Hemorrhagic Cystitis 

Updated: Dec 18, 2018
Author: Joseph Basler, MD, PhD; Chief Editor: Edward David Kim, MD, FACS 

Overview

Practice Essentials

Hemorrhagic cystitis is defined by lower urinary tract symptoms that include hematuria and irritative voiding symptoms. It results from damage to the bladder's transitional epithelium and blood vessels by toxins, pathogens, radiation, drugs, or disease.

Infectious causes of hemorrhagic cystitis include bacteria and viruses. Noninfectious hemorrhagic cystitis most commonly occurs in patients who have undergone pelvic radiation (see the image below), chemotherapy, or both.[1]  Affected patients may develop asymptomatic microscopic hematuria or gross hematuria with clots, leading to urinary retention. Treatment depends on the etiology, severity of the bleeding, and symptoms.[2]

Changes associated with irradiation cystitis, whic Changes associated with irradiation cystitis, which developed after 7200cGy external beam radiation for localized prostate cancer.

Patients who undergo bone marrow transplantation frequently have hemorrhagic cystitis because most are exposed to cyclophosphamide, total-body irradiation, or both. Patients with malignancies and those undergoing chemotherapy are often immunocompromised and are at high risk of acquiring bacterial and viral infections that can cause hemorrhagic cystitis.

Rarely, arteriovenous malformations, stones, metastatic tumors, and, more commonly, urothelial malignancies produce gross hematuria. These are differentiated from hemorrhagic cystitis with imaging and endoscopic evaluation.[3]

For patients receiving drugs or undergoing procedures that are known to cause hemorrhagic cystitis, prevention is essential. Two standard methods of preventing cyclophosphamide-related bladder toxicity are hyperhydration and mesna administration. Controversial methods include prophylactic bladder irrigation and hourly voiding.

Physicians treating oncology patients must be aware of the possible preventive measures against hemorrhagic cystitis.

Patient education

Patients at high risk must be educated about the possibility of the development of hemorrhagic cystitis and the need for early intervention. For patient education information, see Blood in the Urine.

Anatomy

The bladder anatomy relevant to noninfectious hemorrhagic cystitis includes an appreciation of the layers from the lumen outward. The glycosaminoglycan (GAG) layer coats the inner surface over the transitional epithelium. Deep to this transitional epithelium, which is covered superficially by “umbrella” cells, the bladder submucosa with its microvasculature overlies the detrusor muscle, which is smooth muscle oriented in multiple directions to allow for uniform stretching and the storage of urine. A layer of fatty connective tissue surrounds most of the anterior and lateral bladder in the space of Retzius, while, posteriorly, the peritoneal serosal surface separates it from the cul-de-sac and abdominal cavity contents.

In cases of chronic cystitis, neovascularity in the submucosal area is common and is presumably the site of acute hemorrhage. Ischemic changes related to endarteritis can lead to mucosal ulcerations and acute hemorrhage.

Pathophysiology

Hemorrhagic cystitis results from damage to the bladder's transitional epithelium and blood vessels by toxins, viruses, radiation, drugs (in particular, chemotherapeutic drugs), bacterial infections, or other disease processes. Histologically, the bladder wall demonstrates nonspecific findings of intense inflammatory infiltrates, chronic inflammation, and fibrosis.[4]

Cyclophosphamide-induced cystitis

Cyclophosphamide is the most common cause of hemorrhagic cystitis in the oncologic population. The urotoxicity observed with cyclophosphamide is due to its liver metabolite acrolein, which is excreted in the urine. Although the entire urothelium is at risk of urotoxicity, the bladder, which serves as a reservoir, is most frequently affected, because the contact time between acrolein and the urothelium is greatest at this site.

Adverse urologic effects of cyclophosphamide include the following:

  • Frequency
  • Dysuria
  • Urgency
  • Suprapubic discomfort
  • Microscopic and gross hematuria

Rare adverse effects include the following:

  • Bladder wall necrosis
  • Bladder fibrosis with resultant loss of compliance
  • Contracture, or shrinkage of bladder reservoir volume
  • Tumor formation

Radiation-induced hemorrhagic cystitis

Radiation-induced hemorrhagic cystitis is most common in patients receiving pelvic irradiation. Hematuria may develop acutely during radiation treatment or months to years later.

The symptoms of radiation cystitis are caused by a microscopic progressive obliterative endarteritis that leads to mucosal ischemia. The ischemic bladder mucosa then ulcerates and bleeding ensues. Neovascular ingrowth to the damaged area, as shown in the images below, then occurs, causing the characteristic vascular blush on cystoscopic evaluation. The new vessels are more fragile and may leak (petechiae) with bladder distention, minor trauma, infection, or any mucosal irritation.

Changes associated with irradiation cystitis, whic Changes associated with irradiation cystitis, which developed after 7200cGy external beam radiation for localized prostate cancer.
Neovascularity associated with irradiation cystiti Neovascularity associated with irradiation cystitis. When distended, these weak-walled vessels often rupture, resulting in submucosal hemorrhage and gross hematuria.
Bladder neck neovascularity after radiation therap Bladder neck neovascularity after radiation therapy (IMRT) for prostate cancer.

Submucosal hemorrhage and overt hematuria may begin precipitously. Acute episodes of radiation cystitis wane within 12-18 months in most patients following radiation therapy.[5, 6, 7]

Etiology

Hemorrhagic cystitis has both infectious and noninfectious causes. Although the noninfectious causes of hemorrhagic cystitis vary, this condition most commonly develops as a complication of pelvic radiation or from toxicity related to the use of certain chemotherapeutic drugs (eg, cyclophosphamide, ifosfamide). Less commonly, exposure to certain industrial chemicals, such as aniline or toluidine derivatives, causes hemorrhagic cystitis.

