Bethanechol Chloride and the Traumatic Cord Bladder

OD22-5347 /82/1281-0085$02.00/0 VoL 128,

THE JOURNAL OF UROLDGY

Printed in

Copyright© 1982 by The 1Nilliams & Vlilkins Co"

Urological

y and U

BETHANECHOL CHLORIDE AND THE TRAUMATIC CORD BLADDER J. KEITH LIGHT*

AND

F. BRANTLEY SCOTT

From the Roy and Lillie Cullen Department of Urologic Research, Charles Evans Research Laboratory, Department of Urology, Baylor College of Medicine, Urology Service of Texas Institute for Rehabilitation and Research, Houston, Texas

ABSTRACT

The effect of bethanechol chloride was evaluated in 28 men with neurogenic bladder disease secondary to traumatic spinal cord damage. Simultaneous measurements of bladder pressure, electromyography of the pelvic floor and flow rate were obtained to evaluate the effect on voiding. The results of these studies revealed that bethanechol chloride failed to improve voiding dysfunction in these patients in either the supine or sitting position. Functional bladder outlet obstruction was aggravated by bethanechol chloride. It was found that the effect of this drug on the bladder was unpredictable, as evidenced by some patients converting from a definite detrusor contraction to a wave type pattern. Bethanechol chloride failed to induce a detrusor contraction in patients with areflexia or wave pattern bladders. Pharmacologic treatment in the manipulation of voiding dysfunction is now well accepted. 1 Patients with neurogenic bladder disease secondary to spinal cord injury exhibit a variety of abnormal voiding patterns, often resulting in varying amounts of post-void residual. One approach to decrease the post-void residual in this population has been to prescribe a cholinergic agent. Although bethanechol chloride is the most widely used pharmacologic agent prescribed for this purpose, there have been conflicting reports on its effectiveness. 2 - 5 Urodynamic studies used to document the effect of this cholinergic agent on bladder function generally have been of a static rather than dynamic nature, for example cystometrogram and post-void residual. 2- 5 Our experience with pressure flow studies to evaluate the effect of bethanechol chloride on bladder function in patients with traumatic spinal cord damage is reported herein. MATERIALS AND Rl[ETHODS

Included in the study were 28 men with neurogenic bladder disease secondary to traumatic spinal cord damage. The neurological level of the lesion was cervical in 19, thoracic in 7 and lumbar in 2. The interval from the accident to the ranged from 6 months to 22 years, with a mean of 4.9 years. ranged from 19 to 40 years old, with a mean of 25 years. AH patients voided into an external catheter either reflexly or with the Crede maneuver. The urine was rendered sterile before the urodynamic studies were done. Two No. 5 feeding tubes were introduced percutaneously into the bladder for infusion of water and determination of bladder pressure. Wire electrodes were introduced into the periurethral muscle. Simultaneous measurements of bladder pressure, flow rate and electromyography of the pelvic floor were obtained using a 4channel recorder. Three voiding cycles were performed with the patients in the supine and sitting position, and a mean was obtained for each position. Then, 5 mg. bethanechol chloride Accepted for publication November 20, 1981. Read at annual meeting of American Urological Association, Boston, Massachusetts, May 10-14, 1981. * Requests for r,eprints: Department of Urology, St. Luke's Episcopal Hospital, 6720 Bertner, Houston, Texas 77030.

85

were administered subcutaneously and studies were repeated 30 minutes later. Each served as his own control. All 28 patients were studied in the supine position and 17 were studied in the sitting position as well. The parameters measured were maximum detrusor pressure, maximum voiding pressure, peak urinary flow, duration of detrusor contraction and percentage of volume voided. The resistance factor was calculated using the formula resistance= maximum voiding pressure/flow 2 • The results were subjected to the paired t test for statistical analysis. RESULTS

The range, mean and standard deviation of the results for the various urodynamic parameters were measured (tables 1 and 2). Maximum detrusor pressure is defined as the highest pressure obtained during the study. There was a highly statistical increase in the mean maximum detrusor pressure from 67.53 to 82.28 cm, water after bethanechol chloride administration with all 28 patients in the supine position. In the sitting position, however, 17 patients showed no significant change after bethanechol therapy. Maxinmm voiding pressure represents the at peak urinary flow. There were 25 patients urinate in the supine position and the increase in the maximum voiding pressure from 45.40 to 52.32 cm. water was (p <0.1). However, with 16 patients in the sitting position there again was no statistical change in the maximum voiding pressure. In 16 patients in the supine position a detrusor contraction developed, which was defined as an increase in pressure of> 15 cm. water. Of the remaining patients 5 had areflexia, 3 had a wave pattern and 4 with a definite contraction before bethanechol therapy had a wave pattern after bethanechol therapy. There was no significant change in the mean duration of the detrusor contraction with the patient in the supine position. In the sitting position 10 patients had a detrusor contraction, while 2 patients had areflexia, 3 had a wave pattern, 1 converted from a contraction to a wave pattern and l converted to areflexia after bethanechol therapy. There was no significant change in the duration of the detrusor contraction with the patient in the

