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Learning objectives

Upon completion of this activity, participants should be able to:

1. Specify recommended tests for the diagnosis of prostatic hematuria.
2. Describe bladder instillation agents for lower urinary tract hemorrhage.
3. Identify oral medications that may improve prostatic hematuria.
4. Describe invasive treatment for prostatic hematuria.

Competing interests

The authors declared no competing interests. Charles P Vega, the CME questions author, declared that he has served as an advisor or consultant to Novartis, Inc.

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Prostate cancer

Han et al.¹ reported the incidence of hematuria in a prostate-cancer-screening population of 26,126 patients. The incidence of hematuria was 0.7%; a multivariate analysis yielded no correlation with the incidence of prostate cancer. The incidence of hematuria among patients undergoing transrectal ultrasound-guided needle biopsy for the evaluation of prostate cancer has been reported in several series and ranges from 62% for mild hematuria to 0.7% for severe hematuria in the initial period after the procedure (mean 7 days).² The incidence of recurrent mild hematuria at 7 days after biopsy, however, decreases to 15.9%. Rodriguez and Terris³ reported a prospective review of patients undergoing transrectal ultrasound-guided biopsy. The incidence of associated hematuria was 47.1%, but no patient required surgical intervention.

Benign prostatic hyperplasia

The current paradigm that uses luteinizing-hormone-releasing hormone agonists (leuprolide acetate, goserelin acetate) and 5--reductase inhibitors (finasteride) for the treatment of prostatic hematuria was initially reported by Marshall and Narayan.⁴ They detailed the use of androgen deprivation therapy (conjugated estrogens, diethylstilbestrol, flutamide and finasteride) to successfully treat four patients with prostatic hematuria associated with benign prostatic hyperplasia and prostate cancer. The hyperplastic processes lead to increased acinar cell and stromal cell proliferation, increased vascularity and, hence, bleeding. Foley and Bailey⁵ described the increased neovascularity within the prostatic urethra—which is in close proximity to the mucosal surface suburothelial connective tissue—by assessing microvessel density in specimens obtained during transurethral resection of the prostate. This increase in vascularity was believed to result in mucosal ulceration and hemorrhage.

Testosterone is a potent mediator of prostatic hyperplasia, which is an androgen-dependent process.⁶ In the late 1800s, White and Cabot first attempted to popularize the technique of castration in the treatment of benign prostatic hyperplasia, or, as they termed it, prostatism. Later, Peters and Walsh⁷ studied a series of patients who underwent chemical castration with nafarelin acetate; at 4 months, analysis of biopsy samples revealed a decrease in the epithelial component of the prostate and a 75% decrease from initial volume.

Several androgen-dependent factors have been studied in the setting of neovascularization, including vascular endothelial growth factor (VEGF), transforming growth factor , and epidermal growth factor. VEGF, in particular, seems to be an integral part of the neovascularization associated with benign prostatic hyperplasia and corresponding hematuria⁵ VEGF expression is under androgenic control, suggesting that dihydrotestosterone is the active regulatory substance of neovascularization in this context.⁸

Radiation therapy

Radiation therapy is an integral part of the treatment of localized and locally advanced prostate cancer. The incidence of hematuria has been reported as 5% or less in patients with prostate cancer treated with external beam radiation.⁹ By contrast, in one study the 5-year data regarding interstitial brachytherapy for prostate cancer showed a 100% incidence of hematuria in the immediate postoperative period, which resolved within 24 h; in a small subset of patients (5 [2.6%] of 193), hematuria persisted for up to 6 weeks.¹⁰

The effects of radiation on the bladder are well described; however, specific studies of the effects of radiation on the prostate have not been done. We extrapolate from these data on the bladder and apply them to prostatic hematuria. Researchers have reported that radiation to the bladder induces acute mucosal edema and inflammation; the hemorrhagic sequela generally presents several months after treatment. Histologically, the diffuse mucosal edema leads to telangiectasia, submucosal hemorrhage and interstitial fibrosis.¹¹ Finally, obliterative endarteritis leads to mucosal ischemia, ulceration and bleeding.

Continuous bladder irrigation

Mild prostatic hematuria may respond to hydration or diuresis alone. Heavier bleeding will, however, often necessitate clot evacuation and continuous bladder irrigation (CBI) with normal saline. A Foley catheter can be placed on traction to decrease prostatic blood flow and provide direct radial tamponade in the suburothelial areas. The temporary urinary diversion (drainage via the Foley catheter) also decreases exposure of the bleeding sites to urokinases.

