AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Hemorrhagic cystitis (HC) is a common condition observed in pediatric oncology patients, and it is a cause of great morbidity and potential mortality in this already compromised group of patients. HC is defined by lower urinary tract symptoms that include hematuria and irritative voiding symptoms. It results from damage to the bladder transitional epithelium and blood vessels by toxins, viruses, radiation, drugs, or disease. The pediatric oncology patient may be exposed to all of these factors. Patients who undergo bone marrow transplantation frequently have HC 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 HC.

Pathophysiology

HC results from damage to the bladder transitional epithelium and blood vessels by toxins, viruses, radiation, drugs, or disease. Reported causative infectious agents for HC include Escherichia coli; adenoviruses 7, 11, 21, and 35, papovavirus; and influenza A.

Cyclophosphamide is the most common cause of HC in the pediatric oncology population. Urologic adverse effects of cyclophosphamide include frequency, dysuria, urgency, suprapubic discomfort, and both microscopic and gross hematuria. In rare cases, mucosal necrosis, bladder fibrosis, contracture, vesicoureteral reflux (VUR), and tumor formation occur. Urologic adverse effects are observed in 2-40% of patients. HC secondary to cyclophosphamide therapy appears to be dose related and most prevalent in patients who are dehydrated and those receiving intravenous (IV) treatment. The urotoxicity observed with cyclophosphamide is due to its liver metabolite, called acrolein. Although the entire urothelium is at risk of urotoxicity, the bladder, as a reservoir, is most frequently affected because the contact time between acrolein and the urothelium is greatest at this site.

Radiation-induced HC is most common in patients receiving pelvic irradiation. The incidence in the pediatric population is less than that in adults. Hematuria may develop acutely during radiation treatment or months to years later. Mucosal ischemia secondary to radiation injury results from end arteritis that induces hypoxic surface damage, ulceration, and bleeding. Factors that contribute to radiation cystitis include bladder outlet obstruction, infection, previous radiation or surgery, and excessive radiation dosage.

Frequency

United States

HC is common among pediatric oncology patients. Patients treated with cyclophosphamide have a 2-40% incidence of urologic adverse effects. Approximately 10% of patients receiving pelvic radiation develop HC. The incidence in the pediatric population is less than that in adults.

Mortality/Morbidity

Clinically significant morbidity is associated with HC and its treatments. Although uncommon, severe HC refractory to several therapeutic modalities poses a risk of mortality.

Race

No racial predilection is known.

Sex

No sexual predilection is known.

Age

HC manifests in people of any age.

CLINICAL

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History

Hemorrhagic cystitis (HC) is defined by lower urinary tract symptoms that include hematuria and, usually, gross and irritative voiding symptoms; these include urinary frequency, urgency, and dysuria. A history of new urinary incontinence is frequently noted. Patients with HC are commonly oncology patients who have undergone chemotherapy or radiation therapy. Identify factors that contribute to the development of HC. These include bladder outlet obstruction, infection, previous radiation or surgery, previous chemotherapy treatments, and excessive radiation dosage.

Physical

The patients with HC can present with different degrees of hematuria. Patients can have a distended, tender, palpable bladder. Clots retention is common. Urinary incontinence is frequently observed.

Causes

HC results from damage to the bladder transitional epithelium and blood vessels by toxins, viruses, irradiation, drugs, or disease. Patients with malignancies and those undergoing chemotherapy are frequently immunocompromised and at high risk of acquiring the bacterial and viral infections responsible for the HC. Reported causative infectious agents for HC include E coli; adenoviruses 7, 11, 21, and 35; papovavirus; and influenza A.

HC secondary to cyclophosphamide therapy appears to be dose related and is most prevalent in patients who are dehydrated and those receiving IV treatment. The urotoxicity observed with cyclophosphamide is due to its liver metabolite, called acrolein. Although the entire urothelium is at risk of urotoxicity, the bladder, as a reservoir, is most frequently affected because the contact time between acrolein and the urothelium is greatest at this site.

Mucosal ischemia secondary to radiation injury results from end arteritis, which induces hypoxic surface damage, ulceration, and bleeding. Factors that contribute to radiation cystitis include bladder outlet obstruction, infection, previous radiation or surgery, and excessive radiation dosage.

