Fluid complications by liaoqinmei


									CHAPTER 47

Fluid complications
Frederic W. Grannis, Jr., MD, Lily Lai, MD,
Carey A. Cullinane, MD, and Lawrence D. Wagman, MD

Malignant pleural effusions complicate the care of approximately 150,000 people
in the United States each year. The pleural effusion is usually caused by a dis-
turbance of the normal Starling forces regulating reabsorption of fluid in the
pleural space, secondary to obstruction of mediastinal lymph nodes draining
the parietal pleura. Tumors that metastasize frequently to these nodes, eg, lung
cancer, breast cancer, and lymphoma, cause most malignant effusions. It is,
therefore, puzzling that small-cell lung cancer infrequently causes effusions.
Primary effusion lymphomas caused by human herpesvirus 8 and perhaps
Epstein-Barr virus (EBV) are seen in patients with AIDS.
Pleural effusion restricts ventilation and causes progressive shortness of breath
by compression of lung tissue as well as paradoxical movement of the inverted
diaphragm. Pleural deposits of tumor cause pleuritic pain.
Pleural effusions commonly occur in patients with advanced-stage tumors, who
frequently have metastases to brain, bone, and other organs, physiologic defi-
cits, malnutrition, debilitation, and other comorbidities. Because of these numer-
ous clinical and pathologic variables, it is difficult to perform meaningful trials
in patients with pleural effusions. For the same reason, it is often difficult to
predict a potential treatment outcome for the specific patient with multiple
interrelated clinical problems.

The new onset of a pleural effusion may herald the presence of a previously
undiagnosed malignancy or, more typically, complicate the course of a known
Thoracentesis The first step in management in almost all cases is thoracentesis.
An adequate specimen should be obtained and sent for cell count; determina-
                                                                                      FLUID COMPLICATIONS

tion of glucose, protein, lactic dehydrogenase (LDH), and pH; and appropriate
cultures and cytology. A negative cytology result is not uncommon and does
not rule out a malignant etiology.
The Light criteria (LDH > 200 U/L; pleural-serum LDH ratio > 0.6, and
pleural-serum protein ratio > 0.5) help categorize pleural effusions as exu-

FLUID COMPLICATIONS                                                          1035
                       At Churchill Hospital in Oxford,       dates. The majority of undiagnosed exudates
                       UK, a prospective randomized           are eventually diagnosed as malignant,
                       study of needle biopsy with or         whereas < 5% of transudates are shown to be
                       without CT guidance was                caused by cancer.
                       performed. There was a
                                                     Because it is sometimes difficult to prove the
                       statistically significant difference
                       with regard to specificity andmalignant nature of an effusion, many mo-
                       sensitivity favoring CT-guidedlecular tests on pleural fluid have been inves-
                       biopsy (Maskell NA, Gleeson FV,
                                                     tigated. Multiple reports measure pleural tu-
                       Davies RJO: Lancet 361:1326-1330,
                       2003).                        mor marker proteins, cadherins, matrix
                                                     metalloproteins, cytokines, telomerase,
                                                     mRNA, exosomes, and serum and pleural
                      DNA, but to date, no test or panel of tests can reliably diagnose malignant
                      Pleural biopsy If cytology of an exudative effusion is negative and malignant
                      disease is still suspected (approximately 50% of cases), blind pleural biopsy
                      has a low diagnostic yield that can be improved by CT or ultrasonographic
                      Thoracoscopy Thoracoscopic examination is emerging as a reliable diagnostic
                      technique with a low complication rate. It allows comprehensive visualization of
                      one pleural cavity, coupled with the opportunity to biopsy areas of disease. This
                      method provides a definitive diagnosis and allows the pathologist to suggest pos-
                      sible sites of primary disease based on the histopathology. Furthermore, this tech-
                      nique permits the diagnosis and staging of malignant mesothelioma if it is the
                      cause of the effusion. Thoracoscopy also offers the opportunity for simultaneous
                      Bronchoscopy may be helpful when an underlying lung cancer is suspected,
                      especially if there is associated hemoptysis, a lung mass, atelectasis, or a mas-
                      sive effusion. It may also be helpful when there is a cytologically positive effu-
                      sion with no obvious primary tumor.

                      Prognosis of patients with malignant pleural effusion varies by primary tumor.
                      For example, median survival for patients with lung cancer is 3 months, whereas
                      it is 10 months for patients with breast cancer. Median survival is also shorter in
                      patients with encasement atelectasis (3 months).


