Successful hyperbaric oxygen treatment of life-threatening hemorrhagic cystitis after allogeneic bone marrow transplantation


Hemorrhagic cystitis (HC) is a major cause of morbidity after allogeneic bone marrow transplantation (BMT). Many therapies have been investigated to prevent or treat HC, but effective treatment for HC is still limited. While the efficacy of hyperbaric oxygen therapy has been established for HC due to chemotherapy and/or radiation therapy, its role in HC occurring after allogeneic BMT has yet to be defined. We report two cases of life-threatening late-onset HC after allogeneic BMT in children, which resolved after treatment with hyperbaric oxygen. Bone Marrow Transplantation (2001) 27, 1315–1317.


Hemorrhagic cystitis (HC) is a major complication following hematopoietic stem cell transplantation. Severe cystitis has been reported to occur in about 5% of bone marrow transplant (BMT) patients. Allogeneic BMT, grade II–IV graft-versus-host disease (GVHD), use of busulfan (Bu), age at transplantation and adenovirus infection increase the risk of severe HC.1 Many therapeutic approaches have been tried to control pain and bleeding due to HC; despite this, HC can lead to bladder tamponade requiring surgical intervention, and can contribute to death. Hyperbaric oxygen (HBO) therapy has been used extensively in hypoxic tissue in an attempt to stimulate angiogenesis and prompt healing. HBO has been used successfully in the treatment of radiation or cyclophosphamide (CY)-induced HC.2,3 This is the first report in patients with intractable HC after allogeneic BMT who were controlled by HBO.

Case histories

Case 1

An eight-year-old boy with acute lymphocytic leukemia in third remission underwent BMT from an HLA-matched unrelated donor in June 1998. He received a conditioning regimen of Bu 4 mg/kg/day for 4 days, CY 60 mg/kg/day for 2 days, and etoposide 60 mg/kg/day for 1 day. Cyclosporine A (CsA) and prednisolone were administered for GVHD prophylaxis. The clinical course after BMT is shown in Figure 1. By the fifth week after BMT, trilineage engraftment was confirmed. The patient did not develop acute GVHD. At day +4 he had developed dysuria, suprapubic pain and macrohematuria. On day +70 he developed gross hematuria with clots and an abundant residue of bladder mucus. Adenovirus was not cultured from the urine, and HC was not attributed to polyomavirus infection because characteristic morphologic changes in the urinary sediment were not seen in conjunction with the urine culture being negative for other pathogens. During the next 9 weeks, gross hematuria continued, and the patient required seven transfusions of packed red blood cells and 33 transfusion of platelets. Despite conservative treatment with continuous bladder irrigation and intravesicular maalox and prostaglandin E1 (PGE1), he developed bladder tamponade on days +78 and +118 after BMT requiring emergency cystostomy and evacuation of hematomas. Post-renal failure developed, and he was referred for HBO therapy after bilateral tympanostomies. The patient was treated in an enclosed HBO chamber with 100% oxygen for 90 min at an absolute pressure of 202.6 kPa (2 atm) on day +135 post transplant. He received 14 treatments over the next 23 days. After treatment 8, the macrohematuria disappeared and the urine cleared completely 2 months after the start of HBO therapy. At follow-up of 28 months post transplant, the urine remained clear, and renal and bladder function had completely recovered.

Figure 1

Clinical course of case 1. Severe hemorrhagic cystitis resolved after hyperbaric oxygen. RBC, red blood cell transfusion; PGE1, prostaglandin E1; HBO, hyperbaric oxygen.

Case 2

A 6-year old boy was diagnosed with adrenoleukodystrophy (ALD). He received Bu 4 mg/kg/day for 4 days, CY 50 mg/kg/day for 4 days, and antithymocyte globulin (ATG) 2.5 mg/kg/day for 4 days as conditioning prior to allogeneic BMT from an HLA-matched sibling donor in May 1999. CsA was administered for GVHD prophylaxis. Engraftment was rapid, with peripheral white blood cells (WBC) >1.0 × 109/l on day +11 and platelets >50 × 109/l on day +14. The patient did not develop acute GVHD. At day +4 he developed dysuria, suprapubic pain, and gross hematuria with clots. On day +30 post transplant, his urine was positive by PCR for adenovirus; administration of intravenous ribavirin did not result in improvement of symptoms. Polyomavirus infection was excluded from the morphologic changes in the urinary sediment. There was no response to continuous bladder irrigation. Intravesicular maalox and PGE1 did not lead to any improvement. He required repeated red blood cell transfusions. A renal ultrasound showed narrowing of the bladder lumen with multiple hematomas. On day +44 post transplant, HBO treatment was begun after bilateral tympanostomies, at an absolute pressure of 202.6 kPa (2 atm) for 90 min daily, 5 days a week for 7 consecutive weeks. Macroscopic hematuria gradually disappeared, and the urine cleared completely 5 weeks after the start of HBO therapy. At 18 months post transplant the patient was free of hematuria.