• Cyclophosphamide HC
• • Cyclophosphamide is the most common cause of HC.
  • Urologic adverse effects with cyclophosphamide have an incidence of 2-40% and include frequency, dysuria, urgency, suprapubic discomfort, and microscopic or gross hematuria. In rare cases, mucosal necrosis, bladder fibrosis, contracture, VUR, and tumor formation may occur.
  • Risk of adverse effects is dose related (oral >90 g; IV >18 g).
  • Risk factors include dehydration and IV infusion.
  • The urotoxic metabolite is acrolein. Acrolein is a liver metabolite of cyclophosphamide. The bladder is most frequently affected because of its contact time with this agent.
• Radiation-induced HC
• • This is most common with pelvic radiation.
  • The incidence in adults is less than that in the pediatric population.
  • HC may develop acutely or months to years later.
  • Mucosal ischemia secondary to radiation injury results from end arteritis inducing hypoxic surface damage, ulceration, and bleeding.
  • Cystitis is nonspecific.
• Viral-induced HC
• • BK virus (polyoma virus): It usually subclinically infects most of the population in childhood. Polyoma viruses are known to cause HC in children. It persists indefinitely in the kidney after primary infection. It is reactivated and excreted in the urine in patients with depressed cellular immunity.
  • Adenovirus: The species most commonly isolated is adenovirus type 11, which has a propensity for the urinary tract. It reactivates with profound immunosuppression. It is the most common cause of HC in the healthy child.

DIFFERENTIALS

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Other Problems to be Considered

Other causes of gross hematuria should be considered, such as bacterial infection of the bladder, bladder urolithiasis, bleeding caused by a vascular lesion (hemangioma or arteriovenous malformation), urothelial tumor, or interstitial cystitis.

WORKUP

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Lab Studies

• The evaluation of the pediatric oncology patient with hemorrhagic cystitis (HC) includes microbiology, imaging studies, and possibly cystoscopy.
• In all patients, obtain a CBC count with platelet counts and urine cultures for bacteria and virus and, at a minimum, perform bladder and renal ultrasonography.
• • If a bacterial infection is documented, voiding cystourethrography (VCUG) should be performed.
  • Oncology patients with pancytopenia can present with bleeding diathesis, including hematuria.
  • Transfusion with platelets or coagulation products aids in the successful treatment of HC.
  • In addition, patients with pancytopenia are immunocompromised and are at high risk for infections, including bacterial and viral cystitis, and, thus, urine culture for these pathogens should be obtained.
  • Results from both the bacterial and viral cultures guide the selection of antibiotic and antiviral therapy.
  • Potential difficulties with the acquisition of urine cultures arises because of the forced hydration and intravesical irrigation used to evacuate clots.
• Urine studies for viruses include the following:
• • Viral culture
  • Electron microscopy of bladder biopsy specimens
  • Enzyme-linked immunosorbent assay (ELISA)

Imaging Studies

• Renal bladder ultrasonography is an excellent screening test to rule out many causes of hematuria.
• • Because changes in the urothelium can occur in the urinary upper tract, renal ultrasonography is mandatory to identify hydronephrosis.
  • Dilation of the upper tract can be secondary to obstruction at the ureteral level or secondary to bladder-wall thickening.
  • Ultrasonography of the bladder also helps to identify blood clots and evaluate their size.
• In addition, if intravesical sclerotherapy is required, cystography is necessary to determine the bladder capacity and to determine the presence of 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.
• CT scanning or MRI is not routinely used in patients with HC.

Procedures

• Cystoscopy should be considered if the patient has clot retention. Otherwise, cystoscopy contributes little beyond what ultrasonography and VCUG reveal.
• The endoscopic procedure is performed under general anesthesia in the pediatric population.
• Attempts to use the largest caliber scope facilitate removal of clots if needed.
• Most of the time, cystoscopic findings are nonspecific. The bladder appears edematous with multiple punctate hemorrhages. These findings can be isolated to an area of the bladder or diffuse.

Histologic Findings

Nonspecific findings include hemorrhage, intense inflammatory infiltrates, chronic inflammation, and fibrosis.

