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Keywords:

  • ketamine;
  • cystitis;
  • hydronephrosis;
  • detrusor overactivity

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

OBJECTIVE

To report the clinical spectrum seen in young abusers of street-ketamine (regular recreational abusers of street-ketamine, for its hallucinogenic effects) in Hong Kong, presenting with significant lower urinary tract symptoms (LUTS) but with no evidence of bacterial infection.

PATIENTS AND METHODS

We retrospectively analysed the clinical presentations, pelvic pain and urgency/frequency scores, video-urodynamic studies, cystoscopy findings, histological features of bladder biopsies and radiological findings of 59 ketamine abusers who were referred to the urology units of Princess Margaret and Tuen Mun Hospital, Hong Kong, from March 2000 to December 2007.

RESULTS

Of the 59 patients, all had moderate to severe LUTS, i.e. frequency, urgency, dysuria, urge incontinence and occasionally painful haematuria. Forty-two (71%) patients had a cystoscopy that showed various degrees of epithelial inflammation similar to that seen in chronic interstitial cystitis. All of 12 available bladder biopsies had histological features resembling those of interstitial cystitis. Urodynamically, either detrusor overactivity or decreased bladder compliance with or without vesico-ureteric reflux was detected to some degree in all of 47 patients. Thirty patients (51%) had unilateral or bilateral hydronephrosis on renal ultrasonography, and four (7%) showed features suggestive of papillary necrosis on radiological imaging. Eight patients had a raised serum creatinine level.

CONCLUSION

A syndrome of cystitis and contracted bladder can be associated with street-ketamine abuse. Secondary renal damage can occur in severe cases which might be irreversible, rendering patients dependent on dialysis. The present data do not establish the precise cause nor the incidence. Street-ketamine abuse is not only a drug problem, but might be associated with a serious urological condition causing a significant burden to healthcare resources.


Abbreviations
PUF

Pelvic pain and Urgency/Frequency (score)

RUS

renal ultrasonography

PCN

percutaneous nephrostomy

VCMG

video-cystometrogram

ESR

erythrocyte sedimentation rate.

INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

Ketamine available illegally ‘in the street’, which is based on the ketamine used medically as an anaesthetic agent, has gained popularity as a ‘recreational drug’ in discotheques and ‘rave’ parties in Hong Kong in the past 10 years. People take these drugs to enhance their enjoyment at parties or to escape from reality. There is a prevailing view among the youngsters that ketamine, being a short-acting psychotropic agent, is not as harmful as other drugs such as heroin. They believe that ketamine has a wide margin of safety and low potential for dependence. However, studies show that most ketamine abusers (78.9%) had features of physiological dependence after regular ketamine abuse for 1 year, while 53.5% reported withdrawal symptoms on stopping ketamine use, i.e. fatigue, excessive yawning, aggressive or hostile behaviour, feeling angry, irritable or depressed [1]. The effects of ketamine on the urinary tract were reported in a short case-report in 2007 [2] and was previously not known to urologists.

From July to September 2006, two young men in their late twenties were referred to the present authors for severe recurrent LUTS, i.e. dysuria, frequency (every 15–30 min), urgency, urge incontinence and painful haematuria, despite multiple courses of oral antibiotics. Abacterial cystitis was noted in both patients, but other urological investigations were unrevealing. In January 2007, a couple in their mid-twenties was referred with symptoms similar to the previous two patients. Cystoscopy of these two patients showed identical cystitis-like changes and there was decreased cystometric capacity. On taking a detailed history they admitted that they were chronic street-ketamine abusers; the wife had become an abuser 4 years previously after marrying her husband. This raised the suspicion that ketamine might be related to the bladder symptoms.

We reported our first 10 cases of street ketamine-associated bladder dysfunction in August 2007 [3]. In the present report we provide the latest update of the clinical features and urinary tract sequelae based on new cases and a retrospective case-note review.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

The database of the division of urology of the two regional hospitals in Hong Kong (Princess Margaret Hospital and Tuen Mun Hospital) was trawled for patients documented to have abused ketamine regularly for ≥3 months, with the onset of LUTS but no documented bacterial UTI, stone diseases or urological malignancy. From March 2000 to December 2007, 59 ketamine abusers with significant LUTS were assessed (38 men and 21 women, mean age 24.3 years, range 18–35). The mean (sd) duration of ketamine abuse was 3.5 (2.7) years (Table 1).