In summary, both these patients tolerated HBO treatment well and could safely continue with therapy for their underlying disease.


Hemorrhagic cystitis associated with BMT is usually related either to the use of CY in the early post-transplantation period4 or to viral infections occurring late after transplantation.5,6 Seber et al1 have reported that risk factors for HC in allogeneic transplant patients include grade II–IV GVHD, use of Bu, and age of 10 to 30 years at transplantation. Although they did not find any significant association between the risk of HC and the dose of CY, the metabolites of CY are well-known causes of HC.7 Mesna has been used to prevent HC, but Seber et al did not find any significant difference in HC with the use of prophylactic mesna and we used mesna in these two cases without effect. They also reported that seven of 12 patients transplanted for ALD developed HC and that five of these cases were severe, suggesting this group of patients may be abnormally sensitive to chemotherapy. Administration of Bu has also been reported to be a risk factor for HC. In our two cases, the only risk factors of HC were use of BuCy and the diagnosis of ALD in one case.

Injury to the bladder with radiation therapy causes progressive obliterative endarteritis of small vessels with resulting teleangiectasia, submucosal hemorrhage, and fibrosis of smooth muscle and interstitium. The ischemic changes in the mucosa lead to breakdown, with ulceration and bleeding. A urine cytology study of CY-induced bladder damage by Forni et al8 concluded that the cytology of the bladder wash in their patients was similar to that seen in radiation cystitis. Bu-induced HC has also been reported to be indistinguishable from that induced by CY.9

Previous treatments reported for HC have included continuous bladder irrigation, cystoscopy with clot evacuation, fulguration of bleeding sites, intravesicular alum, silver nitrate, formalin, prostaglandins, and estrogen.1 These treatments can be painful. Instillation of formalin has a significant risk of complications such as shock, and results in a small contracted bladder. Most patients have received a combination of treatment modalities, and cystectomy has been required in some patients. According to Seber's data, serious complications of severe cystitis occuring within 100 days post BMT include urinary obstruction (21%), acute renal failure (21%) with need for dialysis in half the cases, hydronephrosis (10%), and death (5%).

Hyperbaric oxygen therapy has been used successfully for the treatment of radiation-induced cystitis. Irradiated tissue has a decreased capacity for revascularization, and oxygen can promote angiogenesis in combination with growth factors released by tissue macrophages. CY-induced HC has also been treated successfully with HBO. Judging from the similarities in urine cytology in cystitis due to radiation or CY/Bu, HBO therapy should be effective for CY or Bu-induced HC. Recently Hughes et al10 reported successful treatment of refractory HC after autologous peripheral blood stem cell transplantation by HBO. The patient in this case received melphalan 140 mg/m2 and Bu 16 mg/m2 as conditioning chemotherapy. Chemotherapeutic agent-induced cystitis after stem cell transplantation is associated with significant morbidity, as seen in our patients. Early institution of HBO following onset of hematuria was associated with more rapid control of bleeding and decreased transfusion requirements. HBO is a safe, non-invasive therapy for children as shown by the cases reported here. Conventional therapies for refractory HC are invasive and may be destructive to bladder tissue. HBO induces neovascularization and permanent tissue healing, preserving bladder function. We strongly believe that further clinical trials of HBO therapy in patients with HC after stem cell transplantation are warranted.


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We are indebted to the medical and nursing staff who cared for the patients.

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Correspondence to M Yabe.

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Hattori, K., Yabe, M., Matsumoto, M. et al. Successful hyperbaric oxygen treatment of life-threatening hemorrhagic cystitis after allogeneic bone marrow transplantation. Bone Marrow Transplant 27, 1315–1317 (2001).

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  • hemorrhagic cystitis
  • hyperbaric oxygen
  • allogeneic bone marrow transplantation
  • children

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