CBI can prevent clot formation in prostatic hematuria and subsequent obstruction to bladder drainage. CBI might in itself provide enough time to permit the bleeding to abate or resolve. Before using CBI, the patient must be clot-free. In order to achieve this goal, treatment can range from vigorous flushing of the bladder with a large-bore, multi-eye catheter, to formal cystourethroscopy with clot evacuation. Frequent monitoring of clot status for the duration of irrigation is important in such patients; if a clot blocks the catheter during CBI, patients are at risk of bladder perforation.

A substantial number of data are available on the addition of medications to the irrigation fluid in cases of bleeding that arises from the bladder. Unfortunately, there is a paucity of information in the literature regarding the use of such adjuncts in prostatic hematuria. In anecdotal reports, success has been variable, but it is reasonable to try one or more of these agents before proceeding to surgical intervention.

Alum (aluminum ammonium sulfate or aluminum potassium sulfate) acts as an astringent directly at the sites of bleeding, causing a protein precipitation at the urothelial surface.¹² The desired 1% alum irrigation solution consists of 50 g alum dissolved into 5 l sterile water. The 1% alum solution is used to irrigate the bladder at a rate of 200–300 ml/h. A drawback of this approach, however, is that alum irrigation can lead to the formation of a precipitant that could block the Foley catheter. Rare toxic effects associated with alum irrigations—such as microcytic hypochromatic anemia, osteomalacia and dementia—have been reported in patients with renal insufficiency and in children.^{13, 14}

Bladder instillations

Silver nitrate bladder instillations cause chemical coagulation and eschar at the sites of bleeding. The solution concentration ranges from 0.5% to 1.0%, and is instilled for 10–20 min. Renal failure secondary to occlusion of the upper tracts by silver nitrate salts has been reported in one case.¹⁵ This complication reiterates the importance of ruling out vesicoureteral reflux before intravesical instillation of silver nitrate, phenol and/or formalin.

Intravesical formaldehyde has been used in patients with intractable hemorrhagic cystitis. A number of cases have been reported in which formalin irrigation completely resolved all hematuria in patients who had been previously unresponsive to numerous other therapies.^{16, 17} Formalin causes precipitation of cellular proteins of the bladder mucosa, and acts by occluding, and by a fixative action upon, telangiectatic tissue and small capillaries. Although formalin irrigation is probably the most effective treatment for hemorrhagic cystitis, with reported success rates of more than 90%,¹⁸ it also has toxic effects.¹⁹ Formalin use can cause edema, necrosis, and inflammation throughout all layers of the bladder. Vesicoureteral reflux, ureteral strictures, fibrosis of the bladder causing reduced capacity, and increased urinary frequency, are also potential adverse effects.²⁰ Vesicoureteral reflux must be ruled out before formalin therapy is started, and patients should be counseled regarding identification of the symptoms that could be associated with decreased bladder capacity.

Aminocaproic acid can be administered orally, parenterally, or intravesically via CBI. Aminocaproic acid inhibits plasminogen activators, which counteracts the effects of urokinases on the bleeding vessels. Before instillation therapy, all clots must be evacuated from the bladder. Aminocaproic acid (administered as 200 mg/l 0.9% in normal saline) can then be instituted via CBI. Once the hematuria has resolved, irrigations should continued for an additional 24 h. This approach has been reported to yield resolution in 91.6% (34 of 37) of patients with hematuria of bladder origin.²¹

Biochemical management

The use of drugs in the prevention or treatment of prostatic hematuria has been an option only since the mid-1990s. Initial reports outlined the use of 5--reductase inhibitors for the treatment of hematuria associated with benign prostatic hyperplasia.²² The rationale for the use of these drugs is that levels of dihydrotestosterone—the major androgen influence on the prostate—could be decreased by inhibition of 5--reductase type 2 isozyme in the prostate, thus decreasing the angiogenesis induced by VEGF. Further investigations focused on the suppression of VEGF levels in the prostate,²³ which resulted in a decrease in suburothelial microvessel density,²⁴ thus decreasing the incidence of prostatic hematuria. Kearney et al.²⁵ reported tests in two different animal models, in which they showed a reduction in prostatic blood flow after treatment with the 5--reductase inhibitor finasteride.