                      INITIAL TREATMENT
                      Because the specific clinical circumstances may vary markedly in different pa-
                      tients, treatment must be individualized to provide the best palliation for each
                      patient. In general, malignant pleural effusion should be treated aggressively as
                      soon as it is diagnosed. In most cases, effusion will rapidly recur after treatment
                      by thoracentesis or tube thoracostomy alone. If the clinician decides to ad-

                      1036                               CANCER MANAGEMENT: A MULTIDISCIPLINARY APPROACH
minister systemic chemotherapy for the underlying primary malignancy, in
tumors such as breast cancer, lymphoma, and small-cell lung cancer, it is im-
portant to monitor the patient carefully for recurrent effusion and treat such
recurrences immediately.
If a malignant pleural effusion is left untreated, the underlying collapsed lung
will become encased by tumor and fibrous tissue in as many as 10%-30% of
cases. Once this encasement atelectasis has occurred, the underlying lung is
“trapped” and will no longer reexpand after thoracentesis or tube thoracos-
tomy. Characteristically, the chest x-ray in such cases shows resolution of the
pleural effusion after thoracentesis, but the underlying lung remains partially
collapsed. This finding is often misinterpreted by the inexperienced clinician
as evidence of a pneumothorax, and a chest tube is placed. The air space per-
sists and the lung remains unexpanded, even with high suction and pulmonary
physiotherapy. Allowing the chest tube to remain in place can worsen the situ-
ation, resulting in bronchopleural fistulization and empyema.

Physical techniques
To avoid encasement atelectasis, pleural effusion should be treated definitively
at the time of initial diagnosis. Multiple physical techniques of producing adhe-
sions between the parietal and visceral pleura, obliterating the space, and pre-
venting recurrence have been used. They include open or thoracoscopic
pleurectomy, gauze abrasion, or laser pleurodesis. Surgical methods have not
been demonstrated to have any advantage over simpler chemical pleurodesis
techniques in the treatment of malignant effusions. Gauze abrasion can
easily be employed when unresectable lung cancer with associated effu-
sion is found at the time of thoracotomy.

Chemical agents
Multiple chemical agents have been used.
Tetracycline Tetracycline pleurodesis results in a lower incidence of recurrence
when compared with tube thoracostomy alone but often causes severe pain.
Doxycycline and minocycline are probably equivalent in efficacy to
Bleomycin Intrapleural bleomycin, in a dose of 60 U, has been shown to be
more effective than tetracycline and is not painful, but it is costly. Absorption
of the drug can result in systemic toxicity. Combined use of tetracycline and
bleomycin has been demonstrated to be more efficacious than the use of either
drug singly.
Talc pleurodesis was first introduced by Bethune in the 1930s. Talc powder
(Sclerosol Intrapleural Aerosol) has demonstrated efficacy in numerous large
studies, preventing recurrent effusion in 70%-92% of cases. Talc is less painful
than tetracycline. Cost is minimal, but special sterilization techniques must be
mastered by the hospital pharmacy. Talc formulations may have significant
differences in the size of particles. Smaller particles may be absorbed and dis-
seminated systemically.

FLUID COMPLICATIONS                                                        1037
 Bondoc, from Memorial Sloan-           Talc can be insufflated in a dry state at the time
 Kettering Cancer Center,               of thoracoscopy or instilled as a slurry through
 reviewed 120 patients who had          a chest tube. The dose should be restricted to
 talc pleurodesis for malignant         no more than 5 g.
 pleural effusion. A total of 7%
 developed a syndrome character-        Multiloculated effusions may follow talc use.
 ized by arterial desaturation, chest   It is important to ensure that talc does not so-
 pain, and fever. Three patients        lidify and form a concretion in the chest tube,
 required ventilatory support. All
 patients survived with oxygen
                                        thus preventing the drainage of pleural fluid
 supplementation and high-dose          and complete reexpansion of the lung follow-
 steroids. Patients with breast and     ing pleurodesis. Such an event is more likely
 ovarian cancer appear to be at         when small-bore chest tubes are used.
 higher risk than others (Bondoc AY,
 Bach PB, Sklarin NT, et al: Cancer Pleurodesis technique With any form of
 Invest 21:848-854, 2003). Kwek,    pleurodesis, a 24- to 32-French tube has cus-
 from Massachusetts General         tomarily been inserted through a lower inter-
 Hospital, reported that PET scans
 performed on nine patients, an
                                    costal space and placed on underwater seal
 average of 22 months following     suction drainage until all fluid is drained and
 talc pleurodesis, showed focal     the lung has completely reexpanded. Because
 nodular fluorodeoxyglucose         severe lung damage can be produced by im-
 (FDG) uptake in the pleura (mean   proper chest tube placement, it is imperative
 standard error of mean 5.4; range:
 1.2-16; Kwek BH, Aquino SL,        to prove the presence of free fluid by a
 Fischman AJ: Chest 125:2356-2360,  preliminary needle tap and to enter the pleu-
 2004).                             ral space gently with a blunt clamp technique,
                                    rather than by blind trocar insertion. If there
is any question about the presence of loculated effusion or underlying adhe-
sions, the use of CT or sonography may enhance the safety of the procedure. In
the case of large effusions, especially those that have been present for some
time, the fluid should be drained slowly to avoid reexpansion pulmonary edema.
Significant complications can occur with both thoracentesis and chest tube tho-
racostomy. These procedures should not be performed by inexperienced prac-
titioners without training and supervision.
Premedications If doxycycline or talc is to be used, the patient should be pre-
medicated with narcotics. Intrapleural instillation of 20 mL of 1% lidocaine
before administration of the chemical agent may help reduce pain.
Following instillation of the chemical agent, the chest tube should remain clamped
for at least 2 hours. If high-volume drainage persists, the treatment can be
repeated. The chest tube can be removed after 2 or 3 days if drainage is < 300
Follow-up x-rays at monthly intervals assess the adequacy of treatment and al-
low early retreatment in case of recurrence.
Alternative approaches Use of small-bore tubes and outpatient pleurodesis
has been advocated by some investigators and has the potential for reducing
hospital stay and treatment cost. Patz performed a prospective, randomized
trial of bleomycin vs doxycycline (72% bleomycin vs 79% doxycycline)
pleurodesis via a 14-French catheter and found no difference in efficacy.

