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CUA Best-Practice Report: Pediatric hemorrhagic cystitis.

Introduction

This best-practice report aims to provide the general practicing urologist with basic background information regarding the pathophysiology and natural history of hemorrhagic cystitis (HC) in the pediatric population, as well as diagnostic and algorithmic therapeutic recommendations. Given that HC in the pediatric population is most frequently diagnosed in the setting of bone marrow (BMT) or stem cell transplantation (SCT), discussion and recommendations will focus largely on this population, but many of the diagnostic and treatment options can be expanded to broader pediatric populations affected by HC.

Methodology

A systematic literature search was performed in the PubMed, Medline, and Cochrane Library databases using the term "hemorrhagic cystitis." The search was limited to articles from 1998 to the present day, with some exceptions made for seminal articles referenced in the bibliographies of multiple manuscripts. Due to the paucity of high-quality systematic reviews, meta-analyses, and large comparative studies written on this topic, the majority of evidence and recommendations are based on lower-quality case series and case reports.

The websites for the American Urological Association, the European Association of Urology, the Societies for Pediatric Urology, the European Society for Paediatric Urology, the National Institute for Health Care and Excellence, the Children's Oncology Group, and the Societe Internationale d'Oncologie Pediatrique were examined for guidelines and policies regarding the management of pediatric hemorrhagic cystitis, but none were available.

All manuscripts were reviewed using the modified Oxford Center for Evidence-Based Medicine grading system for guideline recommendations, as employed by the International Consultation on Urologic Disease (ICUD).

Definition

Hemorrhagic cystitis is defined by the presence of hematuria and lower urinary tract symptoms, such as dysuria, frequency, or urgency, in the absence of other potential contributing factors such as vaginal bleeding or bacterial or fungal urinary tract infections. (1) Multiple grading criteria have been published to distinguish the varied presentations of HC. Frequently referenced grading schema are Droller and Arthur's, which are used to aid the clinician in discerning potential treatment options and inform the clinician about prognosis (Table 1). (2,3) The European Organisation for Research and Treatment of Cancer has combined similar grading criteria along with quality of life parameters to further relay the morbidity and mortality implications of each grade. (4)

Background and natural history

The reported incidence of HC ranges widely from 5-70% irrespective of grade. (5,6) Unlike in adults where radiation is the most common cause, the more frequent causes of HC in children are the immediate and late effects of stem cell and/or bone marrow transplantation for malignant and benign diseases. Rare reports of medications (risperidone) and other disease processes (ataxia telangiectasia) have also been linked to the development of HC. (7-9)

Early-onset HC characterizes the immediate phase following conditioning for transplantation, which carries no absolute definition but has been described as ranging anywhere from 48 hours to 2 weeks after conditioning. (6,10) The early-onset bleeding typically occurs as a result of either the conditioning regimen itself--chemotherapy and/or radiation--and/or the intended myelosuppression and resultant thrombocytopenia. The chemotherapeutic agents most frequently implicated in causing hemorrhagic cystitis are the alkylating agents--cyclophosphamide, ifosfamide, and busulfan--which yield acrolein as a hepatic metabolite which results in bladder mucosal inflammation, sloughing, and thinning. (6,11,12) In attempts to reduce some of these toxicities, attempts have been made to reduce the intensity of conditioning prior to transplantation with shorter durations of chemotherapy, and the use of fludarabine with lower doses of total body irradiation. (5,13) Though Yamamoto et al found the frequency of developing HC was similar in both groups, there was a trend towards less severe grades of HC and the duration of HC (25 days vs 45 days, p=0.016) and transfusion requirements were significantly less than conventional induction therapy. (13) Adopting a similar reduced intensity conditioning (RIC) regimen, Giraud et al found that HC was less common in patients receiving RIC (p<0.01). (5)

Late-onset HC is often immune-related and characterized by reactivation of normally latent, asymptomatic viruses, such as BK virus, CMV, JC virus, adenovirus, and rarely simian virus SV40. (9,14,15)

BK virus, one of the polyomaviruses along with CMV, JCV, and SV40, is found in serum of up to 90% of healthy adults, despite being asymptomatic. (16) The virus lies dormant in the kidney following initial infection in childhood. Immunosuppressive states, such as post-chemotherapy (17) or bone marrow transplant, are thought to result in reactivation and replication of the latent virus. BKV can have various presentations, with HC being the manifestation most of urologic interest. Arthur et al first reported the link between BK viruria and hemorrhagic cystitis, noting that BK viruria frequently preceded the onset of hematuria. (3) HC was noted be four times more likely in patients whose urine tested positive for BKV than those who did not. In 2004, Bogdanovic et al demonstrated that an arbitrarily determined urine viral load >[10.sup.6] copies/[micro]l urine was predictive of the development of HC rather than the presence of BKV alone. Additionally, the best correlation to the development of HC was seen in patients with >[10.sup.6] BKV copies/[micro]l urine and acute graft-versus-host-disease (GVHD) combined (p=0.003). The authors proposed that possibly GVHD therapy with immunosuppressants allowed for BKV reactivation, large viral replication, and consequently the onset of hemorrhagic cystitis. Cesaro et al demonstrated superior prognostic value of plasma rather than urine BKV viral loads. Plasma BKV viral load >[10.sup.3] copies/ml had a sensitivity of 100%, specificity of 86%, negative predictive value (NPV) of 100%, and positive predictive value (PPV) of 39% for developing HC, whereas urine BKV viral load had a sensitivity of 86%, specificity of 60%, NPV of 98%, and PPV of 14%. (18)

Though BKV is the most frequently identified viral etiology of HC amongst the post-allogeneic bone marrow transplant (BMT) population, accounting for 80.8% of viral culprits, Gorczynska et al noted adenovirus in 15.4% and JCV in 3.8% of patients with HC. (1) Furthermore, while not all patients positive for BKV developed HC, all patients positive for adenovirus progressed to HC. Fortunately most hematuria is mild (69.2%) and of short symptomatic duration, mean 3.8 days (range 1-12 days), with a mean duration from day of BMT to hematuria onset of 41.2 days (range 9-144 days). (19)

