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Treatment of recurrent urinary retention in high surgical risk/elderly BPH patients: A pilot study of the use of cholinergic drugs, "Beyond the Abstract," by Kostantinos Stamatiou

BERKELEY, CA (UroToday.com) - Urinary retention (UR) is one of the most usual and significant complications of long-term BPH. The risk is cumulative and increases with age. Moreover, recurrent urinary retention in elderly often indicates a poor detrusor function, which represents a risk factor of both surgical and conservative therapy failure.

Pathogenesis of recurrent and chronic UR seems to imply both bladder obstruction and impaired detrusor contractility. Epidemiologic studies show that bladder outlet obstruction is common among elderly men, while the incidence of urinary retention dramatically increases with age as well. Pathophysiologically, bladder outlet obstruction is initially accompanied by detrusor hypertrophy. Over the course of time, pathological deposition and replacement of detrusor fibbers with collagen occur.[1] In addition to impaired detrusor contractility and reduced bladder compliance, this process may also be implicated with denervation hypersensitivity of the bladder’s neuromusculature, a process which is yet to be accurately defined.[2] Apart from the morphological changes of the bladder, recurrent and chronic urinary tract obstruction can lead to permanent damage to the urinary tract. Progressive back pressure on the ureters and kidneys can occur and can cause hydroureter and hydronephrosis. The ureter can then become dilated and tortuous, with the inability to adequately propel urine forward. Hydronephrosis can cause permanent nephron damage and kidney failure, while urine stasis along any portion of the urinary tract increases the risk of calculus formation, infection, and upper urinary tract injury.

Usual clinical assessment

As mentioned above, although the most usual cause of UR is bladder outlet obstruction, a vast range of conditions can also cause either acute or chronic UR; therefore, many investigations may be used to define the severity of urinary flow disruption and to establish the underlying cause. In most of the cases, however, a digital rectal examination of the prostate and an abdominal ultrasound are used in order to evidenciate prostatomegaly, bladder enlargement, and signs of prostatic carcinoma. In addition, serum urea nitrogen, creatinine, and electrolytes can help assess kidney failure. Further investigations such as uroflowmetry, cystometry, electromyography, urethral pressure profile, video urodynamics, and pressure flow studies of micturitionare are rarely done.[3] In fact, formal urodynamic study of lower urinary tract function is invaluable when investigating symptomatic BPH with acute UR. However, chronic UR and repeated episodes of acute urinary retention suggesting intermittent acute on-chronic-retention should give cause for concern. Patients presenting the above should proceed to a full urodynamic investigation before embarking on treatment.[3]

Current management of chronic urinary retention

While specific clinical recommendations for management of acute UR are well established, a specific clinical recommendation for management of chronic UR does not exist. However, clinical recommendations should be directed at reducing the residual volume, eliminating hydronephrosis (if present), and preventing urosepsis. The first step is to use indwelling or intermittent catheterization to decompress the bladder for up to a month, while reversing potential contributors to impaired detrusor function (fecal impaction and medications).[4] At the end of this time interval patients are usually submitting to surgery. However, it is not known if an attempt to remove the catheter (TWOC) in order to evaluate if patients regained their ability to void could be useful.[5] It seems plausible, however, that patients with chronic UR who did not receive any medication for BPH treatment may have a higher chance of successful trial without catheter (TWOC) than those who receive an α-blocker treatment.[6]

Of note, surgery success rate is inversely proportional to the degree of chronic UR. Studies of the outcome of surgery in patients with chronic retention demonstrated that high postvoid residual volumes, old age, absence of instability, a maximal detrusor pressure of less than 20 cm H2O, poor sensation, large retention volumes, and absence of voluntary detrusor contractions are associated with a poor surgical outcome and failure to void.[7]

Current management of recurrent urinary retention

Current guidelines offer little help to office urologists in deciding how many failed further TWOCs are needed to decide upon final treatment. In the United Kingdom, nearly 71% of urologists start their patients on α-blockers immediately after emergency catheterization, with 64% using a TWOC 2 days after starting them. One failed TWOC is an indication for surgical intervention for 72.8%, while a second TWOC is advocated by only 11.7%.[8] The most possible explanation for the very low number of the reported additional TWOC attempts is probably the established opinion that the majority of patients, both with and without previous symptoms suggestive of outflow obstruction, will have further retentions.[9] In part, these concerns are justified since the risk of recurrence was cited as 76% to 83%.[6] These data, however, have recently been challenged by the results of several observational studies showing that a number of patients presenting with UR regain spontaneously their ability to void. In fact, only 32% of patients with successful TWOC, or even less, will require prostatectomy within 8 to 24 months of follow-up, reinforcing the need to offer more than one TWOC in patients with a first episode of UR.[10] Evidence shows that the risk of a further episode of acute UR is higher when recurrence is close in terms of time to the previous episode of UR.[11] To our best knowledge, the time needed to obtain a successful TWOC is not known. It differs from patient to patient and depends on the underlying pathology. Increasing the period of drainage of the bladder before a TWOC improves the chances of success (44%, 51%, and 62% success at days 0, 2, and 7, respectively).[12] In contrast, it is estimated that the risk of recurrence when TWOC is performed within 1 week of the first episode is as high as 64%.[13] Despite the number of patients with successful TWOC and the improved odds of such intervention, when treating patients with α-blockers, a significant proportion of patients presenting with recurrent UR will ultimately require a definite treatment.

