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Hyperbaric oxygen: an important treatment modality in severe hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation/Hiperbarik oksijen: allojeneik hematopoietik kok hucre nakli sonrasi gelisen agir hemorajik sistit olgularinda onemli bir tedavi secenegi.

Introduction

Hemorrhagic cystitis (HC) is a frequent complication of hematopoietic stem cell transplantation (HSCT). The reported frequency changes mainly with the definition (according to inclusion or exclusion of microscopic hematuria) and preventive manipulations. It may occur in the early or late posttransplant period and can promote sometimes severe morbidity. Several risk factors are reported to date, which include drugs, chemical toxins, infection, and pelvic irradiation [1,2]. It is mostly self-limited, and supportive treatment with hyperhydration and increased transfusion can be sufficient [3]. To facilitate the urinary flow, placement of urinary catheter is sometimes needed for intermittent or continuous bladder irrigation. Instillation of agents such as alum, silver nitrate, prostaglandin (PG) or formalin is the therapeutic intervention used to halt hemorrhage in severe HC [4-7].

Such agents are cumbersome for both patients and physicians and are seldom selected. Hyperbaric oxygen (HBO) therapy is a relatively new treatment modality for HC. The role of HBO therapy in HC was reported firstly in radiation-induced cystitis, but in recent years HBO has also been used in cyclophosphamide (CY)-induced HC [8-13]. It decreases tissue edema and ensures the necessary oxygen gradients required to stimulate continued angiogenesis, fibroblast proliferation, collagen formation, and leukocyte activation, which are required for tissue healing and repair [9]. We analyzed our data regarding HC in allogeneic (allo)HSCT patients in order to establish the efficacy of HBO therapy in severe HC and to document the main problems occurring during its use.

Materials and Methods

Between March 1993 and August 2006, 161 patients underwent alloHSCT (bone marrow transplantation (BMT): n=91; peripheral blood (PB) stem cell transplantation: n=70). All of the patients had hematological malignancies except three (aplastic anemia: n=2; paroxysmal nocturnal hemoglobinuria: n=1). The donors were all HLA-matched siblings. One hundred fifty-three of the patients received CY (60 mg/kg per day-2) as part of the conditioning regimen combined with busulfan (in 136 patients) (4 mg/kg per day divided in 4 doses-4) or total body irradiation (TBI) (in 17 patients) (1200 cGy). Mesna (6 mercapto-ethane sodium sulphonate, a sulfhydryl-containing compound) (1/2 of the CY total dose x 6), hyperhydration (3 L/ [m.sup.2]/day) and forced diuresis were used as early HC prophylaxis of CY-induced HC. The first dose of Mesna was given 30 minutes before CY infusion, and was followed by subsequent infusions every four hours until the day following the last dose of CY. Cyclosporine (CsA, 12.5 mg/kg per day divided in 2 doses) and a short-course of methotrexate (15 mg/[m.sup.2] per day on day-1 and 10 mg/[m.sup.2] per day on days-3,-6 and-11) were given as graft-versus-host disease (GVHD) prophylaxis. Written informed consent was obtained from all patients.

Heme dipstick testing was used as a method for hematuria investigation and was performed on a daily basis beginning with conditioning regimen until the end of hospitalization. When heme was found to be positive, the urine specimen was sent for microscopic analysis and culture. Diagnosis of HC was based on the appearance of microscopic hematuria with negative bacterial and fungal culture. HC was graded according to the following criteria: grade I, microscopic hematuria; grade II, macroscopic hematuria without clots; grade III, macroscopic hematuria with clots; and grade IV, gross hematuria and clinical complications secondary to urinary outflow obstruction. Patients with grade III and grade IV were accepted as having severe HC. Urine culture for adenovirus could be performed in only five patients. Cytomegalovirus (CMV) antigen was screened in both PB and urine samples in all the patients with HC. We did not have the opportunity to screen the urine for BK virus in our patients with HC.

When severe HC is diagnosed in our HSCT unit, forced diuresis with hyperhydration (3 L/[m.sup.2] up to 8 L/day) and transfusion support to maintain a platelet count above 30x109/L are the first-line treatment methods employed. Pelvic ultrasonographic examination is also performed in those patients to determine any obstruction in the vesicle and, if present, continuous bladder irrigation at 6-7 L/day through a tri-lumen irrigation catheter is also started. If severe HC is refractory to the first-line management, we choose alternative therapies such as intravesical instillation of PG (200 micrograms in 50cc isotonic sodium chloride solution), formalin and/or HBO therapy. We could not perform alum irrigation in our patients.

