|Year : 2019 | Volume
| Issue : 5 | Page : 232-237
Augmentation enterocystoplasty for patients with ketamine-induced cystitis: An 8-year experience and a review of series
Chu-Hsuan Hung1, Shu-Wei Hsieh2, Shao-Kuan Chen3, Chih-Ming Lin1
1 Division of Urology, Department of Surgery, Cathay General Hospital, Taipei, Taiwan
2 Department of Anatomic Pathology, Cathay General Hospital, Taipei, Taiwan
3 Division of Urology, Department of Surgery, Sijhih Cathay General Hospital; School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan, R.O.C, Taiwan
|Date of Submission||30-Apr-2017|
|Date of Decision||17-Jul-2018|
|Date of Acceptance||30-Aug-2018|
|Date of Web Publication||24-Oct-2019|
Division of Urology, Department of Surgery, Cathay General Hospital, No. 280 Renai Rd. Sec. 4, Taipei
Source of Support: None, Conflict of Interest: None
Purpose: Ketamine abuse has been a worldwide issue recently. Ketamine-induced cystitis (KC) is an annoying urinary tract symptom secondary to long-term ketamine abuse. The aim of our study is to review clinical outcomes of bladder augmentation enterocystoplasty (AE) for the patients with KC. Materials and Methods: We performed bladder AE for eight patients with refractory symptoms of KC (severe bladder pain, micturition pain, urgency, frequency, and contracted bladder). All the patients received conservative treatment at clinics or referred from other hospital. Results: Between 2007 and 2015, eight patients (seven males and one female), aged 26–48 years (mean 32.7 years), underwent AE as indicated. The duration of ketamine abuse ranged from 2 to 15 years (mean 6.8 years). Contracted bladder was noted in all patients, hydronephrosis in two and hydroureter in one under intravenous pyelography. Postoperative hospitalization ranged from 12 to 47 days (mean 22.4 days). Significant increases in estimated glomerular filtration rate (86.43 ± 21.47 vs. 103.14 ± 29.32 ml/min/1.73 m2,P < 0.05), functional bladder capacity (47.75 ± 10.07 vs. 273.13 ± 54.96 ml,P < 0.0001), and pain visual analog score (6.0 ± 1.2 vs. 1.75 ± 0.89,P < 0.0001) were noted after AE. Surgical complications included adhesion ileus, progressive impaired renal function, and enterovesical fistula. All the patients were satisfied with the outcomes of the surgery, based on their responses to the self-report questionnaires. All patients reported marked improvement in micturition pain and urinary frequency, which greatly elevated life quality. Most patients were followed up at the outpatient department within 1 year or were lost to follow-up after surgery. Conclusion: This case series demonstrated that for surgical management of refractory bladder pain and low bladder capacity resulting from KC, AE might be effective. However, cessation of ketamine use is the most important to prevent recurrence of the above symptoms.
Keywords: Augmentation enterocystoplasty, bladder pain, ketamine, ketamine cystitis, ketamine-induced cystitis, surgery
|How to cite this article:|
Hung CH, Hsieh SW, Chen SK, Lin CM. Augmentation enterocystoplasty for patients with ketamine-induced cystitis: An 8-year experience and a review of series. Urol Sci 2019;30:232-7
|How to cite this URL:|
Hung CH, Hsieh SW, Chen SK, Lin CM. Augmentation enterocystoplasty for patients with ketamine-induced cystitis: An 8-year experience and a review of series. Urol Sci [serial online] 2019 [cited 2020 Jan 19];30:232-7. Available from: http://www.e-urol-sci.com/text.asp?2019/30/5/232/269888
| Introduction|| |
Ketamine, which is a receptor complex antagonist of N-methyl-d-aspartic acid, was first synthesized in 1962. It has been widely used for anesthetic and analgesic purposes since the 1960s. Ketamine has been used as a recreation drug in the United States since the 1990s and has increased in use in other countries.
Owing to its accessibility and low price, it has become more common as a recreational drug in Taiwan. According to the report of the Ministry of Health and Welfare in Taiwan, ketamine abuse is placed second in terms of growth rate and third among all drug abuse events. Teenagers and young adults account for the most involved population. Prevention of ketamine abuse in schools is an important issue in Taiwan.
Ketamine is known to be metabolized by the liver and transformed to norketamine. Thus, liver function may be observed clinically to judge the reliability of cessation of ketamine use. The kidneys excrete the metabolites of ketamine, which we believe is the substance that induces injury of the urinary tract.