86

LIGHT AND SCOTT

static studies, that is cystometrogram and post-void residual, rather than urodynamic studies. Recently, the ability of bethanechol to improve micturition effectively in patients with Before* After* P Value voiding dysfunction of varying causes has been questioned. 67 .53 ± 34.40 82.28 ± 40.55 <0.0001 Max. detrusor pressure (cm. Wein and associates were unable to detect any improvement in water) Max. voiding pressure (cm. 45.40 ± 25.93 52.32 ± 30.27 <0.1 voiding dysfunction among women with a nonneurogenic and water) nonobstructive cause for the residual urine. 5 Again, however, Peak urinary flow (cc/sec.) 8.06 ± 5.88 4.10 ± 2.80 <0.001 urostatic studies were done. Similarly, Y alla and associates Duration of detrusor con1.23 ± 1.12 1.19 ± 1.21 Not significant expressed disappointment with the results of this drug in mantraction (min.) 49.10 ± 29.80 95.50 ± 35.30 <0.1 %vol. voided aging the voiding dysfunction of patients with neurogenic bladResistance factor 4.27 ± 9.10 14.52 ± 11.20 <0.1 der disease. 7 In addition, the danger of using bethanechol in the * Mean ± standard deviation. presence of functional bladder outlet obstruction has been stressed by these and other authors. 3 • 7 TABLE 2. Urodynamic measurements with patient in sitting position Our study confirms that the dose of bethanechol used was before and 30 minutes after bethanechol administration pharmacologically active, as evidenced by the highly significant Before* After* P Value increase in the maximum detrusor pressure in all patients in the supine position, including those with hyperreflexia and Max. detrusor pressure (cm. 69.88 ± 35.28 72.41 ± 36.00 Not significant water) areflexia. The highest pressures seen were among those patients Max. voiding pressure (cm. 41.80 ± 20.21 41.80 ± 22.32 Not significant with detrusor-sphincter dyssynergia and confirm previous obwater) servations that bethanechol chloride will aggravate functional Peak urinary flow (cc/sec.) 9.39 ± 8.20 5.12 ± 3.27 <0.1 bladder outlet obstruction in neurogenic bladder disease. 3• 7 Duration of detrusor contrac1.54 ± 1.16 Not significant 0.81 ± 1.46 tion (min) Bladder pressure of > 100 cm. water were seen commonly in %vol. voided 48.00 ± 29.00 55.0 ± 32.00 Not significant these patients. In addition to aggravating existing functional Resistance factor 3.47 ± 8.52 14.54 ± 10.70 Not significant bladder outflow obstruction bethanechol chloride has been * Mean ± standard deviation. observed to induce a functional obstruction in some patients. One problem in calculating the resistance factor using the supine position. In neither position did an areflexic bladder or maximum voiding pressure is that it does not take into considwave pattern convert to a definite contraction after administra- eration either the pressure height or duration of the isometric tion of bethanechol chloride. phase of bladder contraction, that is the time from the comThe peak urinary flow decreased significantly from a mean mencement of the contraction to actual occurrence of flow. of 8.06 to 4.1 cc per second after bethanechol administration, p Numerous examples were seen when this phase of the bladder <0.001 with the patient in the supine position. There was a less contraction was aggravated, with increased pressure after adsignificant decrease from 9.39 to 5.12 cc per second observed ministration of bethanechol chloride, but patients had a relawith the patient in the sitting position (p <0.1). tively normal resistance factor when the formula was used, Percentage of volume voided is defined as the amount of incorporating the maximum voiding pressure. urine voided, expressed as a percentage of the total bladder The position of the patient, that is supine or sitting, seems to volume. With the patient in the supine position the percentage influence the effect of the drug. Of all the parameters measured of volume voided increased from a mean of 49.10 to 95.5 after only the peak urinary flow showed some change with the bethanechol therapy (p <0.1). However, the flow pattern was patient in the sitting position (p <0.1). One possible explanation characteristically dribbling in nature in the majority of cases for this may be inadvertent kinking of the urethra by the funnel for a prolonged period. There was no significant statistical used to collect the urine in the sitting position, resulting in the alteration in the mean percentage of volume voided with the decreased urinary flow. The results obtained seem to indicate patient in the sitting position. that the drug does not have any beneficial effect with the The resistance factor increased from a mean of 4.27 to 14.52 patient in the sitting position. Even the maximum detrusor after bethanechol therapy with the patient in the supine posi- pressure, which yielded the most significant change with the tion (p <0.1). Again no significant change was noted with the patient in the supine position (p <0.0001), showed no significant patient in the sitting position. Since the maximum voiding change with the patient in the sitting position after bethanechol pressure and not the maximum detrusor pressure was used in administration. It is well known that changes of position in the calculation it was not unexpected that those patients who spinal cord injury patients can set up abnormal reflexes, for showed detrusor-sphincter dyssynergia did not exhibit any in- example changes in spasticity, or prevent compensatory reflexes crease in resistance. This finding is explained by the fact that from occurring, for example postural hypotension. It was not the activity of the external urethral sphincter ranged from a possible from this study to determine whether a similar rationclonic to tonic activity. In patients with clonic dyssynergia the ale could be applied to the bladder. However, these findings maximum voiding pressures were significantly lower than the suggest that the position of the patient may be important when maximum detrusor pressures. In addition, bethanechol was evaluating the pharmacological activity of any drug on the observed to increase the resistance in some patients who did bladder. not exhibit any bladder outflow obstruction before administraThe ability of bethanechol to induce a detrusor contraction tion of the drug. in the areflexic or wave pattern bladder was not observed in our study. DISCUSSION After bethanechol therapy 8 patients in the supine position Bethanechol chloride is favored clinically as a cholinergic and 5 in the sitting position did not have a detrusor contraction. agent because it exerts a relatively selective action on the In addition, 5 patients were converted from a definite detrusor bladder and bowel, with negligible effects on the ganglia or the contraction before bethanechol therapy to a wave pattern after cardiovascular system. There is no doubt that this agent is therapy, indicating that the effect of this drug is unpredictable. pharmacologically active in vitro since numerous reports attest The duration of the detrusor contraction is not influenced by to the contraction of smooth muscle strips from all areas of the bethanechol in either position. It is believed that the percentage of volume voided is a more bladder as a response to bethanechol. 6 Early clinical studies on the use of bethanechol to im- accurate method to assess voiding efficiency than the post-void prove bladder emptying in humans indicated a favorable re- residual because the total bladder volume is taken into account. s_ponse. 2• 3 However, these conclusions were drawn from uro- This is pertinent when a drug is known to decrease bladder TABLE