Rarely, drugs such as penicillins or danazol can also precipitate hemorrhagic cystitis. Other, extremely rare reports include associations with food poisoning (from Salmonella typhi)[8] and prolonged high-altitude air travel (Boon disease).[9]

Regardless of the perceived circumstance, an infectious etiology should be sought as part of the initial assessment, even in the setting of radiation or chemical exposure, as infection may serve as an exacerbating factor. Bacterial, fungal, parasitic, and especially viral bladder infections in immunocompromised patients are often complicated by hemorrhage. Reported causative infectious agents for hemorrhagic cystitis include the following:

  • Escherichia coli
  • Adenoviruses 7, 11, 21, and 35
  • Papovavirus
  • Influenza A

Radiation-induced hemorrhagic cystitis

Nearly 25% of patients who undergo pelvic radiation develop bladder-related complications. Mucosal ischemia secondary to radiation injury results from endarteritis inducing hypoxic surface damage, ulceration, and bleeding. The incidence in the pediatric population is less than that in adults. Slightly less than 50% of these patients develop diffuse hematuria.

Patients with radiation-induced hemorrhagic cystitis have usually undergone radiation therapy for cancer of the prostate, colon, cervix, or bladder. Urgency, frequency, dysuria, and stranguria may develop acutely during radiation or may begin months to years after completion of radiotherapy.

The higher the dose and the wider the field encompassed by the radiation exposure, the more likely radiation cystitis becomes. Because of the cumulative dose effect, patients who have undergone pelvic radiation are at an increased risk for radiation cystitis if additional radiotherapy is performed. Infection, bladder outlet obstruction, and instrumentation are all factors that can exacerbate radiation cystitis.[10]

Drug-induced hemorrhagic cystitis

Chemotherapeutic drugs

The most common pharmacologic causes of hemorrhagic cystitis are the oxazaphosphorine-alkylating agents cyclophosphamide and ifosfamide.[11, 12, 13] Unfortunately, the toxicity of these drugs is not insignificant, and many of the adverse effects are urologic.

Cyclophosphamide (Cytoxan) is used in the treatment of non-Hodgkin lymphoma (as part of the CHOP regimen) and breast cancer, as well as in steroid-resistant nephrotic syndrome, and as an orphan drug in systemic sclerosis. Specifically pediatric uses include juvenile idiopathic arthritis/vasculitis and systemic lupus erythematosus.

The incidence of adverse urologic effects with cyclophosphamide varies from 2-40%, and the toxicity is dose-related. In pediatric patients, adverse effects are typically seen after oral doses greater than 90 g and intravenous doses greater than 18 g, and they occur more commonly in patients receiving intravenous treatment.

Cyclophosphamide can cause microscopic and gross hematuria. The onset of hematuria usually occurs within 48 hours of treatment.[14] Cyclophosphamide is also associated with bladder cancer, which is typically aggressive.[15]

Cyclophosphamide itself is not toxic; the drug's toxicity is due to its hepatic conversion to the metabolite acrolein, which is excreted in the urine and causes bladder edema and bladder hemorrhage. Over time, chronic bladder damage manifests as fibrosis with decreased capacity, trabeculations, and telangiectasias. The adverse effects of cyclophosphamide are more likely due to increased bladder exposure to acrolein.[16]

Hemorrhagic cystitis secondary to cyclophosphamide therapy is most prevalent in patients who are dehydrated. Thus, patients receiving cyclophosphamide should always receive good hydration, and a Foley catheter is often placed to ensure immediate drainage of the bladder.[17, 18] Continuous bladder irrigation is sometimes recommended to hasten acrolein clearance from the bladder.[19]

Ifosfamide (Ifex) is approved for use in germ cell testicular cancer, and as an orphan drug for treatment of sarcomas of soft tissue and bone. Hemorrhagic cystitis due to ifosfamide therapy is generally worse than that caused by cyclophosphamide.[20] Ifosfamide causes the release of tumor necrosis factor – alpha and interleukin-1 beta, mediating the release of nitric oxide and leading to hemorrhagic cystitis.[21, 22]

Penicillins

In rare cases, penicillins have been reported to cause hemorrhagic cystitis. Case reports have implicated the following agents:

  • Methicillin
  • Carbenicillin
  • Ticarcillin
  • Piperacillin
  • Penicillin VK

Most cases of hemorrhagic cystitis in patients taking extended-spectrum penicillins have been reported in individuals with cystic fibrosis who had previously received penicillin antibiotics.

Symptoms can take up to 2 weeks to develop after the drug is started; when symptoms occur, the best treatment is to discontinue the offending drug immediately. Hemorrhagic cystitis in patients taking penicillins is thought to be caused by an immune-mediated hypersensitivity. Examination of the urine frequently reveals eosinophils.[23, 24, 25]

Danazol

Treatment with danazol, a semisynthetic anabolic steroid, has caused hemorrhagic cystitis in patients with hereditary angioedema. Interestingly, the advent of hemorrhagic cystitis in these patients has followed years of symptom-free treatment with the drug. Hematuria developed after 30-77 months of treatment in one study. In almost all cases, the hematuria resolved after cessation of danazol. The dose of danazol did not correlate with the severity of hemorrhagic cystitis. The etiology of hemorrhagic cystitis from danazol is unclear.[26]

Other medications

Medications that have been implicated in the development of hemorrhagic cystitis in limited reports include the following:

  • Temozolomide [27]
  • Bleomycin [28]
  • Tiaprofenic acid [29]
  • Allopurinol [30]
  • Methaqualone [31]
  • Methenamine mandelate [32]
  • Ether
  • Gentian violet inadvertently placed in the urethra [33, 34, 35, 36]
  • Nonoxynol-9 suppositories inadvertently placed in the urethra [37, 38]
  • Intravesical acetic acid. [39]

Risperidone has been associated with hemorrhagic cystitis but is also used as treatment for hemorrhagic cystitis due to JC virus.[40]

A chemical hemorrhagic cystitis can develop when vaginal products are inadvertently placed in the urethra. Gentian violet douching to treat candidiasis has resulted in hemorrhagic cystitis when the drug has been misplaced in the urethra, but this hemorrhagic cystitis has resolved spontaneously with cessation of treatment.[33, 35, 36]

Accidental urethral placement of contraceptive suppositories has also caused hemorrhagic cystitis in several patients. In this case, the bladder irritation was thought to be caused by contact of the acidic compound nonoxynol-9 (pH, 3.35) with the bladder. In the acute setting, the bladder can be copiously irrigated with alkalinized normal saline to minimize bladder irritation.[37, 38]