Table 1.  The physical characteristics, PUF score, cystometric bladder capacity and RUS findings of the 59 patients
Characteristic (n patients)n, n (%) or mean (sd, range)
Male : female ratio 38:21
Age, years 24.3 (4.2, 18–35)
Duration of ketamine abuse, years  3.5 (2.7, 0.5–10)
PUF score (24) 24.7 (7.5, 4–35)
Cystometric bladder capacity, mL (47)154.5 (146.9, 14–600)
Patients with VUR (47)  6 (13)
Patients with unilateral/bilateral hydronephrosis (49) 30 (51)
Patients with renal impairment (serum creatinine >120 µmol/L, 51)  8 (14)

The retrospective nature of the study and the idiosyncrasies of drug-addicted patients inevitably meant that data were incomplete. Symptoms were documented with standardized frequency/voiding charts and the Pelvic pain and Urgency/Frequency (PUF) score questionnaires in only 24 patients. This questionnaire, developed by Parsons et al.[4], has been validated and used in screening and diagnosing patients with interstitial cystitis. It comprises seven questions concerning daytime and night-time frequency, pelvic/urological pain and its severity, urgency and its degree of severity. It includes a symptom score and a bother score, totalling a maximum of 35 points. A PUF score of ≥15 was regarded as indicating significant symptoms, likely to be affected by ketamine abuse. Cystoscopy with bladder biopsies and video-urodynamic studies were available in 42 and 47 patients, respectively. Some upper tract assessment was available in all patients.

The Mann–Whitney U-test was used to compared nonparametric data and the Kolmogorov-Smirnov test for correlation analysis, with P < 0.05 taken to indicate significance.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

All patients had severe LUTS, with frequency, urgency, dysuria, urge incontinence and occasional painful haematuria. None of them had a positive bacterial culture on initial assessment of the mid-stream urine sample, but two (3%) women had a subsequent positive urine culture for Enterococcus species which might signify concomitant bacterial infection. Frequency/volume charts showed that the micturition frequency was every 15–90 min, while the functional voiding capacity was 20–200 mL only.

The PUF score was used as a standard tool in the patients to quantify symptom severity; 24 patients (41%) completed the PUF score at the time of their presentation, when 22 of them were still abusing ketamine, and they all had PUF scores of ≥15. The other two patients who were known to have stopped using ketamine for 6 and 12 months scored 4 and 14, respectively. The frequent small voids made it difficult for patients to maintain their work and daily activities.

Three months after their presentation, nine of these 24 patients who had abstained from ketamine abuse were able to complete the questionnaire and eight of them had a significant decrease in the PUF score from the initial assessment (P < 0.05). This suggests that the LUTS would improve with abstinence from ketamine abuse, although a more conclusive evaluation might be required.

Cystoscopy was performed either under local or general anaesthesia, based on the symptom severity and patient’s choice. For those patients who had cystoscopy under regional or general anaesthesia, a transurethral resection biopsy of the bladder wall was taken, with the aim of obtaining some of the muscularis layer for histological examination.

Forty-two patients (71%) had cystoscopy while the others refused the examination; 30 had cystoscopy under local anaesthesia while the other 12 had cystoscopy and transurethral resection biopsy under regional or general anaesthesia. All 42 patients showed various degrees of epithelial inflammation of the bladder and neovascularization. Severe cases showed petechial haemorrhages, as classically described in patients with interstitial cystitis (Fig. 1).

image

Figure 1. Cystoscopic findings of two daily ketamine abusers who had been inhaling ketamine nasally for 4 years (A) and 7 years (B), respectively. There were varying degrees of inflammation and neovascularization, with petechial haemorrhages in more severely affected patients.

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Histologically, the urinary bladder epithelium was largely denuded, with a focal presence of reactive urothelium. The lamina propria showed granulation tissue and congested vessels, infiltrated predominantly by lymphocytes and a variable number of eosinophils (Fig. 2). Ultrastructural examination by electron microscopy showed querciphylloid muscle cells (vacuoles at the periphery of muscle cells). This feature has also been found in interstitial cystitis.