Other approaches that must be considered experimental at this time include
silver nitrate pleurodesis and the use of various biologic agents, including Coryne-
bacterium parvum, OK-432, tumor necrosis factor, interleukin-2 (Proleukin), in-
terferon-α (Intron A, Roferon-A), interferon-β (Betaseron), and interferon-γ

If encasement atelectasis is found at thoracentesis or thoracoscopy, tube tho-
racostomy and pleurodesis are futile and contraindicated.
Surgical decortication has been advocated for this problem. This potentially
dangerous procedure may result in severe complications, however, such as bron-
chopleural fistula and empyema.
Pleuroperitoneal shunts The Royal Brompton Hospital, London, group re-
ported experience with pleuroperitoneal shunts in 160 patients with malignant
pleural effusion and a trapped lung. Effective palliation was achieved in 95% of
patients; 15% of patients required shunt revisions for complications.
Intermittent thoracentesis, as needed to relieve symptoms, may be the best
option in patients with a short anticipated survival.
Catheter drainage Another new option is to insert a tunneled, small-bore,
cuffed, silicone catheter (PleurX pleural catheter, Denver Biomaterials, Inc.,
Denver, Colorado) into the pleural cavity. The patient or family members may
then drain fluid, using vacuum bottles, whenever recurrent effusion causes
Kakuda reported on placement of 61 PleurX pleural catheters in 50 patients
with malignant pleural effusions at City of Hope. Thirty-four percent had lung
cancer and 24% had breast cancer. There were no operative deaths. In cases
where the catheter was placed under thoracoscopic control, 27 of 38 patients
(68%) had encasement atelectasis visualized. Eighty-one percent had a good
result with control of effusion, with subsequent catheter removal (19%) or inter-
mittent drainage for > 1 month or until death (62%). Five percent of patients
had major complications, including empyema and tumor implant.
Putnam prospectively compared PleurX cath-
eter drainage with doxycycline pleurodesis         In Taiwan, Su treated 27 patients
and found the two to be equally effective.         with NSCLC presenting with a
                                                   malignant pleural effusion with a
Chemotherapy options depend on the cell            regimen of intrapleural cisplatin
type of the tumor and the general condition        and gemcitabine, followed by
of the patient. Although intrapleural chemo-       radiotherapy (7,020 cGy in 39
                                                   fractions), and completed with IV
therapy offers the possibility of high-dose        docetaxel. Only two patients
local therapy with minimal systemic effects,       experienced recurrent pleural
only a few, small pilot studies utilizing          effusion. The median disease-free
mitoxantrone (Novantrone), doxorubicin, and        and overall survival rates were 8
                                                   and 16 months, respectively, and
hyperthermic cisplatin have been published.        63% of patients were alive at 1
Ang and colleagues from Singapore reported         year (Su WC, Lai WW, Chen HH, et
longer mean survival (12 vs 5 months) when         al: Oncology 64:18-24, 2003).

FLUID COMPLICATIONS                                                              1039
systemic chemotherapy was given to 71 patients who initially presented with ma-
lignant pleural/pericardial effusions. New studies in this area are much needed.
Radiation therapy may be indicated in some patients with lymphoma but has
limited effectiveness in other tumor types, particularly if mediastinal adenopathy is
Chylothorax not due to trauma is usually secondary to cancer, most frequently
lymphoma. An added element of morbidity is conferred by the loss of protein,
calories, and lymphocytes in the draining fluid. Chylothorax secondary to lym-
phoma is usually of low volume and responds to talc pleurodesis in combina-
tion with radiotherapy or chemotherapy.