Unfortunately, men with BPH-induced chronic UR are more likely not to be able to return to normal voiding. Factors associated with an unsuccessful TWOC are age higher than 75 years, a residual drained urine volume of greater than 1 L, and a detrusor contraction less than 35 cm H2O.[14]

Is there any option for patients with surgical treatment failure and patients unfit for surgical treatment?

Surgical intervention is generally considered to be the endpoint for recurrent UR. Of note, since a full urodynamic investigation is not routinely performed, it is not surprising that several patients with chronic or recurrent UR fail to urinate after prostate surgery. Also of note, a significant number of patients with chronic or recurrent UR are high surgical risk and/or elderly patients with co-morbidities, usually not eligible for surgical treatment. Currently there is little treatment option for patients with surgical treatment failure and patients unfit for surgical treatment. If the detrusor is acontractile after decompression by either conservative treatment or surgery, patients should be started on intermittent catheterization or an indwelling urethral catheter. Unfortunately, despite the benefits and proven feasibility of intermittent catheterization, most elderly patients choose indwelling catheterization instead.[15] Prolonged use of indwelling catheter, however, is accompanied by several side effects and complications.[16] In addition, the cost implication of having an indwelling bladder catheter is enormous.[17] Therefore, medical treatment targeting to decrease resistance to urine outflow through the prostatic urethra and increase bladder smooth muscle may improve the bladder outlet surgery success rate, and perhaps it might reinforce the need to offer an additional TWOC in those with poor voiding and longstanding symptomatic BPH. From a clinical point of view, the prostatic component of UR can be targeted through androgen blockade (e.g., a 5-α-reductase inhibitor) or by decreasing resistance to urine outflow through the prostatic urethra using α-adrenoreceptors inhibition, or both. In fact, α1-blockers are used routinely before catheter removal and are even considered an appropriate treatment option in the American Urological Association guidelines.[18] On the other hand, the bladder component of UR can be targeted through parasympathomimetic drugs. There are few studies examining the role of parasympathomimetic drugs in the treatment of BPH-related chronic UR and residual urine in the literature to date. Two parasympathomimetic drugs -- the nonselective acetylcholinesterase inhibitor distigmine and the muscarinic agonist bethanechol -- have been studied in clinical trials, while the selective acetylcholinesterase inhibitor TAK-802 has been studied in experimental basis.[19]

Our pilot study was carried out in order to verify whether and if the use of parasympathomimetic drugs, complementary to the traditional a-blockers, may help patients with recurrent urinary retention to regain their ability to urinate. At the time of the study planning, the only available parasympathomimetic drug in the Greek market was distigmine bromide. To our knowledge, while clinical and experimental observations support the use of distigmine bromide in the treatment of BPH-related chronic UR,[20, 21] a number of significant side effects as well as the contraction of the external urethral sphincter muscle and the subsequent increase of the urethral resistance minimise its potential clinical usefulness.[20] However, in our study, the majority of patients on combination therapy had a successful TWOC, similar to all first-time urinary retention patients. Compared to patients on monotherapy, patients on combination therapy needed more TWOCs to void due to gradual increase in the dosage of distigmine bromide. PVR was significantly reduced with treatment in both groups. Statistically, there was no significant difference between the two groups on the PVR and IPSS mean change. According to these results, this combinational treatment seems to be useful to patients with poor voiding and longstanding symptomatic BPH unfit for surgical treatment. Given the higher selectivity for muscarinic actions over nicotinic actions, novel selective acetylcholinesterase inhibitors reinforce the bladder and voiding functions by increasing the bladder contractility without decreasing the storage function.[19] For these reasons, they might be more useful than distigmine bromide in the treatment of BPH-related chronic UR. Currently, there are no randomised, clinical trials supporting this use of parasympathomimetic and so clinical trials are needed in order to confirm our findings.

