British Association of Urological Surgeons Consensus statements on the management of ketamine uropathy

To provide guidance in the form of consensus statement in the management of ketamine uropathy


Introduction
Although the use of ketamine historically has fluctuated, the prevalence of its use in adults aged 16 to 59 years has increased from 0.5% in the year ending March 2010 to 0.8% for the year ending March 2020.Use among those aged 16 to 24 years has almost doubled in the same period, from 1.7% to 3.2% [1].
Patients with ketamine abuse can present with urinary frequency, nocturia, urgency, incontinence, cystitis, bladder or loin pain and haematuria, which are debilitating symptoms causing a profoundly negative impact on quality of life [2].Pain can promote the further use of ketamine or other recreational drugs to help suppress distressing symptoms, so compounding the condition.Onset of urinary symptoms is typically delayed from the time ketamine is first used, and the severity of symptoms appears to be related to the quantity and duration of drug intake [3].
Ketamine uropathy is a challenging condition to treat, and a core principle is patient abstinence from the drug.This usually requires collaboration with drug and alcohol support services and supportive urological management initially, followed by vigilance and management of complications when they arise.
A nationwide prevalence study in the UK has demonstrated that 26.6% of regular ketamine users experience at least a single urinary symptom, with 51% experiencing an improvement of symptoms on cessation [3].Approximately 50% of ketamine users experiencing urinary symptoms do not seek medical attention immediately, with symptoms becoming more apparent after 2 years [4].Nasal inhalation (or 'snorting') of ketamine causes more symptoms than oral ingestion [5].It is essential when seeing patients with storage bladder symptoms that a direct question regarding recreational drug use, and in particular ketamine use, is asked to avoid delay in diagnosis and to consequently offer correct management.Clinical effects of ketamine are shown in Table 1.

Background
Ketamine is a drug that was originally developed as an anaesthetic alternative to phencyclidine.It acts as a non-competitive antagonist of the N-Methyl-D-aspartate acid receptor complex and has various medical uses, including anaesthesia, epilepsy treatment, pain management, and depression treatment [12].
Recreationally, ketamine is known as a dissociative anaesthetic that provides feelings of detachment from oneself and the environment.It has analgesic, stimulant, and psychedelic effects.Most users prefer snorting the drug, with effects taking approximately 20 min to develop and lasting for 1 to 2 h [13].
Ketamine has gained popularity in rave culture and has been classified as a Class B drug since 2014.Its lower cost compared to other substances contributes to its widespread use [14].Regular ketamine use can lead to tolerance and physiological dependence, with withdrawal symptoms such as abdominal pain, anxiety, fatigue, and changes in behaviour.
The effect of ketamine abuse on the urinary tract was first reported in Canada in 2007, with a case series of nine patients presenting with severe LUTS, haematuria and history of recreational ketamine abuse [15], which was followed by a large case series from Hong Kong of 59 patients who had abused ketamine for >3 months with severe storage LUTS and haematuria [16].

Staging System
Adapting and modifying a staging system from Wu et al. [17] (Table 2), patients can be classified into three stages of Ketamine uropathy.Stage 1 is the inflammatory phase where cessation of ketamine and oral medications can resolve the situation.Stage 2 is where structural changes to the bladder occur and the mainstay of treatment includes bladder instillations and intradetrusor botulinum toxin A injections.Stage 3 is the final stage with permanent changes to the bladder, upper tracts and renal function, and is best served by urinary tract reconstruction.

Methods
The BAUS Female, Neurological and Urodynamic Urology Section (FNUU) Executive Committee comprises a group of urological surgeons elected by their peers due to their interest in the field of female urology, neurourology, urodynamics and reconstruction of the urinary tract.It was identified that ketamine-related uropathy is an important and challenging Raretwo case reports of development of leiomyoma [10] and primary yolk sac tumour [11] of the bladder after persistent ketamine misuse ED, erectile dysfunction; LFT, liver function test.
Table 2 Typical finding of the stages of ketamine misuse [17].Staging is indicated in the main text under 'Staging system'.condition to diagnose and treat, and standardisation of urological practice in the UK would be helpful for both general and subspecialist urologists and would ultimately be beneficial for patients.Following FNUU Executive Committee discussion, a thorough literature search was performed on ketamine-related urinary tract dysfunction and this, along with UK best practice, provided the framework for this consensus on the assessment, investigation and management of these patients.The document underwent multiple rounds of review by all FNUU Executive Committee members and an additional two invited specialists with significant experience in ketamine uropathy, and then was submitted for external expert independent review by two further subspecialists.The revised document was further discussed at the Annual BAUS Meeting in June 2023 and amended.This document has been distributed to all the BAUS FNUU membership for widespread scrutiny and further comments from registered medical professionals working in the relevant field to help refine the guidance into a consensus statement.