Staging

The staging system for HC has little clinical significance. The main use for the staging system is the standardization of scientific studies on this subject.

• 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

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Medical Care

The best treatment of hemorrhagic cystitis (HC) is prevention, especially with cyclophosphamide-induced HC. After HC develops, the treatment is the same irrespective of the cause.

The first step in the treatment of HC should be directed toward clot evacuation. Bladder outlet obstruction from clots can lead to urosepsis, bladder rupture, and renal failure. Clot evacuation can be performed by placing a wide-lumen bladder catheter at bedside. The bladder can be irrigated with water or sodium chloride solution. The use of water is preferable because water can help with clot lysis. Care must be taken to not overdistend the bladder and cause a perforation.

After clot evacuation, the patient should be vigorously hydrated using IV fluids to keep clots from reforming. 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. If clot evacuation is unsuccessful with this approach, the patient can undergo cystoscopy in the operating room with clot evacuation and fulguration of bleeding sites. Some have proposed the use of epsilon aminocaproic acid (Amicar). The problem with aminocaproic acid is that it creates large adhesive clots that are difficult to remove. With an upper tract bleed, clots due to aminocaproic acid can cause the loss of the respective renal unit, and use in pediatrics is not recommended.

When hematuria persists after the treatments described above, bladder irrigation can be performed with several astringent intravesical agents, including 1% silver nitrate or alum. Alum is an astringent that causes protein precipitation over bleeding sites. The systemic absorption is minimal, even in the presence of VUR. Alum irrigation tends to create large clots that can block the catheter, especially a pediatric-sized catheter. Aluminum levels must be monitored in patients with renal insufficiency because increased levels can cause encephalopathy and acidosis. Parenteral or intravesical prostaglandins are also used to treat HC. Prostaglandins are cytoprotective and have both anti-inflammatory and vasoconstriction properties. They involve no coagulum formation and few side effects and are easy tolerated by the patients.

Formalin intravesical installations are reserved for severe and intractable HC. It hydrolyzes proteins and coagulates superficial bladder mucosal tissue. The most critical factor in the effectiveness of formalin is its concentration. Installation is painful and requires general or regional anesthesia. The concentration used is 2.5-4% for 10-30 minutes. Intraoperative cystography is mandatory to rule out VUR because formalin contact with ureteral tissue leads to fibrosis, obstruction, and necrosis. In the presence of VUR, formalin can be used if occlusion balloon catheters are inserted in both ureters.

Antiviral agents should be added to bladder irrigation when a viral etiology is suspected or confirmed.

Surgical Care

In patients with refractory HC, surgical intervention is warranted. These include percutaneous nephrostomy drainage, selective hypogastric artery embolization, ileal conduit diversion, cutaneous ureterostomy, and cystectomy. A few reports describe the use of hyperbaric oxygen, with some success in these difficult cases.^{1, 2}

• Hyperbaric oxygen therapy
• • Few reports describe hyperbaric oxygen therapy in the pediatric population.
  • This is an alternative in patients with refractory HC.
  • This treatment is better for radiation-induced HC than for cyclophosphamide-induced HC.
  • Treatment involves 100% oxygenation at 2 atm for 90 minutes 5 times per week. Treatment lasts an average of 40 sessions.
  • Contraindications include active cancer, active viral infection, pneumothorax, treatment with doxorubicin or cisplatin, and ear reconstruction.
• Nd:YAG laser therapy
• • Few reports describe Nd:YAG laser therapy in the pediatric population.
  • It is used for fulguration.
  • Patients may require several treatments.
  • Laser settings should be no higher than 20 W with a 2-second pulse mode to avoid deep penetration and possible bowel injury.
• Use of treatment pearls in pediatric patients
• • A catheter with decreased luminal size is needed because of the small urethra in pediatric patients.
  • Consider the use of a suprapubic tube.
  • Water irrigation is best with clot lysis.
  • The pediatric bladder is small; therefore, watch for overdistention, which can lead to rupture.
  • Always keep patients hydrated.
  • All clots must be removed before intravesical irrigations are started.
  • Do not hesitate to go to the operating room with pediatric patients.
  • Use caution with agents that create large clots.
  • If the bleeding cannot be controlled endoscopically, open cystostomy and temporary packing may be considered.
  • With an upper-tract bleed, use of aminocaproic acid is contraindicated.
  • Always perform cystography before formaldehyde therapy to rule out reflux or perforation.

