Hemorrhagic cystitis treatment

If hemorrhagic cystitis occurs, the goals of treatment are to decrease exposure to the offending etiology, establish and maintain urine outflow, avoid obstruction and renal compromise, and maintain blood and plasma volume. Restoration of normal bladder function is the ultimate goal following acute treatment. 

Treatment of hemorrhagic cystitis. IV, intravenous. (Data from ref. 24.)... 

West NJ. Prevention and treatment of hemorrhagic cystitis. Pharmacotherapy 1997 17 696-706. 

The answer is c. (Hardman, pp 1238-1239.) Remission maintenance can be carried out by combination therapy, which includes cyclophosphamide. Cyclophosphamide causes hemorrhagic cystitis. Doxorubicin and carmustine are useful in the treatment of acute lymphatic leukemia, but neither is known to cause hemorrhagic cystitis. 

Treatment with large doses of cyclophosphamide carries considerable risk of pancytopenia and hemorrhagic cystitis and therefore is generally combined with stem cell rescue (transplant) procedures. Although cyclophosphamide appears to induce tolerance for... 

Levine LA, Jarrard DF. Treatment of cyclophosphamide-induced hemorrhagic cystitis with intravesical carboprost tromethamine. J Urol 1993 149(4) 719-23. 

Cyclophosphamide (Cytoxan and Endoxan) is used in the treatment of Hodgkin s disease, lymphosarcoma, and other lymphomas. It is employed as a secondary drug in patients with acute leukemia and in combination with doxorubicin in women with breast cancer. A drug combination effective in the treatment of breast cancer is cyclophosphamide, methotrexate, fluorouracil, and prednisone (CMFP). Cyclophosphamide is also an immunosuppressive agent. The toxicity of cyclophosphamide causes alopecia, bone marrow depression, nausea and vomiting, and hemorrhagic cystitis. 

Hemorrhagic cystitis and bladder cancer are well-known complications of cyclophosphamide. The damage to the urinary bladder epithelium is caused by acrolein, a metabolite of cyclophosphamide that is excreted in the urine. In bone marrow transplant recipients, prior administration of busulfan, which itself causes hemorrhagic cystitis, can increase this risk (23). Mesna (2-mercaptoethane sodium sulfonate) is used to prevent this adverse effect. It is excreted by the kidney, and it binds and detoxifies acrolein in the urine mesna also prevents the breakdown of acrolein precursors. Intravesical prostaglandin E2 has been suggested as an alternative treatment (23). 

Experience with ifosfamide-contain-ing regimens has revealed a consistent clinical pattern of nephrotoxicity. Fanco-ni syndrome, which is characterized by acid, sodium, potassium, magnesium, and small molecular weight proteins, occurs in 1-5% of the children who have received repeated treatments of ifosfamide [94] [95]. In fact the development of rickets secondary to Fanconi syndrome has been reported following treatment with ifosfamide [96]. Patients who have received therapy with cisplatin or carboplatin in addition to ifosfamide may be at greater risk for development of Fanconi syndrome [97]. Hemorrhagic cystitis is a significant toxicity that occurs with ifosfamide administration [98,... 

Treatment is largely supportive. Cyclophosphamide is adsorbed to activated charcoal and charcoal should be used for substantial, recent ingestions. Patients may require aggressive fluid support. Standard supportive therapies, such as vasopressors, should be utilized as clinically indicated. Patients may require prolonged observation due to the delay in the development of adverse effects. Antibiotics may be needed due to development of immunosuppression. MESNA has been used for management of cyclophosphamide-induced hemorrhagic cystitis. 

Drug therapy may also cause renal insufficiency due to lower urinary tract obstruction. Ureteral obstruction can be caused by calculi or retroperitoneal fibrosis. Bladder dysfunction with urinary outflow obstruction can result, particularly in males with prostatic hypertrophy, from anticholinergic drugs including tricyclic antidepressants and disopyramide. Bladder outlet and ureteral obstruction may result from bladder fibrosis following hemorrhagic cystitis with cyclophosphamide or ifosfamide therapy. Concurrent treatment with mesna can prevent cystitis and this complication. 

The immunosuppressive effect of cytotoxic agents, with or without the concurrent use of steroids, can result in serious infections, which are the primary cause of death in patients with minimal-change nephropathy. Other toxicities associated with cyclophosphamide include gonadal fibrosis, which results in sterility, hemorrhagic cystitis, alopecia, and a potential to develop malignancy in those on long-term treatment. Patients on chronic steroid therapy often develop growth retardation, osteoporosis, obesity, and cataracts. ... 

