The mechanisms that lead to the development of ascites are many, and controversy still exists regarding which factors are most important. The most common cause of nonmalignant ascites is cirrhosis of the liver. In cirrhotic ascites, abnormal sodium retention is mediated by various hormonal and neural mechanisms, similar to those responsible for excess fluid retention in congestive heart failure (CHF). A hemodynamic state exists where total blood volume is increased, cardiac output is increased, and systemic vascular resistance is low. Studies have implicated nitric oxide as one of the potential mediators of this arterial vasodilation (5). In response, the vasoconstrictors of the renin-angiotensin-aldosterone system and the sympathetic nervous system are activated. Although atrial natriuretic peptide levels are increased, there is reduced renal responsiveness (6). In addition, arginine vasopressin, a potent vasoconstrictor, is activated in a manner independent of the osmotic state (7). The net result is an increase in total body sodium and water. In conjunction with cirrhosis, which has caused increased hepatic venous and lymphatic resistance, severe portal hypertension ensues. The increase in hepatic venous sinusoidal and portal pressures causes the excess fluid volume to localize to the peritoneal cavity secondary to fluid transudation from the splanchnic capillary bed. Ascites accumulation is also exacerbated by diminished intravascular oncotic pressure, resulting from hypoalbuminemia due to decreased synthetic capacity of the cirrhotic liver.

Malignant ascites arises through pathophysiologic mechanisms different from those of nonmalignant ascites. First, in peritoneal carcinomatosis, neovascularization and subsequent “leak” from vessels is thought to play a prime role in ascites development. Researchers have identified a vascular growth and permeability factor that increases fluid leak from peritoneal vasculature; vascular endothelial growth factor (VEGF) is a prime candidate for this activity (8). Compared with cirrhotic ascites, high levels of VEGF are present in malignant ascites from gastric, colon, and ovarian cancers (9). In animal models, inhibiting the tyrosine kinase activity of VEGF receptors reduced ascites formation (10). Matrix metalloproteinases (MMPs) also appear to be involved in this process. Breaking down the extracellular matrix is an important step in neovascularization and metastatic spread. In animal models, MMP inhibitors significantly reduced malignant ascites (11). Second, portal pressures may be raised by direct tumor invasion of the liver with resultant hepatic venous obstruction. The resultant portal hypertension leads to transudation of fluid across the splanchnic bed into the abdominal cavity similar to cirrhotic ascites. A final mechanism of ascites formation is due to lymphatic obstruction, commonly caused by lymphoma, resulting in chylous ascites.

The dietary management of ascites with a high SAAG begins with sodium restriction. Patients with cirrhosis may excrete as little as 5 to 10 mEq of sodium/d in their urine. Limiting sodium intake to 88 mmol or 2 g/d (equivalent to 5 g of
sodium chloride/d) is an attainable goal for a motivated patient, but it does make food less palatable. Considering a patient’s goals of care, it may be better to liberalize the sodium intake and control ascites through other methods.

Patients are also prone to develop dilutional hyponatremia. The management of this condition has typically been by fluid restriction to 1 L/d. In the patient with advanced disease, when treatment goals are purely palliative, fluid restriction is usually intolerably burdensome. Judicious medical management may be less burdensome. For patients with cirrhotic ascites, serum sodium levels as low as 120 mmol/L are well tolerated and rarely dictate intervention (1).

For the majority of patients, the pharmacologic management of ascites is palliative. That is, the goal of therapy is to minimize symptoms and optimize quality of life without the expectation that the underlying cause can be reversed.

Systemic chemotherapy may be an effective management strategy for patients with malignant ascites due to a responsive cancer (e.g., lymphoma, breast, or ovarian cancer). In addition to systemic chemotherapy, intraperitoneal chemotherapy is an option. In theory, intraperitoneal chemotherapy can deliver high doses to peritoneal sites with minimal systemic side effects. In practice, intraperitoneal chemotherapy is often limited by uneven distribution and poor tissue penetration. Hyperthermic intracavitary chemotherapy after surgical debulking may overcome some of these limitations and enhance the cytotoxicity of chemotherapy (20,21). Biologically active agents have also been used intraperitoneally to treat malignant ascites. Early clinical trials have used interferon (IFN)-α, IFN-β, and IFN-γ, tumor necrosis factor, interleukin-2, anti-VEGF antibodies, anti-VEGF receptor antibodies, VEGF receptor tyrosine kinase inhibitors, and metalloproteinase inhibitors. To date, no phase III clinical trials have been performed. Overall, the efficacy and role of intraperitoneal chemotherapeutic and biologic agents in both curative and palliative care remain to be determined.

Diuretic therapy could be useful in patients whose ascites has a high SAAG, as opposed to low SAAG ascites that is typically diuretic unresponsive. As with any drug therapy in the supportive care setting, the patient’s symptoms should first be ascertained and the benefit versus the burden of therapy considered. The goal of diuretic therapy is to reduce extravascular fluid accumulation. Diuretic therapy should be directed to achieve a slow and gradual diuresis that does not exceed the capacity for mobilization of ascitic fluid. In the patient with ascites and edema, edema acts as a fluid
reservoir to buffer the effects of a rapid contraction of plasma volume. Approximately 1 L/d (net) can safely be diuresed. In patients with ascites but without edema, diuresis may be achieved at the expense of the intravascular volume, leading to symptomatic orthostatic hypotension. In these patients, a more modest goal is to achieve net diuresis of 500 mL/d. Diuretics should not be administered with the goal to render the patient free of edema and ascites. Rather, only enough fluid should be mobilized to promote the patient’s comfort. Overly aggressive diuretic therapy for ascites in a patient with high SAAG ascites has been associated with the hepatorenal syndrome and death (22).

For patients with high SAAG ascites in whom diuretics may be helpful, the renin-angiotensin-aldosterone system is activated. Therefore, the initial diuretic of choice for management is one that acts at the distal nephron to block the effect of increased aldosterone activity (23,24). Spironolactone, an aldosterone receptor antagonist, is a first-line therapy. Dosing begins at 100 mg/d and can be titrated up to effect or a maximum of 400 mg/d (Table 16.2). Given spironolactone’s long half-life, daily dosing is sufficient. Spironolactone may cause painful gynecomastia (25). Amiloride hydrochloride, 10 mg/d, is an alternative. It acts faster and does not cause gynecomastia. It can be titrated up to a dose of 40 mg/d. Because these diuretics are relatively potassium sparing, patients should be advised not to use salt substitutes, as these are usually preparations of potassium chloride. If patients have a suboptimal response despite maximal use of the distal diuretics, a loop diuretic may be added, beginning at low doses (e.g., furosemide, 40 mg orally daily). There is evidence to support the combined use of a distal tubule diuretic and a loop diuretic at the beginning of therapy (24). This combination may effect a more rapid diuresis while maintaining potassium homeostasis. A ratio of 100 mg of spironolactone to 40 mg of furosemide is recommended as a starting point (1). The ratio can be adjusted to maintain normokalemia. The dosages can be increased in parallel until the goals of therapy have been attained, up to a maximum of spironolactone, 400 mg/d, and furosemide, 160 mg/d, or until therapy is limited by side effects (1). If there is no response to this level of therapy, the ascites is considered refractory to diuretic therapy if the following are true: (a) salt intake is appropriately limited and (b) nonsteroidal anti-inflammatory medications, which can affect glomerular filtration, are not being used.