Hemorrhagic cystitis (HC) is an irritation of the endothelial lining of the bladder characterized by mucosal inflammation and ulceration with bleeding, clotting, or hemorrhage. The severity of bleeding (Table 21-1) can range from microscopic hematuria (5 to 50 RBCs per high-power field) to death from exsanguinating hematuria (Polovich et al., 2005). HC is considered a urologic emergency.
| Also consider: fibrinogen; international normalized ratio of prothrombin time (INR); platelets; partial thromboplastin time (PTT). | ||||||
| *Transfusion implies pRBCs. | ||||||
| Adverse Event | Short Name | Grade 1 | Grade 2 | Grade 3 | Grade 4 | Grade 5 |
|---|---|---|---|---|---|---|
| Hemorrhage GU Select | Hemorrhage GU–Select | Minimal or microscopic bleeding; no intervention indicated | Gross bleeding; medical intervention or urinary tract irrigation indicated | Transfusion, * interventional radiation therapy (i.e., hemostasis of bleeding site), or endoscopic or operative intervention indicated | Life-threatening consequences; major urgent intervention indicated | Death |
| Bladder | ||||||
| Fallopian tube | ||||||
| Kidney | ||||||
| Ovary | ||||||
| Prostate | ||||||
| Retroperitoneum | ||||||
| Spermatic cord | ||||||
| Stoma | ||||||
| Testes | ||||||
| Ureter | ||||||
| Urethra | ||||||
| Urinary NOS | ||||||
| Uterus | ||||||
| Vagina | ||||||
| Vas deferens | ||||||
The three main causes of HC in patients with cancer are treatment with chemotherapy, hematopoietic stem cell transplantation (HSCT), and treatment with radiation, either external beam or brachytherapy.
Signs and symptoms of HC include microscopic or frank hematuria with or without clots; dysuria; urgency; nocturia; frequent urination in small volumes; burning on urination; suprapubic, flank, or back pain; and bladder pain or spasm. Men may experience penile pain, which is referred pain caused by bladder spasm (Polovich et al., 2005; Bramble & Morley, 1997).
Chemotherapy-related HC occurs as a result of drug metabolites or byproducts binding to the bladder lining. A second, more unusual, cause of chemotherapy-related HC is instillation of the chemotherapeutic agent directly into the bladder (intravesically) to treat bladder cancer. The two main chemotherapeutic agents responsible for HC are cyclophosphamide and ifosfamide. Cyclophosphamide breaks down into acrolein, and ifosfamide breaks down into acrolein and chloroacetaldehyde. Other intravenous chemotherapeutic agents (e.g., bortezomib) can cause HC in rare cases. Gemcitabine and irinotecan can cause HC after repeated cycles (Polovich et al., 2005).
HC after radiation therapy (RT) is rare. When it does occur, it causes either early damage or late damage. Early damage can take 4 to 6 weeks to develop after completion of RT. It does not occur immediately unless precipitated by another injury, such as chemotherapy-induced toxicity, because of the slow turnover time of the bladder epithelium. Early damage is characterized by epithelial inflammation and edema. As normal tissue repair occurs, early HC resolves (Crew et al., 2001). Late damage starts 6 months to 2 years after completion of RT. In these cases, the bladder tissue undergoes radiation-related changes. Bladder wall epithelial changes may progress to necrosis of the vascular endothelium. The result is fibrosis and vessel wall thickening. The tissue becomes hypovascular, hypoxic, and ischemic, and further fibrosis results. The damage is progressive and can lead to poorly healing ulcers, superficial bladder epithelial denudation, occasional bladder perforation, and fistula formation. Fibrosis of the bladder, with reduced urine capacity, can occur up to 10 years after RT (Nehman et al., 2005; Crew et al., 2001).
Two types of HSCT-related HC can occur, early onset and late onset. HC that occurs within 72 hours after treatment with high-dose cyclophosphamide is known as early onset HC. Late onset HC usually is virally mediated. Viral infections usually are caused by polyomavirus BK (BK), adenovirus, and cytomegalovirus (CMV). These viral infections occur weeks to months after the conditioning therapy. Virally mediated HC is thought to be due to reactivation of a latent form of the virus that is already present in the patient’s system. The BK virus infects the patient during childhood and remains latent in the kidney until immunocompromise occurs (Azzi et al., 1999). Adenovirus type II has an affinity for the bladder. CMV affects many areas of the body, including the bladder. Graft versus host disease is another cause of late onset HC in patients who have received transplants, but its role is not clearly understood (Ezzone, 2004).
EPIDEMIOLOGY AND ETIOLOGY
Symptomatic or asymptomatic hematuria occurs in 6% to 10% of adults treated with standard low-dose cyclophosphamide (less than 1000 mg). Microscopic or frank hematuria with clotting occurs in up to 40% of adults treated with high-dose cyclophosphamide. Up to 50% of adults treated with ifosfamide develop HC ranging from microscopic to frank hematuria; 18% to 40% of adults treated with this drug develop frank hematuria (Polovich et al., 2005).
