Diuretic resistance

1. Challenging Cases in Acute Heart Failure
Diuretic Resistance
Kevin Damman, MD, PhD
University Medical Center Groningen
Groningen, The Netherlands
k.damman@umcg.nl

2. Disclosures
Supported by the Netherlands Heart Institute (ICIN) and a HFA
Research Grant

3. Scope of the Problem
• Acute (Decompensated) Heart Failure patient
• Treatment with conventional methods:
i.v. Loop Diuretics
Oxygen, morfine if necessary, vasodilators
Either:
No improvement in symptoms/signs or worsening
No increase in diuresis
Increase in serum creatinine
Diuretic Resistance?

4. Contents
Diuretic Resistance
• Definition
• Epidemiology
• Pathyphysiology
• Possible treatments and caveats

5. Definition
No Consensus on definition of Diuretic Resistance
• “Poor response to diuretic therapy”
• Peristent signs and symptoms despite diuretic therapy
• Furosemide > 80mg daily (chronic HF)
• Fractional Sodium excretion < 0.2%
• Failure to excrete at least 90 mmol of sodium within 72h of a 160
mg oral furosemide dose given twice daily
• Lack of weight loss during i.v. loop diuretic therapy
• Lack of negative fluid balance during i.v. Loop diuretic therapy

6. Diuretic Response
No Consensus on definition of Diuretic Resistance
• It might be better to speak of the relative response to diuretics
Diuretic Response
Diuretic Efficacy
• Overcomes the problem of estalishing a ‘cut off’
• Highlights the importance of response to diuretics on a continuous
scale

7. Weight Change
Adapted from Fonarow et al Rev Cardiovasc Med 2003 (ADHERE)
Little / no weight
loss or weight
increase
~50%

8. Diuretic Response
Testani et al Circ Heart Fail 2014

9. Diuretic Response
Testani et al Circ Heart Fail 2014

10. Diuretic Response
Valente et al Eur Heart J 2014 (PROTECT)
Diuretic Response:
Weight Change (kg) / 40 mg Furosemide equivalent

11. Diuretic Response
Valente et al Eur Heart J 2014 (PROTECT)

12. Pathophysiology
Pathophysiology incompletely understood
• Diminished Reponsiveness to Diuretics in Heart failure
• Activation of RAAS by diuretics
• Decreased GFR and Renal Blood Flow
• Braking phenomenon
• Hypoalbuminemia (Furosemide) and Hyperalbuminuria
• High BUN
• Distal tubular Sodium Reabsorption
• (Renal) Venous congestion
Ter Maaten Nat Rev Cardiol 2015

13. Braking Phenomenon
Ellison et al Cardiology 2001

14. Dose Response
Felker Heart Fail Rev 2011

15. Pathophysiology
Ter Maaten Nat Rev Cardiol 2015

16. Diuretic Resistance and WRF
Increase in serum creatinine ≠ Diuretic Resistance
• Worsening Renal Function (WRF) occurs frequently in AHF
• WRF not always associated with poor outcome:
Pseudo WRF during adequate decongestion
Valente et al Eur Heart J 2014 (PROTECT)

17. Treatment
Most importantly: Identify patients experiencing poor diuretic
response early
If using only oral loop diuretics:
Dose appropriately (eGFR)
Consider changing loop diuretic:
Furosemide  Bumetanide -> Torsemide
Add Thiazide
Add Mineralocorticoid receptor antagonist
Switch to intravenous loop diuretic

18. Treatment
Intravenous Loop Diuretics:
• Furosemide
be aware of albumin levels
consider switch to Bumetanide/Torsemide
• Dose properly: High dose in patients with low eGFR

19. I.V. Continuous/bolus
Lahav et al Chest 1992

20. I.V. Continuous/bolus
Felker et al NEJM 2011 (DOSE)
More WRF with high Dose
(despite similar outcome):
23% vs. 17%, P = 0.04

21. Treatment
Ter Maaten Nat Rev Cardiol 2015 / Verbrugge Cardiorenal Med 2014

22. Treatment
Thiazide
Inhibits Na/Cl co-transporter
distal tubules
Increases fractional sodium excretion
Metolazone
Inhibits Na/Cl co-transporter
distal tubules
Increases diuresis, also in patients with
low eGFR
Acetazolemide
Carbon Anhydrase inhibitor
proximal tubule
Inhibits proximal sodium reabsorption
Increases diuresis, caution in low eGFR
Mannitol
Inhibits water reabsorption
Henle’s loop
Increases free water excretion
MRA
Competitive aldosterone
antagonist distal tubules
In natriuretic doses, caution in low
eGFR
Ter Maaten Nat Rev Cardiol 2015 / Verbrugge Cardiorenal Med 2014

23. Treatment
Ter Maaten Nat Rev Cardiol 2015

24. Consider Paracentesis
Mullens et al JACC 2008 and J Card Fail 2008

25. Hypertonic Saline
Ghandi IJC 2014
Mortality
HF Rehospitalisation

26. Ultrafiltration / Dopamine
Bart NEJM 2012 and Chen JAMA 2013
Not as universal therapy, may be considered in selected patients
Placebo Dopamine P-value
N 119 122
Urine volume (72h, mL) 8296 8524 0.59
Change in Cystatin C (mg/L) 0.11 0.12 0.72
Change in Creatinine (µmol/L) 1.8 0 0.78
WRF (%) 22 22 0.88
Sodium excretion (72h, mmol) 540 527 0.75
Weight change (72h, kg) -3.5 -3.3 0.82
CARRESS-HF ROSE-AHF

27. Diuretic Resistance and WRF
Damman and Testani Eur Heart J 2015

28. Diuretic Resistance
Diuretic Resistance / Poor Diuretic Response associated with
worse outcomes
• Early identification pivotal
Weight, fluid balance, signs/symptoms, electrolytes
• WRF ≠ Diuretic Resistance.
• Switch from oral to i.v.. Dose adequately (high in low eGFR)
• Combine diuretics: Acetolemide, Thiazides, MRA, Mannitol
• Some evidence on Hypertonic Saline
• In selected patients: Ultrafiltration, dopamine, inotropes

29. Thank you for your attention!
k.damman@umcg.nl