Complications of Pelvic Exenteration

Pelvic exenteration, the en bloc removal of the pelvic organs, is indicated for central recurrent or persistent gynecologic cancer, including cervical, endometrial, vaginal, or vulvar cancer. Even when performed in the setting of specialized centers by highly skilled surgeons, pelvic exenteration is associated with significant morbidity and mortality. Since the initial series published by Brunschwig in 1948, there has been a dramatic change in the type and frequency of the complications associated with this procedure. A number of factors have influenced the outcomes over the past several years, and these include the integration of broad-spectrum antibiotics, thromboembolic prophylaxis, vessel-sealing devices, multiteam surgical expertise, and critical care teams. In addition, modifications of urinary diversion and pelvic reconstruction procedures have paved the way to provide improved outcomes and lower complications rates. Nevertheless, this operation remains a challenge for all patients, and all involved with the care of the patient must recognize that it is a life-changing experience that affects physical, psychological, and sexual function and leads to major changes in quality of life. The report of a series by Maggioni and colleagues showed that the overall morbidity after pelvic exenteration was 66%, with 48% of patients having early complications (<30 days) and 48.5% of patients having late complications. The MD Anderson Cancer Center published a report on 160 patients who underwent pelvic exenteration for gynecologic malignancies and noted that the postoperative complication rate was as high as 94%, with 60% of all complications described as a potentially life-threatening event. The same group also noted a mortality rate of 1.3%. However, such variation may be secondary to the criteria set forth in the respective studies to define complications in the perioperative period. Overall, it is imperative to ensure careful patient selection, preoperative and postoperative care, and optimal surgical expertise in a tertiary cancer center to improve not only surgical outcomes but also survival for patients undergoing this procedure.

This chapter addresses the potential medical and surgical complications that may arise after pelvic exenteration. The emphasis is on the most common signs and symptoms, detection of such complications, and subsequent management options, highlighting surgical versus nonsurgical options. This chapter is intended as a reference guide to aid gynecologic oncologists in assessing the most common complications that arise after pelvic exenteration, and accordingly we do emphasize that appropriate consultation with indicated services is always encouraged.

Medical Complications

Febrile Morbidity

One of the most common postoperative complications in patients who have undergone pelvic exenteration is fever. Postoperative fever is defined as a temperature above 38°C (100.4°F) on 2 consecutive postoperative days or above 39°C (102.2°F) on any 1 postoperative day. The differential diagnosis is strongly influenced by the time of onset of the fever. The most common cause of fever within the first 48 hours is a pyretic response to the operation, and this is usually self-limiting. Studies have shown that the rate of febrile morbidity after pelvic exenteration can be as high as 71%. In the study by Westin and colleagues from MD Anderson, the rate of early sepsis (<60 days) was 8.8%, and the rate beyond this time point was 1.3%.

Among the most common causes of fever are the following:

Infectious: Surgical site infection, pneumonia, urinary tract infection, and/or intravascular catheter–related infection
Noninfectious: Hematoma or seroma, deep venous thrombosis (DVT) or pulmonary embolism (PE), inflammatory reaction (pancreatitis), vascular complication (hemorrhage, myocardial infarction, bowel ischemia or infarction), medications

After pelvic exenteration, sepsis may also be a great cause of morbidity and mortality. To be diagnosed with sepsis, a patient must have two of the following signs plus a confirmed infection: body temperature above 38.3°C (101°F) or below 36°C (96.8°F), heart rate higher than 90 beats per minute, and respiratory rate higher than 20 breaths per minute. Severe sepsis is diagnosed when a patient has one of the following: decreased urine output, abrupt changes in mental status, thrombocytopenia, dyspnea, myocardial dysfunction, or abdominal pain.

The routine workup of febrile morbidity should be targeted based on the organ system or infectious process of highest suspicion. The need for laboratory testing should be defined by the findings of a careful history and physical examination. The initial approach to the evaluation should include a complete blood count. Chest x-ray examination, urine cultures, and blood cultures are not indicated for all postoperative patients with fever. One should take into account the timing and the causes of fever. In patients with persistent febrile episodes after pelvic exenteration, one should proceed with abdominal and pelvic computed tomography (CT) scanning to rule out the potential possibility of an intraabdominal abscess.

Treatment for febrile morbidity should be tailored according to the source of the fever. Patients with persistent postoperative fever should be started on broad-spectrum antibiotics after cultures have been obtained. Coverage should be against aerobic gram-negative enteric bacilli and anaerobic organisms. If a source of fever is not apparent and blood cultures show no growth after 48 hours, then discontinuation of antimicrobials should be considered. If the cultures are positive, then antibiotic coverage should be focused on the known causative organism(s). All unnecessary treatments including medications, nasogastric tubes, and intravascular and urinary catheters should be discontinued, when possible, in the febrile patient.