Pericardial effusion develops in 5%-15% of patients with cancer and is some-
times the initial manifestation of malignancy. Most pericardial effusions in can-
cer patients result from obstruction of the lymphatic drainage of the heart sec-
ondary to metastases. The typical presentation is that of a patient with known
cancer who is found to have a large pericardial effusion without signs of inflam-
mation. Bloody pericardial fluid is not a reliable sign of malignant effusion.
The most common malignant causes of pericardial effusions are lung and breast
cancers, leukemias (specifically acute myelogenous, lymphoblastic, and chronic
myelogenous leukemia [blast crisis]), and lymphomas.
Not all pericardial effusions associated with cancer are malignant, and cases
with negative cytology may represent as many as half of cancer-associated peri-
cardial effusions. Such effusions are more common in patients with mediastinal
lymphoma, Hodgkin’s disease, or breast cancer. Other nonmalignant causes
include drug-induced or postirradiation pericarditis, tuberculosis, collagen dis-
eases, uremia, and congestive heart failure. Many effusions that initially have
                                   negative cytology will become positive over
 Tomkowski et al from Warsaw,      time.
 Poland, described treatment of
 malignant pericardial effusion in       Tamponade occurs when fluid accumulates
 46 patients using intrapericardial      faster than the pericardium can stretch. Com-
 instillation of cisplatin (1-50 mg)     pression of all four heart chambers ensues, with
 following pericardiocentesis or a       tachycardia and diminishing cardiac output.
 thoracoscopic window. Atrial
                                         Fluid loading can counteract intrapericardial
 fibrillation occurred in15%. A total
 of 82% of patients survived longer      pressure temporarily. Reciprocal filling of
 than 1 month; the median survival       right- and left-sided chambers with inspiration
 in these patients was 102 days.         and expiration, secondary to paradoxical
 They consider the technique to          movement of the ventricular septum, is a final
 be safe and effective in the
 treatment of recurrent malignant        mechanism to maintain blood flow before
 pericardial effusion, particularly in   death.
 patients with lung cancer
 (Tomokowski WZ, Wisniewska J,
 Szturmowicz M, et al: Support Care
 Cancer 12:53-57, 2004).

A high index of suspicion is required to make the diagnosis of pericardial effusion.
Signs and symptoms Dyspnea is the most common symptom. Patients may
also complain of chest pain or discomfort, easy fatigability, cough, and orthop-
nea or may be completely asymptomatic. Signs include distant heart sounds
and pericardial friction rub. With cardiac tamponade, progressive heart failure
occurs, with increased shortness of breath, cold sweats, confusion, pulsus
paradoxus > 13 mm Hg, jugular venous distention, and hypotension.
Chest x-ray Chest radiographic evidence of pericardial effusion includes car-
diomegaly with a “water bottle” heart; an irregular, nodular contour of the
cardiac shadow; and mediastinal widening.
ECG The ECG shows nonspecific ST- and T-wave changes, tachycardia, low
QRS voltage, electrical alternans, and atrial dysrhythmia.
Pericardiocentesis and echocardiography An echocardiogram not only can
confirm a suspected pericardial effusion but also can document the size of the
effusion and its effect on ventricular function. A pericardial tap with cytologic
examination (positive in 50%-85% of cases with associated malignancy) will
confirm the diagnosis of malignant effusion or differentiate it from other causes
of pericardial effusion. Serious complications, including cardiac perforation
and death, can occur during pericardiocentesis, even when performed with
echocardiographic guidance by experienced clinicians.
Tumor markers or special staining and cytogenetic techniques may improve the
diagnostic yield, but ultimately an open pericardial biopsy may be necessary.
CT and MRI as diagnostic adjuncts may provide additional information about
the presence and location of loculations or mass lesions within the pericardium
and adjacent structures.
Cardiac catheterization may occasionally be of value to rule out superior
vena caval obstruction, diagnose microvascular tumor spread in the lungs with
secondary pulmonary hypertension, and document constrictive pericarditis
before surgical intervention. Pericardial fluid has been aspirated in experimen-
tal animals by femoral vein catheterization and needle puncture of the right
atrial appendage from within. This technique has not been used in humans.
Pericardioscopy allows visualization and biopsy at the time of subxiphoid or
thoracoscopic pericardiotomy and can improve the diagnostic yield.

In general, cancer patients who develop a significant pericardial effusion have
a high mortality, with a mean time to death of 2.2-4.7 months. However,
about 25% of selected patients treated surgically for cardiac tamponade enjoy a
1-year survival.

FLUID COMPLICATIONS                                                           1041

As is the case with malignant pleural effusion, it is difficult to evaluate treat-
ments for pericardial effusion because of the many variables. Since malignant
pericardial effusion is less common than malignant pleural effusion, it is more
difficult to collect data in a prospective manner. Certain generalizations can,
however, be derived from available data:
     ■   All cancer patients with pericardial effusion require a systematic evalu-
         ation and should not be dismissed summarily as having an untreatable
         and/or terminal problem.
     ■   Ultimately, both the management and natural course of the effusion
         depend on (1) the underlying condition of the patient, (2) the extent of
         clinical symptoms associated with the cardiac compression, and (3) the
         type and extent of the underlying malignant disease.