Factors predicting a higher risk of developing HC have been widely studied. Among the most widely understood risk factors is undergoing allogeneic versus autogeneic bone marrow/stem cell transplant with HC rates of 5.5% vs 2.5%, respectively, p=0.003, and OR 2.85 for allogeneic transplant on multivariate analysis. Grafts from unrelated allogeneic donors were found to carry an OR 20 for HC. (5) Across various studies, the conditioning regimen (i.e. cyclophosphamide, busulfan, and/or radiation(XRT)), development of acute GVHD, and CMV reactivation were also considered risk factors for the development of HC. (6,20-22) Age less than five years was inversely correlated with HC occurrence (OR 0.21) on multivariate analysis. (20)

As might be expected, the presence of and higher grades of HC are associated with longer times to resolution and consequently longer hospital stays. (20,23) Higher HC grade (III-IV), pelvic XRT, BMT, hematologic malignancy, ifosfamide exposure, and male gender also confer a higher risk of undergoing invasive urologic intervention (p<0.05), HC. (22,24) The development of HC in any patient undergoing BMT/SCT is associated with a greater risk of mortality, particularly if HC presents before 200 days post-SCT (p=0.002). (19) Viral etiology did not affect post SCT survival, rather hematological malignancy (OR 2.74) and ifosfamide exposure (OR 1.988) were associated with higher mortality. (19,22)

Initial management/prevention

Though the source of hematuria is quite clear in pediatric patients undergoing BMT/HSCT, all other potential etiologies must be ruled out, i.e. urinary tract infection, urolithiasis, and urothelial/renal malignancy, through a thorough history and physical examination and laboratory and microbiologic investigations. Imaging with doppler renal and bladder ultrasonography can aid with this evaluation. (25) Upper tract assessment may reveal hydronephrosis indicative of obstruction and subsequent need for operative management. Visualization of the bladder should incorporate measurement of the bladder wall thickness which may be focally or diffusely increased in the setting of HC. Doppler investigation may also reveal focal or diffuse hypervascularity, as well as distinct bleeding which may be amenable to targeted cautery during cystoscopic evaluation.

As there are no discrete guidelines on treatment for this patient population, there is no definitive algorithm of options and recommendations throughout the progression of treatment. Figure 1 provides suggestions for clinicians to guide them through treatment based on several systematic reviews and previously proposed algorithms. (6,20,24) The remainder of this report will follow a similar progression of severity and invasiveness of treatment options.

Because of the well reported incidence of gross-hematuria and hemorrhagic cystitis in patients undergoing conditioning for allogeneic BMT/SCT, these patients are routinely prophylactically treated with continuous bladder irrigation (CBI), 2-mercaptoethanesulfonic acid (mesna), and hyperhydration during their myelosuppressive conditioning. Whereas previously CBI use was based on anecdotal practice, Hadjibabaie et al conducted a study of patients receiving cyclophosphamide conditioning prior to allogeneic BMT who were treated with CBI and compared to historical controls who did not receive CBI. (26) The treatment group received CBI with normal saline at 300ml/hour via a 3-way Foley catheter 12 hours before their first dose of cyclophosphamide through until 48 hours after their last dose of cyclophosphamide, at which point the catheter was removed. The incidence of HC in the treatment group was 32.5% compared to 50% in the control group (p=0.11), and there was no significant difference of the grades of HC. There was, however, a shorter duration of HC and shorter hospitalization in the treatment group, was well as a lower incidence of late-onset HC (7.7% in CBI group, 45% in control group, p=0.009). Though no comparative studies have evaluated its effectiveness alone, using similar rationale to that of CBI, many conditioning protocols incorporate the use of IV hyperhydration (4-5L D5 w/ 0.45% normal saline (NS) with 20mEq KCl/day, starting 24 hours prior to infusion of cyclophosphamide) and forced diuresis (prn to maintain urine output 150-200ml/hr) in attempts to dilute potential damaging therapy byproducts. (2,27)

The addition of mesna to therapy during conditioning targets the acrolein metabolite of cyclophosphamide through binding with mesna's sulhydrl group and consequent deactivation of acrolein. In a prospective, controlled study, Jiang et al compared intermittent to continuous IV mesna during cyclophosphamide conditioning. (11) Patients in the continuous treatment group had significantly less HC occurrences at both 30 and 60 days (continuous: 30 days - 0%, 60 days - 5.88%, intermittent: 30 days - 34.4%, 60 days - 40.6%, p<0.002 for both).

Control of the dysuria or bladder spasms that may be associated with HC and/or Foley catheterization for its prevention and/or treatment is routine. Options for pain management include treatment through the use of various short and long-acting narcotics, (i.e. morphine and derivatives), anticholinergics (i.e. solifenacin, oxybutynin, and tolterodine), penazopyridine, and intravesical lidocaine/bupivacaine. (20,27,28) Many of these patients will also experience marked myelosuppression, therefore close monitoring and replacement of red blood cells, platelets, and plasma is required to ensure the safe and successful resolution of HC. (27)

Recommendation: Routine history and physical with imaging should be performed to confirm the etiology of HC at onset. All patients undergoing chemotherapeutic conditioning prior to allogeneic BMT/SCT should receive preventative hyperhydration, CBI, and mesna, as well as, supportive analgesia with systemic and targeted medications at the onset of HC with symptoms. (Level 3 evidence, Grade C recommendation)

Non-invasive treatment

Antivirals

Given the aforementioned prevalence of viral sources of HC, some have recommended following BK virus titers in urine and blood using DNA PCR assays during the course of conditioning for BMT/SCT. (18) Alternatively, at the onset of HC, viral cultures and viral loads can be measured to target therapeutic intervention. The antiviral cidofovir has become the mainstay of treatment for polyomaviruses, such as BKV and JCV, and adenovirus, though its route of administration and dosage are quite varied in the literature. Given its potential nephrotoxicity and potential preexisting renal compromise in this patient population, lower doses (0.25-1mg/kg/ once/week versus traditional 3-5mg/kg/week), administration through an intravesical route via urethral catheter (invasive), or combination with probenecid, have all been proposed to reduce potential renal injury. (29-31) Other antivirals, leflunomide to treat BKV and ribavirin to treat adenovirus, have also been studied in pediatric patients with virus-induced HC, but rigorous trials assessing their efficacy in this patient population are lacking. (32,33)

Recommendation: In patients with HC proven to be due to a virus on urine culture or urine PCR, targeted treatment with IV or intravesical antivirals is recommended as a relatively low-risk treatment. (Level 3 evidence, Grade C recommendation)

