Updated: Sep 18, 2009
Hemorrhagic cystitis (HC) is a common condition observed in pediatric oncology patients and is a cause of great morbidity and potential mortality in this already compromised group of patients. Hemorrhagic cystitis 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 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.
Hemorrhagic cystitis results from damage to the bladder transitional epithelium and blood vessels by toxins, viruses, radiation, drugs, or disease. Reported causative infectious agents for hemorrhagic cystitis include Escherichia coli; adenoviruses 7, 11, 21, and 35, papovavirus; and influenza A.
Cyclophosphamide is the most common cause of hemorrhagic cystitis 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 who have undergone cyclophosphamide chemotherapy. Hemorrhagic cystitis secondary to cyclophosphamide therapy appears to be dose-related and most prevalent in patients who are dehydrated and those receiving intravenous treatment. The urotoxicity observed with cyclophosphamide is due to its liver metabolite acrolein. 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.
Radiation-induced hemorrhagic cystitis 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.
Hemorrhagic cystitis 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 hemorrhagic cystitis. The incidence in the pediatric population is less than that in adults.
Clinically significant morbidity is associated with hemorrhagic cystitis and its treatments. Although uncommon, severe hemorrhagic cystitis refractory to several therapeutic modalities poses a risk of mortality.
Hemorrhagic cystitis has no known racial predilection.
Hemorrhagic cystitis has no known sexual predilection.
Hemorrhagic cystitis manifests in people of any age.
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 hemorrhagic cystitis are commonly oncology patients who have undergone chemotherapy or radiation therapy. Identify factors that contribute to the development of hemorrhagic cystitis. These include bladder outlet obstruction, infection, previous radiation or surgery, previous chemotherapy treatments, and excessive radiation dosage.
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. Patients with this disease may have a distended, tender, palpable bladder. Clot retention is common and can be very painful. Urinary incontinence is frequently observed.
Hemorrhagic cystitis 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 hemorrhagic cystitis. Reported causative infectious agents for hemorrhagic cystitis include E coli; adenoviruses 7, 11, 21, and 35; papovavirus; and influenza A.
Hemorrhagic cystitis secondary to cyclophosphamide therapy appears to be dose-related and is most prevalent in patients who are dehydrated and those receiving intravenous treatment. The urotoxicity observed with cyclophosphamide is due to its liver metabolite, 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.
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.
Nonspecific findings include hemorrhage, intense inflammatory infiltrates, chronic inflammation, and fibrosis.
The staging system for hemorrhagic cystitis 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 best treatment of hemorrhagic cystitis (HC) is prevention, especially with cyclophosphamide-induced hemorrhagic cystitis. After hemorrhagic cystitis develops, the treatment is the same irrespective of the cause.
The first step in the treatment of hemorrhagic cystitis 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 intravenous 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 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). The problem with aminocaproic acid is that it creates large adhesive clots that are subsequently difficult to remove. With upper tract bleeding, 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 hemorrhagic cystitis. 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 hemorrhagic cystitis. 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.
In patients with refractory hemorrhagic cystitis, surgical intervention is warranted. These include percutaneous nephrostomy drainage, selective hypogastric artery embolization, temporary bladder exteriorization with packing of the bladder, 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
Treatment of the patient with hemorrhagic cystitis should be coordinated among urologists, oncologists, and pediatricians.
No specific diet is indicated.
Patients with active gross hematuria should limit their activities until it resolves. These patients are hospitalized and on bed rest during their therapeutic interventions.
Various intravesical agents are used to treat hemorrhagic cystitis (HC). Ongoing assessment of treatment effectiveness is essential for a successful patient outcome. Changing to a different irrigation agent may be necessary.
Reserved for severe and intractable hemorrhagic cystitis. Hydrolyzes protein and coagulates superficial bladder mucosal tissue. Most critical factor is to administer proper solution (2.5-4% for 10-30 min). Make 4% solution by mixing buffered formalin 10% 200 mL with sterile water for irrigation 300 mL (total volume, 500 mL).
Bladder irrigation: 4% solution; manually fill bladder to capacity under gravity (catheter <15 cm above symphysis pubis); contact time 10-30 min; painful procedure, and general anesthetic needed
Administer as in adults
None reported
Documented hypersensitivity
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Monitor with intraoperative cystography; before installation, rule out VUR; if present, may proceed after placing occlusive balloon catheters in each ureter; rule out bladder rupture before installation; causes ureteral necrosis, obstruction, and fibrosis
Indicated for bladder hemorrhage. Consists of aluminum potassium sulfate or aluminum ammonium sulfate and works as astringent that causes protein precipitation in interstitial spaces and cell membranes. Systemic absorption is minimal. May be administered if VUR present.
