Navigators for medicine: evolution of online point-of-care evidence-based services

In the quiet, green countryside outside Milan one foggy morning a few years back, I was driving 1 along an isolated road. There Miss Murer, one of my patients, was eagerly awaiting my arrival. But 2 long before I was anywhere near the remote property, I was already lost. Beside me a roughly 3 folded map was helpfully leading me away from familiar landmarks. Inhabitants kindly provided 4 directions, but only confused what my sense of direction had left. This was a recurrent situation in 5 my life, until "Sat-navs" became available. These have a clear purpose: to give complete driving 6 directions with the least possible risk of getting lost. In a few years they have become very popular. 7

Innovative features are offered on top of essential information: travel time between destinations, 8 real-time traffic updates, 3D views, to name a few. Now I'm not worried any more when a patient 9 calls me asking for a visit and proudly announces the name of a neighbourhood I never heard of. 10 I need something similar to avoid losing my direction when a doubt comes to my mind in clinical 11 practice: information services I can trust, that provide relevant and reliable information when I'm 12 searching for a correct diagnosis or treatment. However, there is a vital difference: being lost does 13 not kill people, being lost in clinical practice may do. 14 15

Developing information services at the point of care 16

Doctors rely on many online information sources to satisfy their information needs: from primary 17 published evidence such as bibliographic and journal databases (e.g. Pubmed) to secondary sources 18 such as systematic reviews and clinical practice guidelines.[1] Unluckily, the interaction between 19 the clinician and these information sources is largely inefficient, requiring a sum of skills to refine 20 the question and reduce the amount of irrelevant information. It is annoying that it can take several 21 minutes to find the desired information but only a few seconds to incorporate it into the medical 22 decision analysis. 23

Busy exploiting the opportunity to create efficient information services to support the clinical 24 decision workflow of physicians, publishers have invested a remarkable amount of energy in 25 properly orchestrating collections of high-quality online information sources that are critically 26 appraised, synthesized, and delivered in a user-friendly manner. To sustain the added value of these 27 innovative tools, the marketing management of some publishers claims that their use would be 28 appropriate when clinicians and patients interact, at the point of care. The marketing suggestion is 29 powerful: contents conveying a clear and concise message about what to do within the context of a 30 provider-patient dyad become worldwide popular as point-of-care services. [START_REF] Hayward | Patterns of use of decision support tools by 4 clinicians[END_REF] We can distinguish two families of point-of-care information services: the first simply collect and 32 organize relevant and synthesized information sources (e.g. meta-lists, search engines); the second 33 elaborate this information into original and structured contents (summaries, synopses). Both draw 34 selected for relevance and validity (filtering) and presented in a quick, easy, accessible form 2 (organizing). Following Haynes' classification, these services are set at the tip of the pyramidal 6S 3 model [2-4]: comprehensive and sophisticated information tools (systems, summaries) built up on a 4 systematic assembly of the evidence (synthesis, synopsis). Although Haynes gives a thorough 5 perspective of the layer differences in his model, services may overflow between layers, may evolve 6 from one layer to another, or peculiar elements may be attributed to more than one layer. 7

The innovative aspect of these information services relies on how contents are engineered to be 8 used at the point of care. Point-of-care information can be logically grouped around common 9 medical scenarios and translated into sets of actions-what to do -related to diagnosis, treatment and 10 management. Two examples of how these services mime the natural thought flow for treatment and 11 diagnosis are presented in Figures 1 and2, respectively. These sets of actions result in structured 12 lists of items including a summary, definition and key therapeutic and diagnostic steps specific to 13 the patient scenario. Software and interface are the core components of point-of-care service 14 architecture: they should be able to naturally adapt contents to the clinical workflow (i.e. provide 15 the first-line options, then the alternatives), minimising the number of clicks required to reach 16 information and providing the information in real time. Traditional educational contents, paper-17 based books, are abandoned to adopt new media (i.e. smartphone) that push the portability of 18 information and the drive-by consultation (i.e. Skyscape). The quality of point-of-care services 19 indeed depends on two broad dimensions: accessibility and value of information.[5] Ideally, these 20 information resources should excel in both dimensions. 21 22