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Figure 2. Ketamine-associated cystitis shows a variable degree of inflammation (A,B). The infiltrates comprised predominantly lymphocytes and a variable number of eosinophils (C). Ultrastructural examination shows querciphylloid muscle cells (D).

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Of the 59 patients, 47 (80%) had a video-cystometrogram (VCMG) taken, while the other 12 refused the study. The mean (sd, range) cystometric bladder capacities were 154.5 (146.9, 14–600 mL) (Fig. 3). Twenty-four patients (51%) had a bladder capacity of ≤100 mL and nine others were <150 mL. Most of the patients showed decreased bladder compliance and/or detrusor overactivity of different magnitudes at a very low bladder infusion volume (as low as 14 mL) (Fig. 4). Six of 47 patients (13%) showed VUR as a secondary event to the severely contracted bladder with high detrusor pressure (Fig. 5). This finding correlated well with the symptoms of these patients, in that both the functional and cystometric bladder capacities were markedly decreased, causing them to have very frequent small voids.

image

Figure 3. Cystometric bladder capacities in 47 patients who had a video-urodynamic study, showing that most of them had capacities of <150 mL.

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image

Figure 4. Cystometric plot showing severely decreased bladder compliance with detrusor overactivity and leakage when only 22 mL of 0.9% normal saline was instilled to the bladder.

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image

Figure 5. VCMG finding of the same patient in Fig. 1A: the cystometric bladder capacity was 30 mL only, with detrusor overactivity and leakage (A), and bilateral VUR during detrusor overactivity (B).

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Seven patients with capacities of >300 mL had no VUR and normal renal ultrasonography (RUS) findings. Interestingly, four had stopped using ketamine 3 months to 4 years earlier, two had only used it for 3 months and one only used it once a week.

High-dose antimuscarinic agents (e.g. oxybutynin 10 mg three times daily or tolterodine 4 mg twice daily) were tried by these patients but none of them had any response. Augmentation enterocystoplasty was performed on one man in who medication failed and who could not tolerate the markedly diminished bladder capacity. However, he continued to abuse ketamine and had progressive upper tract damage after his operation (see below).

Fifty-one of the 59 patients had a normal serum creatinine level (<120 µmol/L); eight (14%) presented with deranged renal function in addition to LUTS, with serum creatinine levels of 126–554 µmol/L. RUS showed bilateral hydronephrosis and three of the eight patients, required temporary urinary diversion with percutaneous nephrostomy (PCN) because of deteriorating renal function. Subsequent antegrade pyelography showed either near-complete or complete obstruction of both ureters below the PUJ in these three patients. The patient mentioned previously who had an augmentation enterocystoplasty for his severely contracted bladder continued to abuse ketamine and stopped emptying his augmented bladder by clean intermittent catheterization. He was admitted 3 months after surgery with acute renal failure requiring urgent PCN (Fig. 6). A 6-weeks course of empirical steroid therapy was given in view of his raised inflammatory markers (e.g. erythrocyte sedimentation rate, ESR), but a persistent short segment unilateral ureteric stricture was shown on an antegrade nephrostogram after steroid therapy. He had an anastomotic ureteroplasty (Fig. 7). The histological feature of the ureter was fibrosis, secondary to an intense transmural inflammatory response, which might have been caused by the high concentration of ketamine and its metabolites in urine, secondary to reabsorption of ketamine from the augmented bladder, causing chemical irritation of the urothelium.

image

Figure 6. Bilateral antegrade pyelogram of a patient who had used ketamine for 10 years and presenting with acute renal failure 3 months after augmentation enterocystoplasty. He required bilateral PCNs. Nephrostograms subsequently showed bilateral ureteric strictures involving the (A) right upper ureter and (B) left upper ureter.

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Figure 7. Bilateral antegrade nephrostograms of the same patient as in Fig. 6 after a 6-week course of empirical steroid therapy. (A) there is free drainage of contrast medium down to the right ureter but still (B) persistent left ureteric stricture, which was shown to be due to a short-segment stricture in a simultaneous antegrade and retrograde pyelogram (C,D).