Asymptomatic, small effusions may be managed with careful follow-up and
treatment directed against the underlying malignancy. On the other hand, car-
diac tamponade is a true oncologic emergency. Immediate pericardiocentesis,
under echocardiographic guidance, may be performed to relieve the patient’s
symptoms. A high failure rate is anticipated because the effusion rapidly recurs
unless steps are taken to prevent this. Therefore, a more definitive treatment
plan should be made following the initial diagnostic/therapeutic tap.
In patients with symptomatic, moderate-to-large effusions who do not present
as an emergency, therapy should be aimed at relieving symptoms and pre-
venting recurrence of tamponade or constrictive pericardial disease. Patients
with tumors responsive to chemotherapy or radiation therapy may attain longer
remissions with appropriate therapy.
There are two theoretical mechanisms for control of pericardial effusion: creation
of a persistent defect in the pericardium allowing fluid to drain out and be reab-
sorbed by surrounding tissues or injury to the mesothelium resulting in the forma-
tion of fibrous adhesions that obliterate the pericardial cavity.
Postmortem studies have demonstrated that both of these mechanisms are op-
erative. The fact that effusions can recur implies that there is either insufficient
damage to the mesothelial layer or that rapid recurrence of effusion prevents
coaptation of visceral and parietal pericardium and prevents the formation of
adhesions. This, in turn, would suggest that early closure of the pericardial
defect can result in recurrence.

Various methods can be used to treat malignant pericardial effusion.
Observation Observation alone may be reasonable in the presence of small
asymptomatic effusions.

Pericardiocentesis is useful in relieving tamponade and obtaining a diag-
nosis. Echocardiographic guidance considerably enhances the safety of this pro-
cedure. Ninety percent of pericardial effusions will recur within 3 months after
pericardiocentesis alone, with a short median survival.
Pericardiocentesis and percutaneous tube drainage can now be performed
with low risk and are recommended by some clinical groups. Problems that
may occur include occlusion or displacement of the small-bore tubes, dysrhyth-
mia, recurrent effusion, and infections. Mayo Clinic cardiologists recommend
initial percutaneous pericardiocentesis with extended catheter drainage as their
technique of choice.

Intrapericardial sclerotherapy and chemotherapy following percutaneous or
open drainage have been reported to be effective treatments by some groups. Prob-
lems include pain during sclerosing agent treatments and recurrence of effu-
sions. Good results have been reported with instillation of a number of agents,
including bleomycin (10 mg), cisplatin (30 mg), and mitoxantrone (10-20 mg).
Agents are selected based on their antitumor or sclerosing effect.
Pericardiocentesis and balloon pericardial window After percutaneous
placement of a guidewire following pericardiocentesis, a balloon dilating cath-
eter can be placed across the pericardium under fluoroscopic guidance and a win-
dow created by balloon inflation.
At the National Taiwan University, cardiologists performed percutaneous double-
balloon pericardiotomy in 50 patients with can-
cer and pericardial effusion and followed their At City of Hope, Cullinane et al
course using serial echocardiograms. Success reported on 62 patients with
without recurrence was achieved in 88%. Fifty malignant disease who had
                                                  surgical pericardial window for
percent of patients died within 4 months, and management of pericardial
25% survived to 11 months.                        effusion. Windows were created
Subtotal pericardial resection is seldom                either thoracoscopically (32) or
                                                        by subxiphoid (12) or limited
performed today. Although it is the definitive          thoracotomy (18) approaches.
treatment, in that there is almost no chance of         Primary tumors included NSCLC,
recurrence or constriction, higher morbidity            breast, hematologic, and other
and longer recovery time render this opera-             solid-organ malignancies. Three
                                                        recurrent effusions (4.8%)
tion undesirable in patients who have a short           required reoperations. Eight
anticipated survival. Its use is restricted to can-     patients (13%) died during the
cer patients with recurrent effusions who are           same admission as their surgical
in good overall condition and are expected to           procedure. Median survival was
survive for up to 1 year.                               much shorter for patients with
                                                        NSCLC (2.6 mo) than for patients
Limited pericardial resection (pericardial win-         with breast cancer (11 months)
dow) via anterior thoracotomy or a thoracoscopic        or hematologic malignancy (10
                                                        months). Surgical pericardial
approach has a lower morbidity than less invasive       window is a safe and durable
techniques, but recovery is delayed. There is a small   operative procedure that may
risk of recurrence. Cardiac herniation is possible if   provide extended survival in
the size of the opening in the pericardium is not       certain subgroups of cancer
carefully controlled.                                   patients (Cullinane CA, Paz, IB, Smith
                                                        D: Chest 125:1328-1334, 2004).