In the setting of sepsis, all patients should be managed with broad-spectrum antibiotics, hemodynamic support such as crystalloids or albumin, vasopressor therapy, blood product administration, and mechanical ventilation, if needed. Discussion of goals of care and prognosis with the patient or family is paramount. Palliative care principles should be considered when appropriate.

Thromboembolic Events

Incidence and Guidelines

Among women undergoing major gynecologic surgical procedures without thromboprophylaxis, the risk of DVT ranges from 17% to 40%. This risk is even higher among women undergoing operation for gynecologic cancer. Martino and colleagues estimated the incidence of PE among 507 patients with known or suspected gynecologic cancer undergoing intraabdominal operations and found that the risk of postoperative PE in patients with a diagnosis of cancer was 14 times the risk of postoperative PE in those with benign disease.

Current guidelines for thromboprophylaxis are available from a number of groups, including the American College of Chest Physicians (ACCP), American Society of Clinical Oncology (ASCO), National Comprehensive Cancer Network (NCCN), and American College of Obstetricians and Gynecologists (ACOG). All of the aforementioned guidelines support the recommendation that all patients undergoing abdominal or pelvic surgical procedures for malignancy receive pharmacologic prophylaxis. The ASCO, NCCN, and ACOG guidelines recommend the consideration of continuing prophylaxis for up to 28 days after operation. The recommendation for extended prophylaxis in gynecologic cancer patients is derived from two randomized controlled trials indicating that prolonged thromboprophylaxis reduces the incidence of postoperative venous thromboembolism (VTE). The first study was a double-blind multicenter trial in which patients undergoing planned curative open procedures for abdominal or pelvic cancer received enoxaparin (40 mg subcutaneously) daily for 6 to 10 days. Patients were then randomly assigned to receive either enoxaparin or placebo for another 21 days. The results showed a 60% relative reduction and a 7% absolute reduction in the risk of postoperative VTEs in the prolonged thromboprophylaxis group. In a subsequent study, the investigators evaluated the efficacy and safety of thromboprophylaxis with low-molecular-weight heparin (LMWH) (dalteparin) administered for 28 days versus 7 days after major abdominal surgery for cancer. The results showed that the cumulative incidence of VTEs was reduced from 16.3% among patients receiving short-term thromboprophylaxis to 7.3% among patients receiving prolonged thromboprophylaxis.

In patients undergoing pelvic exenteration, the study by Westin and colleagues showed that the rate of thromboembolic events before 60 days was 1.9% and 5% beyond that time. In a study by Jurado and colleagues, the authors reported a rate of DVT among 45 patients who underwent pelvic exenteration of 11% and a rate of PE of 6.7%. Barakat and colleagues reported a mortality rate of 4.5% from PE after pelvic exenteration. It is interesting to note that in a study by Iglesias and colleagues from MD Anderson Cancer Center, the authors showed that the rate of thromboembolic events was not affected by patient body mass index.

Signs and Symptoms

The most common symptoms associated with acute PE include dyspnea (73%), pleuritic chest pain (66%), cough (37%), and hemoptysis (13%). The most common signs are tachypnea (70%), rales (51%), tachycardia (30%), fourth heart sound (24%), accentuated pulmonic component of second heart sound (23%), and circulatory collapse (8%).

Evaluation of Thromboembolic Events

Once a medical history has been taken and physical examination performed, it is recommended that patients undergo a complete blood count, liver and kidney function tests, and chest radiography and electrocardiography as part of the initial evaluation. In patients with PE, the white blood cell (WBC) count may be normal or elevated, with a WBC count as high as 20,000 K/μL noted in some patients. A chest radiograph may be abnormal in most patients with PE, but the findings are not specific. Common radiographic abnormalities include atelectasis, pleural effusion, parenchymal opacities, and elevation of a hemidiaphragm. It is important to note that a normal-appearing chest radiograph in a patient with severe dyspnea and hypoxemia, but without bronchospasm or cardiac shunt, is strongly suggestive of PE. The most common electrocardiographic abnormalities in the setting of PE are tachycardia and nonspecific ST-T wave abnormalities.

It is important to note that the D-dimer test has limited usefulness in the setting of cancer and thus is not routinely recommended in the workup of thromboembolic events in such patients. Similarly, although arterial blood gas determination may show hypoxemia, hypocapnia, and respiratory alkalosis in patients with a PE, it is not routinely used because of its very low predictive value.

