**6.3 Intravesical therapies**

Ketamine and its metabolites cause denudation of the urothelium, exposing the underlying submucosa and stroma of the bladder wall to further toxic damage. This produces the typical LUTS as well as the structural changes such as wall thickening and reduction in compliance. This has prompted investigations into the effectiveness of intravesical therapies that aim to restore the integrity of the urothelium so that the underlying tissue may no longer be exposed to the toxicities of ketamine and its metabolites. Intravesical instillation of a glycosaminoglycan, such as hyaluronic acid or chondroitin sulphate, has been proposed to reconstitute the barrier

function provided by the urothelium and enhance healing. Reports of significant reductions in symptoms in patients treated with weekly intravesical instillations of hyaluronic acid or chondroitin sulphate have been published recently [26]. These patients not only reported a reduction of LUTS, but follow-up cystoscopy with biopsies showed decreased inflammatory cell infiltration, less inflammatory hypervascularity, as well as regeneration of the urothelium [27].

Cystoscopic injection of botulinum toxin into the bladder wall, followed by hydrodistension, is another intravesical treatment that has been shown to relieve symptoms of ketamine cystitis [28]. Botulinum toxin type A inhibits the presynaptic release of neurotransmitters such as acetylcholine, thus inactivating neuromuscular junctions and reducing detrusor activity. The patient is typically put under spinal anaesthesia, and a cystoscope is then advanced into the bladder. 20 ml of botulinum toxin type A at a concentration of 200 IU in 20 ml is then injected into 40 points in the bladder wall. There is currently no standard protocol for the technique of hydrodistension, but authors have performed it by filling the bladder with saline under a pressure of 80 cmH2O, at a volume of 150–200 ml, for a duration of 5 minutes [29].

#### **6.4 Surgical therapies**

The bladder in a patient with severe ketamine cystitis is thickened and fibrotic and has poor compliance. Apart from severe LUTS, these changes may also cause vesicoureteral reflux and upper tract damage. Such patients are at risk of chronic renal failure. Surgical treatment in the form of augmentation cystoplasty is therefore an option to increase the capacity and compliance of the bladder, so that symptomatic improvement and upper tract protection could be brought about through a single procedure. Techniques vary, but an option is to use a 25 cm segment of the ileum and sew it to a surgically created clam-like opening of the bladder in order to augment its volume and compliance [30]. Contraindications to augmentation cystoplasty using bowel include any condition that renders the bowel abnormal at the baseline, for example, inflammatory bowel disease (Crohn's disease, ulcerative colitis) and previous gut resection (such that further resection may predispose the patient to malabsorption or even short gut syndrome). Another alternative is to use a portion of the stomach, termed gastrocystoplasty. This has its own issues, as the hydrochloric acid produced by the stomach mucosa may cause haematuria-dysuria syndrome, peptic ulceration in the bladder, and alkalosis. Complications include a mortality rate of up to 2.7%, small bowel obstruction, fistulation, and renal failure (due to the reabsorption of urinary waste through the bowel segment). Some patients may furthermore require clean intermittent catheterisation to more effectively empty the bladder. Patient selection is paramount when considering augmentation cystoplasty for ketamine cystitis patients. Failure of abstinence after surgery results in rapid reabsorption of ketamine from the urine through the bowel segment. Ketamine and its metabolites are hence recirculated, excreted in the urine again, and once again exerting their toxic effects on the urothelium. Augmentation cystoplasty with bowel may therefore even accelerate upper tract damage should the patient fail to abstain from ketamine postoperatively. The patient should also be willing to comply with clean intermittent self-catheterisation should it be required [30].

An alternative surgical strategy is an ileal conduit [31]. This involves brining both the ureters to an opening in the abdominal wall through a surgically created segment of the ileum. This obviates the need for clean intermittent catheterisation and offers quicker postoperative recovery. However, as this is an incontinent type of urinary diversion, the patient would have to live with a lifelong urostomy bag.