Many terms have been used to describe symptoms, such as ketamine-associated uropathy, ketamine-induced ulcerative cystitis, or ketamine-related contracted bladder. Here, we use the term ketamine-induced cystitis (KC) for further discussion. According to the first ketamine-related uropathy report in 2007, the typical symptoms include hematuria, dysuria, frequency with small amount of urine, urgency, and pelvic pain., An increasing number of studies or case reports revealed urinary tract symptoms in more than a quarter of ketamine users and positive correlations with abuse duration and dosage.
Tam et al. recommended that the patients with KC should undergo bladder scans, renal sonography, and even uroflowmetry tests to evaluate the residual urine volume at the first urology clinic visit. Patients with a history of ketamine use should receive complete management ranging from history taking to invasive examination. History taking could help us to realize the duration and dosage of ketamine use and the severity of urinary symptoms. Basic physical examination would reveal the urinary tract condition (e.g., lower abdominal tenderness implying bladder pain or costovertebral angle knocking pain indicating hydronephrosis). Moreover, radiography provides important evidence for excluding other diseases. Invasive procedures such as cystoscopy could confirm the diagnosis based on a history of ketamine abuse.
The typical image finding in patients with KC includes a contracted bladder with a thickening bladder wall, hydroureter, hydronephrosis, or vesicoureteral reflux (VUR)., Cystoscopic finding revealed erythematous mucosa, ulcerative cystitis, spotting, easy bleeding and mucosal laceration after hydrodistension, or bladder wall fibrosis. Serum chemistry test usually revealed renal function impairment due to urinary tract injury and liver function impairment with persistent use of ketamine.
The pathogenesis of KC is still unclear, but it involves many different mechanisms and pathways rather than a single cause. Jhang et al. summarized that the major causes of KC included direct toxic damage,, bladder barrier dysfunction,, neurogenic inflammation,,, IgE-mediated inflammation and hypersensitivity,, carcinogenesis,, cell apoptosis,, and nitric oxide synthases and cyclooxygenase-mediated inflammation. Thus, the treatment of KC should be multiple tiers for the dissimilar mechanism and different stage of disease. In general, the first step is cessation of ketamine use. Most patients who quit ketamine demonstrate significant clinical improvement of symptoms after 1 year.
The ultimate treatment goal in KC is to increase bladder capacity and decrease bladder pain. AE was an effective surgery to attain the treatment goal in KC in previous studies.,, It could dramatically improve bladder capacity, annoying urinary tract symptoms, and quality of life.
This retrospective study reports our experience with AE for patients with KC and the efficacy of AE for bothersome symptoms such as small bladder volume and bladder pain.
| Materials and Methods|| |
Eight patients with refractory symptoms of KC (severe bladder pain, micturition pain, urgency, frequency, and/or urinary tract damage such as hydronephrosis and contracted bladder) who underwent AE between 2007 and 2015 were included in this study. All these patients had a history of ketamine consumption with nasal snorting for at least 1 year. All the patients presented with urinary urgency, dysuria, urinary frequency, and bladder pain. They all claimed that they had quit ketamine use at that time. They initially received conservative treatment with NSAIDs, anticholinergic agents, an opioid group of analgesics, and intravesical instillation with hyaluronic acid, but the results were all unsatisfactory. The preoperative evaluations of all the patients included history taking, physical examination, urinalysis, urine culture, biochemistry tests (renal function test, liver function tests, and electrolyte analysis), and/or urodynamic study. Imaging studies included renal ultrasonography, intravenous pyelography examination (IVP), and computed tomography (CT). Upper urinary tract damage was defined as hydronephrosis or hydroureter on IVP or CT. A 3–day voiding diary was obtained for functional bladder capacity (FBC). All the patients who underwent AE had a small bladder capacity (<100 mL) or low bladder compliance with or without VUR. We use a self-report questionnaire to evaluate patient satisfaction with treatment.
AE was performed with a 40-cm terminal ileal segment as the neobladder wall in a modified Hautmann's procedure and preserved a 15-cm ileum from the ileocecal valve [Figure 1]a. The resected ileum was detubulized and remodeled into a “U”-shaped pouch [Figure 1]b. Then, partial cystectomy of the contracted bladder was performed. The resection area depended on the injury mucosa area. We resected the damaged bladder wall as much as possible for pain relief and at least preserved the trigone for the normal micturition reflex. The remodeling ileal patch anastomosed to the bladder wall. Ureteral reimplantation was not performed in our series because no VUR was observed during the preoperative survey in all the patients. Furthermore, we also suggest that patients visit a psychiatric outpatient department for ketamine cessation after discharge.
|Figure 1: The procedure of augmentation enterocystoplasty. (a) A 40-cm terminal ileum resected and preserved a 15-cm segment from the ileocecal valve. (b) The resected ileum was detubulized and remodeled into a “U”-shaped pouch|
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Symptom history, treatment history, ketamine consumption, preoperative evaluation, surgical information, and postoperative conditions were obtained from medical records. Differences between preoperative and postoperative data were tested with a paired t-test. Statistical assessments were considered significant when P < 0.05.
