This document discusses causes and treatment of refractory edema. It defines refractory edema as edema resistant to typical doses of loop diuretics. Causes of refractory edema include inadequate diuretic dosing, decreased absorption or secretion of diuretics, enhanced sodium reabsorption, high salt intake, and drugs interfering with diuretics. Treatment involves a stepwise approach starting with intensifying oral diuretics, adding combination diuretic therapy, intravenous bolus diuretic therapy, and continuous infusion if responsive. Patients unresponsive to intravenous diuretics may benefit from ultrafiltration. Maintaining a supine posture can also improve diuretic response.

1. Causes and Treatment
of Refractory Edema

2. Generalized edema can occur in a variety of disorders, including heart failure,
cirrhosis (where ascites is usually most prominent), and the nephrotic
syndrome
Significant edema is not always present in CKD, but CKD can produce resistance
to diuretic treatment.
Edematous patients generally respond to the combination of dietary Na
restriction, treatment of the underlying disease process, and diuretic
therapy, usually with a loop diuretic.
However, some patients are resistant to typical doses of diuretics.

3. Refractory Edema is defined as Edema that is refractory to
typically effective doses of loop diuretics.

4. I. CAUSES OF REFRACTORY EDEMA
1. Inadequate diuretic dose or frequency
2. Decreased oral diuretic absorption
3. Decreased loop diuretic tubular secretion
4. Enhanced tubular sodium reabsorption
5. High salt intake
6. Drugs that interfere with diuretic action
II. MANAGEMENT OF REFRACTORY EDEMA
1. Pretreatment evaluation
2. Stepwise approach to refractory edema
1. Intensification of oral loop diuretic therapy
2. Combination oral diuretic therapy
3. Intravenous loop diuretic bolus therapy
1. Continuous infusion option in patients who respond to bolus therapy
2. Patients unresponsive to intravenous diuretics
3. Benefit from a supine posture
Outline

5. CAUSES OF REFRACTORY EDEMA
1. Inadequate diuretic dose or frequency
2. Decreased intestinal absorption of oral diuretics
3. Decreased diuretic secretion into tubular fluid
4. Increased sodium reabsorption at sites in the nephron other than those inhibited
by the diuretic
5. Excess sodium intake
6. Concomitant administration of other classes of drugs that interfere with diuretic
action

6. 1.Inadequate diuretic dose or frequency
Diuretics do not produce natriuresis until a threshold rate of drug excretion is
attained .
If, for example, a patient does not respond to 40 mg of Furosemide, the dose
may not have exceeded this threshold.
Thus, the single dose should be increased to 60 or 80 mg, rather than giving the 40
mg dose twice a day.
Once a single effective dose has been determined, it is most commonly
administered multiple times per day at a frequency that is individualized to the
diuretic needs of the patient and the pharmacokinetic profile of the agent chosen.

7.  Relation between the rate of furosemide excretion and the increase in sodium excretion in normals (solid
line) and patients with HF (dashed line).
 A diuresis is not seen until a threshold rate of furosemide excretion is reached. Patients with HF show relative
resistance at a given rate of diuretic excretion due to increased sodium reabsorption in other nephron
segments.

8. 2.Decreased oral diuretic absorption
In patients with heart failure, decreased intestinal perfusion, reduced intestinal
motility, and perhaps also mucosal edema can reduce the rate of diuretic
absorption, and therefore reduce the rate of diuretic delivery into the tubular
lumen by as much as 50 to 70 %.
This reduced delivery of diuretic into the renal tubule may keep it below the
threshold .
Thus, patients with acute decompensated heart failure typically require initial
intravenous (IV) therapy.

9. 3.Decreased loop diuretic tubular secretion
• Loop diuretics must enter the tubular fluid in order to exert their diuretic effect .
• Loop diuretics are highly (≥95 %) protein bound.
• As a result, they primarily enter the tubular lumen by secretion by the proximal tubule, not
by glomerular filtration.
• Patients who do not respond to usual doses of loop diuretic therapy may be resistant
because of decreased diuretic secretion into the tubular lumen.
• This may result from decreased renal perfusion in patients with heart failure (due to the
reduced cardiac output), cirrhosis (due to renal vasoconstriction), and renal
impairment (due to competitive inhibition of tubular diuretic secretion by high
concentrations of organic anions that accumulate when the GFR is reduced).

10. 4.Enhanced tubular sodium reabsorption
• Some patients have partial or relatively complete resistance to a loop diuretic despite
adequate secretion of the diuretic into the tubular fluid (ie, despite having the same
rate of urinary diuretic excretion as normal controls) .
• This problem is often due to increased tubular sodium reabsorption by nephron
segments other than the loop of Henle .
• The decreased response to the action of a diuretic that results from increased sodium
reabsorption in other nephron segments has been called the diuretic braking
phenomenon

11. 5.High salt intake
• Maintenance of a high Na intake can prevent net sodium
loss and a reduction in extracellular fluid volume, even if
there is an appropriate natriuretic response to diuretics.