HC-related symptoms occur in children within a few weeks after treatment with cyclophosphamide or ifosfamide. Five percent to 10% of children treated with low-dose cyclophosphamide experience HC ranging from mild dysuria to severe hemorrhage. Children treated with ifosfamide have a higher incidence of HC; 20% to 40% experience mild dysuria to severe hemorrhage (Polovich et al., 2005). One third of patients treated with intravesical thiotepa or mitomycin develop hematuria. Most patients treated with bacilli Calmette-Guerin develop irritative voiding symptoms that are not severe enough to warrant discontinuation of therapy (DeVita et al., 2001). The incidence of HC in all patients treated with RT is less than 5% (Moy & Joyce, 2006). The incidence of HC in patients who receive HSCT is about 30% (Ezzone, 2004).
RISK PROFILE
Because cyclophosphamide and ifosfamide are the main causes of chemotherapy-related HC, patients treated with either of these agents are at risk. Patients treated with high-dose cyclophosphamide and any dosage of ifosfamide have the highest risk. Patients treated with bortezomib, or with repeated doses of gemcitabine or irinotecan, are also at risk (Polovich et al., 2005). Previous treatment with busulfan also increases the risk, because busulfan is excreted in the urine and causes bladder damage (Ezzone, 2004).
Patients with prostate, cervical, or bladder cancer who are being treated with radiation are at the greatest risk of developing radiation-related HC, because the radiation field could be in the area of the bladder. The risk of developing HC depends on the total radiation dose, volume irradiated, fractionation schedule, and method (i.e., external beam or brachytherapy). The higher the dose of radiation, the greater the risk of developing HC (Moy & Joyce, 2006).
With HSCT, patients treated with high-dose cyclophosphamide are at the greatest risk of developing early onset HC. Patients who are expected to have or who already have had long periods of immunocompromise are at increased risk of developing virally mediated, late onset HC. Patients with a known previous infection with the BK virus, adenovirus, or CMV are at additional risk (Ezzone, 2004).
PROGNOSIS
Severe HC across all treatment modalities, including HSCT, occurs in fewer than 10% of patients. HC is associated with a 2% to 4% mortality rate across all treatment modalities (Moy & Joyce, 2006).
PROFESSIONAL ASSESSMENT CRITERIA (PAC)
1. CBC with differential to assess for and/or rule out anemia, neutropenia, and thrombocytopenia (Moy & Joyce, 2006).
2. BUN and creatinine to assess for and/or rule out renal pathology (Moy & Joyce, 2006).
3. Coagulation parameters, including PT/APTT, INR, to assess for and/or rule out coagulopathy (Moy & Joyce, 2006).
4. Monitor vital signs as appropriate to assess hemodynamic stability, specifically pulse, pulse pressure, and temperature, because HC can be life-threatening (Moy & Joyce, 2006).
5. Ensure strict intake and output to monitor fluid status; instruct patient and family in how to participate in this process (Polovich et al., 2005).
6. Obtain baseline urinalysis before beginning therapy and continue to monitor regularly throughout treatment, including subjective reports (Polovich et al., 2005).
7. Visually inspect urine for blood, and instruct the patient and family in this process (Polovich et al., 2005).
8. Test with urine dipstick for blood to monitor for bleeding.
9. Obtain urine cultures at baseline and as needed to rule out urinary tract infection (Moy & Joyce, 2006).
10. Note previous medication history, including previous chemotherapy to assess the patient’s risk of developing HC. Include over-the-counter and herbal medications (Moy & Joyce, 2006), especially those known to increase bleeding, such as bilberry, bromelain from pineapple stem, cayenne, chamomile, coleus, dong quai, feverfew, flaxseed oil, garlic, ginger, ginkgo, American ginseng, green tea, horse chestnut, meadowsweet, motherwort, poplar, shepherd’s purse, and tumeric (Kumar et al., 2002).
11. Note previous radiation treatment to assess the patient’s risk of developing HC (Moy & Joyce, 2006).
12. Use pelvic ultrasound to rule out urinary flow obstruction if the patient is experiencing clots. (Ezzone, 2004).
13. Cystoscopy is done to confirm the diagnosis of HC; it can pinpoint a bleeding source in severe cases (Ezzone, 2004).
14. Bladder biopsy is done to assess for tumor invasion or direct tumor extension into the bladder (Moy & Joyce, 2006).
15. Evaluate for infection with CMV or BK virus by PCR if patient is undergoing HSCT and is symptomatic (Ezzone, 2004).
16. Evaluate for adenovirus with urine culture if patient is undergoing transplantation and is symptomatic (Ezzone, 2004).
NURSING CARE AND TREATMENT
Prevention
The best treatment of HC is to prevent it from occurring. The initial focus of nursing care is on prevention.
Chemotherapy-Induced HC
For chemotherapy-induced HC, preventive measures center around assessment and monitoring, forced hydration, diuresis, free voiding, and treatment with mesna (Strohl, 2000).