1. Urodynamic measurements with patient in supine position before and 30 minutes after bethanechol administration

BETHANECHOL CHLORIDE AND TRAUMATIC CORD BLADDER

capacity owing to increased muscle tone. Again, we observed no significant benefit from bethanechol in this regard with the patient in the sitting position. It is postulated that the lower post-void residual after bethanechol therapy reported previously resulted from a generalized increase in muscle tone, causing a decrease in bladder capacity. In addition, the type of urinary flow observed after bethanechol frequently was constant dribbling, which would support the proposal of a generalized increase in the detrusor muscle tone. It is conceded that this study involved a heterogeneous population and that patients with hyperreflexia, wave patterns and areflexic bladders were included. Ideally, sufficient numbers in each group should be studied. However, unpublished data from our urodynamics laboratory involving a large number of patients have not supported the concept that bethanechol improves voiding, by either improving the quality of the detrusor contraction or actually stimulating a detrusor contraction. Any improvement in voiding appears to be related to an overall increase in bladder muscle tension, as suggested by in vitro studies. The subcutaneous route for administration of bethanechol was chosen since a previous report indicated that this route was more efficient than tablets. 8 Since bethanechol is a drug used commonly in the management of neurogenic bladder dysfunction it is suggested on the basis of these results that there is little place for this drug on its own in the management of voiding dysfunction associated with neurogenic bladder disease. REFERENCES 1. Khanna, 0. P.: Disorders ofmicturition. Neuropharmacologic basis

and results of drug therapy. Urology, 8: 316, 1976. 2. Lapides, J.: Urecholine regimen for rehabilitating the atonic blad-

87

der. J. Urol., 91: 658, 1964. 3. Diokno, A. C. and Koppenhoefer, R.: Bethanechol chloride in neurogenic bladder dysfunction. Urology, 8: 455, 1976. 4. Wein, A. J., Hanno, P. M., Dixon, D. 0., Raezer, D. M. and Benson, G. S.: The effect of oral bethanechol chloride on the cystometrogram of the normal male adult. J. Urol., 120: 330, 1978. 5. Wein, A. J., Malloy, T. R., Shofer, F. and Raezer, D. M.: The effects of bethanechol chloride on urodynamic parameters in normal women and in women with significant residual urine volumes. J. Urol., 124: 397, 1980. 6. Raezer, D. M., Wein, A. J., Jacobowitz, D. and Corriere, J. N., Jr.: Autonomic innervation of canine urinary bladder: cholinergic and adrenergic contributions and interaction of sympathetic and parasympathetic nervous systems in bladder function. Urology, 2: 211, 1973. 7. Yalla, S. V., Blunt, K. J., Fam, B. A., Constantinople, N. L. and Gittes, R. F.: Detrusor-urethral sphincter dyssynergia. J. Urol., 118: 1026, 1977. 8. Diokno, A. C. and Lapides, J.: Action of oral and parenteral bethanechol on decompensated bladder. Urology, 10: 23, 1977. EDITORIAL COMMENT These authors discuss the changes in urodynamic parameters of voiding produced by subcutaneous bethanechol chloride therapy in 28 men with spinal injuries and various lesions. The major conclusions, that bethanechol chloride has an unpredictable result on the bladder in vivo and that it causes no appreciable improvement in voiding, are borne out by the study. On the basis of this study a clinician should not expect to produce voiding in a patient with an areflexic bladder and can probably expect to aggravate any pre-existing functional obstruction caused by a sphincter dyssynergia. Jacek L. Mostwin Brady Urological Institute The Johns Hopkins Hospital Baltimore, Maryland