Evaluation of point-of-care information services 23

At the end of 2008, at least 18 products that could be classified as evidence-based practice point-of-24 care summaries were available at different costs (from free of charge up to US$495).[6] As for all 25 research, the quality of point-of-care products needs to be evaluated to ensure their real usefulness 26 for clinical practitioners and, given the plethora of point-of-care services, the only way to obtain 27 conclusive evidence regarding on the real utility and practicality of one product over the other is to 28 compare two or more products directly. 29 Few articles comparing point-of-care services have been published. Most were aimed at assessing 30 the user's satisfaction and how well different online information services answered questions 31 arising in daily clinical work (Table 1).[5, 7-13] Keeping in mind that any user-centred evaluation 32 to identify the best product can be biased by previous beliefs and habits of a specific service, 33 nevertheless some services, such as UptoDate, were often ranked high. A mixture of general and 34 2) was informed by evidence, whenever possible. 20

For some quality indicators, such as the literature retrieval process and updating, criteria were 21 borrowed from research on good systematic review reporting methods [15], assuming that these 22 apply equally to further synthesised information tools. Other dimensions, such as authors' conflict 23 of interest and peer review, come from peer-reviewed medical journals' policies, and their quality 24 has been extensively debated.[16-18] Services not addressing these quality dimensions were 25 assumed to be associated with an increased risk of bias or scarce reliability. 26

Only few products satisfied the quality criteria: Clinical Evidence, Dynamed, eMedicine, 27 EBMGuidelines, and UpToDate were at the top of our ranking but none of them excelled in all 28 criteria. For instance, one service was outstanding in its editorial and evidence-based methodology 29 but scored at the very bottom of our ranking for the number of conditions covered. The quality of 30 these products was indeed variable but is likely to be progressively reaching more satisfactory 31 standards. The key methodological limitation in content evaluation is the large subjectivity in 32 choosing quality features and-more challenging-assigning their relative weights if the final aim is to 33 rank products. 34 Deleted: ere chosen if there was evidence that not addressing any particular one was associated with an increased risk of bias and where it was clear that information was necessary to appraise the reliability of a point-of-care product. The choice of one product over another depends both on the properties of the service and the 1 preference of users, according to the personal weight attached to different dimensions. The more 2 complete and customisable to different settings and needs is the product the more successful it will 3 be. However, even the most innovative information system must rely on transparent and valid 4 contents. For this reason besides efforts to improve the technology of information vehicles, sound 5 evidence should always be preferred during the development of product content. 6 7 Point-of-care services forecast 8

Deleted

Given the immaturity of point-of-care services, it is challenging to predict how they will affect 9 clinicians. We must take account of several elements that could act interactively, potentially 10 transform the medical profession. In this imaginative model we assume that pressure from patients, 11 insurances and national health systems to adopt evidence-based medicine, boost the reliability of 12 medical decisions, and align practitioners' remuneration with performance metrics and quality 13 indicators will continue. We also assume that local contexts will influence the clinical workflow, 14 with additional micro-legal and organisational requirements. Finally, treatment innovations and 15 best-practice major advances will be increasingly difficult to manage by a single health professional 16 with limited time to access the whole published knowledge. This scenario challenges the medical 17 profession as doctors alone, no matter how wise and up-to-date they may be, can miss important 18 elements integrating evidence-based medicine, performance metrics, reimbursements, legal 19 requirements, professional experience and patient agenda. 20 Clinical workflow based on tacit, collectively reinforced guidelines, internalised (mindlines) is 21 regarded as anachronistic. [19] To migrate toward evidence-based knowledge and quality 22 improvement, clinical decision-making needs to be backed by information systems, such as point-23 of-care services. Some countries are reacting more than others to the integration of information 24 systems into the clinical workflow. Finland's experience with Evidence-Based Medicine electronic 25 Decision Support (EBMeDS) shows the spread of point-of-care services among health care 26 professionals accustomed to using online evidence.[20] The terrain appears to be ready for more 27 evolved health information technology: computerized information and clinical decision support (i.e. 28 reminders) linked to electronic health records have the potential to improve the effectiveness and 29 the efficiency of health care providers. 30 31

