CASE 25-1, QUESTION 4: The 24-hour urinary electrolytes for R.W. were as follows:
Why would sodium or water restriction be appropriate (or inappropriate) for R.W.?
Normally, urine electrolytes mirror serum electrolytes (i.e., sodium concentration
is greater than that of potassium). A reversal of this pattern (i.e., potassium exceeding
sodium) may indicate a relative hyperaldosteronism secondary to diminished renal
blood flow and low oncotic pressure. A small study by Trevisani et al.
renal sodium and potassium handling and plasma aldosterone in a 24-hour period in
cirrhotic patients without ascites, with ascites, and healthy controls. Plasma
aldosterone was significantly higher in patients with ascites, resulting in reduced
renal sodium excretion, and more than doubling renal potassium excretion in
comparison to healthy controls.
43 For urine electrolyte monitoring to be meaningful,
the first sample must be obtained before initiating diuretics.
Although serum sodium in patients with ascites is often low, they are total body
sodium overloaded. Sodium restriction has been shown to enhance mobilization of
ascites, because fluid loss and weight change are directly related to sodium balance
in patients with portal-hypertension–related ascites.
incorporated into the American Association for the Study of Liver Diseases
(AASLD) guidelines for the treatment of ascites. The AASLD recommends that
dietary sodium should be restricted to 2,000 mg/day (88 mmol/day) and R.W. should
be advised to limit his sodium intake accordingly.
38 Historically, bed rest has been
advocated; however, no controlled trials support this practice.
A large prospective, observational study
reported that hyponatremia (sodium <135
mEq/L) is common in patients with cirrhosis, associated with poor ascites control
and a greater frequency of hepatic encephalopathy, hepatorenal syndrome, and
spontaneous bacterial peritonitis compared to patients with normal serum sodium
In addition, very low serum sodium concentrations (<120 mEq/L)
are independent from the MELD score in predicting 3- to 6-month mortality. The
AASLD recommends that water restriction should be implemented in cirrhotic
patients who have severe dilutional hyponatremia (serum Na <125 mEq/L).
restriction is not indicated for R.W. at this time because his serum sodium
concentration is within normal limits (135 mEq/L).
VASOPRESSIN RECEPTOR ANTAGONISTS
A complete discussion of vasopressin receptor antagonists can be found in Chapter
27, Fluid and Electrolyte Disorders. The AASLD guidelines do not recommend the
use of vasopressin (V2) receptor antagonists because of the lack of evidence of
with cirrhosis, side effects, as well as the low cost-effectiveness of these
38 However, it is possible that with more evidence from clinical trials,
this class of medications may find a niche in the treatment of hyponatremia in
other diuretics in the treatment of ascites?
Most patients with cirrhosis have elevated plasma concentrations of aldosterone.
High serum concentrations of aldosterone may be attributed to both increased
production and decreased excretion of the hormone. Increased portal pressure,
ascites, depletion of intravascular volume, and decreased renal perfusion can lead to
In addition, hepatic shunting also increases aldosterone
production by decreasing renal blood flow.
50 The liver metabolizes aldosterone, and
hepatic impairment prolongs the physiologic half-life of aldosterone.
consensus guidelines recommend the use of spironolactone as the initial diuretic of
choice in the treatment of ascites.
38 Although no large comparative studies have
evaluated different diuretics as first-line treatment of ascites, spironolactone is a
rational diuretic choice for R.W. based on its aldosterone antagonist activity. PerezAyuso et al.
52 conducted a small randomized trial to study the efficacy of furosemide
versus spironolactone in non-azotemic cirrhotic patients with ascites. They reported
a higher response to spironolactone than furosemide (18/19 vs. 11/21; p < 0.01). Of
the 10 nonresponders to furosemide, 9 responded to spironolactone. The authors also
found that patients with higher renin and aldosterone levels did not respond to
furosemide and required higher doses of spironolactone to achieve a diuretic
Some clinicians may initiate spironolactone at a dose of 25 mg once or twice
daily; however, much larger doses (100–400 mg/day) are generally necessary to
antagonize the high circulating levels of aldosterone in patients with ascites.
diuretic effect is enhanced when spironolactone is combined with sodium
In addition, furosemide can be started to minimize the risk of
hyperkalemia and enhance diuresis. The AASLD guidelines recommend starting
spironolactone 100 mg and furosemide 40 mg/day simultaneously and maintaining a
100:40 mg ratio. The doses of both oral diuretics can be increased simultaneously
every 3 to 5 days (maintaining the ratio) to achieve adequate response. Usual
maximal doses are 400 mg/day of spironolactone and 160 mg/day of furosemide.
patients without renal failure, sodium restriction and diuretic therapy are effective in
Triamterene and amiloride can be used as alternatives to spironolactone if
intolerable side effects (e.g., gynecomastia) occur with spironolactone.