The diagnostic study of choice for DVT is compression ultrasonography. When a DVT is present, the veins do not collapse when pressure is applied. However, it is important to note that a negative ultrasound Doppler result does not rule out DVT, because a number of DVTs may occur in areas that are inaccessible to the ultrasound evaluation. For the diagnosis of PE, the ideal choice of study is computed tomographic pulmonary angiography ( Fig. 16.1 ). This is for patients with a suspected diagnosis of PE and who are hemodynamically stable. However, in patients who are not stable, bedside echocardiography may be used to obtain a presumptive diagnosis to justify the administration of potentially lifesaving therapies. Ventilation-perfusion (V./Q.) scanning may be used when CT scanning is not available or if the patient has a contraindication to CT scan or use of intravenous contrast material. Brain natriuretic peptides (BNPs) are neither sensitive (60%) nor specific (62%); however, patients with PE tend to have higher BNP levels. Elevated levels tend to be associated with increased risk of subsequent complications and mortality in patients with PE. BNP testing is not routinely recommended as part of the standard evaluation of PE.

Fig. 16.1, Spiral computed tomography image of the chest with intravenous contrast showing an acute pulmonary embolism (arrow) in the thrombus in the segmental branches of the right lobe of the pulmonary artery.

Treatment of Thromboembolic Events

The approach to a patient with a thromboembolic event is to ensure that the patient’s condition has been stabilized after assessment of hemodynamic stability. The first steps should be to provide adequate oxygen supplementation (targeting O ₂ saturation ≥90%), obtain peripheral intravenous access, and begin empiric anticoagulation. The ACCP guidelines recommend starting LMWH or subcutaneous heparin. Once-daily treatment is the preferred choice. The length of anticoagulation for DVT is 3 months, and the recommended length of therapy for PE is 6 months. The ACCP guidelines recommend that thrombolytic therapy should be used in patients with acute PE associated with hypotension (systolic blood pressure BP below 90 mm Hg) who do not have a high risk of bleeding. Embolectomy is recommended in patients with massive PE who have a contraindication to fibrinolysis or who remain unstable after receiving fibrinolysis. It may also be considered in patients with evidence of right ventricular enlargement or dysfunction on transthoracic echocardiogram. Inferior vena cava filters are indicated in the setting of patients with an absolute contraindication to anticoagulant therapy (hemorrhagic stroke or active bleeding). It is also indicated when recurrent embolism is present even after adequate anticoagulant therapy.

Acute Renal Events

Acute kidney injury (AKI) is the abrupt loss of kidney function, resulting in the retention of urea and other nitrogenous waste products and in the dysregulation of extracellular volume and electrolytes. This term has replaced acute renal failure (ARF) after consideration that even small decrements in kidney function are of substantial clinical relevance and are associated with increased morbidity and mortality. In the study by Westin and colleagues, the authors reported that the rate of ARF or AKI after pelvic exenteration was 3.8%.

AKI has multiple possible causes, and it is most commonly due to acute tubular necrosis (ATN) from ischemia, nephrotoxin exposure, or sepsis. Other frequent causes include volume depletion, urinary obstruction, rapidly progressive glomerulonephritis, and acute interstitial nephritis. AKI is typically detected by means of an increase in serum creatinine and/or a decrease in urine output. Among hospitalized patients, ATN and prerenal disease are the most common causes.

Several consensus definitions of AKI have been developed to provide a uniform definition of AKI. The RIFLE criteria are described here; they consist of three graded levels of kidney dysfunction (risk, injury, and failure), based on the magnitude of increase in serum creatinine or urine output, and two outcome measures (loss and end-stage renal disease [ESRD]). The RIFLE strata are described in Table 16.1 .

Table 16.1

RIFLE Criteria for Acute Renal Compromise

Risk	1.5-fold increase in the serum creatinine, or glomerular filtration rate (GFR) decrease by 25%, or urine output <0.5 mL/kg/h for 6 h
Injury	Twofold increase in the serum creatinine, or GFR decrease by 50%, or urine output <0.5 mL/kg/h for 12 h
Failure	Threefold increase in the serum creatinine, or GFR decrease by 75%, or urine output of <0.3 mL/kg/h for 24 h, or anuria for 12 h
Loss	Complete loss of kidney function (e.g., need for renal replacement therapy) for more than 4 weeks
End-stage renal disease	Complete loss of kidney function (e.g., need for renal replacement therapy) for more than 3 months

It has been shown that, compared with patients who did not have AKI, patients in the RIFLE stages of “risk,” “injury,” and “failure” had increased relative mortality risks of 2.4 (confidence interval [CI], 1.94–2.97), 4.15 (CI, 3.14–5.48), and 6.37 (CI, 5.14–7.9), respectively.