Role of publishers 32

Several editorial groups and public health organisations have shown a vivacious interest in point-of-33 care information services, attracted by high profitable gains and/or significant value creation. The 34 Formatted: Highlight Deleted: Limitations in the methodological approach to assess accessibility and quality of online pointof-care information services are even more important when these tools become multifaceted systems integrated into the clinical workflow. For instance, point-ofcare information services can be involved not only when patients and practitioners interact but also when the practitioners interact with their providers which in many cases are also connected with the "payers", public or private. general or specialists formats is perceived as too static and remote from practice. Now publishers 2 are re-focusing their efforts toward "information hubs" in which several information kits widely 3 connected with other informatics systems (e.g. search engines, decision support, computerised order 4 entry, electronic health records, learning interfaces) can be assembled. Healthcare professionals and 5 providers should start to perceive the function of publishing differently, with publishers as 6 rendering services and vendors. Alongside resounding marketing claims, point-of-care products 7 should improve the transparent and accurate reporting of strengths and weaknesses of the 8 information summaries and services they provide. [6] Publishers should find a balance between 9 information consumed at the point of care -necessarily distilled, unnecessarily simplistic -and 10 fidelity to a cumulative and extended approach to information. Final users should value both 11 dimensions: the action "what to do" and the reference content "why we do". An information service 12

Deleted: reliable

proposed by an authoritative and well-known publisher is not a guarantee itself of optimal service, 13 even if "brand" still plays a key role. Start Reviewing process: detailed description of the procedures aimed at assessing and ensuring the scientific quality of output (review process by external peer reviewers and/or by editors).

Updating: frequency of content updating (continuously, periodically, once a year, etc).

Authors' conflict of interests: whether a formal policy on authors' commercial conflict of interests is implemented and this information is reported.

Commercial support: to what extent commercial support and advertising are accepted in the content development policy Literature search/surveillance: whether contents are written on the basis of a specific systematic literature search based on explicit search strategies and aimed at identifying relevant and valid articles or if systematic tracking of the relevant and valid articles based on predefined sample of leading journal and journal review services is utilized.

Cumulative vs. discretionary approach: whether content is preferably written on the basis of systematic reviews rather than other publications.

Critical appraisal methodology: the use of standard and transparent methods to assess articles' validity.

Grading of evidence quality: if a formal system is implemented to grade the level of evidence.

Cite expert opinions: if statements based on experts' opinions are easily recognizable compared to study data and results.

  interests: The Italian Cochrane Centre is an entity of the Cochrane Collaboration which 9 forms a publishing partnership with Wiley-Blackwell to deliver The Cochrane Library through

  of evidence-based information mastery: filtering and organizing. Medical literature is 1

  The combination of "actionable" clinical and interactive content differentiates point-of-care services from t Deleted: : Deleted: "1-minute" consult to an extreme Deleted: , Deleted: or desirability Deleted: Deleted: S Deleted: but the attempt to identify the best product suffered of the problem common to any user-centred evaluation: habits and previous use of a specific tool can introduce bias in the evaluation engines (AltaVista, WebDoctor, MedLine), meta-lists (MD Consult, STATRef!), 1 secondary literature (The Cochrane Library) and point-of-care summaries (Micromedex, UptoDate, 2 Clinical Evidence, Dynamed) was compared. Asking doctors to rate these information services, 3 with different aims achieved through different information and technological solutions, is clearly 4 deceptive. Systematic reviews are an immediate example of this limitation: although Cochrane 5 reviews are long, technical and sometimes hard to read, summaries, systems, and other downstream 6 products are largely based on them. In other words, systematic reviews should be viewed as 7 evidence sources that feed point-of-care services rather than point-of-care services themselves. The 8 results from these studies should be analysed with caution. An inappropriate comparison influences 9 the apparent effectiveness of point-of-care services, but also satisfaction and practical details such 10 as time for successful task realisation. Even seemingly straightforward information services have 11 inherent complexities that can bedevil well-designed comparative research. 12 Beside user-or experience/satisfaction evaluation, research has looked into content-centered 13 evaluation. The pioneering study by Wyatt et al. offered a wide view on the quality of a variety of 14 computer-based evidence services used by oncologists. [14] Authors suggested quality dimensions 15 that can be vital for preferring one online information service over another: what kind of 16 information is included, update frequency, editorial space, and how information is identified and 17 assembled. Focusing on online evidence-based practice point-of-care summaries, Banzi et al. 18 recently reviewed information services at the point-of-care to evaluate their content and editorial 19 policy.[6] Selection of quality dimensions (Table

  decision support systemDeleted: clinical decision support systems, including, for example, automatic reminders.

