Ahmad Shabsigh, MD, FACS
BASICS
DESCRIPTION
• Inflammation leading to damage of the bladder’s urethelium and blood vessels, causing hematuria and irritative voiding symptoms.
• Hemorrhagic cystitis (HC) is commonly caused by severe infection, cyclophosphamide, and radiation therapy induced.
EPIDEMIOLOGY
Incidence
• Cyclophosphamide-induced HC: 5–7%
• Radiation-induced HC: 10–15% in patients with history of pelvic radiation.
• 7–70% of hematopoietic stem cell transplants.
RISK FACTORS
• No age, sex, or race predilection.
• Infections.
• Exposure to certain industrial chemicals, such as aniline or toluidine derivatives.
• Previous treatment with oxazaphosphorine alkylating agents (for lymphoproliferative disorders, solid tumors, collagen diseases) such as cyclophosphamide, isophosphamide.
• History of prior pelvic radiation (prostate and cervical cancers).
• Reactivation of BK virus (BKV) infection in bone marrow transplant patients.
Genetics
N/A
PATHOPHYSIOLOGY
• Cyclophosphamide: Acrolein enters the urethelium. Activates platelet-activating factor, nitric oxide, tumor necrosis factor-α, and IL-1, eventually forming peroxynitrite that causes damage.
• Radiation-induced cystitis results from a progressive obliterative endarteritis leading to mucosal ischemia, ulceration, and neovascularity.
• Penicillin toxicity is immune-mediated, whereas danazol toxicity is likely from damaging vascular changes.
ASSOCIATED CONDITIONS
See “Differential Diagnosis.”
GENERAL PREVENTION
• Patients treated with cyclophosphamide once had a very high incidence of HC (∼70%), with high mortality rates (as high as 75%) if it became severe
• IV hydration, frequent bladder emptying, and sometimes indwelling catheters with bladder irrigations are used to reduce the time toxins are in contact with the bladder wall (1)[A]
• Mercaptoethane sulfonate Na (MESNA) and N-acetylcysteine (Mucomyst) bind to acrolein, creating nontoxic compounds.
• WF-10 (2)[A], sodium pentosan polysulfate (Elmiron), and amifostine (Ethyol) have been investigated in prevention of radiation-induced cystitis.
• Infectious: Minimize bacterial exposure, avoid indwelling Foley catheter if possible; intermittent catheterization if prolonged catheter needed
DIAGNOSIS
HISTORY
• Gross hematuria (with or without pain)
• Frequency, urgency, dysuria
• Urinary retention from clots
• Occasional mucosal sloughing
• Suprapubic pain
• Fevers with chills
• Previous history of cyclophosphamide therapy, pelvic radiation, bone marrow transplant
PHYSICAL EXAM
• Suprapubic pain/mass: Distended bladder, infected and/or clot-filled bladder
• Signs and symptoms of hypovolemia, hemorrhagic shock, or anemia if severe
• Ocular infections: Common with adenovirus infection
• Large hypertrophied tongue: Amyloidosis
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Urine for analysis, cytology, and cultures (including fungal and viral cultures, if indicated)
• Coagulation factors (especially platelets, which can be depleted)
• Serial hematocrits
• Serum creatinine
• Blood tests for collagen disease markers, if indicated
Imaging
• CT urogram:
– Often done as part of hematuria workup
– Rules out other urologic abnormalities
– Usually not able to diagnose HC, but may show clots in the lumen, a thickened irregular bladder wall, and/or small capacity.
Diagnostic Procedures/Surgery
• Cystoscopy ± biopsy, ± clot evacuation
• Consider electro- or laser fulguration if focal bleeding visualized.
Pathologic Findings
• Urothelial damage: Edema, necrosis, ulceration, hemorrhage, leukocyte infiltration, and neovascularization
• May reveal amyloid deposits; eosinophilic inflammatory response of schistosomiasis; IgG, IgM, and C3 depositions; penicillin toxicity; whitish pseudomembranes or plaques of fungal infections; inclusion bodies of viral infections
DIFFERENTIAL DIAGNOSIS
• Oxazaphosphorine agents (cyclophosphamide and isophosphamide):
– Most common cause of severe HC
– Acrolein, a liver metabolite of the agents, is the toxin believed to be directly implicated.
