Effects of Bethanechol Chloride on the External Urethral Sphincter in Spinal Cord Injury Patients

0022-534 7/78/1201-0062$02. 00/0

THE

Vol. 120, July Printed in U.S.A.

JOURNAL OF UROLOGY

Copyright © 1978 by The Williams & Wilkins Co.

EFFECTS OF BETHANECHOL CHLORIDE ON THE EXTERNAL URETHRAL SPHINCTER IN SPINAL CORD INJURY PATIENTS ANDREW SPORER, JOSE FLORANTE J. LEYSON

AND

BOSTON F. MARTIN

From the Department of Urology and Spinal Cord Injury Service, East Orange Veterans Administration Hospital and the New Jersey College of Medicine and Dentistry, Newark, New Jersey

ABSTRACT

The neuropharmacodynamics of bethanechol chloride on the external urethral sphincter in male spinal cord injury patients with chronic lesions have been investigated. There were 90 cystosphincterometric and sphincteroperineal electromyographic studies conducted on 45 subjects in 4 different positions, showing varying urodynamic patterns. A gross postural cystosphincteric discordant reflex was noted in the majority of patients with recent complete upper motor neuron bladders (less than 2 years in duration). The external sphincter tends to be coordinated in late cases of quadriplegics and in all paraplegics. With the administration ofbethanechol chloride there was an increase in the striated sphincter pressure profile when the patient was in the sitting position, resulting in detrusor sphincter dyssynergia. This phenomenon seems to be dose-related. When the dose of bethanechol chloride is adjusted according to the types of vesicourethral dysfunctions or in combination with dantrolene sodium the most beneficial non-surgical rehabilitation of the urinary tract can be obtained in this particular group of patients. Recent advances in neurohistochemical and pharmacologic studies have shed light on the complex neurophysiology of the urethra. 1 Generally, it is accepted that the male and female urethra have a and /3-adrenergic receptors. We do know that the amount ofreceptors gradually diminishes from the vesical neck to the level of the external sphincter (fig. 1). 1 Recent studies clearly indicate the dual sympathetic and parasympathetic innervation of the urethra. 1, 2 It is postulated that the somatic innervated voluntary striated sphincter also receives sympathetic and parasympathetic components of the autonomic nervous system. 1 • 2 Therefore, the external sphincter has triple neurogenic control. We proposed a sympathetic efferent(?) arm 2 • 3 to subserve the effects of posture and the socalled over-facilitation phenomena in patients with high spinal cord lesions. 4 • 5 Under normal conditions the voluntary contraction of the external sphincter before the end of micturition can block detrusor activity. This blockage is caused by the Renshaw cells (interneurons), which are in turn controlled by nuclei in the brain and cerebellum. If the normal physiology of voiding is deranged by vesicourethral incoordination unbalanced bladder function may result, especially in patients with upper motor neuron lesions. r; This abnormal micturition is even more pronounced in those cases in which the neural pathways are hypersensitive, either by the absence of effective central or segmental control or when excessive peripheral stimuli or medications are used. Bethanechol chloride, a cholinergic agent, is used widely to reinforce or induce detrusor activity. However, it also can stimulate part of the urethra and external sphincter (nicotinic effect). 1 We observed that the bladder of recent quadriplegics (less than 2 years after injury) exhibit bethanechol chloride hypersensitivity, resulting in detrusor sphincter dyssynergia much more easily in the early phase of rehabilitation. 7 • 8 Yalla 8 and Dioknof' and their associates condemned the use of bethanechol chloride in the presence of gross (supine) detrusor sphincter discordant reflex, 8 • 10 since it is detrimental to the entire urinary tract. The aim of our study is to evaluate the simultaneous action Accepted for publication June 24, 1977. Read at annual meeting of American Urological Association, Chicago, Illinois, April 24-28, 1977.