Chemically induced hemorrhagic cystitis

Cases of hemorrhagic cystitis with no infectious etiology have been reported in patients who have been in contact with certain urotoxic chemicals, such as derivatives of aniline (found in dyes, marking pens, and shoe polish) and toluidine (found in pesticides and shoe polish). Exposure to these chemicals is usually work-related. Hemorrhagic cystitis caused by these derivatives is self-limiting, and cessation of the exposure usually suffices for cure. Exposure also increases the risk of transitional cell carcinoma. Thus, the workup for gross hematuria should reflect this possibility.[41]

Viral causes of hemorrhagic cystitis

Patients undergoing therapy to suppress the immune system—eg, after solid organ, bone marrow, or cord blood transplantation—are at risk for hemorrhagic cystitis due to either the direct effects of chemotherapy or activation of dormant viruses in the kidney, ureter, or bladder.[34, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52]

In the early 1990s, infection with polyomavirus or adenoviruses was implicated as the likely etiology of this condition. The BK virus (polyomavirus) subclinically infects most of the population in childhood and persists indefinitely in the kidney after primary infection. When the immune system is compromised, as in persons with human immunodeficiency virus (HIV) infection or those undergoing chemotherapy or chemical immunosuppression, the virus can be reactivated, leading to clinical nephritis, ureteritis, or cystitis.[53]

The BK polyomavirus[54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64] and adenovirus types 7, 11, 34, and 35[65, 66, 67, 68, 69, 70, 71, 72] have been the most commonly described viruses in these cases. Cytomegalovirus,[73, 74] JC virus,[75] and herpesviruses[34, 76, 77] have also been identified as causative agents in these scenarios.

In the pediatric population, the species most commonly isolated is adenovirus type 11, which has a propensity for the urinary tract. It reactivates with profound immunosuppression. It is also the most common cause of hemorrhagic cystitis in the healthy child.

HIV itself does not cause hemorrhagic cystitis, but immune suppression from HIV infection can predispose to other viral infections, such as BK virus, leading to the condition.[78] BK virus has also been suggested to be a causal transforming agent for bladder cancer.[79]

Epidemiology

Hemorrhagic cystitis occurs in up to 70% of patients exposed to high doses of cyclophosphamide or ifosfamide chemotherapy[80, 81, 82, 83] and in up to 15% of patients who undergo pelvic irradiation to treat malignancy.[5, 6, 7] In recent years, however, newer irradiation techniques have decreased the incidence of hemorrhagic cystitis to approximately 10% of treated patients.[84] The incidence in the pediatric population is less than that in adults.

A study in patients undergoing allogeneic hematopoietic stem cell transplantation found a 2-year cumulative incidence of 24% for BK polyomavirus–associated hemorrhagic cystitis. These researchers identified three clinical factors associated with hemorrhagic cystitis in these patients: myeloablative conditioning, cytomegalovirus viremia, and severe acute graft versus host disease.[85]

 In a study of 33 haploidentical hematopoietic stem cell transplantation recipients, 20 developed hemorrhagic cystitis during a mediian follow-up of 38 days, and the cumulative incidence of hemorrhagic cystitis at day 180 was 62%. Factors significantly associated with the development of hemorrhagic cystitis were previous transplant and the occurrence of cytomegalovirus reactivation before hemorrhagic cystitis.[86]  In another study of 1321 allogeneic hematopoietic cell transplantation recipients, 219 (16.6%) developed hemorrhagic cystitis at a median of 22 days.[87]

A review of consecutive pediatric patients treated at the Memorial Sloan-Kettering Cancer Center from 1986 to 2010 found that hemorrhagic cystitis was observed in 97 of 6,119 children (1.6%). On univariate analysis, the following factors were significantly associated with increased risk of hemorrhagic cystitis[88] :

  • Age >5 years

  • Male gender

  • Cyclophosphamide or busulfan chemotherapy

  • Bone marrow or peripheral blood stem cell transplantation

  • Pelvic radiotherapy

  • Underlying diagnoses of rhabdomyosarcoma, acute leukemia, or aplastic anemia

Factors associated with greater severity of cystitis were as follows[88] :

  • Older age
  • Late onset of hemorrhagic cystitis
  • Positive urine culture for BK virus
  • Bone marrow or peripheral blood stem cell transplantation

Prognosis

In general, cystitis caused by exposure to chemotherapeutic drugs can be expected to resolve after discontinuation of the agent and treatment with irrigation/fulguration. Conversely, hemorrhagic cystitis due to pelvic radiation therapy tends to recur for months, or even years, after completion of radiotherapy. Seemingly minor events, such as urinary tract infection or bladder distention, may trigger florid hemorrhage. Close follow-up with periodic urinalysis and urine culture and sensitivity testing, along with aggressive management, may prevent recurrences.

The prognosis in pediatric patients with hemorrhagic cystitis is related to successful treatment of their primary oncologic condition. Most patients are successfully treated, with a resolution of hemorrhagic cystitis. However, long-term effects on the bladder may include increased bladder fibrosis, reduced bladder capacity, and upper tract deterioration.

In a retrospective single-instiution study of children who developed hemorrhagic cystitis after bone marrow transplantation, Au et reported high mortality and significant genitourinary morbidity. Factors associated with higher mortality included Foley catheterization, need for dialysis, and BK viremia.[89]

Complications are unusual in patients with chemical cystitis. Wound problems, urinary anastomotic strictures and leaks, and bowel anastomosis problems are more common in patients who have undergone a urinary diversion procedure after radiation therapy.[90, 91] Patients with severe hemorrhagic cystitis refractory to medical intervention are at an increased risk for mortality.

 

Presentation

History

Patients who present with hemorrhagic cystitis usually have a history of radiation or chemical exposure. They are often inpatients or are well known to their respective services.

Noninfectious hemorrhagic cystitis is characterized by inflammation of the bladder associated with hematuria. Patients with this condition usually present with urgency, frequency, dysuria, and, in some cases, abdominal discomfort. A history of new urinary incontinence is frequently noted.

The presence or absence of clotted blood in the urine is not completely helpful in determining the etiology of hemorrhagic cystitis, but the presence of long, stringy clots suggests an upper urinary tract etiology. Symptoms include suprapubic discomfort, urinary frequency, and inability to empty the bladder due to the clots.