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All patients were assessed by RUS on presentation to evaluate their upper urinary tract condition; 30 (51%) presented with either unilateral (four) or bilateral (26, 44%) hydronephrosis on the initial assessment (Fig. 8). In most of these patients IVU showed bilateral hydronephrosis and hydroureters down to the level of the vesico-ureteric junctions (Fig. 9). The upper tract involvement was probably the result of the long-term decrease in bladder compliance, and VUR, as shown in some of the patients. Four patients (7%) were found to have RUS evidence of papillary necrosis (Fig. 10) while two of them even had acute papillary necrosis with para-aortic lymphadenopathy and a thickened ureteric wall, suggestive of marked ongoing transmural inflammatory changes (Fig. 11).

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Figure 8. RUS in a patient showing left (A) and right (B) hydronephrosis, with dilated lower ureters (arrows in C) down to both vesico-ureteric junctions.

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Figure 9. IVU of the same patient in Fig. 8, showing bilateral hydroureteronephrosis.

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Figure 10. RUS of the same patient as in Fig. 6, showing various stages of papillary necrosis.

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Figure 11. CT of another ketamine abuser showing features suggestive of papillary necrosis.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

Ketamine is a noncompetitive N-methyl-d-aspartate receptor antagonist which interferes with the action of excitatory amino acids. It was synthesized by Stevens in 1962 and first used in humans by Corssen and Dormino in 1965 [5]. In 1970, the USA Food and Drug Administration approved ketamine for human use, and since then it has been used in the induction and maintenance of anaesthesia. Ketamine produces dose-related unconsciousness and analgesia. The anaesthetized state has been termed ‘dissociative anaesthesia’ because patients who receive ketamine alone appear to be in a cataleptic state which resembles normal sleep, unlike other states of anaesthesia. It is metabolized by the hepatic microsomal enzymes that are responsible for most drug detoxification. The major pathway involves N-demethylation to form nor-ketamine, which is then hydroxylated to form hydroxyl-norketamines. These products are conjugated to water-soluble glucuronide derivatives and 90% are excreted in the urine. For medical use in humans and animals, ketamine is mostly supplied in vials for i.m. or i.v. injection.

Starting from mid-1980s, ketamine has gained popularity as one of the recreational ‘club’ drugs used by young adults in ‘rave’ and other party settings. In the first half of 2007, street ketamine was the most commonly abused drug among abusers aged <21 years (79.9%, 73% in 2006) [6]. Moreover, the volume of seizures of street ketamine in Hong Kong has increased from 81.5 kg in 2001 to 1006 kg in 2007 [7], probably because of the reduction in retail prices from HKD $325/g in 2001 to $147/g in 2006 [8].

As a street drug, ketamine is available as a white powder, in tablet or capsule form. Ketamine is inhaled into the nasal cavity and the users experience its effects in ≈10 min. When ketamine is taken orally it can take up to 20 min to have an effect. The psychedelic experience (‘trip’) includes the sensation of light throughout the body, sensation of being weightless and floating or hovering, colourful visions and out-of-body experiences [9]. The bulk of the ‘trip’ lasts ≈1 h and the effects diminish gradually over another hour.

There are very few recorded deaths caused by pure ketamine overdose, but its systemic side-effects on the CNS, respiratory system and the cardiovascular system have been well recognized. However, its harmful effects on both the upper and lower urinary tract have not been reported until recently [2,3].

The incidence of ketamine-associated cystitis and urinary tract damage is difficult to estimate. A small-scale survey was conducted by a psychotropic substance abuse rehabilitation centre in Hong Kong. Among the 97 ketamine abusers, 29 (30%) reported the presence of LUTS in the past, or during their stay in the centre (unpublished data). Abuse of ketamine is likely to be under-reported. Epidemiological studies on soft-drug abusers are difficult to obtain, as many are poly-drug abusers and rarely seek medical advice, unless they develop significant symptoms. Many abusers admitted that their peers in the community had similar symptoms but refused to seek medical advice.