  is changing: the traditional medical journal publishing trials and reviews in 1

Figure 1 :Page

 1 Figure 1: mimic of an hypothetical thought flow targeting the treatment for acne vulgaris (adapted 1 from BestPractice, http://bestpractice.bmj.com/best-practice/welcome.html) 2 3 Figure 2: mimic of an hypothetical thought flow targeting the diagnosis of obstructive sleep apnea 4 (adapted from Dynamed, http://www.ebscohost.com/dynamed/ ) 5

Table 1 :

 1 Studies evaluating online information services' ability to answer clinical questions. 1

	14	-up companies mostly connecting clinical databases, with
	15	a limited publishing tradition, should demonstrates to account for the complexity behind the clinical
	16	decision-making.	Deleted: ¶ ¶
	17		Deleted: ¶
			¶

Table 2 :

 2 Quality criteria to evaluate the content and editorial policy of evidence-based practice 1

	2	point-of-care summaries (adapted from [6])
	3
		Editorial quality	Evidence-based methodology
		Authorship: clear indication of the author(s) of a
		specific content reported in the output.


Seshikanth Mr

Middela

Seshikanth Middela

-Ketamine Induced Vesicopathy: A Literature Review

Introduction -Ketamine consumption in on the increase as a recreationally abuses substance. It is reported to cause lower urinary tract symptoms and published accounts of its deleterious effects are increasing. We reviewed the available literature regarding the urological impact of Ketamine abuse and its management.

Methods -twenty two publications were found in total after a search of all databases including Pubmed, Medline and Google Scholar using the words "ketamine", "bladder" and "cystitis" with no limits imposed.

Results -There are approximately 110 cases reported in the literature in the form of case series, case reports and letters. The effect of ketamine abuse on the bladder is universally similar however there is no uniform method adopted in reporting the symptoms, diagnosis and management. Very little is known regarding the pathogenesis of its effects on the urinary tract.

Discussion -Patients with severe irritative lower urinary tract symptoms, a positive history of ketamine abuse and the absence of any other aetiology should be considered to have ketamine induced vesicopathy, (KIV).

Effort must be made to elicit the history of drug abuse in those with no found cause of lower urinary tract symptoms especially in the young. Presently ketamine cessation is only effective treatment modality to prevent deterioration of the renal function and indeed offer the possibility of symptom resolution. Management akin to that formulated for IC patients would appear to offer the greatest opportunity for effective treatment Page 2 of 11

Introduction -

Ketamine is a dissociative anaesthetic agent commonly utilised as a horse tranquiliser and is often prescribed for chronic pain conditions. Its main function is that of an N-methyl D-aspartate (NMDA) receptor antagonist. The ability of Ketamine to remove the subject from his or her surroundings with no response to pain and its highly addictive nature has led to a massive increase in its social consumption. Also known as K, Super K, vitamin K and special K, Ketamine may be consumed via inhalation, smoking or intravenous injection.

As consumption of ketamine has increased, so too have the number of published accounts of its deleterious effects both urological and otherwise. Recent reports suggest that approximately 20%-30% of ketamine abusers suffer from lower urinary tract symptoms [START_REF] Muetzelfeldt | Journey through the K-hole: phenomenological aspects of ketamine use[END_REF][START_REF] Chu | The destruction of the lower urinary tract by ketamine abuse: a new syndrome?[END_REF]. We reviewed the available literature regarding the urological impact of Ketamine abuse and its management

Materials and Methods -

All databases including Pubmed, Medline and Google Scholar were searched using the key words "ketamine", "bladder" and "cystitis", no limits were imposed. 22 publications were found (Table 1) comprising three case series, four case reports, one review and numerous letters. Of these, five reports are regarded as extension of case series. As a result twenty reports involving 111 patients were taken into consideration.

Epidemiology

Ketamine abuse is on the increase with a recent British Crime Survey [3] reporting an increase from 0.30% in 2006 to 0.40% in 2007 amongst 16 to 59 years old. The life time use of ketamine in was found to be 1% in those aged 14 and above with a many reporting increased usage in recent years [START_REF] Degenhardt | The epidemiology of GHB and ketamine use in an Australian household survey[END_REF]. In general, affected patients tend to be young, with a peak age range of 16-35 years [START_REF] Chu | The destruction of the lower urinary tract by ketamine abuse: a new syndrome?[END_REF][START_REF] Grégoire | A pediatric case of ketamine-associated cystitis. Letter-to-the-Editor RE[END_REF]. Whilst some series have reported a slight male predominance, this is insignificant and not universally witnessed. At the present time it would seem that ketamine induced vesicopathy does not exhibit any gender bias. [START_REF] Chu | The destruction of the lower urinary tract by ketamine abuse: a new syndrome?[END_REF]

