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Phenol is a chemical compound that was first used medically as an antiseptic. At low concentrations, phenol exerts local anesthetic effects achieved through denervation; at high concentrations, it exerts a potent protein-denaturing effect that induces apoptosis. Phenol injection therapy has a long history of use in urology. It is reportedly effective for hemorrhagic cystitis, benign prostate hyperplasia, overactive bladder, hydrocele, bladder tumors, interstitial cystitis and other benign urologic diseases, and it is also used as a tool to decrease bleeding during prostate surgery. The present review article summarizes the medical applications of phenol in urological field. The articles available on the medical uses of phenol are primarily older and retrospective, involving small numbers of patients. In the absence of comparative studies with other treatments, it is impossible to determine the relative benefit of phenol. However, the treatment outcomes of phenol injection are fairly well-established. Phenol therapy may be an option for patients who are poor candidates for invasive treatment. Further studies are required, however, as are improvements in the injection technique to reduce the rate of complications.
Joseph Lister first used phenol in a medical capacity in 1865, as an antiseptic to sterilize operating fields, with favorable results ( 1 ). In addition to its antimicrobial actions, phenol exerts local anesthetic effects at low concentrations. These effects are achieved through denervation ( 2 , 3 ). At high concentrations, phenol exerts a potent protein-denaturing effect ( 4 ). Due to its various effects, phenol is used in a wide range of fields ( 3-9 ). However, there are only a limited number of reviews available on the medical applications of phenol. In the present review, the medical applications of phenol in urological field are summarized.
HC is a condition associated with certain disease states, as well as with exposure to drugs, viruses and toxins. Diffuse inflammation causes bleeding from the bladder mucosa (9). Management options include coagulation, embolization, fulguration, hyperbaric oxygen therapy and surgical treatment (10). However, some patients experience intractable HC that is difficult to manage, particularly when the condition develops after the use of cyclophosphamide chemotherapy. In such patients, the intravesical instillation of phenol is an effective, minimally invasive and less morbid option compared with conventional treatments (11). The intravesical instillation of phenol is reportedly effective for chemical cauterization in patients with severe bladder hemorrhage (11,12). In a clinical experiment, phenol was shown to destroy the urothelium, but not muscle (13). The bladder capacity diminishes temporarily and then returns to its normal size with the complete epithelialization of the urothelium. The treatment is associated with a low incidence of bladder fibrosis (13). A reported complication of phenol involved failure to drain the bladder following instillation. The infant suffered severe methemoglobinemia (14).
Previous case reports describe two children with leukemia, 12 and 16 years of age, who were administered phenol for refractory HC following cyclophosphamide therapy (14,15). The method requires suprapubic cystostomy under anesthesia. A total of 30 cc of 100% phenol with 30 cc of glycerin is instilled and left in the bladder for 1 min. The mixture is then removed by suction followed by the instillation of 60 cc absolute ethanol (90 or 95%) to neutralize the effect of any remaining phenol. After 1 min, the ethanol is suctioned out and the bladder is irrigated with copious amounts of saline. The bladder is closed, and a 30 F suprapubic Foley catheter is left in place (14,15). Both case reports describe the immediate post-operative clearing of the urine, and both patients had their suprapubic catheter removed 6 weeks after surgery (14,15). Initially, the patients had a small bladder capacity on intravenous pyelogram and were unable to feel the sensation of needing to void. Within 2-4 weeks, the patients recovered sensation, reasonable bladder control and adequate bladder capacity. Both of these reports describe the use of ethanol to wash out the remaining phenol in the bladder (14,15). Phenol does not dissolve in water at relatively high concentrations, although it does dissolve uniformly in water at low concentrations (≤7%) (16). Thus, it may be possible to omit the step of ethanol instillation.
Phenol is also effective when silver nitrate fails to control bleeding (17). The mucosa is swabbed with a 1:1 phenol-alcohol solution, and bleeding is immediately terminated. Duckett et al (15) described the successful control of HC by phenol cauterization in three patients, although the details of treatment are unclear.
Severe vesical bleeding in children is difficult to manage as the small urethra precludes the use of large catheters for bladder irrigation and clot removal. Thus, phenol may be particularly useful in pediatric patients (18). However, since experience with phenol is limited, further investigations are required to determine the usefulness of injection therapy.