Pentosan polysulfate (PPS)

The use of pentosan polysulfate has been primarily studied in interstitial cystitis. As a semisynthetic glycosaminoglycan, it's proposed mechanism of action is through adherence to the bladder wall glycosaminoglycan layer and replacement of already damaged areas in order to protect the bladder from irritants such as urine, bacteria, and other toxic substances. (6) Duthie et al tested the application of PPS to the pediatric post-BMT HC population through the introduction of a protocol for HC management and retrospectively compared this to historical controls. (34) Once HC was diagnosed, protocol patients were hydrated and treated with analgesia and oral PPS 100mg TID. Bladder catheterization was avoided, escalating from in/out to CBI if patients had repeat clot retention, and cystoscopy with clot evacuation in refractory bleeding. The authors noted that the diagnosis of HC was made significantly quicker with the introduction of the protocol (39 days vs 76, p<0.01) and transfusions of blood and platelets were significantly reduced in the protocol group. No side effects of the drug were noted. Both groups had similar duration of HC (protocol 32 days vs control 36 days, p =0.84), though 4/5 controls died with active HC and 0/5 protocol patients died, so this may not reflect the full duration of HC.

Recommendation: There is limited evidence on the positive benefits of using PPS in pediatric patients with HC, therefore further studies are needed prior to broad implementation. (Level 4 evidence, Grade D recommendation)

Estrogen

Conjugated estrogen has been used in the management of HC, either in oral or intravenous form. It is thought to treat HC by promoting stabilization of small blood vessels, suppressing the immune response, and facilitating the repair of injured tissues. (35,36) Potential side effects that have been proposed or observed, however, have been liver dysfunction, hypercoagulability, hypertension, facial flushing, feminization in males, and malignant transformation, a grave risk in patients with pre-existing histories of malignancy. Heath et al evaluated 10 children with HC following high-dose chemotherapy and SCT who received estrogen. (37) The treatment was started IV and transitioned to oral after 2-3 days, which liver function tests (LFTs) were monitored every 48 hours. Duration of therapy ranged from 5-23 days resulting in reductions in HC symptoms in 90%, though two required repeated IV and oral dosing after initially being partial or non-responders. One patient had existing liver GVHD and developed elevation in LFTs so was therapy was stopped. Mousavi et al's study of oral estrogen only noted no benefit in the management of HC. (38) This randomized, case-control study of fifty-six adult and pediatric patients post-SCT demonstrated an insignificant downgrading of HC in treatment relative to control groups.

Recommendation: There is conflicting evidence regarding benefit versus harm with estrogen therapy. Additional prospective, randomized, controlled studies are indicated to clarify its use in managing HC. (Level 4 evidence, Grade D recommendation)

Hyperbaric oxygen therapy

Hyperbaric oxygen therapy (HOT) has wide-reaching uses within urology, particularly in the management of radiation-induced hematuria, but has also recently come to be recognized as a potential therapeutic option for pediatric patients with post-BMT HC. It is thought to assist in the resolution of HC by inducing neovascularity and permanent tissue healing in the damaged bladder tissue. (39) Following a positive case report by Furness et al, where the only notable side effect was bilateral otitis media, multiple institutions have reported case series on their similarly positive results. (40-42) Though the exact protocols of HOT therapy are varied, it was typically initiated once HC reached grade II-III and patients had failed prior conservative therapies. Patients underwent multiple dives (total dive time 85-90 minutes) for 5-6 days a week at 2.1-2.5 atm with either 100% oxygen only or a mixture of 100% oxygen and chamber air dives. Complete resolution of HC in these studies has reported to range from 70% - 94%. A median of 10 to 13 sessions were needed to yield complete resolution of HC. Savva-Bordalo et al also noted a strong correlation between the time from HC onset to the initiation of HOT and the time from HOT to HC resolution (r=0.70, p<0.05). In this study, three patients did end therapy early due to ear barotrauma, pressure intolerance, and claustrophobia, indicating that patients with a history of claustrophobia and diving intolerance should avoid HOT. Patients with active cancer, active viral infection, or Fanconi's anemia are also advised to avoid HOT. (6,43)

Recommendation: Hyperbaric oxygen therapy (HOT) has been proven to be safe, effective, and relatively low risk in treating pediatric patients with HC. Its widespread use, however, may be limited due to cost and access to facilities with HOT. (Grade 3 evidence, Level B recommendation)

Invasive treatment

Prostaglandin (E1/E2)

Several reports exist on the use of prostaglandin (PG) E for the management of HC, though the exact mechanism of action is not widely understood. In a review of practice in Italy, Cesaro et al noted that intravesical PGE2 use at the discretion of the physician for severe and/or refractory HC post-SCT in children resulted in 37% success, though success was not well defined. (40) The therapy was diluted, instilled intravesically, and then allowed to dwell for 1-2 hours. Instillation was repeated daily until HC resolution or for at least 1 week until being considered unsuccessful. No patient experience complications or intolerability necessitating therapy withdrawal despite concerns over its potential for inducing bladder spasms or flushing. Trigg et al noted more positive results in their pediatric post-BMT study with intravesical PGE1, as PGE2 was not commercially available in the United States. (44) All children were sedated during therapy, which targeted a therapeutic dwell time of 1 hour. HC was eliminated in 5/6 patients over a seven-day course, and in some cleared in as little as 24 hours. No apparent side effects were noted.

Recommendation: Prostaglandins may be of modest benefit as an intravesical therapy in pediatric patients with HC with urethral catheters, though additional studies are needed to clarify its efficacy and if sedation or general anesthesia is needed to administer the therapy due to concerns for its potential to cause painful bladder spasms. (Level 3 evidence, Grade C recommendation)

Hyaluronic acid

Much like PPS, the use of hyaluronic acid (HA) has predominantly been seen in the interstitial cystitis population for its role in enhancing connective tissue healing within the bladder. (10) Additionally, it has been proposed that the HA may alter a step of the polyomavirus' life cycle and that its breakdown products may trigger the secretion of various cytokines and chemokines by macrophages that inhibit viral replication. (45) In their case report of a 7.5 year-old boy with HC refractory to conservative therapy post BMT, Cipe et al administered intravesical HA (40mg in 50ml solution) via catherization, clamped for 1 hour, drained, and then repeated dosing a week later after an initial partial response, and later complete resolution within four days of the second dose. Miodosky et al used a similar protocol prospectively in a group of pediatric and adult post-SCT HC patients with no control group and repeat dosing after 1 week if no response in HC was noted. (46) Of the seven patients treated, four responded after an initial dose, and two responded after a second dose. Complete response was noted in five of the seven patients at a median of 12 days (range 7-23).

