
Thiazide-sensitive transporter mRNA
Chronic Furosemide Increases
Thiazide-sensitive transporter Activity
Control
Furosemide
Obermüller et al. Am J Physiol 269: F900
NaCl Cotransport
Chronic Furosemide Increases
Thiazide-sensitive transporter protein
Control
Furosemide
Furo + Spiro C F +S
Abdallah et al. J Am Soc Nephrol 12: 1335, 2001
Ellison et al.
JCI 83: 113, 1989

16. Therapeutic Approaches
Block Adaptive Processes
Post Diuretic Na Retention
Chronic infusion
Long-acting diuretics (thiazides, spironolactone)
Structural Adaptations
DCT diuretics (thiazides, spironolactone, ACEI/ARBs)
CD diuretics (spironolactone, ACEI/ARBs)
Neurohormonal Activation
ACE Inhibitors
Spironolactone
Beta blockers
Nesiritide
Ultrafiltration

17. Fluid Removal by Ultrafiltration
Section 4: Ultrafiltration History and Physiology
Fluid Removal by Ultrafiltration
Interstitial
Space (Edema)
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 elicits a compensatory mechanism, called plasma or intravascular refill (PR), aimed at minimizing this reduction1,2 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.
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
1. Lauer et al. Arch Intern Med. 1983;99:
2. Marenzi et al. J Am Coll Cardiol. 2001;38:4.

18. Simplified Veno-Venous Ultrafiltration
0.12 m2 polysulphone filter
Blood flow adjustable ( ml/minute)
Total extracorporeal blood volume 33 ml
Peripheral, midline, or central venous access
Anticoagulation with heparin recommended A c c e s s R e t u r n
SCUF, or Slow Continuous Ultrafiltration, provides patient fluid removal by ultrafiltration only.
No replacement fluid is used.
The maximum Patient Fluid Removal Rate in SCUF is 2000 ml/hr. E f f l u e n t

19. Changes in Plasma Volume and Refilling Rate During UF
ΔPV = 100/(100-Hctpre) x [100(Hctpre-Hctpost)]/Hctpost
PRR (ml/min) =Ultrafiltrate volume/Ultrafiltration time
Marenzi GC et al. JACC 2001; 38:

20. Ultrafiltration versus IV Diuretics for Patients Hospitalized for Acute Decompensated Congestive Heart Failure: A Prospective Randomized Clinical Trial UNLOAD Trial
Principal Findings
At 48 h after randomization early Ultrafiltration compared with IV Diuretics produces:
greater weight loss
(5.0 ± 0.68 Kg vs. 3.1 ± Kg; p= 0.001)
greater fluid loss
(4.6 ± 0.29 L vs. 3.3 ± 0.29 L; p= 0.001)
similar changes in sCr
(0.12 ± 0.42 mg/dL vs ± 0.41 mg/dl; p=0.356)
Costanzo MR, Guglin ME, Saltzberg MT et al. J Am Coll Cardiol 2007; 49:675-83

21. Freedom From Re-hospitalization for Heart Failure
Costanzo MR, Guglin ME, Saltzberg MT et al. J Am Coll Cardiol 2007; 49:675-83

22. Differential Oucomes after
Ultrafiltation, Bolus IV Diuretics and Continuous IV Diuretics
Net Fluid Loss at 48 Hr
m = 4.6, CI
m =3.1, CI
m =3.9, CI
Re-Hospitalization Equivalents at 90 Days
m = 0.31, CI
m =1.31, CI
m =2.29, CI
Costanzo MR et al. J Am Coll Cardiol 2007: 49 (Suppl.): 56 A

23. Urine electrolyte concentrations measured after a dose of IVD.
Enhanced Sodium Extraction with Ultrafiltration Compared to Intravenous Diuretics
15 hospitalized ADHF patients with presumed diuretic resistance and clinical evidence of volume overload.
Urine electrolyte concentrations measured after a dose of IVD.
UF was then begun and ultrafiltrate electrolyte concentrations were measured 8 hours later and compared to the initial urine values.
Ali SS et al. Congest Heart Fail. 2009; 15: 1-4

24. Ali SS et al. Congest Heart Fail. 2009; 15:1-4P= P=
P= 0.017
Sodium
Potassium
Magnesium

25. Randomized to isolated ultrafiltration (500 cc/h) or IV furosemide
Sustained Improvement in Functional Capacity after Removal of Body Fluid with Isolated Ultrafiltration in Chronic Cardiac Insufficiency: Failure of Furosemide to Provide the Same Result Agostoni P. et al. The American Journal of Medicine 1994; 96:
16 stable, NYHA II-III chronic HF patients matched by age, gender and peak VO2
Randomized to isolated ultrafiltration (500 cc/h) or IV furosemide
Removal of the same amount of fluid in both arms (≈ 1,600 cc)
Measurement of hemodynamics, peak VO2, NE, PRA and Aldosterone at baseline, end of treatment and 3 months