of bethanechol chloride on the urethra and the rhabdourethral sphincter with patients in 4 different positions. Our clinical data also attempt to determine whether dose titration of bethanechol chloride alone or in combination with other medication could be used beneficially in patients with bladder sphincter dyssynergia in the presence of postural changes. MATERIAL AND METHODS

We performed 90 urodynamic studies on 45 male spinal cord injury patients. There were 20 patients with an upper motor neuron bladder (15 complete and 5 incomplete lesions, and 1 brain stem injury), 24 with a lower motor neuron bladder (all complete lesions) and 1 with a mixed lesion. The patients ranged in age from 18 to 73 years. The injuries in all subjects were present for 6 months to 22 years. Cystourethroscopy was done to preclude any anatomic outlet obstruction. Perinea! sensation, bulbocavernosus reflex, sphincter tone and extensor plantar reflexes were determined. A continuous technique of intravesical and intrasphincteric activity recordings was done using a special calibrated 12F vinyl catheter.* The urethral pressure profile determinations were based on the constant flow principle of Brown and Wickham. 11 A 5 cc 12F balloon catheter was inserted into the bladder and inflated, and plain films were taken to identify the position of the bladder neck in relation to the anatomic pelvic landmarks. The position of the external sphincter zone in relation to the pubic bones was determined at the beginning of each examination by gradually injecting 5 ml. hypaque-M into the urethra to a total of 7 ml. The contrast medium stops and delineates the site of the external sphincter. With fluorscopic monitoring and with the aid of the catheter calibration marks it was possible during each profile measurement to identify when the catheter hole (single side hole approximately 1 by 2 mm.) reached the external sphincter area. Urodynamic investigations (using Urolab 1053*) were done with the patients in 4 positions. Quadriplegics were kept in the supine and sitting positions, while paraplegics were studied in these positions as well as standing and walking in place. Cystometrics were done by filling the bladder with sterile water at the rate of 10 cc per minute up to approximately 600 cc capacity or less. If the patient did void or if there was

* Life Tech Instrurr ents, Houston, Texas. 62

EFFECTS OF BETlIP::.l~ECHOL C~HLORIDE ON EX.TER.l\T A_L ·uRET}IR,.<\L SPIIINCTER,

63

Fm. 1. Location of autonomic neuroreceptors oflower urinary tract (new concepts). Reprinted with permission 1

leakage around the catheter the urodynamic study was stopped and repeated. During this procedure and with the same catheter a urethral pressure profile with a profilometer model 1700T* was obtained (withdrawal of transducer at a rate of 1 cm. per minute). Striated sphincter-perineal electromyography was done with an anal plug electrode. Internal and external sphincterometrics and perineal electromyographic readings were done on full and empty bladders. The effects of coughing, bulbocavernosus reflex and straining were recorded while the urodynamic studies were being done. Base line readings were obtained from all µo.csc•uc,c, in different without bethanechol chloride. we ~I/,~'~"'"" of the profile and 10 mg. doses were uCU,K>UU-m_y and the recording Residual urine was measured before and

recordings demonstrated an insignificant or mild increase with patients in the supine position. These pressure profiles also were reproducible. However, external sphincter urethral pressure readings with the patients in a sitting position were increased (approximately 10 to 20 cm. water) after the administration of bethanechol chloride. This form of dyssynergia was only seen in external sphincter pressures but no internal sphincter hyperactivity was demonstrated. In a few quadriplegics a coordinated vesicourethral activity was noted (in the sitting position), in which voiding was forceful and complete despite mild increased urethral pressure. Patterns of dyssynergic cystosphincteric activity often were with recent (less than 2 years after motor neuron lesions. Figure 4 details av·h"""" documented urethral pressure profile and after 5 mg. bethanechol chloride to a VV.. CH,H,OU