Initial Evaluation After Diagnosis

All patients with AKI must be carefully evaluated both for reversible causes (hypotension, volume depletion, or obstruction) and for the presence of complications (volume overload, hyperkalemia, metabolic acidosis, hypocalcemia, and hyperphosphatemia). The initial evaluation of the patient with AKI is directed at determining the cause and identifying the complications that may require immediate attention. The timing of onset often suggests the underlying cause. A careful review of medications is imperative. Often, nephrotoxic medications have been started before the onset of AKI, which suggests a cause. In addition, even long-standing medications (particularly angiotensin-converting enzyme [ACE] inhibitors or angiotensin receptor blockers) render patients vulnerable to AKI from prerenal factors or ATN.

Patient Evaluation

The initial assessment should include the careful evaluation of volume status and measurement of serum electrolytes, particularly potassium and bicarbonate, and serum phosphate, calcium, and albumin. One should also check serum uric acid and magnesium and perform a complete blood count. Initial testing should include reagent strip urinalysis (dipstick) with automated urine microscopy and the quantification of urine protein or albumin (by random or “spot” protein-to-creatinine ratio or albumin-to-creatinine ratio).

A physical examination may reveal the cause. Signs of volume contraction suggest a prerenal cause of AKI. An ultrasound examination could be an option if renal function does not improve; ultrasonography is the most commonly used imaging technique in patients with AKI. Ultrasonography is safe, easy to perform, and sensitive for obstruction. Magnetic resonance imaging (MRI) with gadolinium should be avoided in patients with AKI because of the nephrotoxicity of the agent. In patients with moderate to advanced kidney disease with estimated glomerular filtration rate (eGFR) below 30 mL/min, the administration of gadolinium has been associated with the potentially severe syndrome of nephrogenic systemic fibrosis (NSF).

The results of the urinalysis and ultrasound examination generally direct the remainder of the diagnostic evaluation. Patients who have evidence of obstruction require further investigation and usually intervention to relieve the obstruction and determine the cause. For patients who have normal renal imaging findings, minimal proteinuria, benign urine sediment on urinalysis and microscopy (no red cells or cellular casts), and no clear explanation for AKI, further evaluation is determined by the severity of disease and rate of further decline.

If the creatinine level is persistently elevated or if an initially mild increase in the creatinine level worsens over the course of days, then a kidney biopsy should be performed. A biopsy is often performed when the diagnosis is uncertain. A biopsy usually enables a more definitive tissue diagnosis and may allow a therapeutic intervention to prevent ESRD.
In patients who have signs and symptoms of rapidly progressive or unexplained systemic disease, a renal biopsy is warranted, even if the eGFR remains stable after initial increase.
In patients who have mild decrements in eGFR (e.g., to 45 to 60 mL/min/1.73 m ² ) where the eGFR subsequently remains stable, one should just follow the serum creatinine. If the creatinine level remains stable, one should continue to follow creatinine level, the results of urine studies (urinalysis, microscopic studies, urine protein and creatinine), and blood pressure until a clear temporal pattern has been established.

Urinalysis

The urinalysis involves both use of a urine dipstick and microscopic examination of the urine sediment. The dipstick can be used to test for protein (albumin), pH, glucose, hemoglobin (or myoglobin), leukocyte esterase (reflecting pyuria), and specific gravity.

Urine Sodium Excretion

The fractional excretion of sodium (FENa) measures the percent of filtered sodium that is excreted in the urine.

The FENa is commonly used to assist in differentiating prerenal disease (a reduction in glomerular filtration rate [GFR] due solely to decreased renal perfusion) from ATN, the two most common causes of AKI.
In patients with suspected prerenal disease or ATN, it is recommended that the FENa be measured. A value of the FENa below 1% commonly indicates prerenal disease; in comparison, a value between 1% and 2% may be seen with either disorders, and a value above 2% usually indicates ATN.

Urine Volume

Trends in and comparisons between the volumes of fluid going into and coming out of a patient (including urine output) are helpful physiologic parameters in patients with AKI. Oliguria (typically defined as <0.3 mL/kg/h or <500 mL/day of urine output) may or may not occur in patients with AKI. Normal urine output can be maintained even with an abnormally low GFR in patients with nonoliguric ATN. The prognosis of nonoliguric AKI is generally better than that of oliguric or anuric disease.

Management

Volume Issues

An assessment of volume status is performed in all patients with AKI because correction of volume depletion or volume overload (especially when associated with worsening cardiac output) may reverse or ameliorate AKI.

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