FLUID COMPLICATIONS                                                                      1043
Subxiphoid pericardial resection can be performed with the patient un-
der local anesthesia and may be combined with tube drainage and/or peri-
cardial sclerosis. Our group and others have noted recurrences following
this technique.
Subxiphoid pericardioperitoneal window through the fused portion of the
diaphragm and pericardium has been developed to allow continued drainage
of pericardial fluid into the peritoneum. Experience with the procedure is lim-
ited, but recurrences may be less frequent than those associated with subxiphoid
drainage alone.
Technical factors Prior pleurodesis for malignant pleural effusion makes an
ipsilateral transpleural operation difficult or impossible. In lung cancer patients,
major airway obstruction may preclude single-lung anesthesia and, thus, thora-
coscopic pericardiectomy. Prior median sternotomy may prohibit the use of a
subxiphoid approach.
Complications A 30-day mortality rate of 10% or higher has been reported
for all of these modalities but is related more to the gravity of the underlying
tumor and its sequelae. A small percentage of patients will develop severe prob-
lems with pulmonary edema or cardiogenic shock following pericardial de-
compression. The mechanisms of these problems are poorly understood. Late
neoplastic pericardial constriction can occur following initially successful par-
tial pericardiectomy.

External-beam irradiation is utilized infrequently in this clinical setting but may
be an important option in specialized circumstances, especially in patients with
radiosensitive tumors who have not received prior radiation therapy. Responses
ranging from 66% to 93% have been reported with this form of treatment,
depending on the type of associated tumor.

Systemic therapy
Chemotherapy Systemic chemotherapy is effective in treating pericardial ef-
fusions in patients with lymphomas, hematologic malignancies, or breast
cancer. Long-term survival can be attained in these patients. If the pericardial
effusion is small and/or asymptomatic, invasive treatment may be omitted in
some of these cases. Data regarding the effectiveness of systemic chemotherapy
or chemotherapy delivered locally in prevention of recurrent pericardial and
pleural effusion are limited. New studies in this area are badly needed.
Biologic therapy with various agents is in the early stages of investigation.

Malignant ascites results when there is an imbalance in the secretion of pro-
teins and cells into the peritoneal cavity and absorption of fluids via the lym-
phatic system. Greater capillary permeability as a result of the release of cytokines
by malignant cells increases the protein concentration in the peritoneal fluid.

Recently, several studies have demonstrated higher levels of VEGF, a cytokine
known to cause capillary leak, in the sera and effusions of patients with malig-

Signs and symptoms
Patients with malignant ascites usually present with anorexia, nausea, respira-
tory compromise, and immobility. Complaints of abdominal bloating, heavi-
ness, and ill-fitting clothes are common. Weight gain despite muscle wasting is
a prominent sign.

A malignant etiology accounts for only 10% of all cases of ascites. Nonmalig-
nant diseases causing ascites include liver failure, congestive heart failure, and
occlusion of the inferior vena cava or hepatic vein. About one-third of all pa-
tients with malignancies will develop ascites. Malignant ascites has been de-
scribed with many tumor types but is most commonly seen with gynecologic
neoplasms (~50%), GI malignancies (20%-25%), and breast cancer (10%-18%).
In 15%-30% of patients, the ascites is associated with diffuse carcinomatosis of
the peritoneal cavity.
Physical examination does not distinguish whether ascites is due to malignant
or benign conditions. Patients may have abdominal fullness with fluid wave,
anterior distribution of the normal abdominal tympany, and pedal edema. Oc-
casionally, the hepatic metastases or tumor nodules studding the peritoneal
surface can be palpated through the abdominal wall, which has been altered by
ascitic distention.

Radiographs Ascites can be inferred from plain radiographs of the abdomen.
Signs include a ground-glass pattern and centralization of the intestines and ab-
dominal contents.
Ultrasonography Abdominal ultrasonography has been shown to be the most
sensitive, most specific method for detecting and quantifying ascites. It also per-
mits delineation of areas of loculation.
CT Abdominal and pelvic CT is very effective in detecting ascites. In addition,
CT scans may demonstrate masses, mesenteric stranding, omental studding,
and diffuse carcinomatosis. Intravenous and oral contrasts are necessary, thus
increasing the degree of invasiveness of this modality.
Paracentesis After the diagnosis of peritoneal ascites has been made on the
basis of the physical examination and imaging, paracentesis should be per-
formed to characterize the fluid. The color and nature of the fluid often suggest
the diagnosis. Malignant ascites can be bloody, opaque, chylous, or serous.
Benign ascites is usually serous and clear.

FLUID COMPLICATIONS                                                          1045
Analysis of the fluid should include cell count, cytology, LDH level, proteins,
and appropriate evaluation for infectious etiologies. In addition, the fluid can
be sent for the determination of tumor markers, such as CEA, CA-125, and p53,
and human chorionic gonadotropin-β (hCG-β). The hCG-β level is frequently
elevated in malignancy-related ascites and has been combined with cytology to
yield an 89.5% efficiency in diagnosis. The use of DNA ploidy indices allowed
a 98.5% sensitivity and a 100% sensitivity in the identification of malignant
cells within ascitic fluid. The use of the telomerase assay, along with cytologic
evaluation of the ascitic fluid contents, has a 77% sensitivity in detecting malig-
nant ascites.
Laparoscopy Several studies have utilized minimally invasive laparoscopy as
the diagnostic tool of choice. The fluid can be drained under direct visualiza-
tion, the peritoneal cavity can be evaluated carefully, and any suspicious masses
can be biopsied at the time of the laparoscopy.

