Treatment of refractory edema

Jul 30, 2001

Burton D Rose, MD

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Generalized edema can occur in a variety of disorders, including congestive
heart failure, cirrhosis, the nephrotic syndrome, and renal failure; when
massive, the excess fluid accumulation is called anasarca. These patients
generally respond to the combination of dietary sodium restriction and diuretic
therapy, usually with a loop diuretic. Some patients, however, are resistant to
this regimen. Although the treatment of the individual disorders is discussed
separately, the sequential approach to the patient with refractory edema will be
reviewed here.

A variety of factors can account for persistent fluid retention, including
inadequate diuretic dose, excess sodium intake, delayed intestinal absorption
of oral drug, decreased diuretic excretion into the urine, and increased sodium
reabsorption at nondiuretic-sensitive sites in the nephron [1-3]. In addition,
nonsteroidal antiinflammatory drugs should be discontinued, if possible, since
diminished synthesis of vasodilator and natriuretic prostaglandins can impair
diuretic responsiveness [3,4].

DIURETIC DOSE The approach to diuretic dosing in refractory edema
should consider each of the above factors [1-3]:

The single effective dose should be determined. Diuretics have a dose-
response curve, with no natriuresis seen until a threshold rate of drug excretion
is attained (show figure 1). A patient who does not respond to 40 mg of
furosemide may not be exceeding this threshold. Thus, the single dose should
be increased to 60 or 80 mg, rather than giving the same dose twice a day.
(See "Optimal dosage of loop diuretics" for the equivalent doses of bumetanide
and torsemide).

Maintenance of a high sodium intake can prevent net fluid loss even though
an adequate diuresis is being achieved. Thus, a 24 hour urine should be
collected to assess sodium excretion; a value above 100 meq per day in a
patient whose daily weight is stable indicates an adequate diuretic response
and the likelihood that noncompliance with sodium restriction is responsible for
the apparent resistance to therapy.

Some patients with severe or unstable heart failure may require initial
intravenous therapy, since decreased intestinal perfusion, reduced intestinal
motility, and perhaps mucosal edema may substantially slow the rate of drug
absorption and therefore the rate of drug delivery to the kidney [5,6]. This
defect is often reversible (thereby allowing the use of oral therapy) with
removal of some of the edema fluid with intravenous diuretics and stabilization
of cardiac function [5]. Similar considerations may also apply to patients with
advanced cirrhosis [7].

In general, a patient who is resistant to furosemide is not likely to respond
to a similar dose of another loop diuretic such as bumetanide or torsemide. It is
important to appreciate, however, that there are differences in bioavailability
among the oral preparations of these drugs. Only about 50 percent of oral
furosemide is absorbed in edematous states and some patients are well below
this level. In this setting, apparent resistance to seemingly adequate doses of
oral furosemide may be overcome by increasing the dose of furosemide or by
switching to oral bumetanide or torsemide, agents which are much more
completely absorbed.

DECREASED DIURETIC SECRETION Patients who do not respond to the
above modalities may be resistant because of decreased diuretic secretion into
the tubular lumen. As examples, decreased renal perfusion in heart failure
(due to the reduced cardiac output) and cirrhosis (due to renal vasoconstriction
induced in part by splanchnic vasodilation) and competitive inhibition of tubular
secretion in renal failure may contribute to diuretic unresponsiveness. (See
"Optimal dosage of loop diuretics"). An additional problem may be present in
patients with the nephrotic syndrome in whom binding of the diuretic within the
lumen by filtered albumin may render the drug ineffective. (See "Mechanism
and treatment of edema in nephrotic syndrome").

The treatment of impaired efficiency of secretion is to raise the plasma level
and therefore the rate of urinary excretion by increasing the diuretic dose to the
maximum effective dose; this regimen will also be effective with drug binding in
the lumen. The maximum effective dose, which has been derived empirically,
represents the dose at which loop sodium chloride transport is presumably
completely inhibited [2]. High dose intravenous therapy should be given slowly
over 30 to 60 minutes to minimize the risk of ototoxicity, which is most likely to
occur with bolus therapy in patients with renal insufficiency or heart failure [8-
10].

For intravenous furosemide, the maximum effective dose in most patients is:
80 to 120 mg in heart failure, cirrhosis, or the nephrotic syndrome (in which
renal function is relatively normal); 160 to 240 mg in chronic renal failure; and
as high as 500 mg in severe acute renal failure [1,2]. The recommended
doses for the first three disorders should be adjusted upward if there is
concurrent renal insufficiency. In addition, the oral dose of furosemide is
generally twice the intravenous dose (because of incomplete absorption). The
dose of intravenous or oral bumetanide is usually one-fortieth the intravenous
dose of furosemide, but falls to one-twentieth in advanced renal failure due to
increased extrarenal metabolism [11]. (See "Optimal dosage of loop diuretics"
for a more complete discussion and equivalent doses of bumetanide and
torsemide).