This study was approved by IRB of Cathay General Hospital (IRB no. CGH-P108090 obtained on October 4th, 2019) with the requirement of obtaining informed consent from the patient participants.
| Results|| |
Eight patients (seven men and one woman) who underwent AE as indicated between 2007 and 2015 were included in this study. [Table 1] lists the patient demographics and characteristic changes after AE. Their ages ranged from 26 to 48 years (mean age, 32.7 years) at the time of surgery. The duration of ketamine abuse ranged from 2 to 15 years (mean, 6.8 years). All the patients had severe frequency, urgency, nocturia, and refractory bladder pain after conservative treatment. Of the eight patients, five (62%) had recurrent urinary tract infection (UTI), three (37%) had gross hematuria, three (37%) had painful micturition, and two (25%) had incontinence. The definition of UTI is pyuria and bacteriuria in urine routine examination (U/A) in our series. A contracted bladder was observed in all the patients [Figure 2], hydronephrosis in three (37%) (bilateral and right-side hydronephroses in two and one patient, respectively) and bilateral hydroureter in two (25%) on ultrasonography, IVP, or CT. The typical cystoscopic findings of patient with severe KC include diffuse erythematous bladder mucosa and erosive lesion with decreased bladder volume. In some cases, we even saw stone formation coating on the affected bladder mucosa [Figure 3].
|Figure 2: The pyelography of patient no. 3, a 32-year-old male with a 3-year history of ketamine abuse, who had markedly contracted bladder with severe trabeculation, before surgery (a) and 3 months after surgery at 5 min (b) and 60 min (c)|
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|Figure 3: Cystoscopy of a patient with ketamine-induced cystitis before and after surgery. A 32-year-old female with a 7-year history of ketamine abuse. (a) Erosive mucosa with multiple bleeding spot and diffuse stone formation coating on the mucosa. (b) After augmentation enterocystoplasty, intact intestinal mucosa at the follow-up cystoscopy|
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Simple AE was performed in all the eight patients, but no ureteral reimplantation was performed. Postoperative hospitalization ranged from 12 to 47 days (mean, 22.4 days). Surgical complications included adhesion ileus, progressive impaired renal function, and enterovesical fistula. One patient with adhesion ileus received colonoenteric bypass 1 month after surgery. One patient had progressive impaired renal function 3 years later and received peritoneal hemodialysis 7 years after surgery. One developed urine leakage from a lower abdominal surgical wound due to an enterovesical fistula, after postoperative loss to follow-up for 2 years due to being in jail. This series had no cases of mortality.
We compared the changes of symptoms and bladder data at 3–6 months after surgery. Significant increases in estimated glomerular filtration rate (86.43 ± 21.47 vs. 103.14 ± 29.32 ml/min/1.73 m2, P < 0.05), FBC (47.75 ± 10.07 vs. 273.13 ± 54.96 ml, P < 0.0001), and pain visual analog score (6.0 ± 1.2 vs. 1.75 ± 0.89, P < 0.0001) were noted after AE [Table 2].
|Table 2: The changes of symptoms and bladder parameters after augmentation enterocystoplasty|
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All the patients were satisfied with the outcome of the surgery, based on their responses to the self-report questionnaires. However, most patients were followed up at the outpatient department within 1 year or were lost to follow-up after surgery.