Physical Examination

Upon examination, the patient often demonstrates suprapubic fullness and discomfort or pain to palpation, as well as costovertebral angle tenderness if the bladder obstruction is chronic.

Patients with hemorrhagic cystitis can present with variable degrees of hematuria, ranging from slightly blood-tinged urine to massive gross hematuria with passing of clots that may cause urinary retention. Clot retention is common and can be very painful. Urinary incontinence is frequently observed.

 

Workup

Approach Considerations

Documentation of noninfectious hemorrhagic cystitis requires a negative urine culture for bacteria and viruses. If even "insignificant" growth on an adequately collected voided specimen or any growth on a catheterized specimen is present, antibiotics should be initiated. Certain circumstances seem to predispose to urinary tract infections and cause signs and symptoms disproportionate to the amount of pathogen growth, especially in hemorrhagic cystitis due to radiation treatment or chemotherapy. Empiric antibiotics should be switched to culture-directed agents as soon as sensitivities are available.

In all patients, obtain a complete blood count (CBC), basic metabolic profile, and coagulation studies. The hematocrit is rarely below the reference range during an initial occurrence of hemorrhagic cystitis; however, patients with chronic hemorrhagic cystitis may have a lower hematocrit level and prevailing signs of chronic anemia. The white blood cell (WBC) count may be elevated because of a concurrent infection or because of the treatment (eg, chemotherapy) of the underlying malignancy.

Basic metabolic profile (SMA-7) findings are usually normal but may reflect sequelae due to treatment of the primary condition. Liver function test abnormalities related to the primary process may be found but are generally not related to the hemorrhagic cystitis.

Imaging of the upper tracts and bladder is recommended in all cases of hemorrhagic cystitis to assist in ascertaining the etiology and/or confounding variables. At a minimum, perform bladder and renal ultrasonography with a KUB (kidney, ureter, bladder) film to assess for radio-opaque stones (see the diagnosis algorithm below).

In patients with normal  renal function, computed tomography (CT) urography is the most helpful imaging test in most cases. Cystoscopy is indicated in all but straightforward cases of uncomplicated bacterial cystitis. If a bacterial infection is documented, voiding cystourethrography (VCUG) may be performed, if indicated, after the infection has been cleared.

Diagnosis algorithm. R/O = rule out; US = ultrason Diagnosis algorithm. R/O = rule out; US = ultrasonography; VUR = vesicoureteral reflux.

Potential difficulties with the acquisition of urine cultures may arise because of the forced hydration and intravesical irrigation used to evacuate clots. Because of this, it is important to have evaluation protocols that put a high priority on obtaining cultures.

Urine studies for viruses, when indicated, include the following:

  • Viral culture

  • Electron microscopy of bladder biopsy specimens

  • Enzyme-linked immunosorbent assay (ELISA)

Urinary Tract Imaging

Renal and bladder ultrasonography along with a KUB film is an excellent initial screening test to evaluate many causes of hematuria. Anatomic and pathologic changes in the urothelium can occur in the upper urinary tract, which may result in hematuria and possible hydronephrosis.

Renal ultrasonography is a reliable and cost-effective initial modality to identify hydronephrosis. Dilatation of the upper urinary tract can be secondary to obstruction at the ureteral level, secondary to bladder wall thickening, or secondary to reflux of urine. Ultrasonography of the bladder may also help to identify blood clots and evaluate their size.

Evaluation of the complete ureter and enhanced anatomic detail is limited with ultrasonography. Evidence of hydronephrosis or a high index of suspicion should prompt further evaluation with CT or MR urography or retrograde pyelography.

In general, the evaluation of any patient with gross hematuria should include an assessment of the upper urinary tract. Imaging studies are as follows, in descending order of helpfulness:

  • CT urography

  • Magnetic resonance (MR) urography

  • Intravenous pyelography

  • CT scanning without contrast (stone protocol, prone scanning)

  • Renal ultrasonography

When only renal ultrasonography or noncontrast CT scanning is performed, retrograde intravenous pyelography may be necessary to further evaluate urothelium of the upper urinary tract. Even if upper urinary tract lesions are identified, a bladder etiology for hematuria should be suspected and then checked with cystoscopy.[92, 93]

If intravesical sclerotherapy (eg, formalin, silver nitrate) is planned after exhaustion of other control measures, cystography is necessary to determine the bladder capacity and to determine the presence of vesicoureteral reflux (VUR). The administration of sclerotherapy in the presence of VUR can lead to ureteral fibrosis, obstruction, and possible renal failure, as well as systemic absorption of the agent.

Cystoscopy

Cystoscopy, with or without retrograde pyelography, is indicated in all cases of hemorrhagic cystitis. This may be delayed until the acute bleeding has been treated with successful use of conservative measures; ie, manual irrigation and continuous bladder irrigation. In this case, outpatient flexible cystoscopy is used typically without need for general anesthesia.

However, cystoscopic clot evacuation is often necessary to facilitate complete clot removal. This allows close inspection of the bladder urothelium and assessment of potential neoplasm(s) as the bleeding source. Use of a rigid cystoscope of the largest possible caliber permits improved removal of clots. Endoscopic inspection is essential in planning treatment and in preventing future episodes.