HBO therapy: Patients were referred to the HBO center. All patients received HBO therapy in a single room. They received 100% oxygen at 2.5 atmospheres chamber pressure for 120 minutes daily at least one month but continued until the symptoms subsided and bleeding completely disappeared. All calculations were performed using the SPSS software package, version 14 (SPSS Inc, Chicago, IL, USA)

Results

Hemorrhagic cystitis was diagnosed in 49 of 161 (30%) HSCT recipients at a median +39 days (range: from -2 to +241 days). HC occurred in 25 of the 70 alloPBSCT group (36%) and in 24 of the 91 BMT group (26%), and the difference was not statistically significant (p=0.228).

Seventeen of the 49 HC cases (8 BMT, 9 PBSCT) were described as severe HC (>grade II). Although most of our patients with HC responded to the first-line therapies, HC affected the morbidity in a median of 12 days (range: 4- 90 days). Nine of the patients died before resolution of HC with complications of severe GVHD.

Four of the HC cases (8.1%) developed in the first week of the transplantation and preparative regimens in these cases included CY and busulfan. Urine culture for adenovirus was found to be positive in one case. CMV antigenemia was also observed in six of the patients with HC.

The results of all patients with HC: Forced diuresis with hyperhydration up to 8 L/day and transfusion support to maintain a platelet count above 30x[10.sup.9]/L were sufficient in all the patients with mild HC and in eight of the 17 patients with severe HC. Cystoscopy was needed in 14 of the patients and evacuations of the hematoma were performed before increasing the irrigation solutions up to 30-40 L/day. Vesical sarcoma was diagnosed in one case with cystoscopy and the patient underwent radical cystectomy. Alternative therapies were applied in eight of the patients. The first patient was successfully treated with intravesical formalin irrigation therapy. The next patient did not respond to formalin and then intravesical PGF2 alpha irrigation and was successfully treated with HBO 2.4 atmospheres absolute (30 minutes 3 times daily for 8 days).

The results of HBO therapy: We performed HBO as a first-choice alternative therapy in another six patients. All results for these seven cases are summarized in Table 1. We found HBO therapy quite useful in our first four cases. We followed our patients with weekly CMV antigenemia and noted CMV reactivation in our fifth patient after three days of HBO and stopped the therapy. This patient died with multiorgan failure after three months follow-up and HC never resolved. We only used three and four days of HBO therapy, respectively, in our last two patients and they also died with severe GVHD and severe HC in a short period of two weeks.

Discussion

Hemorrhagic cystitis can occur at any time after HSCT and may affect the morbidity of the procedure. The incidence of HC varies considerably according to the preparative regimen, the preventative measures employed and perhaps the incidence of GVHD. HC occurring during or shortly after the conditioning regimen of high-dose chemotherapy or chemoradiotherapy is referred to as early-onset [14]. Oxazaphosphorine drugs such as CY or ifosfamide have been widely used as preparative regimen agents. The acrolein formed as a urinary byproduct of the metabolism of these drugs is thought to be responsible for the urothelial toxicity [1]. We use Mesna and hyperhydration protocol for the prevention of CY-induced HC in our Unit. In our study, since only four out of 49 HC cases (8.1%) developed in the first week of the transplantation, we consider this to be quite effective in preventing early-onset HC. Preparative regimens of these cases were also composed of busulfan, which may have been an additional risk factor for early HC in these patients [15]. We observed an incidence of HC of 30% in our study, which is comparable with the other reports (1,16). We analyzed our patients to see if stem cell source had any effect on this complication, but were unable to determine any statistically significant difference with respect to incidence or severity of the HC (p=0.228 and p=0.445, respectively).

Hemorrhagic cystitis cases occurring weeks to months after HSCT are referred to as late-onset HC. Early HC is one of the recognized risk factors for late HC, but significant proportions of the late HC cases are reported to be associated with viruria and/or GVHD. The viruses most frequently implicated in HC are BK polyomavirus and adenovirus type 11 [16-18]. HC is generally self-limited and usually resolves in a few days to weeks without any sequelae. Occasionally, intermittent or persistent hematuria may be severe enough to require frequent transfusions. In more severe cases, cystoscopy should be performed to determine any problems with the vesical mucosa and to remove blood clots, followed by continuous bladder irrigation [19]. We diagnosed vesical sarcoma in one of our patients who required cystoscopy. Eight of the severe HC cases in our study failed to respond to standard management. Formalin and PGF2a were chosen for intravesical instillation in addition to bladder irrigation and platelet transfusions in two patients, respectively. Formalin was effective in controlling bleeding but PGF2 was not, which was likely due to insufficient doses because of the limited supply of this drug in our country [20]. Our first patient became asymptomatic in eight days with HBO therapy. We used this treatment modality in all seven cases with intractable HC. We used HBO therapy without any other alternative therapies in our other three responding patients, who became asymptomatic in 10, 14 and 9 days of HBO, respectively. We used HBO until microscopic hematuria disappeared in those patients. We followed our patients with weekly CMV antigenemia and determined CMV reactivation in our fifth patient after three days of HBO therapy. Although it might have been a coincidental finding in such a patient with severe GVHD, we thought HBO therapy might have facilitated the reactivation of GVHD and stopped the therapy despite persistent HC in that patient. We were unable to use HBO effectively in our last two patients because of severe CMV infection and graft failure symptoms and death was anticipated. We did not want to accept these cases as HBO- unresponsive because of the very short duration of the therapy.