Recommendation: Hyaluronic acid intravesical therapy may be of benefit in treating HC via bladder instillation, though repeated applications may be required, and thus more robust evidence is required to demonstrate its efficacy. (Level 4 evidence, Grade D recommendation)

Alum

The use of intravesical alum in patients with gross hematuria is well noted in the adult literature. Alum is thought to work by precipitating to raw protein surfaces, resulting in decreased vascular permeability, vasoconstriction, and reduced inflammation. (47) As its mode of administration is relatively similar to CBI, it is commonly used when patients demonstrate HC refractory to CBI alone. Typically, a solution of 1% alum (10g aluminum potassium sulfate mixed in 1L distilled water) is instilled via a three-way Foley catheter at a rate of 300ml/hour or less. Prior to initiation, patients must be cleared of all intravesical blood clots, either manually or surgically, otherwise they may suffer from difficult to resolve "alum balls" which can precipitate urinary obstruction. Praveen at al evaluated the effectiveness of alum for treating hematuria in a prospective, randomized, controlled comparison with PGF2 instillation. (48) Of the nine patients treated with alum, 6 had complete resolution of hematuria and 3 had partial resolution, however, 3 had recurrent bleeding. Along with bladder spasms, as were seen in all of Praveen's alum patients, alum toxicity can lead to encephalopathy and seizures, particularly in patients with renal insufficiency. (6,27,49) Patients receiving alum therapy should be monitored with serial aluminum levels and evaluated regularly with a high index of suspicion for toxicity should any neuropsychiatric symptoms arise.

Recommendation: Alum bladder irrigation is effective in treating pediatric HC, though the patient's bladder must be fully cleared of blood clots prior to initiation of therapy. Patients must also be monitored closely for potential aluminum toxicity, particularly in the setting of renal failure. (Level 3 evidence, Grade C recommendation)

Cystoscopy, clot evacuation, and fulguration

Following failure of conservative therapies, cystoscopy offers both a diagnostic and therapeutic opportunity for the urologist to escalate management of the HC patient. Cystoscopic evaluation aids the clinician in ruling out any potential malignant causes of HC while also distinguishing bleeding as originating from a focal vessel or a diffuse source. The small diameter of the pediatric urethra, especially in prepubertal males, can be quite problematic however, hence limiting the ability to pass a reasonably sized scope that will allow effective irrigation and evacuation of clots. When possible, with the larger diameter of the cystoscope relative to a Foley catheter, effective clot evacuation can proceed, possibly concomitant with the placement of a suprapubic catheter for more facile post-operative bladder irrigation. (6) Focal bleeding vessels can be cauterized either with a Bugbee electrode or laser fiber, though aggressive, diffuse fulguration risks potential late scar formation and bladder capacity compromise. (8,20)

Recommendation: Though evidence is lacking, cystoscopy, clot evacuation, and fulguration of bleeding is a mainstay of therapy in management of pediatric HC for its capacity to both diagnose and treat HC, as well as provide symptom relief from patients in clot retention. (Level 4 evidence, Grade C recommendation)

Fibrin glue

Though a relatively new phenomenon, fibrin glue application at the time of cystoscopy has demonstrated substantial success in HC refractory to non-invasive conservative therapies. Tirindelli et al have published multiple accounts of their work with fibrin glue. (50,51) The fibrin glue is generated in 6ml aliquots from 120mls of the patient's own virus-inactivated blood or fresh-frozen plasma over 30 minutes. In their cases, cystoscopy is performed with a 24Fr nephroscope and the bladder insufflated with carbon dioxide at 12mmHg, and the glue then sprayed evenly over the bleeding, raw surfaces where it polymerizes on contact and sets over several days. A catheter is left in place without CBI post-operatively. In their earlier study, 4/5 (80%) patients had a rapid, good response, one of whom was a 17 year-old female, the rest were adults. (50) In a later study with 35 patients, there was 83% complete response rate, which was achieved after 1, 2, or >/= 3 FG applications in 60%, 17%, 6% respectively. The procedure was well tolerated with no adverse events observed. (51) Given the protocol recommended by Tirindelli et al, however, the 24Fr nephroscope will limit applicability in the pediatric population, as most children younger than adolescents will not be able to accommodate this caliber in their urethra.

Recommendation: Intravesical fibrin glue application is a promising treatment option in patients undergoing cystoscopy with clot evacuation, as it can be applied focally or diffusely to hemorrhagic areas. Additional research is needed to expand its applicability, as current recommendations for large caliber cystoscopes limit its use in children. (Level 3 evidence, Grade C recommendation)

Formalin

As in adults, in severe cases of refractory HC, sclerotherapy is a consideration in the pediatric population, but often a last-resort prior to irreversible management options. The proposed mechanism of action of formalin, much like its derivative formaldehyde, is to precipitate proteins by reducing amino acids and fixing blood vessels, thus achieving hemostasis. (52) Due to pain associated with bladder instillation, general anesthesia is necessary whenever formalin is instilled intravesically. Furthermore, prior to any consideration of formalin instillation, patients must be evaluated for vesicoureteral reflux (VUR) with a voiding cystourethrogram due to potential for irreversible damage to the upper tracts with VUR. Should VUR be present, the ureteral orifices can be occluded during instillation with Fogarty catheters. Using traditional concentration of 4% formalin, Cheuk et al noted "satisfactory responses" in all 5 children with instillation of the solution, an indwelling period of 10-20 minutes, and then a wash-out. (23) Four of the five children had improvement after one treatment, whereas the fifth needed three treatments in two months to yield an adequate response. Other case reports have documented success with lower concentrations such as 1% and 2%, though often with repeated courses of therapy needed. (20,53) Alternatively, cystotomy with application of 4% formalin soaked swabs or endoscopic placement of formalin soaked pledgets have also been reported in cases. (52) Silver nitrate irrigation has also been used to treat HC, but is notable for bladder fibrosis and contracture. (6) Formalin and silver nitrate are therefore typically avoided or considered last-resort options due to their potential for bladder scarring and long-term compromise of bladder function. (6) Especially in the pediatric population, significant consideration of long-term implications of therapy must be considered prior to pursuing these options.