In the pediatric population, cystoscopy should be considered a first-line therapy in the setting of clot retention or failure of initial conservative therapy. Cystoscopy also allows for evaluation of concomitant neoplasm (fairly uncommon in pediatric population). The endoscopic procedure is performed under general anesthesia in the pediatric population. Complete removal of clot is paramount prior to beginning intravesical irrigation due to the risk of overdistention and potential for bladder rupture in children. Most of the time, cystoscopic findings are nonspecific. The bladder may appear edematous with multiple punctate hemorrhages. Visible areas of active bleeding can be identified and judiciously fulgurated to control bleeding.[94]

Staging

Although a staging system for hemorrhagic cystitis has been devised, it has little clinical significance and does not really help in the management of this condition. The main use for the staging system is the standardization of scientific studies on this subject. The stages are as follows:

  • 0 - No symptoms of bladder irritability or hemorrhage

  • 1 - Microscopic hematuria/frequency/dysuria

  • 2 - Macroscopic hematuria

  • 3 - Macroscopic hematuria with small clots

  • 4 - Massive macroscopic hematuria requiring instrumentation for clot evacuation and/or causing urinary obstruction

 

Treatment

Approach Considerations

It is best to assume that a bacterial urinary tract infection is present until cultures return as ”no growth.” Empiric antibiotics to cover the usual flora are indicated during initiation of other measures. Regardless of the cause of noninfectious hemorrhagic cystitis, treatment follows the same course. In the absence of obstructing clots and if the patient is voiding well, hydration with careful observation may be the only treatment required. If the patient demonstrates difficulty with urination, clots are likely occluding the bladder outlet and clot evacuation is indicated. Continuous bladder irrigation with normal saline is started after clots are cleared.

If bladder irrigation with a hematuria catheter to clear the clots is not possible, cystoscopy with clot evacuation under anesthesia and antibiotic coverage are necessary. Fulguration of bleeding sites and biopsies of suspicious areas may be performed at that time. Although continuous bladder irrigation with saline solution cannot replace manual irrigation for removal of the clots, it can aid in preventing further clotting. For persistent hematuria, the bladder can be irrigated with a variety of agents. Hyperbaric oxygen therapy has been used with some success in difficult cases.[6, 10, 95, 96]

In immunocompromised patients, who are at high risk for infections, results from the bacterial and viral cultures guide the selection of antibiotic and antiviral therapy. In chemically induced cases, elimination of the agent predisposing to cystitis is paramount. Transfusion with platelets or coagulation products may be indicated.

Patients with active gross hematuria should limit their activities until it resolves. These patients are typically hospitalized and put on bed rest during their therapeutic interventions. The patient should remain well hydrated after the resolution of the hematuria. If a urethral catheter is left in place for monitoring purposes, providers must pay careful attention to reinitiation of hematuria, clot formation, and development of catheter-related urinary tract infections.

The oncologic patient with hemorrhagic cystitis should be treated at an institution familiar with this condition. The patient with severe hemorrhagic cystitis should be transferred only after his or her condition is stabilized. Only a few facilities may offer hyperbaric oxygen therapy. Patients requiring this therapy should be transferred early to these facilities.

The best treatment of hemorrhagic cystitis is prevention, especially with cyclophosphamide-induced hemorrhagic cystitis. Adequate hydration to induce brisk diuresis, continuous bladder irrigation, and prophylactic dosing of mesna are important preventive measures. Prompt recognition and treatment of urinary tract infections is also a prudent preventive measure. After hemorrhagic cystitis develops, the treatment follows the same guidelines irrespective of the cause, although most infectious cases resolve with appropriate antibiotics.

In patients with refractory hemorrhagic cystitis, surgical intervention is warranted (see the management algorithm below). This may include any of the following:

  • Open cystostomy and temporary packing
  • Percutaneous nephrostomy drainage
  • Selective hypogastric artery embolization (very rarely effective)
  • Ileal conduit diversion
  • Cutaneous ureterostomy
  • Cystectomy
Management of hemorrhagic cystitis. PCN = percutan Management of hemorrhagic cystitis. PCN = percutaneous nephrostomy.

Advances in the management of bleeding related to soft-tissue trauma have had application to hemorrhagic cystitis. These include the following:

  • Argon beam coagulators [97]
  • Activated thrombin and fibrin agents (eg, Evicel, FloSeal) [98, 99, 100]
  • Angiogenesis inhibitors (for cyclophosphamide cystitis) [101]

Clot Evacuation

The first step in the treatment of hemorrhagic cystitis should be directed toward making sure that the bladder does not become overly distended. Bladder outlet obstruction from clots can lead to urosepsis, bladder rupture, and renal failure. Clot evacuation can be performed at the bedside by carefully placing a large, stiff-walled hematuria catheter. In pediatric patients, a catheter with decreased luminal size is needed because of the small urethra. Consideration should be given to the use of a suprapubic tube, but only under the direction of a trained urologist.

Initial irrigations may be performed manually with sterile water; water is preferable to sodium chloride solution because it helps to lyse red blood cells and clots. Care must be taken to not overdistend the bladder and cause a perforation, especially of the small pediatric bladder.

After clot evacuation, if hematuria persists, a 3-way catheter can be inserted and continuous bladder irrigation with saline can be started. All clots must be removed before continuous irrigation is started to avoid overdistention and potential bladder ruptures. The patient should be vigorously hydrated using oral and/or intravenous fluids to keep clots from reforming.

If clot evacuation is unsuccessful with this approach, the patient should undergo cystoscopy in the operating room with clot evacuation and fulguration of bleeding sites. Some have proposed the use of epsilon aminocaproic acid (Amicar) as an aid to stopping small vessel bleeding at this point.

Epsilon aminocaproic acid can be used either orally or parenterally. It works by inhibiting clot lysis by urinary urokinase. It is contraindicated in patients with upper urinary tract bleeding because it can cause extremely dense clots, resulting in ureteral obstruction and potential loss of the kidney. These clots are also often difficult to manually evacuate through a catheter; thus, evacuation via cystoscopy or cystotomy in the operating room may be required.[102]  Use of this agent in pediatric patients is not recommended.

Bladder Irrigation Agents

If hematuria persists after the treatments described above, bladder irrigation can be performed with carboprost, 1-2% alum, or silver nitrate. Alum and silver nitrate, which are astringents, work by forming precipitates over the bleeding surfaces of the bladder wall.

These agents are not significantly absorbed through an intact bladder wall but may enter the circulation under pressure through open veins. Rarely, alum irrigation causes encephalopathy and acidosis in patients with renal insufficiency, in whom serum aluminum level monitoring is advisable.[103] Both agents are somewhat caustic to the bladder, and alum can cause bladder wall necrosis and even perforation.

Because alum and silver nitrate irrigations are not without risk, the importance of constant monitoring to ensure low-pressure bladder irrigation is paramount and may warrant performing the procedure in an intensive care unit setting. One drawback to alum irrigation is that it imparts a leathery consistency to any clot present in the bladder at the time of irrigation, thus precluding easy clot evacuation. Occlusion is especially likely with a pediatric-sized catheter.