Presentation -

The time of onset of lower urinary tract symptoms (LUTS) following ketamine abuse varies from a few days to a few years following the onset of abusive use with the severity being, in part, determined by the chronicity of the abuse with up to 100% of those using more than 5gm/day reporting urinary symptoms [START_REF] Cottrell | 197 THE RELATIONSHIP OF CHRONIC RECREATIONAL KETAMINE USE AND SEVERE BLADDER PATHOLOGY: PRESENTATION, MANAGEMENT OF SYMPTOMS AND PUBLIC HEALTH CONCERNS[END_REF]. It is unclear whether the severity of abuse with respect to regular ingested dosage also influences the time to onset and the severity of LUTS but it is likely that this will eventually prove to be the case just as it is within the context of intermittent ketamine use [START_REF] Trujillo | Increased response to ketamine following treatment at long intervals: implications for intermittent use[END_REF]. In fact Tsai TH et al have documented that although symptoms have appeared after a month of starting the usage they became severe by the end of one year [START_REF] Tsai | Increased prevalence of interstitial cystitis: previously unrecognized urologic and gynecologic cases identified using a new symptom questionnaire and intravesical potassium sensitivity[END_REF].

The symptoms of ketamine induced vesicopathy include a range of LUTS mainly irritative in nature. Typically the patients will complain of intense urgency, extreme frequency, and intractable dysuria while gross haematuria is also a frequent symptom in those suffering from ulcerative cystitis. Only one series used a validated Pelvic pain and Urgency/Frequency (PUF) scoring in 24/59 patients with a PUF score > 15 being regarded as significant [START_REF] Chu | The destruction of the lower urinary tract by ketamine abuse: a new syndrome?[END_REF].

PUF scoring uses symptom and bother scoring to grade the symptoms. It has been validated with potassium sensitivity test (PST) and high scores have been found to correlate with symptoms. The PUF score has previously proved useful in detecting interstitial cystitis. 91% of those scoring > 20 are more likely to have a positive PST, whilst scores of 10-14, and 15-19, have a 74% and 76% likelihood of a positive test respectively;

[9, 10].

Patients with ketamine induced vesicopathy often exhibit urge incontinence and decreased bladder compliance with all of them demonstrating detrusor overactivity with low volumes [START_REF] Chu | The destruction of the lower urinary tract by ketamine abuse: a new syndrome?[END_REF][START_REF] Tsai | Increased prevalence of interstitial cystitis: previously unrecognized urologic and gynecologic cases identified using a new symptom questionnaire and intravesical potassium sensitivity[END_REF]. This is in contrast to IC where urge incontinence is not common [START_REF] Neal | Interstitial cystitis: evaluation and related conditions[END_REF]. Symptom scoring can be useful in research purposes when trialling a new drug or monitoring the progress of the patient while undergoing treatment.

Investigations -

Renal function estimation is required both at the time of initial assessment and during management, particularly when management is conservative and focussed around ketamine withdrawal.

Sterile urine is the norm although an occasional contaminated growth may be encountered [START_REF] Chu | The destruction of the lower urinary tract by ketamine abuse: a new syndrome?[END_REF] and occasionally sterile pyuria may be present [START_REF] Tsai | Increased prevalence of interstitial cystitis: previously unrecognized urologic and gynecologic cases identified using a new symptom questionnaire and intravesical potassium sensitivity[END_REF][START_REF] Tsai | Ulcerative cystitis associated with ketamine[END_REF][START_REF] Storr | Can ketamine prescribed for pain cause damage to the urinary tract?[END_REF][START_REF] Chiew | Disabling frequent urination in a young adult. Ketamine-associated ulcerative cystitis[END_REF] A voiding diary including fluid intake, voided volumes and frequency is mandatory in the assessment of such patients with the typical picture being one of increased frequency and small voided volumes usually in the region of 200mls or less, [START_REF] Chu | The destruction of the lower urinary tract by ketamine abuse: a new syndrome?[END_REF][START_REF] Tsai | Increased prevalence of interstitial cystitis: previously unrecognized urologic and gynecologic cases identified using a new symptom questionnaire and intravesical potassium sensitivity[END_REF].