The gross pathological findings of resected bladder specimens are mixed acute and chronic inflammation with erosive mucosa and adhesion to surrounding tissue. In microscopic hematoxylin and eosin stains, the bladder urothelium is extensive denuded with some granulation tissue formation [Figure 4]a. Moreover, inflammatory cells, including eosinophil, lymphocytes, neutrophil, and plasma cells infiltration in the mucosa, submucosa, and even the muscle layer were observed. Fibrinopurulent debris coating on the mucosa was also noted [Figure 4]b. Submucosal fibrosis, edematous change, and muscle hypertrophy [Figure 4]c may be the result of a contracted bladder. While the above histopathological findings are not specific to KC, they could help us to exclude other diseases, such as interstitial cystitis or infectious cystitis.
|Figure 4: Histopathological finding of ketamine-induced cystitis. A 32-year-old female with a 7-year history of ketamine abuse underwent augmentation enterocystoplasty. Bladder specimens were stained with hematoxylin and eosin. (a) Denuded urothelium (black arrow) with submucosal and muscular congestion, edema, and hemorrhage. (b) Extensive mucosal denudation with fibrinopurulent debris coating on the residual urothelium (black arrow) (c) Bladder muscle layer hypertrophy with inflammatory cell infiltration and hemorrhage|
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| Discussion|| |
Shahani et al. reported the first case series of ketamine cystitis in 2007. Since then, many similar conditions have been reported.
Due to the different pathogenesis of KC, we should take the multiple strategies for treatment. Medical treatments include nonsteroidal anti-inflammatory drugs (NSAIDs), anticholinergic agents, and opioid group of analgesics for symptom relief. If the symptom control is still inadequate, intravesical instillation of sodium hyaluronate for mucosal protection is considered. Finally, if the above-mentioned treatment was suboptimal, surgical intervention (e.g., intravesical botulinum toxin A injection, cystoscopic hydrodistention, and augmentation enterocystoplasty [AE]) should be performed when indicated. On the other hand, surgical intervention could be performed in the early stage of KC to relieve urinary symptoms, preserve renal function, and improve quality of life. The previous study demonstrated AE for the patients with KC could reduce bladder pain, urinary frequency, and restoring normal lower urinary tract function.,
Cessation of ketamine is the most important key in the management of KC in the current consensus.,,, Mak et al. suggested that the symptoms of KC will gradually improve after long-term abstinence from ketamine. Nevertheless, ketamine abuse is not only a medical problem but also a major issue of the government because ketamine dependence is more of a psychological status than a physical status. Paramedical assistance such as from social workers, psychologists, family support, or religious belief is also needed. In our series, many people could not quit ketamine use completely because they wanted to alleviate bladder pain using ketamine. This results in a vicious circle. In our experience, with persistent ketamine use, the new bladder wall, consisting of the intestine, will still be damaged even after AE. A previous study reported that recurrent UTI and the aforementioned urinary symptoms may still be observed if those patients reuse ketamine. Thus, we should put extra effort in ketamine abstinence in different aspects, including government policy, medical treatment, social worker involvement, and family support.
AE was initially developed in the 1950's for the treatment of contracted bladders secondary to tuberculosis or other cause. The major purposes of AE are to provide a compliant bladder with adequate end-filling pressure, increase bladder capacity, and resect the injury bladder. Thus, AE could allow the upper urinary tracts to remain intact, preserving renal function, and keep urinary continence at the same time.,,,
The exact pathogenesis of KC still not clear until now. Chu et al. proposed several different mechanisms of KC. These include (1) direct toxicity of ketamine or its metabolites on the bladder interstitial cells; (2) microvascular changes in the bladder and possibly the kidney induced by ketamine or its metabolites; (3) an autoimmune reaction to the bladder urothelium and submucosa triggered by ketamine or its metabolites; and (4) bacteriuria causing cystitis. Any of the above mechanism causes cystitis that results in bladder pain. Resection of the unhealthy bladder tissues is the reason we supposed to relieve bladder pain.
Although a previous study and ours had demonstrated AE is an effective treatment for patients with KC, we still should be careful with the following complication. The three major complications are bladder calculi, perforation of the augmentation, and upper tract deterioration. The need for high volume (>250 ml) bladder irrigation could both prevent the development of bladder calculi and reduce the incidence of symptomatic UTI.
The limitation of this study is small case number. Many of our patients lost to follow-up 3–6 months after surgery, resulting that we could not take more examination to evaluate the outcomes of AE. Besides, the reliability of self-report of ketamine cessation is doubtful among the patients with drug addiction. Further studies with larger case numbers and longer follow-up duration will be essential to establish the protocol of surgical treatment and to demonstrate the efficacy and safety of AE for the patients with KC.
| Conclusion|| |
This case series demonstrated that for surgical management of refractory bladder pain and low bladder capacity resulting from KC, AE might be effective. Due to the limited number of cases in this series and the retrospective nature of the study, further research may be required to consolidate the benefit of AE for patients with KC. Again, cessation of ketamine use is the milestone for patients with KC. Hence, a multiple disciplinary approach, including medication, clinicians, psychiatrists, and social workers, should be taken for these patients.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]