Recommendation: Though effective, the need for anesthesia with formalin instillation and the potential long-term compromise of bladder function must be heavily considered when resorting to this therapeutic option for children with HC. (Level 3 evidence, Grade D recommendation)

Percutaneous nephrostomy tubes

Often considered a last-resort stabilizing measure, urinary diversion with bilateral percutaneous nephrostomy tubes (PNTs) has become more a commonly utilized option in patients with HC refractory to all conservative therapies whose next only option is cystectomy. The theory behind diverting upper tract urine with nephrostomy tubes as that downstream persistent urine bathes the bladder in urokinase, the proteolytic enzyme present in urine, which may contribute to persistent gross hematuria. (6) By removing this fibrinolytic activity, which degrades beneficial fibrinogen and fibrin clots, clot formation in the bladder can be promoted so that the bladder eventually becomes filled with clot and bleeding ceases. Eventually clamping trials of PNTs can be attempted, the blood clot disintegrates, is passed per urethra, and the tubes are ultimately removed. Lukasewycz et al reported on PNTs placed in children undergoing HSCT with HC refractory to conservative measures. (54) Five of eleven had improvement within 30 days, and four of those five had complete response with the fifth passing of their disease. Two of the eleven were stabilized with the PNTs, one progressed and needed clot evacuation, and the remaining three passed of unrelated causes. The average time to stabilization was 12.4 days, and average duration of PNTs being in place was 8.8 weeks. No long-term sequelae were reported.

Recommendation: Bilateral percutaneous nephrostomy tube urinary diversion is a temporizing measure to allow the bladder to clot off, thus managing stable or unstable HC patients refractory to all other conservative and moderately invasive therapies short of performing irreversible surgical urinary diversion. Persistent bladder spasms from blood clots may limit its tolerability in pediatric patients. (Level 3 evidence, Grade C recommendation)

Treatment options for refractory, life-threatening HC

Supraselective bilateral vesical artery embolization (SVAE)

With progressive advances in interventional radiologic techniques, targeted embolization of bladder vasculature has added an additional tool to the urologist's armamentarium for management of the acutely ill HC patient refractory to prior conservative and invasive therapies. (24,55,56) Embolization is employed using either gelatin sponge microparticles, gelfoam pledgets, or alcohol microspheres following angiography to identify the bilateral arterial vesical branch targets. Often SSAE is considered in patients with HC and hemorrhagic shock and massive blood product requirements, though it may also be considered in patients for which conservative and other less invasive therapies have proven ineffective and HC has persisted for months. Garcia-Gamez et al noted complete resolution of HC within 1-2 weeks in their three patient case series of children with post-BMT/SCT HC. (55) Han et al reported on their aggressive case series of pediatric and adult patients with grade III-IV HC following post-allogeneic SCT who failed to improve with hyperhydration, platelet/blood transfusion, CBI, and pain management. (56) Patients had HC for a median of 20 days prior to undergoing SVAE. SVAE yielded a complete response in 60% and partial response in 20%, with a median time to complete response of 26 days. Morbidity was noted in 20% of patients who complained of gluteal claudication the day following embolization, however this spontaneously resolved within one day of the intervention in all patients. Data are lacking on the long-term sequelae of bladder function following SVAE.

Recommendation: Supraselective bilateral vesical artery embolization offers modest control of HC refractory to conservative therapy, however, outside of unstable patients, the appropriate timepoint for its use along the HC treatment pathway and the long-term safety of its application require further investigation. (Level 3 evidence, Grade C recommendation)

Cutaneous vesicostomy

Short of proceeding with cystectomy, an alternative to bilateral PNTs for urinary diversion is the cutaneous vesicostomy. Among the case reports describing its use, it is typically employed in the setting of hemodynamic instability with high transfusion requirements or in patients with terminal disease. (24,25) In Gander et al's case, a gel-port was used to secure the bladder mucosa against the abdominal wall as severe bladder wall edema prevented adequate suture fixation. A urinary ostomy bag can be applied overlying the vesicostomy to collect urine, more easily remove clots, and continue CBI through a urethral catheter if so desired. (57) In the author's experience, bladder packing with lidocaine with epinephrine soaked sponges can also aid with local analgesia and vasoconstriction to reduce hematuria. This approach can allow for removal of urethral catheters, which, particularly in children, can be a source of much distress and discomfort.

Recommendation: Despite a lack of high-quality studies, cutaneous vesicostomy in the terminal or refractory pediatric patient offers potentially reversible direct bladder access for clot evacuation and application of topical therapies, while also allowing for possible removal of painful urethral catheters. (Level 4 evidence, Grade C recommendation)

Cystectomy

When all conventional and invasive options have been exhausted, and HC persists, the urologist can turn to extirpative surgery to remove the source of HC. As this is an irreversible option, it should only be considered in intractable, life-threatening HC. The surgical approach and urinary diversion selection are at the discretion of the patient and surgeon, however, most reports describe the construction of an ileal neobladder either with preservation of the bladder trigone and ureteral insertion or without trigonal preservation and ureteral reimplantation. (58) As with neobladder creation for other indications, the detubularized Studer type has largely become the surgical approach of choice due to its increased bladder capacity and decreased bladder spasms from gut peristalsis. Regarding management of the trigone, Sebe et al favor subtotal cystectomy with bladder neck preservation if the ureters are unobstructed. (58) Should there be concern for irreversible ureteral obstruction, however, ureteral reimplantation is recommended.