Carboprost

Carboprost tromethamine (prostaglandin F2 [Hemabate]) is approved by the US Food and Drug Administration (FDA) for uterine bleeding and induction of second-trimester abortion. It induces smooth-muscle contraction in blood vessel walls and has been used off-label for bladder irrigation in the treatment of hemorrhagic cystitis due to cyclophosphamide.[104, 105, 106, 107] The main advantages of carboprost are that it is easy to use and that it does not cause bladder pain with irrigation.

Prostaglandin E1 and E2

Other prostaglandins have also been used intravesically or parenterally in the treatment of pain associated with hemorrhagic cystitis, including prostaglandin E1 and prostaglandin E2. These agents cause vasodilation, which improves blood flow to the bladder wall, and presumably decrease pain because of their anti-inflammatory properties. These agents are expensive, and their efficacy in bleeding reduction is marginal.[108] However, they involve no coagulum formation, have few side effects, and are easily tolerated by patients.

Formalin

In severe, refractory cases of hemorrhagic cystitis, formalin can be instilled in the bladder.[109] Formalin coagulates the bleeding bladder surface by hydrolyzing and cross-linking proteins. Prior to instillation, reflux into the ureters must be assessed with cystography. Formalin must not reflux into the upper urinary tract, because this can cause irreversible fibrosis, papillary necrosis, or ureteral obstruction. If reflux is present, formalin can be used if occlusion balloon catheters are inserted into both ureters prior to proceeding.

A 2.5-4% formalin solution is instilled in the bladder and left for up to 30 minutes, after which the bladder is meticulously irrigated with continuous bladder irrigation. Intravesical formalin instillation must be performed with the patient under anesthesia because it is otherwise excruciatingly painful.[110, 111, 112, 113] Placement via cutaneous vesicostomy has also been described.[114]

Pharmacologic Therapy

Radiation-induced hemorrhagic cystitis

Although radiation-induced hemorrhagic cystitis cannot be prevented at this time, encouraging research with pentosan polysulfate sodium is ongoing. This compound resembles heparin and may prove to be uroprotective.

Amifostine (Ethyol) has been used with mixed results in preventing radiation damage, and its use should still probably be limited to clinical trials. Amifostine is a prodrug that is dephosphorylated by alkaline phosphatase to a pharmacologically active free thiol metabolite, which, in studies of head and neck cancer, is believed to be responsible for the reduced renal toxicity of cisplatin and reduced side effects of radiation on the normal oral tissues. The active thiol metabolite is thought to scavenge reactive oxygen species generated in irradiated cells.

Amifostine is thought to protect the normal tissues, since they have higher pH, higher alkaline phosphatase activity (and produce more active metabolite), and better vascularity than the tumor tissue.[115, 116]

Once radiation cystitis begins to develop, treatment with hyperbaric oxygen[117, 10, 118, 119, 120] or conjugated estrogen[121] has demonstrated moderate effectiveness. Hyperbaric oxygen is thought to promote granulation tissue and neovascularization and to cause vasoconstriction. Estrogen may decrease the fragility of the mucosal microvasculature.

Anticholinergic and antispasmodic drugs may also be helpful in limiting the discomfort and inconvenience of the frequency and urgency associated with radiation cystitis. Because these drugs are used to control irritative symptoms, any concurrent bladder outlet obstruction should be assessed and treated separately. Treatment options are alpha blockade (eg, terazosin, doxazosin, tamsulosin, alfuzosin) alone or in combination with 5-alpha-reductase inhibitors (finasteride, dutasteride) and/or surgical intervention (eg, transurethral incision of the prostate [TUIP], transurethral resection of the prostate [TURP]) to prevent urinary retention.

Intravenously administered WF10 (tetrachlorodecaoxygen) is an investigational therapy used to treat late-onset (>3 mo following treatment), radiation-induced hemorrhagic cystitis. Studies have shown that WF10 may improve hematuria and reduce its recurrence in these patients.[122, 123]

Chemotherapy-induced hemorrhagic cystitis

Cyclophosphamide and ifosfamide toxicity can be minimized with hydration[18] and with the concurrent use of the following drugs:

  • 2-Mercaptoethanesulfonate (mesna [Mesnex])[124, 125, 126, 127, 128, 129, 130]

  • N -acetylcysteine (Mucomyst)

  • S-2-(3-aminopropylamino) ethyl phosphorothioic acid (amifostine)[116]

  • Pentosan polysulfate sodium

Mesna binds to acrolein, the caustic metabolite of cyclophosphamide and ifosfamide, creating stable thioester compounds with no bladder toxicity.[131] Because it decreases the chemotherapeutic efficacy of cyclophosphamide, N-acetylcysteine is less desirable than mesna, which is generally not reported to decrease the efficacy of cyclophosphamide.

Mesna can be given either orally or intravenously, and its routine concurrent administration has been recommended in the treatment of patients receiving cyclophosphamide and ifosfamide chemotherapy. In patients receiving cyclophosphamide and mesna who develop hemorrhagic cystitis, discontinuation of mesna is recommended. Unfortunately, mesna is much more successful at preventing active bleeding than it is at treating it.

Discontinuation of cyclophosphamide is mandatory in patients with developing hemorrhagic cystitis, because hematuria can subside with this maneuver in most patients.