Bladder irrigation: Extemporaneously prepared as 1% solution; administer as continuous bladder irrigant until bleeding stops
Administer as in adults
None reported
Documented hypersensitivity
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Large blood clots may develop, particularly in pediatric-sized catheters; encephalopathy or acidosis may occur with increased ammonia levels; monitor blood pH and aluminum blood levels
Used because of caustic, antiseptic, and astringent qualities. Mixed results observed.
Bladder irrigation: Instill 0.5-1% solution in sterile water into bladder with dwell time of 10-20 min
Administer as in adults
None reported
Documented hypersensitivity; broken skin
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Renal failure and anuria reported
Various prostaglandins studied. Elicits cytoprotective, anti-inflammatory, and vasoconstriction properties and produces no coagulum.
Bladder irrigation: Instill 0.1-0.4% solution; contact 45-60 min
Not established, suggested to administer as in adults
Limited data exist; no interactions reported
Documented hypersensitivity; active cardiac, pulmonary, renal, or hepatic disease
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Parenteral administration may cause hypertension, leukocytosis, nausea, vomiting, diarrhea, bronchoconstriction, and pulmonary edema; irrigation may cause flushing or severe bladder spasms
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.
Also known as 2-mercaptoethane sulfonate. In kidney, mesna disulfide reduced to free mesna. Free mesna has thiol groups that react with acrolein, ifosfamide and cyclophosphamide metabolite considered responsible for urotoxicity. Inactivates acrolein and prevents urothelial toxicity without affecting cytostatic activity. Also directly reacts with 4-hydroxy metabolites, inhibiting breakdown and release of acrolein.
IV mesna dose:
With ifosfamide: 20% of ifosfamide dose; administered 15 min before ifosfamide is started, repeat dose 4 and 8 h later or combined with ifosfamide infusion
With high-dose ifosfamide: 20% of ifosfamide dose; administered 15 min before ifosfamide started, then q3h for 3-6 doses or combined with ifosfamide; total daily mesna doses 60-160% of ifosfamide dose
With cyclophosphamide: 20% of cyclophosphamide dose, administered 15 min before and q3h for 3-4 doses or combined with cyclophosphamide; total daily mesna doses 60-100% of cyclophosphamide dose
Administer as in adults
May increase warfarin effects
Documented hypersensitivity
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Does not prevent hemorrhagic cystitis in all patients (monitor for hematuria in morning before ifosfamide or cyclophosphamide dose); does not prevent or alleviate other toxicities associated with ifosfamide or cyclophosphamide; common adverse effects include hypotension, headache, GI toxicity, and limb pain
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hemorrhagic cystitis, gross hematuria, HC, urinary frequency, urgency, dysuria, cyclophosphamide HC, cyclophosphamide hemorrhagic cystitis, viral-induced HC, viral-induced hemorrhagic cystitis, radiation-induced HC, radiation-induced hemorrhagic cystitis, bone marrow transplantation
Marcos Perez-Brayfield, MD, Consulting Staff, HIMA-San Pablo, San Juan, Puerto Rico
Marcos Perez-Brayfield, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, and American Urological Association
Disclosure: Nothing to disclose.
Andrew J Kirsch, MD, FAAP, FACS, Clinical Professor of Urology, Emory University School of Medicine, Children's Healthcare of Atlanta; President, Georgia Urology, PA
Andrew J Kirsch, MD, FAAP, FACS is a member of the following medical societies: American Academy of Pediatrics, American Urological Association, and Society for Fetal Urology
Disclosure: QMED Grant/research funds Investigation, Consulting; COOK Urological Royalty Consulting
Howard M Snyder III, MD, Professor, Department of Surgery, Division of Pediatric Urology, University of Pennsylvania School of Medicine
Howard M Snyder III, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Surgeons, American Medical Association, American Urological Association, and National Kidney Foundation
Disclosure: Nothing to disclose.
Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner
Harry P Koo, MD, Chairman of Urology Division and Director of Pediatric Urology, Virginia Commonwealth University; Professor of Surgery, VCU School of Medicine, Medical College of Virginia; Director of Urology, Children's Hospital of Richmond
Harry P Koo, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Surgeons, and American Urological Association
Disclosure: Nothing to disclose.
Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.
Marc Cendron, MD, Associate Professor of Surgery, Harvard School of Medicine; Consulting Staff, Department of Urological Surgery, Children's Hospital Boston
Marc Cendron, MD is a member of the following medical societies: American Academy of Pediatrics, American Urological Association, European Society for Paediatric Urology, Johns Hopkins Medical and Surgical Association, New Hampshire Medical Society, Society for Fetal Urology, and Society for Pediatric Urology
Disclosure: Nothing to disclose.
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