26. Ultrafiltration vs. Furosemide in HF
Body Weight Plasma Renin Activity kg % *
* p<0.01 vs. day 0 * * * * * * * * * * * * * *
UF (n=8; 1710 ml)
day
day
Furosemide (n=8; 248 mg i.v.)
Agostoni PG et al. Am J Med 1994; 96:191-9

27. Ultrafiltration vs. Furosemide in HF
Peak VO2 Tolerance Time
ml/kg/min * * *
seconds * * *
* p<0.01 vs. day -1
day
UF (n=8; 1710 ml)
day
Furosemide (n=8; 248 mg i.v.)
Agostoni PG et al. Am J Med 1994; 96:191-9

28. Guidelines Issued before the Publication of the UNLOAD Trial for the Use of UF in the Management of HF
Expert Group
Comment
ACC/AHA1
If the degree of renal dysfunction is severe or if edema becomes resistant to treatment, ultrafiltration or hemofiltration may be needed to achieve adequate control of fluid retention. This can produce clinical benefits and may restore responsiveness to conventional doses of loop diuretics.
CCVS 2
In highly selected patients, intermittent slow continuous venovenous ultrafiltration may be considered. This should be performed in comsultation with a nephrologist or a specialist physician* who has experience using ultrafiltration in a setting of close inpatient observation.
ESC 3
In chronic heart failure, ultrafiltration can resolve pulmonary edema and overhydration in case of refractoriness to pharmacological therapies. In most patients with severe disease the relief is temporary. In acute heart failure, ultrafitration or dialysis can be considered if other strategies are ineffective.
Hunt SA et al. Circulation 2005;112:e154-e235
Arnold JM et al. Can J Cardiol 2007; 23: 21-45
Swedberg K et al. Eur Heart J 2005; 26:
* Heart Failure Specialist?

29. CARdiorenal REScue Study in Acute Decompensated Heart Failure (CARESS-HF)
NIH Heart Failure Network trial
Prospective, randomized trial
100 patients each arm
Patient Population:
Patients hospitalized with ADHF will be eligible for enrollment if they develop cardiorenal syndrome (defined as an increase in sCr of > 0.3 mg/dl from baseline) while demonstrating signs and symptoms of persistent congestion
Primary endpoint
Change in sCr and weight together as a “bivariate” endpoint assessed at 96 hrs post enrollment
Secondary Endpoint
PE assessed at days 1-3 and 7 days
Treatment failure, weight and fluid loss, clinical decongestion, peak sCr, change in electrolytes, LOS, biomarkers, change in diuretic doses all at various time points

30. CARESS-HF Clinical Trial
Primary endpoint
Change in sCr and weight together as a “bivariate” endpoint assessed at 96 hrs post enrollment
Red= Ultrafiltration
Black= Stepped Pharmacologic Care

31. CRS Type I (Acute Cardiorenal Syndrome)
Cardiorenal Syndrome (CRS) General Definition:
A pathophysiologic disorder of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction in the other organ
CRS Type I (Acute Cardiorenal Syndrome)
Abrupt worsening of cardiac function (e.g. acute cardiogenic shock or decompensated congestive heart failure) leading to acute kidney injury
CRS Type II (Chronic Cardiorenal Syndrome)
Chronic abnormalities in cardiac function (e.g. chronic congestive heart failure) causing progressive and permanent chronic kidney disease
CRS Type III (Acute Renocardiac Syndrome)
Abrupt worsening of renal function (e.g. acute kidney ischaemia or glomerulonephritis) causing acute cardiac disorder (e.g. heart failure, arrhythmia, ischemia)
CRS Type IV (Chronic Renocardiac Syndrome)
Chronic kidney disease (e.g. chronic glomerular disease) contributing to decreased cardiac function, cardiac hypertrophy and/or increased risk of adverse cardiovascular events
CRS Type V (Secondary Cardiorenal Syndrome)
Systemic condition (e.g. diabetes mellitus, sepsis) causing both cardiac and renal dysfunction
Ronco C et al. J Am Coll Cardiol 2008; 52:

32. Managing Volume Overload in Acute Decompensated Heart Failure - Conclusions -
Optimal volume management in ADHF requires in depth knowledge of the mechanisms leading to salt and water retention despite hypervolemia.
Apart from intrinsic renal insufficiency, venous congestion, rather than reduced CO, may be the primary hemodynamic factor driving WRF in ADHF pts.
Loop diuretics reduce congestion, but their effectiveness is reduced by excess salt intake, underlying CKD, renal adaptation to diuretics and neurohormonal activation
Compared with removal of hypotonic fluid with diuretics, withdrawal of isotonic fluid with ultrafiltration may result in enhanced sodium extraction, lesser neurohormonal activation, and improved outcomes
A consensus definition of the cardiorenal syndrome may help to design RCTs aimed at identifying pathophysiologically sound interventions targeting specific patient populations