RESULTS

The cystometrics showed hunn,·n-n (areflexia) bladders in paraplegic and quadriplegic patients in the supine before injection of the bethanechol chloride. However, there vvas postural detrusor hyperreflexia in most quadriplegic patients in the sitting position (fig. 2, A). Cystosphincterometrics before bethanechol chloride demonstrated an average increase of 5 cm. water external urethral sphincter pressure with the patient in the sitting position (fig. 2, B). Cystometrograms with the patient sitting after the administration of bethanechol chloride exhibited dose-related denervation hypersensitivity in most cases, with varying degrees of contracting waves (fig. 3). Urethral pressure readings in all paraplegics essentially were unchanged before and after the application of bethanechol chloride in patients in all 4 positions. In the majority of quadriplegics after the subcutaneous injection of bethanechol chloride the external sphincter profile * Life Tech Instruments, Houston, Texas.

tion. The striated sphincter hyperactivity precipitated by bethanechol chloride in most recent quadriplegics in the sitting position3 seems to be dose-related. DISCUSSION

Normal vesicourethral function is a complex process characterized by volitional control of detrusor reflex and the ability to control on command contraction and relaxation of the periurethral striated sphincter to maintain continence and to effect complete urine emptying. 12 However, various voiding patterns are not uncommon in spinal cord injury patients. The syndrome of detrusor external sphincter dyssynergia as described by several investigators 8 • 12 is also typical in the majority of our patients with complete upper motor neuron lesions. It is characterized by total cessation of voiding, with

64

SPORER, LEYSON AND MARTIN

high intravesical pressure or interrupted spurts of urination and large residual urine volumes. Some patients who have recovered from spinal shock (6 months post-injury) demonstrated bladder areflexia with persistent spastic external urinary sphincter owing to various afferent impulses. 8 Persistent detrusor hyporeflexia or areflexia after the end of spinal shock may be owing to overdistension of the bladder or chronic infection. 13 However, a change in posture (sitting) or administration of bethanechol chloride can induce detrusor reflex activation resulting in detrusor hyperreflexia. 5 • 12 The syndromes of

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bladder areflexia and hyperreflexia have been reported in association with sphincter dyssynergia in a variety of neurological disorders, including spinal cord injuries. 12• 14 This association also was seen in our data. In addition, we noted that the majority of old cases (more than 2 years after injury) with complete upper motor neuron lesions had synergism. We believe that striated sphincter dyssynergia subsides with time, as observed by Yalla and associates. 8 In cases of incomplete upper motor neuron and all types of lower motor neuron lesions vesicourethral synergism was the rule. This decreased excitability of the external sphincter is probably owing to fibrous and muscle fiber degeneration. 15 • A postural hyperreflexic bladder with a detrusor sphincter discordant syndrome was seen in 80 per cent of the patients with recent complete upper motor neuron lesions. The exaggerated dyssynergic activity of the bladder and urethra in patients with upper motor neuron lesions can be owing to multiple factors. It can be caused by a urethral reflex through the interneuron pathway, blocking the reflex arc in the spinal cord. 7• 16 Osterholm has observed that in spinal cord trauma there is cellular leakage of epinephrine and norepinephrine (excess). 17 These adrenergic agents (catecholamines) can excite sympathetic ganglion activity that may influence urethral pressure. 18 We also believe that bethanechol chloride can stimulate the cholinergic receptors along the entire urethral lumen and also may induce contraction of the striated muscle component of the bladder neck. This chain reaction augments urethral resistance and contributes to the syndrome of dyssynergia. 19 The possible mechanisms to explain the concept of bethanechol chloride-induced postural detrusor urethral sphincter dyssynergia are outlined in figure 5. We observed that in the majority of recent complete quadriplegics (6 months to 2 years after spinal shock) there was some form of outlet periurethral obstruction when voiding in a sitting position with high residual urine volumes. This phenomenon is not present when these subjects are in the supine position. From these clinical observations we started a preliminary combined drug regimen, the results of which are reported in the table. As previously noted most of these quadriplegics exhibited postural (sitting) detrusor sphincter dyssynergia. After 3 to 6 weeks of dual drug therapy it seemed that low doses of bethanechol chloride (100 mg. per day orally) produced ineffective detrusor contraction, resulting in high residual urine volumes despite low urethral pressure. On the other hand, when the bethanechol chloride was increased to 250 mg. orally per day there was an exaggeration of the external sphincter urethral resistance, resulting with signifi-