Consultations

Treatment of the patient with HC should be coordinated among urologists, oncologists, and pediatricians.

Diet

No specific diet is indicated.

Activity

Patients with active gross hematuria should limit their activities until it resolves. These patients are hospitalized and on bed rest during their therapeutic interventions.

MEDICATION

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Drug Category: Bladder irrigants

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

Drug Category: Antidotes

Antidotes are used to manage poisoning and overdose, prevent toxic effects, or 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.

FOLLOW-UP

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Further Inpatient Care

• The patient should remain well hydrated after the resolution of the hematuria.
• If a urethral catheter is still in place, pay careful attention to clot formation and urinary tract infections.

Further Outpatient Care

• Close follow-up is warranted.
• 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.
• The oncology service must be aware of the patient's history of hemorrhagic cystitis (HC) and maximize preventive measures before given any additional oncologic therapy.

Transfer

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

Deterrence/Prevention

• Preventive approaches are available to decrease the urotoxicity related to cyclophosphamide therapy, unlike the other causes of HC.
• • 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.
• Two medications, N-acetylcysteine (Mucomyst) and 2-mercaptoethane sulfonate (ie, mesna [Mesnex]), bind to acrolein and form a nonurotoxic compound.
• • Unlike acetylcysteine, mesna specifically binds to acrolein and does not interfere with its therapeutics effects when administered systemically.
  • Routine prophylactic administration of mesna is recommended in patients receiving cyclophosphamide therapy.
• Discontinuation of cyclophosphamide is mandatory in patients with developing HC because hematuria can subside with this maneuver in most patients.
• Unlike cyclophosphamide HC, no effective preventive measures are available for radiation-induced HC.

Complications

• HC is considered a complication from previous oncologic treatments.
• Additional complications are related to the agents used to control the bleeding.
• The specific complications were discussed previously.

Prognosis

• The prognosis for patients with HC is related to successful treatment of their primary oncologic condition.
• Most patients are successfully treated, with a resolution of HC.
• Patient with severe HC refractory to medical intervention are at an increased risk for mortality.

Patient Education

• The physicians treating oncology patients must be aware of the possible preventive measures against HC.
• Patients at high risk must be educated about the possibility of the development of HC and the need for early intervention.
• For excellent patient education resources, visit eMedicine's Kidneys and Urinary System Center. Also see eMedicine's patient education article Blood in the Urine.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Potential medicolegal problems are present in patients with hemorrhagic cystitis (HC) who are in fragile condition.
• HC is a complication from previous therapy with potential morbidity and mortality.
• The possibility of developing HC must be addressed with every patient undergoing oncologic treatment.
• After a patient develops HC, detailed discussion of the treatments, complications, and possible mortality risk should be presented to the patient.

Special Concerns

• Prevention is essential in this condition.
• • Two standard methods of prevention are hyperhydration and mesna administration.
  • Controversial methods include prophylactic bladder irrigation and hourly voiding.
• HC is source of great morbidity and mortality.
• • Prevention is the most important factor.
  • Diagnosis and treatment should be prompt.
  • In a few patients, an aggressive approach is warranted to save their lives.

MULTIMEDIA

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Media file 1:  Diagnosis algorithm. R/O = rule out; US = ultrasonography; VUR = vesicoureteral reflux.
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Media file 2:  Management of hemorrhagic cystitis. PCN = percutaneous nephrostomy.
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Media file 3:  Grading of hemorrhagic cystitis.
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REFERENCES

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16. Raboni SM, Siqueira MM, Portes SR, Pasquini R. Comparison of PCR, enzyme immunoassay and conventional culture for adenovirus detection in bone marrow transplant patients with hemorrhagic cystitis. J Clin Virol. Aug 2003;27(3):270-5. [Medline].
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21. Vicente J, Rios G, Caffaratti J. Intravesical formalin for the treatment of massive hemorrhagic cystitis: retrospective review of 25 cases. Eur Urol. 1990;18(3):204-6. [Medline].
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Article Last Updated: Nov 1, 2007