Recommendation: Cystectomy is reserved as a treatment option when all other efforts to control hemorrhagic cystitis have failed. Long-term implications of this option must be considered in the pediatric population, as well as the fitness and hemodynamic stability of the patient for whom it is chosen. (Level 4 evidence, Grade C recommendation)

Experimental therapies

Numerous experimental therapies are being studied for patients with HC that either focus on rebuilding injured bladder mucosa or augmenting the coagulation cascade. Recombinant human keratinocyte growth factor, epidermal growth factor, placenta-derived stromal cells, mesenchymal stem cells, and adoptive transfer of viral-specific T cells for virus-associated HC in patients with slow immune reconstitution have been studied in case reports in patients refractory to conservative therapies such as CBI and HOT. Though preliminary reports with some of these therapies are promising, minimal evidence exists to support their effectiveness and safety. (59-62)

Recommendation: Due to the experimental nature of therapies such as recombinant human keratinocyte growth factor, epidermal growth factor, placenta-derived stromal cells, adoptive transfer of viral-specific T cells, factor VII, factor XIII, and mesenchymal stem cells, their therapeutic use to treat HC is not recommended until further robust trials demonstrate safety and benefit. (Level 4 evidence, Grade D recommendation)

Conclusion

Though the age-old saying, "children are not little adults," is true when dealing with most pediatric illnesses, many of the management strategies used to manage adult hemorrhagic cystitis have been tested and successful in pediatric populations as well. As this report has demonstrated, whereas hemorrhagic cystitis in children more frequently rises from complications of oncologic regimens and immunosuppression, and in adults, radiation is often the culprit, similar management algorithms and therapies can yield effective illness resolution. Anatomic, psychosocial, and pain threshold considerations pose differences in these two populations which may lead the clinician to one treatment over another. These pediatric-specific factors, along with each unique patient presentation must be factored into the experienced clinician's treatment plan for efficiently, effectively, and conscientiously treating this challenging disease entity.

References

(1.) Gorczynska E, Turkiewicz D, Rybka K, et al: Incidence, clinical outcome, and management of virus-induced hemorrhagic cystitis in children and adolescents after allogeneic hematopoietic cell transplantation. Biol. Blood Marrow Transplant. 2005; 11: 797-804.

(2.) Droller MJ, Saral R and Santos G: Prevention of Cyclophosphamide-Induced Hemorrhagic cystitis. Urology 1982; XX: 256-258.

(3.) Arthur RR, Shah K V, Baust SJ, et al: Association of BK Viruria with Hemorrhagic Cystitis in Recipients of Bone Marrow Transplants. N. Engl. J. Med. 1986; 315: 230-234.

(4.) DHHS, NIH and NCI: Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. 2010: 148. Available at: https://www.eortc.be/services/doc/ctc/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf, accessed December 7, 2018.

(5.) Giraud G, Bogdanovic G, Priftakis P, et al: The Incidence of hemorrhagic cystitis and BK-viruria in allogeneic hematopoietic stem cell recipients according to intensity of the conditioning regimen. Stem Cell Transplant. 2006; 91: 401-404.

(6.) Decker DB, Karam JA and Wilcox DT: Pediatric hemorrhagic cystitis. J. Pediatr. Urol. 2009; 5: 254-264.

(7.) Hudson RG and Cain MP: Risperidone associated hemorrhagic cystitis. J. Urol. 1998; 160: 159.

(8.) Cohen JM, Cuckow P and Davies EG: Bladder wall telangiectasis causing life-threatening haematuria in ataxia-telangiectasia: a new observation. Acta Paediatr. 2008; 97: 667-669. Available at: http://doi.wiley.com/10.1111/j.1651-2227.2008.00736.x.

(9.) Christmann M, Heitkamp S, Lambrecht E, et al: Haemorrhagic cystitis and polyomavirus JC infection in ataxia telangiectasia. J. Pediatr. Urol. 2009; 5: 324-326. Available at: http://dx.doi.org/10.1016/j.jpurol.2009.02.198.

(10.) Cipe FE, Soygur T, Dogu F, et al: Late onset hemorrhagic cystitis in a hematopoietic stem cell recipient: Treatment with intravesical hyaluronic acid. Pediatr. Transplant. 2010; 14: 79-82.

(11.) Jiang Q, Huang H, Liu Q, et al: Continuous IV infusion of MESNA can prevent hemorrhagic cystitis in HSCT and retain MESNA concentration in urine. Bone Marrow Transplant. 2015; 50: 1490-1492.

(12.) Saito Y, Kumamoto T, Makino Y, et al: A retrospective study of treatment and prophylaxis of ifosfamide-induced hemorrhagic cystitis in pediatric and adolescent and young adult (AYA) patients with solid tumors. Jpn. J. Clin. Oncol. 2016; 46: 856-861.

(13.) Yamamoto R, Kusumi E, Kami M, et al: Late hemorrhagic cystitis after reduced-intensity hematopoietic stem cell transplantation (RIST). Bone Marrow Transplant. 2003; 32: 1089-1095.

(14.) Bielorai B, Shulman LM, Rechavi G, et al: CMV reactivation induced BK virus-associated late onset hemorrhagic cystitis after peripheral blood stem cell transplantation. Bone Marrow Transplant. 2001; 28: 613-614.

(15.) Comar M, D'Agaro P, Andolina M, et al: Hemorrhagic cystitis in children undergoing bone marrow transplantation: A putative role for simian virus 40. Transplantation 2004; 78: 544-548.

(16.) Shah K: Polyomaviruses. In: Fields Virology. 3rd ed. Philadelphia: Lipincott-Raven 1996.

(17.) Al Barrak M Al, Al Fawaz T Al, Al Shehri M, et al: BK virus-induced severe hemorrhagic cystitis in non-transplant oncology patients: A case series. J. Pediatr. Infect. Dis. 2014; 9: 183-187.

(18.) Cesaro S, Tridello G, Pillon M, et al: A prospective study on the predictive value of plasma BK Virus-DNA load for hemorrhagic cystitis in pediatric patients after stem cell transplantation. J. Pediatric Infect. Dis. Soc. 2015; 4: 134-142.

(19.) Bil-Lula I, Ussowicz M, Rybka B, et al: Hematuria due to adenoviral infection in bone marrow transplant recipients. Transplant. Proc. 2010; 42: 3729-3734.

(20.) Riachy E, Krauel L, Rich BS, et al: Risk factors and predictors of severity score and complications of pediatric hemorrhagic cystitis. J. Urol. 2014; 191: 186-192. Available at: http://dx.doi.org/10.1016/j.juro.2013.08.007.

(21.) Anoop P, Shaw BE, Riley U, et al: Clinical profile and outcome of urotheliotropic viral haemorrhagic cystitis following haematopoietic stem cell transplantation: a 7-year tertiary centre analysis. Hematology 2011; 16: 213-220. Available at: http://www.tandfonline.com/doi/full/10.1179/102453311X13025568941763.

