Hemorrhagic Cystitis Treatment & Management

Updated: Nov 22, 2017
  • Author: Joseph Basler, MD, PhD; Chief Editor: Edward David Kim, MD, FACS  more...
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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]

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 [96]
  • Activated thrombin and fibrin agents (eg, Evicel, FloSeal) [97, 98, 99]
  • Angiogenesis inhibitors (for cyclophosphamide cystitis) [100]
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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. [101]  Use of this agent in pediatric patients is not recommended.

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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. [102] 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. [103, 104, 105, 106] 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. [107] 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. [108] 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. [109, 110, 111, 112] Placement via cutaneous vesicostomy has also been described. [113]

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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. [114, 115]

Once radiation cystitis begins to develop, treatment with hyperbaric oxygen [116, 10, 117, 118, 119] or conjugated estrogen [120] 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. [121, 122]

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]) [123, 124, 125, 126, 127, 128, 129]

  • N -acetylcysteine (Mucomyst)

  • S-2-(3-aminopropylamino) ethyl phosphorothioic acid (amifostine) [115]

  • Pentosan polysulfate sodium

Mesna binds to acrolein, the caustic metabolite of cyclophosphamide and ifosfamide, creating stable thioester compounds with no bladder toxicity. [130] 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. [131]

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. [120, 132, 133] Hyperbaric oxygen has also been, used with moderate success, in refractory hematuria due to cyclophosphamide chemotherapy. [134]

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

  • Intravesical epinephrine [135]

  • Oral tadalafil [136]

  • Oral vitamin C and histidine [137]

  • Pentoxifylline [138]

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. [139, 140, 141, 142, 66, 143, 144, 145, 146, 147] 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, 148] Ciprofloxacin has been reported to decrease the BK viral load in these patients. [149] 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. [150]

Continuous bladder irrigation in combination with mesna, hydration, and urinary alkalization during bone marrow transplantation may prevent hemorrhagic cystitis. [151] 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. [152, 153, 154, 155, 103, 104] Antiviral agents should be added to bladder irrigation when a viral etiology is suspected or confirmed.

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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. [156]

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. [157] Intravesical balloons to tamponade the vessels have resulted in some transient improvement; however, the therapy is not widely accepted. [158]

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 [159, 160, 161, 162] or with use of the argon beam coagulator have been described as successful measures. [96]

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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. [163, 150]

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. [156] Subtotal cystectomy with augmentation of the bladder with ileum is another option in these patients. [164]

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]

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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.

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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]

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