Staging
The consensus statement was approved by BAUS council in November 2023, and the recommendations, which are all consensus-based are summarised below.
Assessment 1.Take a full urological history including relevant medications, previous medical, surgical, and psychosocial histories (summarised in Fig. 1).2. Establish if ketamine use is a potential cause of symptoms and, if so, take a ketamine-specific history detailing dosage (g) duration, frequency, route of administration and additional illicit drugs usage (Fig. 2).3. Perform a chaperoned abdominal and pelvic examination where appropriate.4. Check urine dipstick to assess for infection and/or haematuria. 5. Perform renal profile, liver function tests (LFTs) and full blood count as a baseline and document any future deterioration.Ketamine is known to affect liver function and can require referral to a hepatologist/gastroenterologist.6. Bladder diary, uroflowmetry and postvoid residual urine volume measurement are helpful discriminators on a first clinic visit.They provide an objective assessment of functional bladder capacity when considered together.7. Request renal tract ultrasonography.This is important as a baseline and to screen for any upper tract involvement in the form of hydronephrosis.8. Complete validated questionnaires such as the Pelvic Pain and Urgency/Frequency (PUF) questionnaire which has been validated in ketamine uropathy populations internationally [18] or standardised questionnaires such as the International Consultation on Incontinence Questionnaire (ICIQ)-LUTS.9. Perform a cystoscopy with or without a biopsymost patients will have visible haematuria and require cystoscopic inspection.Local anaesthetic flexible cystoscopy can be used in milder forms of ketamine uropathy but is usually poorly tolerated in the majority of this patient group and is likely to result in abandonment and proceeding to general anaesthetic.Therefore, a rigid cystoscopy under general anaesthetic is often preferred.In addition, a poor experience of flexible cystoscopy may mean the patient may be reluctant to consider bladder instillation treatment in the future.Bladder capacity under general anaesthetic may be a marker of disease severity and will help plan future reconstructive surgery.It may provide therapeutic relief of symptoms in a minor cohort of patients.A bladder biopsy is useful in the initial assessment.Cystoscopic findings are erythematous bladder mucosa with petechial haemorrhages, inflammation and neovascularisation.In severe forms, the bladder mucosa tends to be very friable and 'shed'.On distension ulcerations/lacerations can develop [19,20].

CT urogram and MAG3 renogram may be useful for the assessment of any detected hydronephrosis on
ultrasonography.The diuretic phase of a renogram may be poorly tolerated.2. Video-urodynamics.This test can provide both the anatomical and functional information that is needed for accurate diagnosis of the underlying issues, particularly if there is a suspicion of upper urinary tract involvement or poorly compliant bladders.However, commonly, this tends to be poorly tolerated and can be reserved for whom urinary tract reconstruction might next be considered.

BAUS Recommendation
The recommendations are to ensure initial assessment of urinary tract with ultrasonography and renal function blood tests and for further investigation with additional imaging if abnormalities detected.
In addition, it is recommended to ensure a liver function blood test check and referral to hepatology if abnormal.If possible, a joint clinic with drug cessation nurse is recommended or, failing that, significant input from the substance misuse team within the service.

Initial Management (Stages 1 and 2)
1.In the initial management, stopping ketamine should be the primary goal, with signposting to the local substance misuse services.2. A trial of anticholinergic and/or beta 3 agonist medication for overactive bladder symptoms can be tried, especially at early stage of ketamine uropathy.3. A referral to the pain team should be made and may aid the cessation of ketamine abuse.An analgesic ladder of NSAIDs, opioid analgesics and neuroleptic drugs (amitriptyline, gabapentin and pregabalin) has been used successfully for bladder pain [9].4. Pentosan polysulphate (Elmiron), an oral glucosamine glycan (GAG) replacement may also be considered and commenced at the time of cessation of ketamine, but the evidence is limited [21].5.After cessation of ketamine for 1 month, intravesical instillations such as Parson's cocktail or modified Whitmore cocktail (typically containing combinations of heparin, lignocaine, sodium bicarbonate +/À hydrocortison)Ketamien, chondroitin sulphate [Gepan] and sodium hyaluronate [Cystistat], alone or in combination [iAuril]) can be offered in these patients with ongoing symptoms.In general, regimens are weekly instillation for 4 to 6 weeks and then monthly instillations for 4 to 6 months initially, and may be continued after assessment if effective.In small case series these have been shown to be beneficial [22].6.If the above measure fails to be of benefit, a trial of botulinium toxin A injection into the bladder under general anaesthesia can be considered to treat the urinary symptoms and has been shown to reduce urinary symptoms and increase bladder capacity [23].7. A combination therapy of bladder instillations and or intradetrusor botulinium toxin A can be helpful in some patients [24].