(22.) Johnston D, Schurtz E, Tourville E, et al: Risk Factors Associated with Severity and Outcomes in Pediatric Patients with Hemorrhagic Cystitis. J. Urol. 2016; 195: 1312-1317. Available at: http://dx.doi.org/10.1016/j.juro.2015.11.035.

(23.) Cheuk DKL, Lee TL, Chiang AKS, et al: Risk factors and treatment of hemorrhagic cystitis in children who underwent hematopoietic stem cell transplantation. Transpl. Int. 2006; 20: 73-81.

(24.) Gander R, Asensio M, Guillen G, et al: Hemorrhagic cystitis after hematopoietic stem cell transplantation: A challenge for the pediatric urologist. J. Pediatr. Urol. 2018.

(25.) McCarville MB, Hoffer FA, Gingrich JR, et al: Imaging findings of hemorrhagic cystitis in pediatric oncology patients. Pediatr. Radiol. 2000; 30: 131-138.

(26.) Hadjibabaie M, Alimoghaddam K, Shamshiri AR, et al: Continuous bladder irrigation prevents hemorrhagic cystitis after allogeneic hematopoietic cell transplantation. Urol. Oncol. 2008; 26: 43-46. Available at: https://www.cochranelibrary.com/central/doi/10.1002/central/CN-00622225/full.

(27.) Harkensee C, Vasdev N, Gennery AR, et al: Prevention and management of BK-virus associated haemorrhagic cystitis in children following haematopoietic stem cell transplantation - A systematic review and evidence-based guidance for clinical management. Br. J. Haematol. 2008; 142: 717-731.

(28.) Mahawar B, Mahawar V, Joajodia A, et al: Excellent response of solifenacin in chemotherapy-induced hemorrhagic cystitis in a child with non-Hodgkin's lymphoma. South Asian J. cancer 2018; 7: 213.

(29.) Cesaro S, Hirsch HH, Faraci M, et al: Cidofovir for BK Virus--Associated Hemorrhagic Cystitis: A Retrospective Study. Clin. Infect. Dis. 2009; 49: 233-240. Available at: https://academic.oup.com/cid/article-lookup/doi/10.1086/599829.

(30.) Faraci M, Zuzzubbo D, Lanino E, et al: Low Dosage Cidofovir without Probenecid as Treatment for BK Virus Hemorrhagic Cystitis after Hemopoietic Stem Cell Transplant. Pediatr. Infect. Dis. J. 2009; 28: 55-57.

(31.) Foster JH, Cheng WS, Nguyen NY, et al: Intravesicular cidofovir for BK hemorrhagic cystitis in pediatric patients after hematopoietic stem cell transplant. Pediatr. Transplant. 2018; 22.

(32.) Wu KH, Weng T, Wu HP, et al: Effective treatment of severe BK virus-associated hemorrhagic cystitis with leflunomide in children after hematopoietic stem cell transplantation: A pilot study. Pediatr. Infect. Dis. J. 2014; 33: 1193-1195.

(33.) Miyamura K, Hamaguchi M, Taji H, et al: Successful ribavirin therapy for severe adenovirus hemorrhagic cystitis after allogeneic marrow transplant from close HLA donors rather than distant donors. Bone Marrow Transplant. 2000; 25: 545-548.

(34.) Duthie G, Whyte L, Chandran H, et al: Introduction of sodium pentosan polysulfate and avoidance of urethral catheterisation: Improved outcomes in children with haemorrhagic cystitis post stem cell transplant/chemotherapy. J. Pediatr. Surg. 2012; 47: 375-379. Available at: http://dx.doi.org/10.1016/j.jpedsurg.2011.11.037.

(35.) Ashcroft G, Dodsworth J, van Boxtel E, et al: Estrogen accelerates cutaneous wound healing associated with an increase in TGF-beta1 levels. Nat Med 1997; 3: 1209-15.

(36.) Deshpande R, Khalili H, Pergolizzi R, et al: Estradiol down-regulates LPS-induced cytokine production and NFkB activation in murine macrophages. Am J Reprod Immunol 1997; 38: 46-54.

(37.) Heath JA, Mishra S, Mitchell S, et al: Estrogen as treatment of hemorrhagic cystitis in children and adolescents undergoing bone marrow transplantation. Bone Marrow Transplant. 2006; 37: 523-526.

(38.) Mousavi SA, Moazed V, Mohebbi N, et al: Conjugated estrogen in late-onset hemorrhagic cystitis associated with hematopoietic stem cell transplantation. Int. J. Hematol. Stem Cell Res. 2017; 11: 13-18.

(39.) Furness PD, Palmer LS, Palmer JS, et al: Hyperbaric oxygen therapy for pediatric hemorrhagic cystitis. J. Urol. 1999; 161: 1596-1597. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24907729.

(40.) Cesaro S, Brugiolo A, Faraci M, et al: Incidence and treatment of hemorrhagic cystitis in children given hematopoietic stem cell transplantation: A survey from the Italian association of pediatric hematology oncology-bone marrow transplantation group. Bone Marrow Transplant. 2003; 32: 925-931.

(41.) Zama D, Masetti R, Vendemini F, et al: Clinical effectiveness of early treatment with hyperbaric oxygen therapy for severe late-onset hemorrhagic cystitis after hematopoietic stem cell transplantation in pediatric patients. Pediatr. Transplant. 2013; 17: 86-91.

(42.) Savva-Bordalo J, Pinho Vaz C, Sousa M, et al: Clinical effectiveness of hyperbaric oxygen therapy for BK-virus-associated hemorrhagic cystitis after allogeneic bone marrow transplantation. Bone Marrow Transplant. 2012; 47: 1095-1098.

(43.) Al-Seraihi A and Ayas M: Hyperbaric Oxygen Should Not be Used in the Management of Hemorrhagic Cystitis in Patients with Fanconi Anemia. Pediatr Blood Cancer 2007; 49: 854-856.

(44.) Trigg ME, O'Reilly J, Rumelhart S, et al: Prostaglandin E1 bladder instillations to control severe hemorrhagic cystitis. J. Urol. 1990; 143: 92-94.

