Significant bleeding from the bladder in the absence of trauma is usually associated with hemorrhagic cystitis. This can result from a variety of infectious and noninfectious etiologies. Sports hematuria or stress hematuria is a well-known cause of vesical hemorrhage seen mainly in marathon runners and other athletes. It is believed to be caused by the repeated impact of the posterior wall and base of the bladder, which results in mucosal contusions. An empty bladder at the time of running facilitates this process. Maintaining a partially full bladder in which the urine acts as a hydrostatic cushion will help prevent it.

Infections with various viruses such as the BK virus, adenovirus, and the influenza A virus can result in hemorrhagic cystitis. Bacterial infections, most often with E. coli, can also result in hemorrhagic cystitis. Fungal infections seen frequently after treatment with broad-spectrum antibiotics can also result in this condition. Parasitic infections with organisms such as Schistosoma hematobium are known to be associated with this form of cystitis. This indicates that hemorrhagic cystitis is a symptom of an underlying condition rather than a disease in itself. Infection-related hemorrhagic cystitis is usually treatable by addressing the underlying cause.

Radiation therapy to the prostate, bladder, or other pelvic organs can result in hemorrhagic cystitis. Initially there is mucosal edema with submucosal hemorrhage. Chronically, radiation causes obliterative endarteritis with subsequent urothelial ischemia. Various measures such as steroids, vitamin E, and trypsin have proved futile in treating radiation-induced cystitis, which can manifest many years after exposure. Coating the bladder mucosa with synthetic agents such as sodium pentosanpolysulfate has some beneficial effect. Hyperbaric oxygen therapy has also proved effective.

Amyloidosis of the bladder, which tends to occur in patients with rheumatoid arthritis and Crohn’s disease, can also result in hemorrhagic cystitis. The hemorrhage can be particularly severe after instrumentation or biopsy of the bladder. This hemorrhage may require aggressive treatment measures including angiographic vessel occlusion or cystectomy.

Urothelial malignancies can also cause significant bleeding, which can be controlled by transurethral resection of tumor and fulguration with electrocautery in most cases. In patients with metastatic or unresectable bladder tumors and severe hematuria, local radiation can be used to palliate the symptoms. In some cases, cystectomy or urinary diversion by means of percutaneous nephrostomy or conduit urinary diversion may be the only viable option.

A wide range of drugs and industrial toxins can also give rise to hemorrhagic cystitis. Aniline and toluidine dyes are well known to be associated with this side effect. Treatment is largely conservative, as the cystitis is self-limiting and resolves after removal of the offending agent. Antibiotics such as nitrofurantoin, ether, and accidental insertion of spermicidal contraceptives into the urethra can also result in severe hemorrhage from the bladder. Conservative treatment with adequate hydration, bladder irrigation, and discontinuing the causative agent would suffice as treatment for most cases.

Chemotherapeutic agents are a major cause of hemorrhagic cystitis. Busulfan, commonly used for treatment of leukemia, can give rise to hemorrhagic cystitis. Administration of N-acetylcysteine (mucomist), used to treat some other forms of chemically induced cystitis, would only worsen the condition. Most other measures are also ineffective in this situation. Intravesical administration of Thiotepa can result in this complication, which can occur up to 6 months after cessation of therapy. Alkylating agents such as cyclophosphamide and isophosphamide, which are employed in chemotherapeutic regimens for various solid tumors and lymphoproliferative disorders, are common culprits for hemorrhagic cystitis. The incidence ranges from 2% to 40%, and significant mortality rates have also been reported. It is dose dependent and related to the route of administration of the chemotherapeutic agent (higher with intravenous administration). It is more severe in dehydrated patients. Acrolein, which is a liver metabolite of cyclophosphamide, is the principal inciting agent and acts by direct contact with the bladder mucosa. Histologic changes that occur in the bladder are similar to those seen with radiation and include edema, ulceration, neovascularization, hemorrhage, and necrosis. Prophylactic hydration and the use of protective agents such as mucomist or 2-mercaptoethane sulfonate (Mesna) can reduce the incidence of this complication. Systemic administration of mucomist can decrease the antineoplastic effect of cyclophosphamide.

Treatment of Hemorrhagic Cystitis

Mild hematuria can be managed by vigorous hydration and oral administration of agents such as aminocaproic acid or conjugated estrogens, which inhibit fibrinolysis and promote coagulation.

Moderate hematuria can be treated with continuous saline irrigation through a Foley catheter after all clots have been evacuated. In some situations such as with radiation cystitis, irrigation with cold saline for 24 to 48 hours may prove more effective. If hematuria persists, continuous bladder irrigation with 1% alum (potassium or ammonium aluminum sulfate) is helpful. The alum acts as an astringent and precipitates the surface proteins. Aluminum levels must be monitored, particularly in patients with renal insufficiency. Severe acidosis and encephalopathy can occur in such patients as a result of high aluminum levels. Periodic intravesical instillation of prostaglandins (PGE2, PGF2a) and PGF2a analogs (Carboprost) have also proved effective. They decrease the inflammatory response and reduce the hemorrhage. They can be used prophylactically or therapeutically. Prostaglandin E2 has been used in a dose of 0.75 mg in 200 cc of normal saline instilled for 4 hours. The effective dose of PGF2a has been 1.4 mg in 200 cc of normal saline. Carboprost has been used in a dose of 0.8 mg/dl diluted in normal saline instilled for 1 hour at 6-hour intervals with good results in 62% of patients according to one study.8 Instillation of silver nitrate (0.5% to 1% solution) for short periods of time followed by saline irrigation of the bladder to remove residual silver nitrate is also an effective technique.

Persistent severe hemorrhage that has not subsided in spite of the above-mentioned measures can be treated with intravesical instillation of carbolic acid (phenol) or 1% formalin. This requires general anesthesia. Phenol is instilled in a dose of 30 cc of a 100% solution mixed with an equal volume of glycine for 1 minute. This is washed out with 95% ethanol (60 cc) and saline to prevent methemoglobinemia. It is necessary to rule out vesicoureteral reflux by performing a voiding cystourethrogram before using formalin, as it can cause fibrosis and scarring of the ureters and renal pelvis. If need be, the ureters can be occluded with Fogarty balloon catheters to prevent reflux while formalin is instilled. Fifty milliliters of 1% formalin (0.37% formaldehyde) diluted with saline should be instilled for 4 to 10 minutes. This should then be washed out with saline, and the saline irrigation is continued for 24 hours. The external genitalia are covered with towels or Vaseline to prevent irritation.

In recalcitrant cases, use of medical antishock trousers and cryotherapy have been reported. Embolization of the hypogastric arteries with autologous clot, Gelfoam, coils, or ethanol can also be resorted to in such cases. This may result in temporary gluteal claudication. Open ligation of the hypogastric artery can also be performed. Supravesical urinary diversion by means of percutaneous nephrostomy tubes or ileal or sigmoid conduit urinary diversion with or without cystectomy remains as a final but viable option.

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