1. Have the patient urinate every 2 to 4 hours (Polovich et al., 2005; West, 1997).
2. Maintain strict intake and output, and instruct the patient and family in the process (Polovich et al., 2005; West, 1997).
3. Weigh the patient daily (Polovich et al., 2005; West, 1997).
4. Report urine output that is less than 100 mL/hr (Polovich et al., 2005; West, 1997).
5. Instruct the patient to increase oral intake to 2 to 3 L a day. Increased fluid intake should begin 12 to 24 hours before chemotherapy and continue for 2 to 3 days after chemotherapy (Polovich et al., 2005; West, 1997).
6. If the patient is unable to drink an adequate amount of fluids, before and after chemotherapy administration, begin intravenous hydration (Polovich et al., 2005; West, 1997).
7. Forced saline hydration and diuresis are necessary for high-dose cyclophosphamide and ifosfamide to minimize the contact metabolites have with the bladder (Polovich et al., 2005; West, 1997).
8. Inspect the patient’s urine at each void to detect frank blood.
9. Administer cyclophosphamide or ifosfamide early in the day so that metabolites do not sit in the bladder during the night (Wilkes & Barton-Burke, 2005).
10. Administer mesna as prescribed. Mesna is a bladder protectant that is administered with high doses of cyclophosphamide and all doses of ifosfamide. Mesna works by binding to the drug metabolites, allowing them to be inactivated and detoxified. NOTE: Never administer ifosfamide without mesna (Polovich et al., 2005).
11. Mesna can be administered by several different methods, depending on the dose of cyclophosphamide and ifosfamide and the route of mesna administration.
• For adult patients receiving standard-dose ifosfamide, the total dose of mesna is equal to 60% of the total ifosfamide dose. The IV bolus doses of mesna are divided into 15 minutes before and 4 and 8 hours after ifosfamide administration (Polovich et al., 2005).
• Another method of mesna administration in adults receiving standard-dose ifosfamide is to give an IV bolus dose of mesna equal to 20% of the total daily ifosfamide dosage before starting the ifosfamide infusion. Then, give a continuous mesna infusion at 50% to 100% of the daily ifosfamide dosage while the ifosfamide is infusing.This allows continuous contact of mesna with metabolites traveling through the bladder (Polovich et al., 2005).
• A third method of mesna administration in adults receiving standard-dose ifosfamide is to begin with an IV bolus dose of 20% of the total daily dose of ifosfamide; this is followed by a continuous infusion of mesna of up to 40% of the total daily ifosfamide dose, which is continued for 12 to 24 hours after ifosfamide infusion is complete (Polovich et al., 2005).
12. For patients who are to be treated with oral mesna, the first dose is still given intravenously, in an amount equal to 20% of the daily ifosfamide dose; this is followed at 2 and 6 hours by a dose equal to 40% of the total daily ifosfamide dose. Oral mesna can be used only if the ifosfamide regimen calls for a total daily ifosfamide dose of less than 2 g/m2 (Schucnter et al., 2002).
13. No clinical evidence supports the administration of mesna at doses greater than 60% of the total daily ifosfamide dose. Higher doses of mesna are associated with increased gastrointestinal toxicity (Polovich et al., 2005).
14. No guidelines have been established for mesna dosing with high-dose ifosfamide in adults. However, it is known that in these patients, more frequent and prolonged mesna dosing than is used for standard-dose ifosfamide is necessary to prevent HC (Polovich et al., 2005).
15. Total mesna doses for high-dose cyclophosphamide in adults should be 40% of the total cyclophosphamide dose administered intravenously 15 minutes before and 4 and 8 hours after cyclophosphamide in bolus doses (Polovich et al., 2005).
16. The IV mesna dose in children usually is 60% of the total daily dose of either the cyclophosphamide or ifosfamide. A 1:1 ratio sometimes is used. The most common mesna administration schedule is an IV bolus dose given 15 minutes before and 4 and 8 hours after cyclophosphamide or ifosfamide. The prechemotherapy bolus dose is given intravenously, but the subsequent doses may be administered orally. NOTE: The oral dose is higher than the IV dose (Polovich et al., 2005).
17. Monitor the patient for side effects of mesna, including nausea, vomiting, diarrhea, abdominal pain, taste changes, rash, urticaria, headache, and hypotension (SLOCR, 2004).
HSCT-Related HC
Prevention of early onset HC in HSCT is also the initial focus of nursing management in patients receiving transplants. Preventive measures center on assessment and monitoring, hyperhydration, diuresis, free voiding, continuous bladder irrigation, and treatment with mesna.
1. Maintain IV hydration of 3 L/m2/day (Ezzone, 2004).
2. Encourage the patient to increase oral intake (Ezzone, 2004).
3. Administer continuous-infusion mesna as prescribed at 100% to 160% of the total daily dose of either cyclophosphamide or ifosfamide (Ezzone, 2004).
4. Continuous bladder irrigation of 300 to 1000 mL/hr (Ezzone, 2004).
5. Hourly voids if no bladder irrigation (Ezzone, 2004).
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