Urodynamic studies have been utilised, in particular to assess bladder capacity with most values being less than 150mls and very few being greater than 300mls [START_REF] Chu | The destruction of the lower urinary tract by ketamine abuse: a new syndrome?[END_REF][START_REF] Tsai | Increased prevalence of interstitial cystitis: previously unrecognized urologic and gynecologic cases identified using a new symptom questionnaire and intravesical potassium sensitivity[END_REF]. It has been postulated that in established KIV cases, vesico-ureteric reflux (VUR) occurs due to a small bladder capacity combined with high bladder pressures (detrusor overactivity) [START_REF] Chu | The destruction of the lower urinary tract by ketamine abuse: a new syndrome?[END_REF] whilst early VUR cases in general commonly exhibit large bladder capacity with detrusor overactivity being rare [START_REF] Lahdes-Vasama | Urodynamical findings on women with voiding problems and earlier vesico-ureteral reflux[END_REF].

Upper renal tract imaging in the form of simple ultrasonography will showed bilateral hydronephrosis in 50% of patients (35/73), Papillary necrosis suggestive of transmural necrosis has also been reported [START_REF] Chu | The destruction of the lower urinary tract by ketamine abuse: a new syndrome?[END_REF]. In addition ultrasonography also allows assessment of bladder wall thickness. Bilateral hydronephrosis is seen in those patients with transmural inflammation at the VUJ [START_REF] Chu | The destruction of the lower urinary tract by ketamine abuse: a new syndrome?[END_REF][START_REF] Tsai | Increased prevalence of interstitial cystitis: previously unrecognized urologic and gynecologic cases identified using a new symptom questionnaire and intravesical potassium sensitivity[END_REF][START_REF] Chiew | Disabling frequent urination in a young adult. Ketamine-associated ulcerative cystitis[END_REF][START_REF] Selby | Obstructive nephropathy and kidney injury associated with ketamine abuse[END_REF][START_REF] Colebunders | Cystitis due to the use of ketamine as a recreational drug: a case report[END_REF][START_REF] Shahzad | UP-3.073: Dystrophic Calcification of Urinary Bladder Associated with Ketamine Use[END_REF]. Whilst IVU will demonstrate both dilated upper tracts and a contracted bladder [START_REF] Chu | The destruction of the lower urinary tract by ketamine abuse: a new syndrome?[END_REF][START_REF] Huang | Ketamine-associated Ulcerative Cystitis[END_REF]20,[START_REF] Lee | Street ketamine-associated bladder dysfunction: an emerging health problem[END_REF], this will also be visible on CT Urography which is certain to become the imaging modality of choice when faced with possible ketamine induced vesicopathy. Recent evidence in mice has shown that ketamine addiction leads to mono nuclear inflammatory infiltration in the renal papilla suggesting a possible pathogenesis of papillary necrosis [START_REF] Yeung | Mice are prone to kidney pathology after prolonged ketamine addiction[END_REF].

Rigid cystoscopy should be considered essential in the initial assessment, not least of all to exclude any other cause of haematuria and severe LUTS eg: Carcinoma in situ. Cystoscopy also allows detection of ulceration if present and is unlikely to be tolerated whilst awake due to intense urgency and bladder pain, both of which are hallmark symptoms of ketamine induced vesicopathy. Cystoscopic findings are consistent with ulcerative cystitis with severe inflammation and epithelial denudation. (Table 2) Many features of ketamine induced vesicopathy are common to those of interstitial cystitis (IC) as determined by the NIDDK criteria. Bladder biopsies typically show ulceration, inflammatory cell infiltrate and a varying degree of fibrosis. Some have likened the appearances to those of interstitial cystitis based on the presence of vacuoles at the periphery of the biposied muscle (querciphylloid feature) [START_REF] Muetzelfeldt | Journey through the K-hole: phenomenological aspects of ketamine use[END_REF]. The cystoscopic picture and the presence of an eosinophilic infiltrate may suggest eosinophilic cystitis, but the absence of documented peripheral eosinophilia and eosinophilic sediment excludes this diagnosis. Whether ketamine induced vesicopathy represents a new type of eosinophilic cystitis is unclear at the present time.