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EFFECTS OF BETI-iAJ\fECHOL c:HLORIDE 01'.:f EXTERJ:IAL -uRI!?l'I"lRAL SFHI1'TCI'ER

cant residual urine volumes augmented detrusor activity. With the combined use of bethanechol chloride and dantrolene sodium in titrated dosages the urethral resistance was reduced and residual urine decreased to 80 cc with the elimination of urinary tract infections. The ideal pharmacological manipulations were 150 mg. oral bethanechol chloride per day and up to 300 mg. oral dantrolene sodium per day. The use of dantrolene sodium to treat striated sphincter spasms has been advocated by Murdock and associates. 20 In patients with lower n1.otor neuron lesions, whether complete or incomplete, no spontaneous postural (bethanechol chloride-induced) detrusor sphincter hyperactivity was noted. Therefore, it is safe to suggest that we can give up to 300 mg.

bethanechol chloride daily to all types of -~·-•-"''- if indicated without effects. Urodynamics have a vital part in the diagnostic armamentarium in the urological assessment of the spinal cord injury patient. This evaluation should be done with the patient in 4 different positions (whenever feasible) to detect postural changes. To evaluate the continual changing patterns of vesico-striated sphincter activity, 21 we advise that urodynan1ic studies be done every 3 months during the first year of injury and 6 to 12 months thereafter for the entire life of the spinal cord patient. Bethanechol chloride, having a dual pharmacological effect, also can sensitize external sphincter pressure' (especially in patients in the sitting position) that seems to be dose-related. Therefore, we believe that the use of bethanechol chloride (as confirmed by other authors 8• H) is injudicious in the presence of supine and sitting detrusor sphincter discordant reflex. 1. 10 However, titration ofbethanechol chloride can be beneficial to a postural type of neuropathic bladder. Our initial study showed that the combined use of titrated bethanechol chloride and dantrolene sodium seems to be the most logical approach in the medical management of patients with high spinal cord lesions with postural detrusor external sphincter dyssynergia. Continuing clinical trials are underway to evaluate whether combined pharmacological manipulations of bethanechol chlo-

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Combined use of bethanechol chloride and dantrolene sodium on urethral resistance (including external urethral sphincter) and their effects on residual urine Bethanechol chloride dosages (orally/day) (100 mg.)

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66

SPORER, LEYSON AND MARTIN

ride and dantrolene sodium (additional cases) and other aadrenergic blocking agents (phentolamine) 16 could reduce the external sphincteric zone resistance, thereby enhancing the effectiveness of bethanechol chloride in this selected group of patients. REFERENCES