– Higher dosages, IV route of administration (vs. oral), and increased contact time between the bladder wall and the acrolein (because of dehydration and/or infrequent emptying) all worsen HC.
• Pelvic radiation:
– Usually initiated by bladder distension, minor trauma, infection, instrumentation
– Acute episodes wane within 12–18 mo
– Can occur as late as 15–20 yr after exposure
• Viral infection:
– Adenovirus 11 and 35, influenza A, CMV, Polyomavirus hominis 1, the BKV, and JC viruses
– Typically seen in immunocompromised patients after BMT
– May present dramatically, but usually resolves spontaneously in <2 wk
• Other infections rarely cause severe HC:
– Bacterial: Escherichia coli, Staphylococcus saprophyticus, Proteus, Klebsiella, Mycobacterium tuberculosis
– Fungal: Candida, Aspergillus, Cryptococcus, Torulopsis
– Parasitic: Schistosoma haematobium, Echinococcus granulosus
• Systemic hematologic disease: Rare; often refractory to fulguration and irrigation
• Systemic amyloidosis associated with rheumatoid arthritis or Crohn disease
• Chemical toxins:
– Anilines, toluidines, and chlordimeform are common industrial exposures (dyes, pesticides).
– Overdoses of methenamine mandelate; accidental urethral instillation of gentian violet douche or nonoxynol-9 contraceptive
– Thiotepa and acetic acid intravesically
• Medications:
– Penicillin, piperacillin, methicillin, carbenicillin, danazol, bleomycin, allopurinol, busulfan
• Prolonged high-altitude travel (Boon disease)
• Carcinomas of the urinary tract
• Acute UTIs
• Benign prostatic hypertrophy
• Trauma to the urinary system
• Arteriovenous malformation, vascular fistulae
TREATMENT
GENERAL MEASURES
• Catheterization/bladder irrigation with normal saline to clear bleeding and evacuate clots
• Remove the offending toxin.
• Treat the infectious agent.
• Hydration and diuresis
• Blood products transfusion, when necessary
MEDICATION
First Line
• Alum irrigation often considered 1st line:
– Astringent, forms precipitates over bleeding surface
– 1–4% solution at 300–1,000 mL/h
– No need for anesthesia
– Adverse effects: Spasms, precipitation and clogged catheters, rare encephalopathy from aluminum toxicity
• ε-Aminocaproic acid (Amicar):
– Inhibits clot lysis by urinary urokinase
– Can be given orally or parenterally
– Contraindicated in upper-tract bleeding, as dense clots can lead to ureteral obstruction
• Silver nitrate instillation:
– 0.5–1% solution in bladder for 10–20 min, followed by saline flush
– Causes a chemical cauterization
– Painful, requires anesthesia
– Adverse effect: Build-up can clog catheters
– Duration of response is often short
• Prostaglandin instillation:
– Carboprost tromethamine (synthetic PGF2) 0.1–0.8 mg/dL solution. Dwell for 1–4 hr, 4 times a day for 5–7 days
– Stabilizes membranes, decreasing edema; causes vasoconstriction and platelet aggregation
– Low morbidity: No anesthesia required, no precipitate forms, so no clogging of catheters
– Adverse effects: Cost, requires intensive nursing care, moderate bladder spasms
• Phenol instillation:
– 30 mL 100% phenol in 30 mL of glycine for 1 min, then ethanol and saline washes
– Destroys urothelium, not muscularis; less bladder fibrosis than with formalin
– Painful, requires anesthesia
– Duration of response is often short
• Low-dose cidofovir (3)
– 5 mg/kg in 60 mL of 0.9% NaCl intravesical over 15 min.
Second Line
• Hyaluronic acid:
– Constitutes a protective barrier.
– Intravesical treatment of 40 mg every week for 4–6 wk. If responds add monthly treatments
• Formalin instillation:
– 1–4% solution of ≤50 mL for 5–30 min, with patient in reverse Trendelenburg to minimize vesicoureteral reflux.
– Check cystogram before instillation to rule out reflux or extravasation; may need to occlude ureter with balloon to prevent potentially fatal renal absorption.
– Hydrolyzes proteins, coagulating mucosa and submucosa; 80% effective
– Very painful, requires anesthesia.
– Adverse effects: Reflux could cause ureteral fibrosis and obstruction or papillary necrosis; extravasation causes peritonitis and/or fistulas.