Foley and co-workers²⁶ reported a prospective, randomized trial of 57 patients separated into two groups: one group received 5 mg oral finasteride daily and the other underwent watchful waiting. Before entering the study, participants' hematuria was graded according to the criteria set out by Puchner and Miller (Box 1).²² A total of 55 patients completed 1 year of follow-up. The severity of hematuria, initially and at 1 year, is shown in Table 1. In the untreated group, 17 (63%) of 27 individuals developed a recurrence of hematuria, compared with 7 (14%) of 38 patients in the finasteride group. Kearney et al.²⁵ reported the successful prevention of hematuria with finasteride in 53 patients, reinforcing the evidence of efficacy. In 16 patients with active bleeding at baseline, a mean of 12 days of finasteride therapy was required for resolution of hematuria. Time to resolution differed significantly by prostate size (Figure 2).²⁵

Figure 2 Time to resolution of hematuria according to initial size of the prostate in 16 patients who were treated daily with finasteride.

 

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Table 1 Severity of prostatic hematuria, initially and after 1 year, in a study population treated with finasteride and in a control group.²⁶

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Previous published data indicate that 6 months of finasteride therapy is required for a reduction in prostatic size. Donohue et al.²⁷ reported a randomized, placebo-controlled trial in which prostatic vascularity decreased within 2 weeks of starting finasteride therapy. An additional study by Donohue and colleagues²⁸ found a decrease in operative blood loss during transurethral resection of the prostate in finasteride-treated patients. The difference was significant, at 2.64 g versus 4.65 g hemoglobin per gram of prostate resected in finasteride versus control patients, respectively (P <0.01).

The use of aminocaproic acid to treat hemorrhagic cystitis has been described; this agent can also be applied for the treatment of refractory prostatic hematuria. Aminocaproic acid can be administered orally or intravenously. For the intravenous regimen 4–5 g is given during the first hour of treatment, followed by a continuous infusion of 1 g/h.²⁹ Deysine and Clifton³⁰ recommended that a total dose of aminocaproic acid should not exceed 12 g per day because of the increased risk of thromboembolic events. However, physicians should refer to their institution's current protocol for the use of intravenous aminocaproic acid due to some variation in the total recommended daily dose, but this agent is usually administered until bleeding resolves. The major disadvantage of using aminocaproic acid is the formation of hard clots that are not easily flushed from the bladder. This therapy is contraindicated in patients who have upper-tract bleeding, so it is important to localize the site of bleeding to the prostate and avoid acute renal failure due to obstruction.

Surgery

Persistent bleeding might mandate operative intervention. Endoscopic techniques are the first-line surgical therapy. If the prostate is large, however, the patient might require open procedures to avoid risk of transurethral resection syndrome. The use of endoscopic treatments that involve a potassium-titanyl-phosphate laser might eliminate the need for open prostatectomy for benign prostatic hyperplasia patients with in large prostates.³¹ Prostate bleeding after radiation therapy is challenging and, in rare circumstances, urinary diversion may be pursued. Treatments must be individualized and address the underlying etiology.

Embolization

The goal of selective arterial prostatic embolization is adjunctive, curative or palliative. Hald and Mygind³² were the first to describe nonselective embolization of the hypogastric artery for the treatment of severe bladder hemorrhage. Advances in percutaneous catheters,³³ embolization agents, and fluoroscopic imaging have allowed for highly selective embolization. Indeed, fourth-order and fifth-order arterial branches can now be catheterized.

Rastinehad et al.³⁴ reported on eight patients undergoing selective arterial prostatic embolization for definitive treatment of refractory prostatic hematuria. In these individuals, conservative, biochemical and minor surgical therapies (cystoscopy with fulguration or resection of the prostate) had been unsuccessful. Six of the patients had a history of adenocarcinoma of the prostate, and four had been previously treated with external beam radiation. The remaining patients' histories were consistent with a diagnosis of benign prostatic hyperplasia. Embolization was successfully performed in all eight patients (Figure 3), and in all patients cessation of gross hematuria occurred within 2 days. Mean time of follow-up after embolization was 20 months. Nabi and co-workers³⁵ also reported a small series of six patients with hematuria after pelvic radiation for bladder and prostate cancer who underwent embolization and in whom a 100% resolution rate was seen after 22 months of follow-up. One of the most notable risks with this therapy is embolization of nontargeted areas. Use of selective embolization can decrease the risk of this adverse effect.

Figure 3 Digital subtraction angiography of a patient with refractory gross hematuria of prostatic origin.

Selective arterial prostatic embolization has been used to treat refractory prostatic hematuria. (A) Before embolization. Prostatic hematuria and neovascularity can be observed on the angiogram. The microcatheter is indicated on the figure by the arrow and the right-hand side of the prostate is indicated by 'right'. (B) After embolization. Hematuria is completely resolved. The right-hand side of the prostate is indicated on the figure by the arrow.

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