Even if hemorrhagic cystitis does not develop during the use of cyclophosphamide, the patient’s lifetime risk of developing bladder cancer is increased 9-fold after receiving the agent. Mesna administration may decrease this risk. The addition of dexamethasone with mesna may improve the results.[132]

Treatment with estrogen has been shown to control hemorrhagic cystitis in children, adolescents, and adults with hemorrhagic cystitis due to various causes, including cyclophosphamide chemotherapy.[121, 133, 134] Hyperbaric oxygen has also been, used with moderate success, in refractory hematuria due to cyclophosphamide chemotherapy.[135]

Studies in rats have shown the following agents to be effective for prevention and/or treatment of cyclophosphamide-induced hemorrhagic cystitis

  • Intravesical epinephrine[136]

  • Oral tadalafil[137]

  • Oral vitamin C and histidine[138]

  • Pentoxifylline[139]

Viral hemorrhagic cystitis

In immunosuppressed patients with viral hemorrhagic cystitis, decreased immunosuppression and the use of antiviral agents (cidofovir, vidarabine, ribavirin), administered orally, intravenously, intramuscularly, or intravesically, is recommended.[140, 141, 142, 143, 66, 144, 145, 146, 147, 148]  In patients who have an unsatisfactory response to anti-infection therapies, the addition of corticosteroids may promote complete remission.[149]

Reviews of intravenous or intravesical cidofovir for hemorrhagic cystitis due to BK polyomavirus in allogeneic stem cell transplant recipients have reported at least partial response in approximately two thirds of patients. Acute kidney toxicity is a potential complication, especialliy with intravenous use.[150, 151]

Intravesical hyaluronate has been used to treat BK virus hemorrhagic cystitis, while risperidone has been used to treat hemorrhagic cystitis due to JC virus.[75, 152] Ciprofloxacin has been reported to decrease the BK viral load in these patients.[153] A study of leflunomide for the treatment of BK virus–associated hemorrhagic cystitis in allogeneic hematopoietic stem cell transplantation recipients found that the drug was potentially effective and without significant toxicity.[154]

Continuous bladder irrigation in combination with mesna, hydration, and urinary alkalization during bone marrow transplantation may prevent hemorrhagic cystitis.[155] Treatment with continuous bladder irrigation and clot evacuation is implemented as in other cases of hematuria.

In bone marrow recipients who develop hemorrhagic cystitis, presumably due to latent viral infections, infusions of factor VII, factor XII, epidermal growth factor, and carboprost have been described as effective.[156, 157, 158, 159, 104, 105] Antiviral agents should be added to bladder irrigation when a viral etiology is suspected or confirmed.

Surgical Embolization and Urinary Diversion

Surgical intervention other than cystoscopy with cauterization is reserved for cases in which medical management fails. In extreme cases, when all other treatment options have failed, selective or superselective hypogastric branch artery embolization can be considered.

Intervention to eliminate the influence of urokinase on the clots in the bleeding bladder in the form of percutaneous nephrostomies or other supravesical diversions has been met with mixed success. Because up to half of patients who undergo urinary diversion later require cystectomy, bladder removal at the time of diversion should be strongly considered.[160]

In extreme cases, when all other treatment options have failed, selective hypogastric branch artery embolization can be considered. This surgical procedure is associated with a low success rate because most cases are associated with diffuse venous bleeding that cannot be controlled with embolization.[161] Intravesical balloons to tamponade the vessels have resulted in some transient improvement; however, the therapy is not widely accepted.[162]

Urinary flow diversion via percutaneous nephrostomy tube placement is often successful, presumably because it decreases the exposure of the nascent clots to urokinase, a potent clotting inhibitor in urine. Often, permanent urinary diversion (ie, ileal conduit, colon conduit, cutaneous ureterostomy) is necessary to prevent future hemorrhagic episodes. Cystostomy for vesical installation and cystotomy with temporary packing of the bladder[163, 164, 165, 166] or with use of the argon beam coagulator have been described as successful measures.[97]

Cystectomy

Cystectomy may be necessary to control pain but may be avoided in some patients once the urine stream is diverted. Cystectomy poses a significant risk of perioperative complications and mortality, because the patient is usually compromised from chemotherapy or radiation therapy.[167, 154]

Neobladder creation and continent catheterizable pouches from uninvolved bowel segments, with or without removal of the bladder, are options in certain patients with severe, refractory hemorrhagic cystitis.[160] Subtotal cystectomy with augmentation of the bladder with ileum is another option in these patients.[168]

Preoperative details

Prior to urinary diversion and cystectomy, culture-directed antibiotics or preoperative, second-generation cephalosporins are usually administered after a mechanical bowel preparation. The latter is accomplished with oral sodium phosphate (Fleets Phosphosoda) or a polyethylene glycol electrolyte solution (GoLYTELY, NuLYTELY) with enemas on the evening prior to surgery.

Oral erythromycin base and neomycin are also administered upon completion of the mechanical bowel preparation. This minimizes peritoneal contamination when the bowel is entered for creation of the conduit or substitute.[90, 91]

Intraoperative details

Radical cystectomy to manage cancer usually involves anterior exenteration in female patients and cystoprostatectomy in male patients. However, for benign causes (eg, hemorrhagic cystitis), a more conservative approach can be used.

The so-called simple cystectomy is accomplished in the standard fashion, but the removal of the ovaries, fallopian tubes, uterus, and anterior vagina in female patients can be avoided, if desired. Similarly, prostatectomy in male patients may be avoided if indicated by anatomical concerns or a desire for cavernosal nerve sparing (erectile nerve preservation) or neobladder creation.

The choice of conduit material (eg, ileum, sigmoid colon, transverse colon) depends on the underlying etiology of the cystitis. In cases of radiation cystitis, a transverse colon conduit may be the best option, since it is generally out of the radiation field.

The ureters must be taken well above the bladder to avoid implanting an ischemic, irradiated ureter in the conduit. The latter often requires the creation of a longer conduit than would be performed otherwise. This, in turn, may lead to other metabolic consequences (eg, hyperchloremic metabolic acidosis) that must be considered postoperatively.[90, 91]

Postoperative details

Stabilization of hematocrit levels is the rule. Electrolyte abnormalities may supervene if preoperative renal insufficiency was present. Postoperative care is similar to that in other patients who have undergone cystectomy.[90, 91]

Hyperbaric Oxygen Therapy and Fulguration

Hyperbaric oxygen therapy is an alternative in patients with refractory hemorrhagic cystitis. (Few reports describe its use in the pediatric population.) This treatment is better for radiation-induced hemorrhagic cystitis than for cyclophosphamide-induced hemorrhagic cystitis. Treatment involves 100% oxygenation at 2atm for 90 minutes 5 times weekly. On average, 40 sessions are given. Contraindications include active cancer, active viral infection, pneumothorax, treatment with doxorubicin or cisplatin, and ear reconstruction.[6, 10, 95]

Fulguration with a neodymium-doped yttrium aluminium garnet (Nd:YAG) laser has been used for hemorrhagic cystitis. (Few reports describe Nd:YAG laser therapy in the pediatric population.) Patients may require several treatments. Laser settings should be no higher than 20W with a 2-second pulse mode to avoid deep penetration and possible bowel injury. Green-light laser has also been helpful in coagulating the areas of telangiectasia seen after radiotherapy.