The presence of ascites in a patient with malignancy often portends end-stage
disease. Median survival after the diagnosis of malignant ascites ranges from
7 to 13 weeks. Patients with gynecologic and breast malignancies have a better
overall prognosis than patients with GI malignancies.

The primary goal of treatment is the palliation of symptoms. Management can
be divided into medical and surgical modalities.

Medical therapy
Traditionally, the first line of treatment is medical management. Medical thera-
pies include repeated paracentesis, fluid restriction, diuretics, chemotherapy,
and intraperitoneal sclerosis.
Repeated paracentesis, probably the most frequently employed treatment
modality, provides significant symptomatic relief in the majority of cases. The
procedure is minimally invasive and can be combined with abdominal ultra-
sonography to better localize fluid collections. High-volume paracentesis has
been performed without inducing significant hemodynamic instability and with
good patient tolerance.
Significant morbidity occurs with repeated taps and becomes more severe with
each tap necessary to alleviate symptoms. Ascitic fluid contains a high concen-
tration of proteins. Routine removal of ascites further depletes protein stores.
The removal of large volumes of fluid also can result in electrolyte abnormali-
ties and hypovolemia. In addition, complications can result from the proce-
dure itself. They include hemorrhage, injury to intra-abdominal structures, peri-
tonitis, and bowel obstruction. Contraindications to repeated paracentesis are
viscous loculated fluid and hemorrhagic fluid.

With the placement of an intraperitoneal port, used also for the instillation of
intraperitoneal chemotherapy, removal of ascitic fluid is possible without the
need for repeated paracentesis. Other possible catheters for use in repeated
paracentesis include PleurX and Tenckoff catheters (used for intraperitoneal
dialysis). Placement of a semipermanent catheter minimizes the risk of injury
to intra-abdominal structures. However, the benefits are tempered by increased
infectious risks as well as the possibility of a nonfunctioning catheter requiring
removal and replacement.
Diuretics, fluid and salt restriction Unlike ascites from benign causes such
as cirrhosis and congestive heart failure, malignant ascites responds poorly to
fluid restriction, decreased salt intake, and diuretic therapy. The most com-
monly used diuretics (in patients who may have some response to diuretic
treatment) are spironolactone (Aldactone) and amiloride (Midamor). Patients
with massive hepatic metastases are most likely to benefit from
The onset of action for spironolactone is delayed (3-4 days), whereas the effects
of amiloride are seen after 24 hours. The most common complications associ-
ated with these diuretics are painful gynecomastia, renal tubular acidosis, and
Chemotherapy, both systemic and intraperitoneal, has had some success in
the treatment of malignant ascites. The most commonly used agents are
cisplatin and mitomycin (Mutamycin). Intraperitoneal hyperthermic chemo-
therapy has been used with some efficacy in GI malignancies to decrease
recurrence of ascites as well as to prevent the formation of ascites in patients
with peritoneal carcinomatosis.
Sclerotherapy Sclerosing agents include bleomycin (60 mg/50 mL of
normal saline), tetracycline (500 mg/50 mL of normal saline), and talc
(5 g/50 mL of normal saline). Responses are seen in ~30% of patients treated
with these agents.
Theoretically, intraperitoneal chemotherapy
and sclerosis obliterate the peritoneal space and   VEGF     (vascular endothelial
prevent future fluid accumulation. If sclerosis     growth factor) has been
is unsuccessful, it may produce loculations and     associated with the development
make subsequent paracentesis difficult.             of ascites in animal and cell
                                                    culture models. When adminis-
Other systemic therapies There are several          tered subcutaneously, a recently
reports of the use of gold-198 or phosphorus-       developed, high-affinity, soluble
32 in patients with peritoneal effusions, with      decoy receptor for VEGF (VEGF-
                                                    Trap) prevented the development
response rates of 30%-50%. Experimental             of any measurable ascites in a
models and early clinical trials have shown         mouse model of ascites producing
that an intraperitoneal bolus of tumor necro-       ovarian cancer. This new protein
sis factor (45-350 µg/m2) given weekly may          working against VEGF may be a
                                                    viable treatment for ascites in the
be effective in resolving malignant ascites.
                                                    future (Byrne AT, Ross L, Holash J, et
Other cytokines, including interferon-α, had        al: Clin Cancer Res 9:5721-5728,
varying success. A randomized, prospective          2003).
trial definitively addressing the role of