Clinical and experimental studies suggest that HBO could be useful in preventing chemotherapy-induced HC [21-23]. HBO is considered as an adjunctive treatment to medical and surgical care. HBO induces the healing of tissue damage, decreases edema and promotes capillary angiogenesis by increasing tissue oxygen levels. Plafki et al. [24] reviewed complications and side effects in 782 patients treated for various indications, with a total of 11,376 HBO therapy sessions, and summarized that the predominant complication is related with pressure equalization problems within the middle ear. We did not observe any complication directly related with HBO therapy. We did observe CMV reactivation coincidentally during HBO therapy, and even though we could not determine any deleterious effect such as viral reactivation, we stopped the therapy. There are some reports speculating that HBO therapy has an antiviral effect in hepatitis B and human immunodeficiency virus infection [25,26]. We conclude that moder ately severe HC can be treated conservatively in most patients. When hyperhydration, transfusion support and intravesical irrigation fail to treat HC, addition of HBO therapy may be beneficial, and HBO treatment should be considered without further delay.

No author of this paper has a conflict of interest, including specific financial interests, relationships, and/or affiliations relevant to the subject matter or materials included in this manuscript.

Received: March 17, 2009 Accepted: September 1, 2009

Gelis tarihi: 17 Mart 2009 Kabul tarihi: 1 Eylul 2009

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Mustafa Nuri Yenerel, Sevgi Kalayoglu-Besisik, Oktay Perdeci, Nuray Gurses, Murat Tunc, Deniz Sargin

Istanbul University, Istanbul Faculty of Medicine, Department of Internal Medicine, Division of Hematology, Istanbul, Turkey

Address for Correspondence: Assoc.Prof. Mustafa Nuri Yenerel, Istanbul University, Istanbul Medical Faculty, Department of Internal Medicine, Hematology Field, Capa, Istanbul, Turkey Phone: +90 212 414 20 00-31613 E-mail: mnyenerel@gmail.com
Table 1. Clinical findings and therapy results of 7 patients with
intractable hemorrhagic cystitis (HC)

 Case 1 Case 2 Case 3

Age, sex 42, Male 32, Female 22, Male

Disease CML CML CML

Stem cell source PBSC PBSC BMT

Preparative regimen Bu/CY Bu/CY Bu/CY

GVHD grade - 2 -

HC grade and time III, day +69 II, day +32 III, day +27

Alternative therapies Intravesical - -
 formalin, PGF2

Duration 3 weeks 21 days 5 weeks

HBO response in 8 days in 10 days in 14 days
(Until asymptomatic)

HBO duration 35 days 40 days 60 days

HBO complication none none none

Last visit Exitus Alive Alive

 Case 4 Case s

Age, sex 20, Female 26, Male

Disease CML T-ALL

Stem cell source PBSC BM

Preparative regimen Bu/CY Bu/CY

GVHD grade - 22

HC grade and time III, day +60 IV, day +45

Alternative therapies - -

Duration 21 days 3 months

HBO response in 9 days -
(Until asymptomatic)

HBO duration 40 days 3 days

HBO complication none CMV
 reactivation??

Last visit Alive Exitus

 Case 6 Case 7

Age, sex 23, Female 21, Female

Disease B-ALL CML

Stem cell source BM BM

Preparative regimen Bu/CY Bu/CY

GVHD grade 2

HC grade and time IV, day +60 IV, day +32

Alternative therapies -

Duration ? ?

HBO response -
(Until asymptomatic)

HBO duration 3 days 4 days

HBO complication none none

Last visit Exitus Exitus

CML: Chronic Myelogenous Leukemia ALL: Acute Lymphoblastic Leukemia
PBSC: Nenpheral blood Stem Cell BM: Bone Marrow
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Title Annotation:Research Article
Author:Yenerel, Mustafa Nuri; Kalayoglu-Besisik, Sevgi; Perdeci, Oktay; Gurses, Nuray; Tunc, Murat; Sargin,
Publication:Turkish Journal of Hematology
Article Type:Report
Geographic Code:7TURK
Date:Dec 1, 2009
Words:3042
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