When used in combination with corticosteroids, cyclophosphamide is dosed at 1-3 mg/kg for oral therapy and 0.5-1.0 g/m of body surface area for intravenous therapy. The most common route of cyclophosphamide administration is intravenous, although there is little evidence that this is better than oral administration. Likewise, there is no evidence to suggest the optimal duration of treatment. Based on empirical experience, cyclophosphamide generally is dosed monthly for 6 months and then every 3 months for a period of either 2 years or for 1 year after the nephritis is in remission." " Of course, cyclophosphamide therapy is not without risk. Serious toxic effects include suppression of hematopoiesis, opportunistic infections, bladder complications (e.g., hemorrhagic cystitis and cancer), sterility, and teratogenesis. White blood cell counts must be monitored during cyclophosphamide therapy, and if the nadir is less than 1500/mm, the dose must be adjusted to keep the white cell count above 1500/mm. Nausea and vomiting associated with cyclophosphamide can be controlled with oral ondansetron plus dexamethasone. ... 

Cyclophosphamide prodnces a similar response rate as chlorambucil (30% to 40%) and can be used in patients who have difficulty tolerating chlorambncU or in whom response is not optimal. Some patients refractory to chlorambucil will respond to cyclophosphamide. Cyclophosphamide is less commonly used because of its risk of hemorrhagic cystitis and bladder cancer with prolonged treatment. ... 

Level II (non-randomized) evidence of effect is available supporting the efficacy of HBO for the treatment of severe radiation-indnced hemorrhagic cystitis refractory to conventional measures. The largest study describes 40 patients treated for 20 sessions of HBO." ° A total of 37 of the 40 patients showed marked and durable (up to 5 years) reductions in bleeding frequency, including need for blood transfusions, and no adverse effects were reported. A consecutive series of 20 patients treated between 1989 and 1992 reported improvement of hematuria in 90% of cases." Similar experiences based on smaller patient numbers are available." " No adverse effects of HBO were reported in any of these studies. 

Weiss, J.P. et al., Primary treatment of radiation-induced hemorrhagic cystitis with hyperbaric oxygen 10-year experience, J. Urol, 151 (6), 1514-1517,1994. 

Electrolyte balance In a retrospective analysis of data obtained from 84 patients with lupus nephritis or non-Hodgkin s lymphoma, 112 treatment episodes with low-dose intravenous pulse cyclophosphamide (500-750 mg/m ) were evaluated [28. All received 0.45% saline as hydration to prevent hemorrhagic cystitis. There was cyclophosphamide-induced hyponatremia during 15 treatment episodes in 12 patients. Patients with hyponatremia were significantly older than those without, although no factors independently predicted hyponatremia in a multivariate analysis, including cyclophosphamide dose. Cyclophosphamide potentiates the renal action of vasopressin, thereby reducing the ability of the kidney to excrete water, which should warrant the use of hypotonic solutions for prophylactic hydration to prevent hyponatremia. 

C. lavazzo, S. Athanasiou, E. Pitsouni, and M.E. Falagas, Hyaluronic acid An effective alternative treatment of interstitial cystitis, recurrent urinary tract infections, and hemorrhagic cystitis , Eur. Urol, 51 (6), 1534-1540, discussion 1540-1541, 2007. 

Nervous system Neurotoxic effects of aluminium are regularly reported as a result of intravesical treatment of hemorrhagic cystitis, as a pediatric case illustrates [2 ]. 

Bogris SL, Johal NS, Hussein I, Diffy PG, Mushtaq I. Is it safe to use aluminum in the treatment of pediatric hemorrhagic cystitis J Pediatr Hematol Oncol 2009 31(4) 285-8. 

A retrospective study reports the efficacy and safety of leflunomide for treatment of BK virus-associated hemorrhagic cystitis in allogeneic haematopoietic stem cell transplantation recipients (n=14). Three days of oral lOOmg/day leflunomide as loading doses followed by maintenance doses of 20mg/day resulted in complete remission in seven patients, six patients achieved partial remission and two patients had a reduction in urinary BKV-DNA load after leflunomide treatment (>l-log BKV-DNA load reduction). One patient discontinued leflunomide therapy because of GI symptoms and 2 case developed neutropenia. Al ough the role... 

Chen XC, Liu T, Li JJ, He C, Meng WT, Huang R. Efficacy and safety of lefltmomide for the treatment of BK virus-associated hemorrhagic cystitis in allogeneic hematopoietic stem cell transplantation recipients. Acta Haematol 2013 130(l) 52-6. 

A toxicity that is unique to cyclophosphamide and ifosfamide is cystitis. Dysuria and decreased urinary frequency are the most common symptoms. Rarely, fibrosis and a permanently decreased bladder capacity may ensue. The risk of development of carcinoma of the bladder also is increased. Large intravenous doses have resulted in impairment of renal water excretion, hyponatremia, and increased urine osmolarity and have been associated with hemorrhagic subendocardial necrosis, arrhythmias, and congestive heart failure. Interstitial pulmonary fibrosis may also result from chronic treatment. Other effects of chronic drug treatment include infertility, amenorrhea, and possible mutagenesis and carcinogenesis. 

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