12. 6. Drugs that interfere with diuretic action
NSAIDs, which reduce the synthesis of vasodilator and natriuretic prostaglandins
and impair diuretic responsiveness
Thiazolidinediones, such as Rosiglitazone, increase renal salt retention as a result
of upregulation of the ENaC in the collecting ducts and also increase proximal
tubule sodium reabsorption

13. MANAGEMENT OF REFRACTORY EDEMA
•Pretreatment evaluation
•Stepwise approach to refractory edema
• Intensification of oral loop diuretic therapy
• Combination oral diuretic therapy
• Intravenous loop diuretic bolus therapy
• Continuous infusion option in patients who respond to bolus therapy
• Patients unresponsive to intravenous diuretics
•Benefit from a supine posture

14. Pretreatment Evaluation
Exclude excessive sodium intake – It is important to evaluate the patient's dietary
sodium intake and attempt to reduce it, if excessive. To estimate sodium intake, a 24-
hour urine should be collected.
Confirm that the patient requires a reduction in extracellular fluid volume –
While the mere presence of residual edema or pulmonary congestion (crackles or
breathlessness) is suggestive, the decision to further reduce the extracellular fluid
volume requires careful clinical judgement.
Before intensifying diuretic therapy, the following steps should be taken:

15. Stepwise approach to refractory edema
1- Intensification of oral loop diuretic therapy
Starting dose
(oral or intravenous)
Maximum effective dose
(higher individual doses or more frequent
dosing intervals are unlikely to produce
substantial additional diuresis)
Maximal recommended daily dose
(greater daily total doses are associated
with a risk for toxicity)
Furosemide Furosemide Furosemide
Heart failure 20 mg once or twice daily 80 mg 3 times daily 600 mg
Cirrhotic ascites 40 mg once or twice daily 40 mg 3 times daily 160 mg
Nephrotic syndrome 40 mg once or twice daily 120 mg 3 times daily 600 mg
Chronic kidney disease ‡ 200 mg 3 times daily 600 mg
Acute kidney injury 80 mg once or twice daily 500 mg once 600 mg
‡ Initial diuretic doses for patients with CKD depend on its stage .

16. Oral Furosemide Therapy
Starting dose
(oral or intravenous)
Maximum effective dose
(higher individual doses or more frequent
dosing intervals are unlikely to produce
substantial additional diuresis)
Maximal recommended daily dose
(greater daily total doses are associated
with a risk for toxicity)
Heart failure 20 mg once or twice daily 80 mg 3 times daily 600 mg
Cirrhotic ascites 40 mg once or twice daily 40 mg 3 times daily 160 mg
Nephrotic syndrome 40 mg once or twice daily 120 mg 3 times daily 600 mg
Chronic kidney disease ‡ 200 mg 3 times daily 600 mg
Acute kidney injury 80 mg once or twice daily 500 mg once 600 mg
‡ Initial diuretic doses for patients with CKD depend on its stage .

17. Stepwise approach to refractory edema
2. Combination oral diuretic therapy
When an adequate response to loop diuretics is not obtained, concurrent administration of a thiazide-
like (Metolazone) or thiazide-type (Hydrochlorothiazide) diuretic to block distal sodium chloride
reabsorption should be employed:
Without hypokalemia    Metolazone (5 to 10 mg once daily initially, increased
to a maximum dose of 20 mg once daily) , although Hydrochlorothiazide (25 to 50 mg
twice daily initially, increased to a maximum dose of 200 mg per day) is likely just as
effective.
With hypokalemia  Potassium-sparing diuretic first (eg, Amiloride or, particularly in
patients with heart failure, a mineralocorticoid receptor antagonist).

18. Stepwise approach to refractory edema
3- Intravenous loop diuretic bolus therapy
1. The initial dose of IV loop diuretic should be ~ 2 or 2.5 times the patient's total maintenance daily
oral dose
2. If there is little or no response to the initial dose, the dose should be doubled at two-hour
intervals, as needed, up to the maximum recommended doses rather than repeated at the
same dose.
3. Patients who do not have an adequate response to a maximal dose of one IV loop diuretic are
unlikely to respond to another loop diuretic since their mechanisms of action are similar.

19. Stepwise approach to refractory edema
3- Intravenous loop diuretic bolus therapy
4. Loop diuretics should not be administered IV as a rapid "push." Although there are no
data related to the optimal time over which a single IV dose of a loop diuretic should be
administered, the following approach seems reasonable; the doses are given
for Furosemide :
 20 to 40 mg over five minutes
 60 to 120 mg over 20 minutes
 160 to 200 mg over 40 to 50 minutes (4 mg/min)
5. In patients who fail to respond to maximal IV bolus doses of a loop diuretic, a thiazide-like or
thiazide-type diuretic can be coadministered.

20. 3- Intravenous loop diuretic bolus therapy
a. Continuous infusion option in patients who respond to bolus therapy
1. In patients with refractory edema who respond to an IV bolus of a loop diuretic
but need ongoing diuresis   Initiate a continuous loop diuretic infusion.
2. Continuous diuretic therapy may be less ototoxic than bolus therapy and
maintains a sustained effective rate of diuretic excretion.

21. 1. An IV loading dose of 40 to 80 mg of Furosemide is typically given over five minutes prior to
initiating the continuous infusion.
2. After the loading dose, the starting infusion rate with Furosemide varies with the level of kidney
function:
 Acute Kidney Injury or CKD with eGFR less than 30 mL/min per 1.73 m2)  
Initial Furosemide infusion rate of 20 mg per hour. If the diuresis is not sustained, a second bolus
is given followed by a higher infusion rate of 40 mg per hour.
 eGFR greater than or equal to 30 mL/min per 1.73 m2   Initial Furosemide infusion rate of 5
mg per hour. If the diuresis is not sustained, a second bolus is given followed by a higher infusion
rate of 10 mg per hour. This rate may then be increased further to the maximum recommended
furosemide infusion rate of 40 mg per hour if response to lower doses is poor.
Continuous Infusion Protocol

22. 3- Intravenous loop diuretic bolus therapy
b. Patients unresponsive to intravenous diuretics
The excess fluid can be removed by ultrafiltration during renal
replacement therapy.

23. Benefit from a Supine posture
The supine position was associated with significantly higher mean creatinine
clearance (100 versus 66 mL/min) and diuretic response
The upright position was associated with significant increases in plasma
norepinephrine, renin, and aldosterone.

24. Thank You