Management -

At the present time, there is no single definitive management pathway to suit every patient and the key issues in patient management are those of individualised care plans and emphasis on compliance which has previously been shown to be poor in patients suffering addiction. Compliance is often poor and failure to abstain may lead to disease progression [START_REF] Chu | The destruction of the lower urinary tract by ketamine abuse: a new syndrome?[END_REF][START_REF] Tsai | Ulcerative cystitis associated with ketamine[END_REF][START_REF] Selby | Obstructive nephropathy and kidney injury associated with ketamine abuse[END_REF][START_REF] Hoskins | Ketamine associated cystitis -a case report[END_REF]. Various treatment regimens have been employed ranging from antibiotics, oral NSIADS, steroids, anticholinergic therapy [START_REF] Chu | The destruction of the lower urinary tract by ketamine abuse: a new syndrome?[END_REF] and cystodistension [START_REF] Tsai | Increased prevalence of interstitial cystitis: previously unrecognized urologic and gynecologic cases identified using a new symptom questionnaire and intravesical potassium sensitivity[END_REF]. All have failed to provide significant and lasting improvement but again, experience is lacking and the only universally held belief is that ketamine withdrawal often results in some degree of symptom resolution. It is unclear whether this is the case in all scenarios and it is likely that full symptomatic resolution will not be achieved in more advanced cases with severely reduced bladder capacity and compliance and resultant hydronephrosis. Nevertheless, it is worth persevering with withdrawal before undertaking invasive management provided renal function is both stable and regularly monitored. Renal function deterioration mandates more aggressive therapy, which may initially involve insertion of nephrostomies.

The theory of impaired epithelial impermeability leading to leakage of glycosaminoglycans has led to the use of intravesical instillation of Hyaluranic acid (Cystitstat) and oral Pentosan polysulphate (Elmiron) in the treatment of IC. Applying the same corollary, two case series have used the above substances in the treatment of ketamine induced vesicopathy. Shahani R et al [START_REF] Shahani | Ketamine-associated ulcerative cystitis: a new clinical entity[END_REF] has found varying degrees of symptomatic relief in all patients with the use of Pentosan sulphate and cessation of ketamine. It is unclear whether it is purely due to the abstinence, therapy or both. All patients who had hyaluronic acid instillation had symptomatic relief but long time follow up is needed [START_REF] Tsai | Increased prevalence of interstitial cystitis: previously unrecognized urologic and gynecologic cases identified using a new symptom questionnaire and intravesical potassium sensitivity[END_REF]. These two options may provide a sense of direction but longer follow up is needed.

Ultimately urinary diversion may be required which usually leads to symptom resolution akin to that experienced by the advanced IC patient undergoing the same procedure. Whether the bladder must be removed synchronously is unclear. From a symptomatic view, it would appear un-necessary but with further experience, phantom bladder pain may be experienced and the long term potential risks in terms of pyocystis and malignancy in a remaining defunct bladder are unclear [START_REF] Adeyoju | The fate of the defunctioned bladder following supravesical urinary diversion[END_REF][START_REF] Singh | Supravesical diversion for incontinence: a long-term follow-up[END_REF]. There are two reported cases of augmentation cystoplasty in the literature but in both cases ketamine abuse continued leading to continued symptoms and disease progression to ureteric stricturing and renal failure. [START_REF] Chu | The destruction of the lower urinary tract by ketamine abuse: a new syndrome?[END_REF][START_REF] Selby | Obstructive nephropathy and kidney injury associated with ketamine abuse[END_REF]

Conclusion -

Patients with severe irritative lower urinary tract symptoms, a positive history of ketamine abuse and the absence of any other aetiology should be considered to have ketamine induced vesicopathy, (KIV). Investigations will provide information about the effect of the drug on the renal tracts and in particular will enable the assessment of potential irreversible renal deterioration. At the present time, ketamine cessation is only effective treatment modality but the effect is likely to be dependent upon the severity and duration of the abuse. Individualised It is difficult to prognosticate the exact time at which the symptoms and changes are irreversible. The pathogenesis of ketamine induced vesicopathy is unclear, although may share similarities with IC.

More research is required in order to understand its genesis, consequences and possible management but clinicians should have a high index of suspicion in those with a higher incidence of drug abuse suffering from unexplained lower urinary tract symptoms.

  that formulated for IC patients would appear to offer the greatest opportunity for treatment success.

Table 2 :

 2 Cystoscopic findings

	Table 1
	number

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