56 non-azotemic, cirrhotic patients with ascites were randomly assigned to
receive amiloride (20–60 mg/day) or potassium canrenoate (150–500 mg/day, an
active metabolite of spironolactone not available in the United States). A higher
response rate was seen in the canrenoate group versus the amiloride group (14/20 vs.
7/20; p < 0.025). The authors also assessed plasma aldosterone activity and found
that all responders to amiloride had normal plasma aldosterone concentrations, and
all nonresponders to amiloride who later responded to potassium canrenoate had
increased levels of plasma aldosterone.
Eplerenone (a selective aldosterone blocker, more specific for the aldosterone
receptor with a lower affinity for progesterone and androgen receptors than
spironolactone) has been studied in patients with heart failure, hypertension, and
57,58 The usual dose for eplerenone is 25 to 50 mg/day,
adjustment needed in mild-to-moderate liver disease. However, severe liver disease
60 Approximately 10% of patients treated with spironolactone
develop gynecomastia or breast pain, with 2% requiring drug discontinuation.
contrast, gynecomastia occurs at a similar rate with eplerenone as with placebo
62,63 Unfortunately, eplerenone is much more expensive than spironolactone.
The lower risk of gynecomastia with eplerenone may make it a useful alternative to
spironolactone; however, given its higher cost and the lack of data in the treatment of
ascites in patients with severe liver disease, its role in ascites treatment remains
R.W. should receive spironolactone 100 mg and furosemide 40 mg simultaneously
(maintaining a 100:40 mg ratio) as recommended by the AASLD.
carefully monitored for diuretic complications and clinical response (see Case 25-1,
CASE 25-1, QUESTION 6: What clinical responses should be monitored to ensure the therapeutic
effectiveness of spironolactone therapy for R.W.?
Because ascitic fluid is slow to re-equilibrate with vascular fluid, diuresis greater
than 0.5 to 1 kg/day (>0.5–1 L) may be associated with volume depletion,
hypotension, and compromised renal function.
38 Patients may tolerate a faster diuresis
if peripheral edema is present. Once edema has resolved, a scaled-back weight loss,
not to exceed 0.5 kg/day, can be used as a rule of thumb to minimize the risk of renal
insufficiency induced by plasma volume contraction and other diuretic-induced
38,64 Monitoring body weight and abdominal girth are routinely
performed in both the inpatient and outpatient settings. Monitoring fluid intake and
urine output are performed primarily for inpatients, owing to practical constraints in
the outpatient setting. Ideally, urine output should exceed fluid intake by about 300 to
1,000 mL/day. These measurements do not account for nonrenal fluid losses;
therefore, total fluid loss will be somewhat higher. Abdominal girth measurement
(circumference around the abdomen) is subject to error, because of its dependence on
patient position and measurement location on the abdomen.
made to standardize patient position (e.g., sitting at a 45-degree angle) and location
of measurement (level of umbilicus) to minimize variability in abdominal girth
CASE 25-1, QUESTION 7: What laboratory parameters could be monitored to assess the therapeutic
efficacy of R.W.’s spironolactone treatment?
Serum concentrations of creatinine and urine chemistries (sodium and potassium)
can be monitored to define and guide the need for increasing dosage of
spironolactone. A low baseline urine Na:K ratio (<1.0) suggests high intrinsic
aldosterone activity and that larger dosages of spironolactone may be needed, as is
the case for R.W. If necessary, the dosage of diuretic therapy may be doubled after a
49 AASLD recommends increasing both spironolactone and furosemide
simultaneously every 3 to 5 days (maintaining a 100:40 mg ratio) to achieve adequate
diuresis and maintain a normal serum potassium.
DIURETIC COMPLICATIONS AND MANAGEMENT
CASE 25-1, QUESTION 8: The spironolactone and furosemide dosages were increased to 200 and 80
R.W. and how can they be minimized?
Electrolyte and Acid–Base Disturbances
Hyponatremia, hyperkalemia, metabolic alkalosis, and, uncommonly, hypokalemia
occur as side effects of diuretic therapy in patients with ascites. Hyponatremia results
from a reduction in free water clearance (dilutional hyponatremia). Diuresis
exacerbates hyponatremia by causing volume depletion and antidiuretic hormone
(ADH) release. Hyponatremia usually can be corrected by temporary withdrawal of
diuretics and free water restriction.
53,66–68 Although serum sodium may be low, these
patients are total body sodium overloaded. Hyperkalemia is common in patients with
refractory ascites and impaired renal function requiring high doses of diuretics such
as spironolactone. Hyperkalemia can be approached in multiple ways, depending on
the clinical situation (see Chapter 27, Fluid and Electrolyte Disorders). Furosemide
is added to spironolactone to maintain normal serum potassium.
holding spironolactone may be appropriate depending on the patient’s renal function
24 Metabolic alkalosis, a result of loop diuretics, occurs
because of increased urinary hydrogen loss from enhanced distal hydrogen secretion.
Hypokalemia often accompanies metabolic alkalosis owing to loop diuretics.
Furosemide can be temporarily withheld in patients presenting with hypokalemia.
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