FLUID COMPLICATIONS                                                                  1047
 Intraperitoneal   hyperthermic
                                          cytokines and other biologic treatments in the
 perfusion of cisplatin and               management of malignant ascites has yet to
 mitomycin or doxorubicin when            be completed.
 combined with cytoreductive
 surgery in patients with                 Surgery
 peritoneal mesothelioma was
 successful, preventing the               Limited surgical options are available to treat
 recurrence of ascites. Of 18             patients who have refractory ascites after maxi-
 patients, 17 (84%) experienced           mal medical management, demonstrate a sig-
 resolution of ascites (Deraco M,
 Casali P, Ingese MG, et al: J Surg
                                          nificant decrease in quality of life as a result of
 Oncol 83:147-153, 2003).                 ascites, and have a life expectancy of > 3
Peritoneovenous shunts have been used since 1974 for the relief of ascites
associated with benign conditions. In the 1980s, shunting was applied to the
treatment of malignant ascites.
The LeVeen shunt contains a disc valve in a firm polypropylene casing, whereas
the Denver shunt has a valve that lies within a fluid-filled, compressible silicone
chamber. Both valves provide a connection between the peritoneal cavity and
venous system that permits the free flow of fluid from the peritoneal cavity when a 2-
to 4-cm water pressure gradient exists.
Success rates vary with shunting, depending on the nature of the ascites and
the pathology of the primary tumor. Patients with ovarian cancer, for example,
do very well, with palliation achieved in ≥ 50% of cases. However, ascites
arising from GI malignancies is associated with a poorer response rate (10%-
Patient selection Candidates for shunt placement should be carefully selected.
Cardiac and respiratory evaluations should be performed prior to the procedure.
Shunt placement is contraindicated in the presence of the following:
     ■   a moribund patient whose death is anticipated within weeks
     ■   peritonitis
     ■   major organ failure
     ■   adhesive loculation
     ■   thick, tenacious fluid.

 A total of 49 patients with              Complications of shunting Initial concerns
 peritoneal carcinomatosis from           about the use of a shunt in the treatment of
 gastric cancer were treated with         malignant ascites centered around intravas-
 intraperitoneal hyperthermic             cular propagation of tumor. In practice, there
 perfusion of mitomycin. Of the 49
                                          has been little difference in overall mortality
 patients, 21 also had undergone
 cytoreductive surgery at the time        in patients with and without shunts.
 of intraperitoneal treatment. This       Disseminated intravascular coagulation During
 regimen was successful in the
 resolution of malignant ascites in       the early experience with shunting, particu-
 47% of patients (8 of 17; Glehen O,      larly in cirrhotic patients, symptomatic clini-
 Schreiber V, Cotte E, et al: Arch Surg   cal disseminated intravascular coagulation
 134:20-26, 2004).                        (DIC) developed rapidly and was a major

source of morbidity and mortality. However, overwhelming DIC occurs infre-
quently in the oncologic population.
The pathophysiology of DIC has been studied extensively and is thought to be
multifactorial. The reinfusion of large volumes of ascitic fluid may cause a defi-
ciency in endogenous circulating coagulation factors by dilution. Secondarily,
a fibrinolytic state is initiated by the introduction of soluble collagen (contained
within the ascitic fluid) into the bloodstream, leading to a DIC state. Infre-
quently, full-blown DIC results and requires ligation of the shunt or even shunt
removal. Discarding 50%-70% of the ascitic fluid before establishing the
peritoneovenous connection may prevent this complication but may increase
the risk of early failure due to a reduced initial flow rate.
Commonly, coagulation parameters are abnormal without signs or symptoms.
In some institutions, these laboratory values are so consistently abnormal that
they are used to monitor shunt patency. Abnormalities most commonly seen
include decreased platelets and fibrinogen and elevated prothrombin time,
partial thromboplastin time, and fibrin split products.
Other common complications include shunt occlusion (10%-20%), heart failure (6%),
ascitic leak from the insertion site (4%), infection (< 5%), and perioperative
death (10%-20% when all operative candidates are included).
Shunt patency may be indirectly correlated with the presence of malignant
cells. One study found that patients with positive cytology results had a 26-day
shunt survival, as compared with 140 days in patients with negative cytology
results. Other studies have failed to demonstrate a correlation between ascites
with malignant cells and decreased survival.
Clearly, shunting is not a benign procedure, but in carefully selected patients
who have not responded to other treatment modalities and who are experienc-
ing symptoms from ascites, it may provide needed palliation. Because of the
limited effectiveness of peritoneovenous shunts, patients should be carefully
selected prior to shunt placement.
Radical peritonectomy Other surgical procedures used to treat malignant
ascites have been proposed. They include radical peritonectomy combined
with intraperitoneal chemotherapy. This is an extensive operation with signifi-
cant morbidity, although initial results appear to demonstrate that it decreases
the production of ascites. To date, no randomized trial has demonstrated that
radical peritonectomy increases efficacy or survival.


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