Intravenous infusion A possibly safer and more effective alternative to
bolus injections in refractory patients is to administer the loop diuretic as a
continuous intravenous infusion. The enhanced efficacy of constant infusion is
related to the rate of drug excretion. The advantage of a constant infusion is
that it maintains an optimal rate of drug excretion and therefore of inhibition of
loop NaCl reabsorption (show figure 1). Bolus therapy is associated with
initially high and then low rates of diuretic excretion; as a result, sodium
excretion may be at near maximal levels for the first two hours but then
gradually falls until the next dose is given. Furthermore, the high initial plasma
level may be associated with ototoxicity, a rare complication that is now
primarily seen in patients receiving other ototoxins such as an aminoglycoside.

Two studies have illustrated the potential utility of a continuous intravenous
infusion of a loop diuretic compared to conventional bolus therapy. In one,
patients with stable chronic renal failure (mean creatinine clearance 18
mL/min) were treated with either a constant infusion of bumetanide (1 mg
bolus followed by 1 mg per hour) or standard bolus therapy (6 mg every 6 to
12 hours) [12]. The infusion produced a 30 percent greater increase in sodium
excretion (show figure 2).

The second study evaluated twenty patients with heart failure who were
treated in a randomized crossover fashion with furosemide given as a single
bolus injection or as a continuous intravenous effusion (mean daily dose, 690
mg with both regimens) [9]. Patients treated with the continuous infusion had a
greater urine volume (2860 versus 2260 mL/day) and urinary sodium excretion
(210 versus 150 meq/day). Five cases of reversible ototoxicity were seen, only
with bolus injection.

The risk of ototoxicity is more pronounced at doses of furosemide above 240
mg/h [8]. However, deafness, which may be permanent, has been reported in
patients with acute renal failure receiving the equivalent of 80 to 160 mg/h (2 to
4 g/day) of furosemide [10]. Patients concurrently treated with an
aminoglycoside may be at risk at even lower doses.

The main utility of continuous intravenous loop diuretics is in hospitalized
patients with marked edema in the intensive care unit who show a response to
a standard intravenous bolus that is not sustained. Patients who show no
response to a large bolus (such as 240 to 320 mg of furosemide) are unlikely
to respond to an infusion, since bolus therapy results in higher initial plasma
and urinary diuretic levels.

After the initial bolus, we generally begin with furosemide at a dose of 20 mg/h.
If the diuresis is not sustained, a second bolus is given followed by a higher
infusion rate of 40 mg/h. The risk associated with higher infusion rates of 80 to
160 mg/h must be weighed against alternative strategies such as the addition
of a thiazide-type diuretic or fluid removal via hemofiltration (see below).

Equivalent doses include:

For bumetanide 1 mg/h, increasing to 2 mg/h
For torsemide 10 mg/h, increasing to 20 mg/h

Concurrent albumin infusion Some patients with hypoalbuminemia are
relatively resistant to conventional diuretic therapy. It has been proposed that
these patients may respond to the administration of 40 to 80 mg of furosemide
added to 6.25 to 12.5 g of salt-poor albumin. Infusion of the furosemide-
albumin complex is thought to act by increasing diuretic delivery to the kidney
by keeping furosemide within the vascular space. In an initial report, this
approach led to a substantial increase in sodium excretion in some patients
[13]. However, a subsequent study in patients with nephrotic syndrome (mean
plasma albumin 3.0 g/dL) found that combination therapy (60 mg of furosemide
infused in 200 mL of a 20 percent albumin solution) produced only a modest
increase in sodium excretion compared to furosemide alone that was not
associated with an increase in the rate of furosemide excretion [14]. The
increase in sodium excretion was roughly equivalent to the amount of sodium
contained in the colloid solution, and volume expansion appeared to be the
probable explanation for the enhanced natriuresis.

A similar lack of efficacy of the furosemide-albumin combination has been
demonstrated in hypoalbuminemic patients with cirrhosis (mean plasma
albumin 3.0 g/dL) [15]. Compared to furosemide alone, combination therapy
did not increase the rate of either furosemide or sodium excretion.

It is possible that infusion of furosemide-albumin would be effective in patients
with refractory edema and severe hypoalbuminemia (plasma albumin less than
2.0 g/dL). However, this has not been studied.

Posture Another factor that can enhance diuretic responsiveness is posture.
Patients with heart failure, for example, are unable to increase cardiac output
appropriately with assumption of the upright position. As a result, renal
perfusion and therefore diuretic delivery are further diminished. In this setting,
assumption of the supine position can increase the creatinine clearance by as
much as 40 percent and the diuretic response to a loop diuretic by as much as
two-fold [16].

ENHANCED TUBULAR SODIUM REABSORPTION Some patients have
partial or relatively complete resistance to a loop diuretic as evidenced by a
decreased natriuresis (compared to normals) at a given rate of diuretic
excretion (show figure 1). This problem is often due to increased tubular
sodium reabsorption in other nephron segments: in the proximal tubule, due to
enhanced release of angiotensin II and norepinephrine [17]; in the distal
tubule, due to flow-dependent hypertrophy since chronic therapy with a loop
diuretic increases sodium delivery to the distal tubule (show figure 3) [18,19];
and in the collecting tubules, due to enhanced secretion of aldosterone [1-3].