BAUS Recommendation
The importance of ketamine cessation should be made clear to the users, emphasising the benefit of preventing deterioration of the urinary tract, with appropriate signposting to drug cessation and pain services.
Medication, bladder instillations and intradetrusor botulinium toxin A injections are the mainstay of managing Stages 1 and 2 of ketamine uropathy.
Stage 1 and Stage 2 ketamine uropathy can be managed in all urology centres but Stage 3 should be managed in specialist centres with the appropriate expertise.

Upper Tract Monitoring
Ongoing ketamine misuse can cause upper tract dysfunction, either due to vesico-ureteric reflux from a poorly compliant bladder or due to ureteric stricture formation.Obstruction due to stricture formation seems to occur more commonly in patients with deranged liver and kidney function.Patients who continue to abuse ketamine should have renal function and LFTs monitored regularly.
1. Renal function and LFTs are recommended to be monitored on a 3-monthly basis.2. Renal tract ultrasonography should be performed on a 6-monthly basis.

BAUS Recommendation
Regular monitoring and surveillance are required in those with ketamine uropathy.

Upper Tract Management
Active ketamine users often have a poor tolerance to urethral catheters and ureteric stents.This should be considered when planning interventions or considering long-term management options.It is recommended to delay definitive reconstruction for end-stage bladder patients until they have stopped ketamine for at least 6 months.

Surveillance of Complications and Reconstructive Management
After cessation of ketamine for 6 months, reconstruction can be considered in those with end-stage ketamine bladder.Referral to a tertiary centre is highly recommended.
All reconstruction has been associated with a high complication rate and all patients need to be carefully counselled [14,23] (Fig. 3).Cessation should be confirmed with random urine toxicology testing.
1. Videourodynamic testing is useful to determine the compliance, bladder capacity and any reflux prior to surgery.2. Augmentation enterocystoplasty has been the main reconstructive option to increase bladder capacity and improve compliance and reduce pressure [25,26].3. Supratrigonal cystectomy to preserve the micturition reflex can be combined with augmentation [27].4. Benign cystectomy (ideally nerve sparing) can be combined with an ileal conduit or orthotopic neobladder formation.
5. Ureteric involvement may require reimplantation, ileal substitution / interposition or kidney auto-transplantation depending on the severity.6.All reconstructive cases should be discussed in a reconstructive urology multidisciplinary team meeting and a bespoke solution provided, depending on patient factors and clinical findings.This should include a psychological assessment to determine the risk of ketamine relapse.7. Life-term follow-up is recommended after performing reconstructive surgery.

BAUS Recommendations
It is recommended to delay definitive reconstruction for end-stage ketamine uropathy until ketamine cessation has occurred for at least 6 months.
Ketamine cessation should be confirmed with urine testing prior to any major surgical intervention.
All reconstructive surgery should be discussed in a reconstruction or functional multidisciplinary team meeting and referred to a tertiary unit with the appropriate experience.

Ketamine Testing
Table 3 shows the different methods of detecting ketamine.
Urine tests are commonly used in detecting ketamine use.The standard detection time for ketamine in urine is up to 5 days.However, in some cases, traces of ketamine may be found in the urine for up to 14 days in those with an excessive use of ketamine [28].The advent of commercially available CE-marked and US Food and Drug Administration-approved ketamine urine dipstick tests means such testing may prove to be the best practical method of monitoring abstinence.

Conclusion
Ketamine misuse has a significant effect on the urinary tract.Every effort should be made to help with the cessation of the drug and prevent irreversible damage to the urinary tract.Detailed assessment of patients is key in areas of high ketamine misuse.A multidisciplinary approach is required in dealing with the consequences of misuse and for consideration of urinary tract reconstruction.

Fig
Fig. 2 Assessment of patients with urology complications of ketamine misuse.FBC, Full Blood count; ICIQ-LUTS, International Consultation on

Fig. 3
Fig.3Further management of patients with upper tract complications relating to ketamine misuse.MDT, multidisciplinary team.

Table 1
Clinical effects of ketamine.
4 Ó 2024 The Authors.BJU International published by John Wiley & Sons Ltd on behalf of BJU International.Review 1464410x, 0, Downloaded from https://bjui-journals.onlinelibrary.wiley.com/doi/10.1111/bju.16404by Test, Wiley Online Library on [30/05/2024].See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions)on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License BJU International published by John Wiley & Sons Ltd on behalf of BJU International. 5 Downloaded from https://bjui-journals.onlinelibrary.wiley.com/doi/10.1111/bju.16404by Test, Wiley Online Library on [30/05/2024].See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions)on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Ó 2024 The Authors.

Table 3
Methods of ketamine testing.1464410x, 0, Downloaded from https://bjui-journals.onlinelibrary.wiley.com/doi/10.1111/bju.16404by Test, Wiley Online Library on [30/05/2024].See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions)on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License BJU International published by John Wiley & Sons Ltd on behalf of BJU International.Review