Subtrigonal phenol injection has been employed since 1982 for patients with detrusor instability, detrusor hyperreflexia and bladder hypersensitivity who have not had success with more conservative treatments (19). Ewing et al (19) were the first to describe this technique in 1982. Cystoscopy is performed under general anesthesia, and a 35-cm, 20-gauge Shuttleworth needle is passed through the bladder wall and advanced to midway between the bladder neck and the ureteric office on each side. A total of 10 ml 6% phenol solution is injected into each side through transvaginal approach. An indwelling Foley catheter is left overnight and removed the following morning. The overall response rate in the 30 patients in the study by Ewing et al (19) was 62.5% at 1 year. In subsequent studies, the results of treatment in the early post-injection period ranged from 29 to 63% (20-25). Blackford et al reported the highest number of patients: 62 of their 116 patients (53%) had a symptomatic response at 3 months after the phenol injection (25). A satisfactory response rate was more likely in patients with detrusor hyperreflexia (82%), older patients with detrusor instability (69%) and patients with idiopathic bladder hypersensitivity (68%), but less likely in younger patients with detrusor instability (14%) and in patients who had bladder hypersensitivity with a definable cause, such as interstitial cystitis (0%) (25). Other researchers have noted a diminishing effect of infusion therapy over time. Rosenbaum et al (23) reported that the overall success rate at 1 month was 48%, decreasing to 16% at 6 months and to 3% at 1 year. Chapple et al (21) also reported that 10 of their 18 female patients exhibited an improvement in their condition at 1 month; however, this figure decreased to 7 out of 18 at 3 months and to 2 out of 18 at 6 months. These results demonstrate that clinical denervation following a transtrigonal phenol injection with a 6% phenol aqueous solution may be, at best, only transient.
Some concerning complications are sometimes observed after the injection. Ewing et al (19) reported that 5 of their 30 patients experienced chronic urinary retention, and 2 patients experienced a trigonal ulcer and transient ureteric reflux; the ulcer and the reflux resolved spontaneously. Mclnerney et al (20) also described a significant complication rate (17%) for phenol injection. The most common complication in their study was urinary retention, occurring in 8 of 72 patients (20). In addition, 4 patients experienced nerve palsies, and 2 patients developed localized bladder mucosal necrosis at the injection site; one of these patients experienced calculus formation. One of the 9 male patients developed erectile dysfunction (20). The authors of other series have reported fistula formation, significant hematuria and ureteric stenosis (21-25). Vesicovaginal fistula is a particularly severe complication that can arise from placing phenol too medially. Extreme caution should be exercised when a second injection is necessary, e.g., in patients with an inadequate response to an initial injection.
These findings suggest that the use of transtrigonal phenol for the treatment of overactive bladder is difficult to justify using the reported methods. One reason for the poor results and the resultant complications may be that phenol diffuses widely through the perivesical fat (23). Improving the injection technique to prevent phenol diffusion could lead to greater efficacy and may prevent complications. Further research and development in this area is required.
Multiple papillomatosis of the bladder and diffuse non-infiltrating papillary carcinoma of the bladder are conditions that are difficult to assess using transurethral techniques. Unless each individual lesion is removed and staged, the variation in malignant potential among lesions cannot be accurately assessed. Vermooten et al (26) overcame this difficulty by using phenol to induce complete destruction of the bladder mucosa in the hope that the newly regenerated epithelium would not show a neoplastic tendency. Modifying a suggestion of Kirwin (27), they reported the successful use of phenol for chemical cauterization of bladder mucosal tumors in 13 patients with papillomatosis (26), using a solution consisting of equal parts pure phenol and glycerin. The bladder capacity was initially diminished but later returned to an adequate size. Treatment appears to be efficient in ridding the bladder mucosa of papillary lesions, and recurrences are infrequent following the complete destruction of the bladder mucosa, though they do occasionally occur. Filling the bladder with phenol does not appear to be associated with treatment-related mortality.
To investigate how deeply phenol penetrates and the time required for regeneration of the bladder epithelium, Vermooten et al (26) performed experiments using canines. Under general anesthesia, the bladder was filled with 150 cc of a solution of equal parts pure phenol and glycerin; the solution was left in place for 2 min. The mixture was then removed and the bladder was washed with 95% alcohol. The animals were serially sacrificed. At 5 days, the intravesical ureter and ureteral orifice were noted to have an intact epithelium with a fibropurulent eschar replacing the destroyed bladder epithelium. Edema and infiltration did not extend into the muscular layer. At 7 days, the epithelium had begun to regenerate from the ureteral orifices, replacing the eschar on the mucosal surface. At 21 days, the bladder mucosal epithelium had regenerated to its normal thickness, inflammation and edema had diminished, and there was no evidence of dysplasia or neoplasia. Cystography revealed no evidence of reflux. Phenol injection for chemical cauterization of the bladder mucosa for papillomatosis appears to be safe, based on this animal model (26).
Interstitial cystitis is a disease of unknown etiology in which the main symptoms are bladder pain, urinary frequency and urgency (28). Particularly in the presence of Hunner's ulcers, it is associated with severe, recurrent bladder pain. The glycosaminoglycan layer of the bladder mucosa is impaired in patients with interstitial cystitis, and sensory nerves, such as the unmyelinated C-fibers are stimulated by urine, causing pain. A number of types of treatment have been advocated (29,30), including denervation using local application of phenol in the bladder. Investigators have applied various strengths of phenol solution directly to the ulcer (31,32); the use of 50% phenol and pure phenol are reportedly effective (29). The application of phenol causes protein coagulation, which leads to non-selective tissue destruction and the initiation of degeneration in nerve fibers, with a neurolytic effect that lasts for several months (32). However, neurodestructive modalities, including phenol, have potential complication and adverse effects. Advances in phenol injection techniques are required to solve these issues. The authors of the present review previously developed a novel, in situ permeation system that controlled the intratissue diffusion of therapeutic agents (33). This system will enable the localized ablation of target lesions.
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