The neurohumoral activation occurs both as part of the primary disease (as in
heart failure or cirrhosis) and as a consequence of diuretic-induced fluid loss.
One consequence of activating compensatory sodium-retaining mechanisms
as soon as the extracellular fluid volume falls is that the maximum response to
an intravenous diuretic is seen with the first dose (show figure 2); even with
continuous infusion, the natriuresis begins to diminish within the first 12 hours
[12]. Similar considerations apply to oral therapy assuming no defect in drug
absorption. (See "Time course of diuretic-induced electrolyte complications").

Two strategies may be helpful in overcoming this increment in sodium
reabsorption at non-diuretic-sensitive sites. The efficacy of either of these
regimens is enhanced with concurrent sodium restriction; diuretics only
transiently reverse the sodium-avid state and substantial sodium retention
can occur when the diuretic effect wears off [19].

If the patient has a partial but inadequate diuresis, the loop diuretic can be
given twice or even three times a day.

Sodium reabsorption can be blocked at multiple sites within the nephron by
the concurrent administration of a thiazide diuretic to block distal reabsorption;
a potassium-sparing diuretic can also be added, more to prevent potassium
wasting than to significantly increase the diuresis) [3,20-23]. (Chlorothiazide is
the only thiazide in that can be given intravenously; however, its availability is
limited and a rapidly absorbed oral preparation, such as hydrochlorothiazide
should be given). Combination therapy, must be given with careful initial
monitoring, since an excessive diuresis can occur in which daily sodium and
potassium losses can be greater than 500 meq and 200 meq, respectively [22].
(See "Mechanism of action of diuretics").

The timing of combination therapy depends upon the route by which the
diuretics are given. The drugs can be administered at the same time if given by
the same route (intravenous or oral). If, however, a thiazide such as
hydrochlorothiazide is given orally with an intravenous loop diuretic, then the
thiazide should precede the loop diuretic by 30 to 60 minutes.

It has been suggested that metolazone is the thiazide of choice in refractory
patients with advanced renal failure (GFR below 20 mL/min), since other
thiazide-type drugs were thought to be ineffective in this setting [24]. This
report, however, used extremely high doses (the equivalent of 200 to 1500 mg
of hydrochlorothiazide). There is at present no convincing evidence that
metolazone has any unique efficacy when comparable doses are given [3].
Furthermore, a thiazide may be effective in patients with renal failure at normal
doses when given with a loop diuretic [20,21].

One study, for example, evaluated 10 patients with a mean creatinine
clearance of 13 mL/min [21]. The loop diuretic torsemide, in a dose of 50 mg
(equivalent to 150 to 200 mg of furosemide), increased cumulative sodium
excretion from 154 to 232 meq/day. On a separate day, the administration of
the same dose of torsemide plus the equivalent of 30 mg of
hydrochlorothiazide resulted in a further rise in sodium excretion to 290
meq/day. The added natriuresis induced by the longer acting thiazide occurred
both while torsemide was acting and after its effect had worn off.

Use of dopamine It has been proposed that the natriuretic and renal
vasodilator activity of dopamine can be used to potentiate the effect of diuretics
in patients with resistant edema. (See "Renal actions of dopamine"). There is
little published data on this subject. One report evaluated six patients with
stable congestive heart failure (New York Heart Association class II and III)
[25]. The following results were obtained:

Baseline sodium excretion increased from 7 to 37 meq per three hours with
dopamine (1 to 3 g/kg per min as tolerated).
A furosemide infusion produced a much larger natriuresis to 277 meq per
three hours
The addition of dopamine to furosemide had no effect.

Thus, this study does not support a significant role of dopamine which also
requires intravenous therapy in a monitored setting. However, the lack of
potentiation in these stable patients with moderate disease does not
necessarily preclude some benefit in more severely affected patients.

HEMOFILTRATION Some patients with advanced heart failure or renal
failure will not respond to any of the above modalities. In this setting, the
excess fluid can be removed by dialysis or hemofiltration [26-28]. With
hemofiltration, either arterial pressure (from a catheter inserted into an artery)
or an external pump (with blood coming from a catheter inserted into a large
vein) can be used to perfuse a hemofilter (similar to a dialysis cartridge); the
blood leaving the filter then returns to the patient through a separate venous
catheter. (See "Continuous renal replacement therapies: Overview").

The rate of fluid removal (called ultrafiltration) can exceed 500 to 1000 mL/h in
this setting and careful monitoring is required to prevent volume depletion. It
might be expected that the hemodynamic consequences after hemofiltration
would be similar to those induced by fluid removal with diuretics: decreases in
cardiac filling pressures and cardiac output; and increased activation of the
renin-angiotensin and sympathetic nervous systems [28]. (See "Use of
diuretics in congestive heart failure"). However, some patients treated with
hemofiltration have a sustained increase in urine output and a late decrease in
neurohumoral activation [27,28]. Why this might occur is not clear.

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