(45.) Focosi D and Kast RE: Hyaluronate and risperidone for hemorrhagic cystitis. Bone Marrow Transplant. 2007; 39: 57.

(46.) Miodosky M, Abdul-Hai A, Tsirigotis P, et al: Treatment of post-hematopoietic stem cell transplantation hemorrhagic cystitis with intravesicular sodium hyaluronate. Bone Marrow Transplant. 2006; 38: 507-511.

(47.) Choong S, Walkden M and Kirby R: The management of intractable haematuria. BJU Int 2000; 86: 951-9.

(48.) Praveen B, Sankaranarayanan A and Vaidyanathan S: A comparative study of intravesical instillation of 15(s) 15 Me alpha and alum in the management of persistent hematuria of vesical origin. Int J Clin Pharmacol Ther 1992; 30: 7-12.

(49.) Bogris SL, Johal NS, Hussein I, et al: Is it safe to use aluminum in the treatment of pediatric hemorrhagic cystitis?: A case discussion of aluminum intoxication and review of the literature. J. Pediatr. Hematol. Oncol. 2009; 31: 285-288.

(50.) Tirindelli MC, Flammia G, Sergi F, et al: Fibrin glue for refractory hemorrhagic cystitis after unrelated marrow, cord blood, and haploidentical hematopoietic stem cell transplantation. Transfusion 2009; 49: 170-175.

(51.) Tirindelli MC, Flammia GP, Bove P, et al: Fibrin glue therapy for severe hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation. Biol. Blood Marrow Transplant. 2014; 20: 1612-1617.

(52.) Joseph CM, Bowley DM and Pitcher GJ: Formalin treatment of refractory hemorrhagic cystitis. J. Pediatr. Urol. 2005; 1: 365-367.

(53.) Fu L, Chen W, Wang H, et al: Formalin treatment of refractory hemorrhagic cystitis in systemic lupus erythematosus. Pediatr. Nephrol. 1998; 12: 788-789.

(54.) Lukasewycz SJ, Smith AR, Rambachan A, et al: Intractable hemorrhagic cystitis after hematopoietic stem cell tranplantation - Is there a role for early urinary diversion in children? J. Urol. 2012; 188: 242-246. Available at: http://dx.doi.org/10.1016/j.juro.2012.03.020.

(55.) Garcia-Gamez A, Bermudez Bencerrey P, Brio-Sanagustin S, et al: Vesical Artery Embolization in Haemorrhagic Cystitis in Children. Cardiovasc. Intervent. Radiol. 2016; 39: 1066-1069.

(56.) Han Y, Wu D, Sun A, et al: Selective embolization of the internal iliac arteries for the treatment of severe hemorrhagic cystitis following hematopoietic SCT. Bone Marrow Transplant. 2008; 41: 881-886.

(57.) Ritch CR, Poon SA, Sulis ML, et al: Cutaneous vesicostomy for palliative management of hemorrhagic cystitis and urinary clot retention. Urology 2010; 76: 166-168.

(58.) Sebe P, Garderet L, Traxer O, et al: Subtotal cystectomy with ileocystoplasty for severe hemorrhagic cystitis after bone marrow transplantation. Urology 2001; 57: 168. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11164170.

(59.) Dorticos E, Pavon V, Jaime JC, et al: Successful application of epidermal growth factor for treatment of hemorrhagic cystitis after bone marrow transplantation [1]. Bone Marrow Transplant. 2003; 31: 615-616.

(60.) Bhaskaran S, Abu-Arja RF, Abusin G, et al: Recombinant human keratinocyte growth factor: Successful treatment of severe, refractory hemorrhagic cystitis after allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. 2014; 49: 1550-1551. Available at: http://dx.doi.org/10.1038/bmt.2014.205.

(61.) Baygan A, Aronsson-Kurttila W, Moretti G, et al: Safety and side effects of using placenta-derived decidual stromal cells for graft-versus-host disease and hemorrhagic cystitis. Front. Immunol. 2017; 8: 1-10.

(62.) Apiwattanakul N, Hongeng S, Anurathapan U, et al: Viral-specific T-cell response in hemorrhagic cystitis after haploidentical donor stem cell transplantation. Transpl. Infect. Dis. 2017; 19: 1-7.

Figures and Tables

Jessica H. Hannick (1,2); Martin A. Koyle (2,3)

(1) Division of Urology, McMaster Children's Hospital and McMaster University, Hamilton, ON, Canada; (2) The Hospital for Sick Children, Toronto, ON, Canada; (3) Division of Urology, Department of Surgery, University of Toronto, Toronto, ON, Canada

http://dx.doi.org/10.5489/cuaj.5993

Caption: Fig. 1. Proposed algorithm for treatment of pediatric hemorrhagic cystitis
Table 1. Grading definitions of hemorrhagic cystitis

          Droller 1982 (2)    Arthur 1986 (3)   CTCAE (4)

Grade 0                       No hematuria
Grade 1   Microscopic         More than 50      Asymptomatic;
          hematuria/dysuria   RBCs/HPF          clinical or
                                                diagnostic
                                                observations
                                                only;
                                                intervention
                                                not indicated
Grade 2   Macroscopic         Macroscopic       Symptomatic;
          hematuria           hematuria         urinary
                                                catheter or
                                                bladder
                                                irrigation
                                                indicated;
                                                limiting
                                                instrumental
                                                activities of
                                                daily living
                                                (ADL)
Grade 3   Macroscopic         Macroscopic       Gross
          hematuria           hematuria         hematuria;
          with small          with clots        transfusion,
          clots passed                          IV
          with voiding                          medications
                                                or
                                                hospitalization
                                                indicated;
                                                elective
                                                endoscopic,
                                                radiologic
                                                or operative
                                                intervention
                                                indicated;
                                                limiting
                                                self-care ADL
Grade 4   Macroscopic         Macroscopic       Life-threatening
          hematuria           hematuria with    consequences; urgent
          with clots          clots and an      radiologic or operative
          causing upper       elevated          intervention indicated
          tract obstruction   creatinine
          requiring           secondary to
          instrumentation     obstruction
          for clot
          evacuation
Grade 5                                         Death


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Title Annotation:Best Practice Report
Author:Hannick, Jessica H.; Koyle, Martin A.
Publication:Canadian Urological Association Journal (CUAJ)
Date:Jun 27, 2019
Words:7872
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