1. Khanna, 0. P.: Disorders of micturition. Neuropharmacologic basis and results of drug therapy. Urology, 8: 316, 1976. 2. Elbadawi, A. and Schenk, E. A.: A new theory of the innervation of bladder musculature. Part 4. Innervation of the vesicourethral junction and external urethral sphincter. J. Urol., 111: 613, 1974. 3. Shishito, S., Saito, T., lmabayashi, K., Nakano, N., Shiraiwa, Y. and Aizawa, M.: The role of the spinal ganglion of the sacral nerve on the function of the urinary bladder. Acta Neuroveg., 25: 435, 1963. 4. Ruch, T. C. and Tang, P. C.: The higher control of the bladder. In: Neurogenic Bladder. Edited by S. Boyarsky. Baltimore: The Williams & Wilkins Co., pp. 34-36, 1967. 5. Bradley, W. E . and Timm, G. W.: Cystometry. VI. Interpretation. Urology, 7: 231, 1976. 6. Rossier, A. B. and Ott, R.: Urinary manometry in spinal cord injury: a follow-up study. Value of cysto-sphincterometrography as an indication for sphincterotomy. Brit. J. Urol., 46: 439, 1974. 7. Tulloch, A. G. S. and Rossier, A. B.: The action of neuropharmacologic agents on the bladder and urethra during experimental spinal shock. Invest. Urol., 14: 312, 1977. 8. Yalla, S. V., Rossier, A. B. and Fam, B. A.: Dyssynergic vesicourethral responses during bladder rehabilitation in spinal cord injury patients: effects of suprapubic percussion, Crede method and bethanechol chloride. J. Urol., 115: 575, 1976. 9. Diokno, A. C. and Koppenhoefer, R.: Bethanechol chloride in neurogenic bladder dysfunction. Urology, 8: 455, 1976. 10. Scott, F. B., Quesada, E. M. and Cardus, D.: The use of combined uroflowmetry, cystometry and electromyography in evaluation of neurogenic bladder dysfunction. In: N eurogenic Bladder. Edited by S. Boyarsky. Baltimore: The Williams & Wilkins Co., pp. 106-114, 1967. 11. Brown, M. and Wickham, J. E. A.: The urethral pressure profile. Brit. J. Urol., 41: 211, 1969.

12. Andersen, J. T. and Bradley, W. E.: The syndrome of detrusorsphincter dyssynergia. J. Urol., 116: 493, 1976. 13. Bradley, W. E., Chou, S. and Markland, C.: Classifying neurologic dysfunction of the urinary bladder. In: Neurogenic Bladder. Edited by S. Boyarsky. Baltimore: The Williams & Wilkins Co., pp. 139-146, 1971. 14. Bors, A. and Comarr, A. E.: Neurological Urology. Physiology of Micturition, Its Neurological Disorders and Sequelae. Baltimore: University Park Press, 1971. 15. Cukier, J., Leger, P., Benhamou, G., Lacombe, M., Maury, M. and Couvelaire, R.: La myotomie chirurgicale du sphincter strie de l'urethre. Une nouvelle voie d'abord sous-pubienne. Contribution a l'etude de la pathologie du sphincter strie du paraplegique. J. Urol. Nephrol., 77: 27, 1971. 16. Awad, S. A., Downie, J. W., Lywood, D. W., Young, R. A. and Jarzylo, S. V.: Sympathetic activity in the proximal urethra in patients with urinary obstruction. J. Urol., 115: 545, 1976. 17. Osterholm, J. L.: Early management of spinal cord injury: theory and practice. The vascular and cellular basis for spinal cord hemorrhage necrosis. In: Current Controversies in Neurosurgery. Edited by T. P. Morley. Philadelphia: W. B. Saunders Co., chapt. 5, pp. 100-109, 1976. 18. Bissada, N. K., Finkbeiner, A. E. and Welch, L. T.: Lower urinary tract pharmacology. III. N europharmacologic basis for lower urinary tract dynamics. Urology, 9: 357, 1977. 19. Yalla, S. V., Gabilondo, F. B., Blunt, K. J., Fam, B. A., Castello, A. and Kaufman, J.M.: Functional striated sphincter component at the bladder neck: clinical implications. J. Urol., 118: 408, 1977. 20. Murdock, M. M., Sax, D. and Krane, R. J.: Use of dantrolene sodium in external sphincter spasm. Urology, 8: 133, 1976. 21. Thomas, D. G., Smallwood, R. and Graham, D.: Urodynamic observations following spinal trauma. Brit. J. Urol., 47: 161, 1975.

EDITORIAL COMMENT This is an interesting study, further confirming the limitation of bethanechol chloride in the management of patients with spinal cord injury. The authors also used the techniques of urodynamics to investigate the effects of posture on sphincter function. Obviously, the future application of pharmacologic techniques to restoration of voiding will require increasingly extensive urodynamic investigation of postural reflex activating procedures. W.E.B.