• Pentosan polysulfate 100 mg TID
SURGERY/OTHER PROCEDURES
• Repeated cystoscopic laser ablation or cauterization
• Consider the following after all conservative modalities have failed, and patient is unstable.
– Bilateral percutaneous nephrostomy tubes with occlusive balloons decrease the exposure of new clots to urokinase, allowing bladder to self-tamponade. Would consider this option prior to formalin instillation.
– Supravesical urinary diversion, cutaneous ureterostomy, ureterosigmoidostomy, cystectomy in severe retractable cases.
ADDITIONAL TREATMENT
Radiation Therapy
Contraindicated; a recognized cause of HC
Additional Therapies
• Hyperbaric oxygen (4):
– Promotes granulation tissue and neovascularization, causes vasoconstriction.
– Better for radiation-induced cystitis.
– Requires a hyperbaric chamber, which may not always be readily available.
– May require 30–60 daily treatments.
– High rate of recurrence.
• Selective hypogastric artery embolization:
– Under local anesthesia on risky patients.
– Complications: Gluteal claudication, bladder necrosis, lower limb paralysis, or impotence.
– Low success, as most bleeding is venous.
Complementary & Alternative Therapies
Supportive care. Blood products, platelets, reverse anticoagulation.
ONGOING CARE
PROGNOSIS
• Related to the successful treatment of etiology of HC.
• Long term increases risk of secondary urothelial malignancy.
COMPLICATIONS
• Anemia, renal failure.
• Bladder fibrosis with small, noncompliant bladder; may need surgical reconstruction.
• Bladder perforation.
• Increased risk for transitional cell carcinoma from radiation, cyclophosphamide, and similar agents; may be years later
• Secondary UTIs from prolonged catheterization.
• Vesicoureteral reflux resulting from bladder fibrosis.
FOLLOW-UP
Patient Monitoring
• Repeated hematocrit, platelets, renal function, urine culture, and sensitivities.
• Maintain sterile urine.
• Continue hydration for many days after bleeding ceases as rebleeding is common.
• Evaluate long-term sequelae after acute episode.
• May need repeat cystoscopy
Patient Resources
http://emedicine.medscape.com
REFERENCES
1. Vose JM, Reed EC, Pippert GC, et al. Mesna compared with continuous bladder irrigation as uroprotection during high-dose chemotherapy and transplantation: A randomized trial. J Clin Oncol.1993;11:1306–1310.
2. Veerasarn V, Khorprasert C, Lorvidhaya V, et al. Reduced recurrence of late hemorrhagic radiation cystitis by WF10 therapy in cervical cancer patients: A multicenter, randomized, two-arm, open-label trial. Radiother Oncol.2004;73:179–185.
3. Ganguly N, Clough LA, Dubois LK, et al. Low-dose cidofovir in the treatment of symptomatic BK virus infection in patients undergoing allogeneic hematopoietic stem cell transplantation: A retrospective analysis of an algorithmic approach. Transpl Infect Dis. 2010;12(5):406–411.
4. Del Pizzo JJ, Chew BH, Jacobs SC, et al. Treatment of radiation induced hemorrhagic cystitis with hyperbaric oxygen: Long-term followup. J Urol. 1998;160:731–733.
ADDITIONAL READING
Decker DB, Karam JA, Wilcox DT. Pediatric hemorrhagic cystitis. J Pediatr Urol. 2009;5(4):254–264.
See Also (Topic, Algorithm, Media)
• Chemotherapy Toxicity, Urologic Consideration
• Cystitis, General Considerations
• Cystitis, Hemorrhagic (Infectious, Non-Infectious, Radiation) Image 
• Cystitis, Radiation
• Cystitis, Viral
• Cytoxan (Cyclophosphamide) Toxicity
• Polyoma Virus (BK, JC), Urologic Consideration
CODES
ICD9
• 595.4 Cystitis in diseases classified elsewhere
• 595.82 Irradiation cystitis
• 595.89 Other specified types of cystitis
ICD10
• N30.40 Irradiation cystitis without hematuria
• N30.90 Cystitis, unspecified without hematuria
• N30.91 Cystitis, unspecified with hematuria
CLINICAL/SURGICAL PEARLS
Optimum treatment for chemotherapy-induced HC is prevention (aggressive hydration and/or prophylactic mesna therapy).