The underlying pathophysiological mechanism for the destruction of the urinary tract by ketamine is unknown. Whether the lower and upper urinary tract damage is caused by the same mechanism remains an open question. Moreover, the reason why the lower urinary tract is affected more frequently than the upper tract, as shown in the present patients, is unknown, although the longer contact time of the ketamine metabolite in urine with the bladder might be a contributing factor. From the cystoscopy, urodynamic and histopathological findings, we postulated the following pathophysiological mechanisms that might account for the urinary tract damage:

(i) The high concentration of ketamine and its metabolites in the urine might cause direct toxic effects on the bladder interstitial cells, causing a significant chronic submucosal inflammatory response. This would result in submucosal oedema, vascular ectasia, fibrosis, detrusor muscle inflammation and fibrosis. This would account for the severe dysuria and diminished bladder capacity. The presence of papillary necrosis in some of the chronic high-dose ketamine abusers might be caused by its irreversible toxic effects on the papillary medullary interstitial cells, leading to interstitial fibrosis and structural damage, resulting in chronic renal insufficiency. This was the also model suggested for analgesic- or aspirin-induced nephropathy [10,11], Whether NSAIDs or steroids are able to reverse the process needs further study.

(ii) Ketamine and its metabolites might induce microvascular changes in the bladder and possibly the kidney, causing endothelial cell injury of microvessels and leading either to compromised intrinsic microcirculation, or decreased microvascular density in the subendothelium [12,13]. The presence of neovascularization in the cystoscopic finding as shown in Fig. 1A supports this hypothesis. The symptoms of severe suprapubic pain and dysuria could be due to bladder ischaemia during bladder filling. With time, the bladder ischaemia could lead to interstitial fibrosis and diminished bladder capacity. The presence of papillary necrosis in some patients could result from micro-angiopathy or capillary sclerosis in the renal medulla causing hypoperfusion of the papilla. It might then end with tubulo-interstitial nephropathy and cortical atrophy. The pathophysiology might be similar to that of papillary necrosis induced by diabetes or analgesic nephropathy, as described by some authors [14–16]. Further clinical research or animal studies would be helpful to see whether some vessel-dilating agents like angiotensin-converting enzyme inhibitor or prostaglandin E1 would be useful in these patients [17–20].

(iii) An autoimmune reaction to the bladder urothelium and submucosa triggered by the presence of circulating ketamine or urinary ketamine and its metabolites. This might explain the raised ESR and C3/C4 found in some of the present patients [21]. This reaction could result in autoimmune-mediated vascular congestion, submucosal oedema and scarring, leading to diminished bladder capacity and poor compliance.

(iv) Bacteriuria as the possible cause for the cystitis and papillary necrosis is unlikely in these patients, compared with other possible causes as described above. All of the patients had abacterial cystitis on presentation. The positive bacterial culture in the subsequent urine test of two patients signified concomitant bacterial UTI instead of a genuine cause of the initial urinary symptoms. None of the patients showed any improvement after antibiotic treatment.

Besides the LUTS, acute papillary necrosis in patients abusing ketamine is worthy of attention, as patients could present with anuria and biochemical renal failure. It has been recognized that papillary necrosis can cause complete ureteric obstruction by migration of the sloughed papilla into the ureters [22].

The present patients were mainly identified retrospectively; there was no consistent diagnosis or management. In patients presenting with hydronephrosis and renal failure, early treatment with endoscopic insertion of JJ stents or nephrostomy tubes preserved renal function before irreversible damage occurred.

In seven patients with near-normal cystometric bladder capacities stopping or reducing ketamine abuse led to a return of normal bladder function.

One patient had an augmentation cystoplasty, but he continued to abuse ketamine and his symptoms progressed. Unpublished data from other centres (Gillat D, Woodhouse CRJ, personal communications) suggest that symptoms are relieved by substitution cystoplasty and good voiding is achieved.

Whether chronic ketamine abuse with chemically induced cystitis or renal papillary necrosis would give rise to urothelial carcinoma is not known and needs further longitudinal follow-up of the present patients [23].

In conclusion, our series shows a spectrum of presentation of a new syndrome probably associated with ketamine abuse. The limited data available suggest that urinary symptoms can occur in ≈30% of ketamine abusers. The duration and frequency of abuse apparently correlated with the severity of the symptoms and degree of damage to the urinary tract. The pathophysiology and the causative biochemical process remain to be determined.

The information gathered in this series could serve to guide the management of urinary symptoms in these patients. Abstinence from ketamine abuse is strongly advocated before any irreversible damage to the urinary tract occurs. The authors would like to alert all front-line health professionals, medical social workers (not only in Hong Kong but elsewhere in the world) to this new syndrome. Early referral for urological assessment would help to reduce not only the detrimental effects to the abusers, but also the health cost to society.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES
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