References:

  1. Deveaud CM, Macarak EJ, Kucich U, Ewalt DH, Abrams WR, Howard PS. Molecular analysis of collagens in bladder fibrosis. J Urol. 1998;160:1518-27
  2. Brading AF, Turner WH. The unstable bladder: towards a common mechanism. Br J Urol. 1994;73:3-8.
  3. Roehrborn CG, McConnell JD. Etiology, pathophysiology, epidemiology and natural history of benign prostatic hyperplasia. In: Walsh PC, Retik AB, Vaughan ED Jr, et al, editors. Campbell’s Urology. 8th ed. Philadelphia: WB Saunders; 2002. p. 1297-336
  4. Selius BA, Subedi R. Urinary retention in adults: diagnosis and initial management. Am Fam Physician. 2008;77:643-50.
  5. Nyman MA, Schwenk NM, Silverstein MD. Management of urinary retention: rapid versus gradual decompression and risk of complications. Mayo Clin Proc. 1997;72:951-6.
  6. Jacobsen SJ, Jacobson DJ, Girman CJ, et al. Natural history of prostatism: risk factors for acute urinary retention. J Urol. 1997;158:481-7.
  7. Dubey D, Kumar A, Kapoor R, Srivastava A, Mandhani A. Acute urinary retention: defining the need and timing for pressure-flow studies. BJU Int. 2001;88:178-82
  8. Gopi SS, Goodman CM, Robertson A, Byrne DJ. A prospective pilot study to validate the management protocol for patients presenting with acute urinary retention: a community-based, non-hospitalised protocol. ScientificWorldJournal. 2006;6:2436-41.
  9. Hastie KJ, Dickinson AJ, Ahmad R, Moisey CU. Acute retention of urine: is trial without catheter justified? J R Coll Surg Edinb. 1990;35:225-7.
  10. McNeill SA, Hargreave TB, Gallagher H. Longterm follow-up following presentation with a first episode of acute urinary retention. J Urol 2000;163:307.
  11. Okeke LI, Aisuiodione-Shadrack OI. Self-reported QoL measures of patients with benign prostatic hyperplasia on indwelling urethral catheter. Afr J Urol. 2006:12:287-95.
  12. Djavan B, Shariat S, Omar M, et al. Does prolonged catheter drainage improve the chance of recovering voluntary voiding after acute urinary retention of urine (AUR). Eur Urol. 1998;33:110.
  13. Khoubehi B, Watkin NA, Mee AD, Ogden CW. Morbidity and the impact on daily activities associated with catheter drainage after acute urinary retention. BJU Int. 2000;85:1033-6.
  14. Djavan B, Madersbacher S, Klingler C, Marberger M. Urodynamic assessment of patients with acute urinary retention: is treatment failure after prostatectomy predictable? J Urol. 1997;158:1829-33.
  15. Bakke A, Brun OH, Hoisaeter PA. Clinical background of patients treated with clean intermittent catheterization in Norway. Scand J Urol Nephrol. 1992;26:211-7.
  16. Drinka PJ. Complications of chronic indwelling urinary catheters. J Am Med Dir Assoc. 2006;7:388-92.
  17. Ikuerowo SO, Ogunade AA, Ogunlowo TO, Uzodimma CC, Esho JO. The burden of prolonged indwelling catheter after acute urinary retention in Ikeja - Lagos, Nigeria. BMC Urol. 2007;7:16.
  18. [No author listed]. AUA guideline on management of benign prostatic hyperplasia (2003). Chapter 1: Diagnosis and treatment recommendations. J Urol. 2003;170:530-47.
  19. Hashimoto T, Nagabukuro H, Doi T. Effects of the selective acetylcholinesterase inhibitor TAK-802 on the voiding behavior and bladder mass increase in rats with partial bladder outlet obstruction. J Urol. 2005;174:1137-41.
  20. Yamanishi T, Yasuda K, Kamai T, et al. Combination of a cholinergic drug and an alpha-blocker is more effective than monotherapy for the treatment of voiding difficulty in patients with underactive detrusor. Int J Urol. 2004;11:88-96.
  21. Katsumi T, Murayama K. [Clinical effects of distigmine bromide (Ubretid), a cholinesterase inhibitor, on micturition disturbance by benign prostatic hypertrophy--comparative study of distigmine bromide and the combination of distigmine bromide and adrenergic blocker. Hinyokika Kiyo. 1992;38:1089-92.

 

Written by:
Kostantinos Stamatiou as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

General Hospital of Thebes, Thebes, Greece

 

Cholinergic drugs for treatment of recurrent urinary retention in high surgical risk/elderly BPH patients. A pilot study - Abstract

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