Prevention of Recurrence and Long-Term Monitoring

Preventive approaches are available to decrease the urotoxicity related to cyclophosphamide therapy, unlike the other causes of hemorrhagic cystitis. The goal of this strategy is aimed at neutralization or detoxification of acrolein. Most oncology centers recommend vigorous hydration combined with frequent voiding or use of an indwelling bladder catheter to reduce acrolein contact time with the bladder.[18]

Patients who have experienced previous injury to the bladder by radiation and chemotherapy agents and possible damage to urothelium and bladder muscle by therapeutic agents, such as formalin, require routine evaluation of upper tracts and bladder with renal bladder ultrasonography and additional studies, as needed. Lifelong follow-up may be required.

The oncology service must be made aware of the patient's history of hemorrhagic cystitis and must maximize preventive measures before the patient is given any additional oncologic therapy. Surgical patients with longer conduits and bladder substitutions require close follow-up and monitoring for sequelae of metabolic acidosis that may accompany these diversions. Vitamin B-12 deficiency and steatorrhea have been reported in patients in whom the distal ileum and ileocecal valve were used for diversion.[91]

 

Medication

Medication Summary

Persistent hematuria can be treated with bladder irrigation, using carboprost, 1-2% alum, or silver nitrate. If hemorrhagic cystitis does not resolve despite clot evacuation and irrigation, a variety of agents may be instilled into the bladder to promote local hemostasis. Systemic agents may also prove useful. In patients undergoing chemotherapy with cyclophosphamide, which is known to cause hemorrhagic cystitis, use of antidotes may have prophylactic benefit. Mesna binds to the urotoxic cyclophosphamide metabolite acrolein, creating stable thioester compounds with no bladder toxicity.

Astringents

Class Summary

Various intravesical agents are used to treat hemorrhagic cystitis. Ongoing assessment of treatment effectiveness is essential for a successful patient outcome. Changing to a different irrigation agent may be necessary.

Silver nitrate

Silver nitrate is administered intravesically because of its caustic, antiseptic, and astringent qualities. Mixed results have been observed.

Prostaglandins, Endocrine

Class Summary

Prostaglandins are useful for their cytoprotective properties.

Carboprost (Hemabate)

Carboprost is a prostaglandin that elicits cytoprotective, anti-inflammatory, and vasoconstrictive properties and produces no coagulum.

Urologics, Other

Class Summary

Antidotes are used to manage poisoning and overdose, prevent toxic effects, and treat metabolic disorders in which toxic substances accrue. Mechanisms of action vary and include antagonism, toxin transformation, altered metabolism, chelation, and interactions with directed antibodies.

Mesna (Mesnex)

Mesna is also known as 2-mercaptoethane sulfonate. In the kidney, mesna disulfide is reduced to free mesna, which has thiol groups that react with acrolein, the metabolite of ifosfamide and cyclophosphamide considered responsible for urotoxicity. Mesna inactivates acrolein and prevents urothelial toxicity without affecting cytostatic activity. It also directly reacts with 4-hydroxy metabolites, inhibiting breakdown and release of acrolein.

 

Questions & Answers

Overview

What is hemorrhagic cystitis?

What is included in patient education about hemorrhagic cystitis?

What is the anatomy of the bladder relevant to hemorrhagic cystitis?

What is the pathophysiology of hemorrhagic cystitis?

What is the pathophysiology of cyclophosphamide-induced hemorrhagic cystitis?

What is the pathophysiology of radiation-induced hemorrhagic cystitis?

What causes hemorrhagic cystitis?

What are the causes of radiation-induced hemorrhagic cystitis?

What are the causes of drug-induced hemorrhagic cystitis?

What are the causes of chemically-induced hemorrhagic cystitis?

What is the prevalence of hemorrhagic cystitis?

Which factors increase the risk for hemorrhagic cystitis?

Which factors are associated with greater severity of hemorrhagic cystitis?

What is the prognosis of hemorrhagic cystitis?

Presentation

Which clinical history findings are characteristic of hemorrhagic cystitis?

Which physical findings are characteristic of hemorrhagic cystitis?

Workup

How is hemorrhagic cystitis diagnosed?

What is the role of imaging in the workup of hemorrhagic cystitis?

What is the role of cystoscopy in the workup of hemorrhagic cystitis?

How is hemorrhagic cystitis staged?

Treatment

How is hemorrhagic cystitis treated?

What is the role of clot evacuation in the treatment of hemorrhagic cystitis?

What is the role of bladder irritation in the treatment of hemorrhagic cystitis?

What is the role of carboprost in the treatment of hemorrhagic cystitis?

What is the role of prostaglandins in the treatment of hemorrhagic cystitis?

What is the role of formalin in the treatment of hemorrhagic cystitis?

How is radiation-induced hemorrhagic cystitis treated?

How is chemotherapy-induced hemorrhagic cystitis treated?

How is viral hemorrhagic cystitis treated?

What is the role of surgery in the treatment of hemorrhagic cystitis?

What is the role of cystectomy in the treatment of hemorrhagic cystitis?

What is included in preoperative care prior to cystectomy for hemorrhagic cystitis?

How is cystectomy performed for the treatment of hemorrhagic cystitis?

What is included in postoperative care following cystectomy for hemorrhagic cystitis?

What is the role of hyperbaric oxygen therapy in the treatment of hemorrhagic cystitis?

How is hemorrhagic cystitis recurrence prevented?

Medications

What is the role of medications in the treatment of hemorrhagic cystitis?

Which medications in the drug class Urologics, Other are used in the treatment of Hemorrhagic Cystitis?

Which medications in the drug class Prostaglandins, Endocrine are used in the treatment of Hemorrhagic Cystitis?

Which medications in the drug class Astringents are used in the treatment of Hemorrhagic Cystitis?