Treatment of Female Stress Incontinence with Midodrine: Preliminary Report

Vol. 118, December Printed in U.SA.

THE JOURNAL OF UROLOGY

Copyright © 1977 by The Williams & Wilkins Co.

TREATMENT OF FEMALE STRESS INCONTINENCE WITH MIDODRINE: PRELIMINARY REPORT D. JONAS From the Department of Urology, University of Frankfurt Medical School, Frankfurt, Federal Republic of Germany

ABSTRACT

For 10 days 21 female patients with clinical stages I to III stress incontinence and 4 continent control female patients were treated with the alpha-sympathomimetic midodrine. Urethrometry revealed that alpha-adrenergic stimulation resulted in an increase in the urethral occlusion pressure of up to 30 per cent and, cystometrically, to an increase in the detrusor pressure of up to 35 per cent without impairment of bladder capacity. In the stage I group 83 per cent and in the stage II group 63 per cent of the patients became continent. Midodrine, the advantage of which over comparable sympathomimetics, such as ephedrine, synephrine and norphenylephrine, lies in the absolutely sure and sustained action in oral use, is recommended as an alternative therapy to traditional surgical procedures in the treatment of stages I and II female stress incontinence. Urinary incontinence can be influenced pharmacologically by stimulating the alpha-adrenergic receptors in the bladder occlusion zone, 1 • 2 resulting in an increase in resistance to vesical discharge that may improve continence. 3, 4 However,

With the same doses synephrine and norphenylephrine were inactive in this test arrangement (fig. 1). The importance of midodrine in the treatment of female stress incontinence is verified herein.

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an obstacle to the wide use of drug incontinence therapy is the short period of action of the oral drugs used previously (ephedrine, synephrine and norphenylephrine). Midodrine* is an alpha-sympathomimetic that has the advantage over other oral substances of a protracted onset of action and a longer period of activity. Pittner was able to show that after intraduodenal introduction of 10 mg. per kg. midodrine, ephedrine, synephrine and norphenylephrine in anesthetized rats midodrine resulted in a maximum rise in blood pressure in the carotid artery of 64 mm. Hg after 38 minutes with a period of activity of 210 minutes. 5 The comparable values for ephedrine were about 70 per cent lower. Accepted for publication February 18, 1977.

* Gutron, Chemie Linz AG, A 4021 Linz, Austria. 980

MATERIAL AND METHODS

A control group of 4 continent female patients was matched against 21 incontinent female patients who were classified according to the method of Ingelman-Sundberg. 6 There were 6 patients with stage I, 11 with stage II and 4 with stage III incontinence. The average age of all patients was between 52 and 57 years. Of the 21 incontinent patients 8 had undergone gynecological operations with prolapse, rectocele or cystocele in some cases (table 1). All patients received 5 mg. midodrine orally 3 times a day for 10 days. Before and after treatment the neuropharmacological effects on the inferior urinary tract were monitored by cystometry and urethrometry, and the pulse and blood pressure were checked.

TREATMENT OF FEMALE STRESS INCONTINENCE WITH MmODRINE TABLE

l. Cases and results after 10 days of midodrine therapy Present State

No. Pts.

4 6

H 4,

Average Age (yrs.) 57 57 53 52

Stage of Incontinence (degree)

Previous Operations*

0

I IT

m

2/6 (33%) 4/11 (36%) 2/4 (50%)

DescendinJ Uterus an Vagina 1/4 (25%) 3/6 (50%) 3/11 (27%) 1/4 (25%)

Cystocele

2/6 (33%) 4/11 (37%) 2/4 (50%)

Rectocele

Results Improved

Continent

5/6 (83%) 7/11 (63%) 0/4 (0%)

1/11 (9%) 1/4 (25%)

No Success

1/6 (17%) 2/11 (l.8%) 3/4 (75%)

2/11 (18%) 1/4 (25%)

* Vaginoplasty and myoma extirpation. Cystometry. After the determination of residual urine with a 12 Charr polyvinyl nelaton catheter with the patient in the supine position a 4 Charr polyvinyl measuring catheter was inserted also into the bladder. The 12 Charr catheter was used to achieve continuous retrograde filling of the bladder to ~LJ""~''"'"·' with 0.9 per cent saline (constant inflow speed 50 ml. per minute). At the same time the intravesical pressure was transmitted through the measuring catheter to a pressure transformer,* amplified t and recorded. :j: After the end of measurement the capacity was determined by voiding through the inserted catheter. To prepare the next measurement the bladder was filled with 50 ml. 0.9 per cent saline and both catheters were removed. Cystourethrometry. A 12 Charr 3-channel urethrometry catheter with a central tip opening was inserted transurethrally in.to the bladder (fig. 2). The 12 Charr catheter contains 2, 4 Charr measuring catheters, of which one is for measuring the pressure in the urethra and the other is for measuring the pressure in the bladder. The •1rethral and bladder catheters extend beyond the thin calibu perfusion catheter by 0.2 and 6 cm., respectively. Directly bt•hind the tip of the perfusion catheter, with an interval of 1 cm., is a double mark for x-ray examinations. Before descending simultaneous cystourethrometry7 the marked catheter tip is placed under x-ray monitor control into the bladder outlet. On continuous perfusion (5 ml. per minute) with 0.9 per cent saline with a perfusor§ at a constant speed (3 cm. per minute) the catheter is drawn. back mechanically through the entire urethra. The measuring urethral catheter transmits continuously the urethral resistance and the measuring bladder catheter, which for most of the investigation remains in the bladder, transmits continuthe intravesical pressure to 1 Statham element each. The 2 pressure sign.als are recorded through separate amplifiers. RESULTS

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Cystometry. All patients were free of residual urine before and after midodrine therapy. Before the administration of midodrine the bladder capacity was highest in the continent patients (465 ml.) and lowest in patients with stage III incontinence (275 ml.). The maximum detrusor pressure in the continent and incontinent patients was, except for a value of 13 cm. water in stage I incontinence, between Hi and 18 cm. water . .,After therapy with midodrine the bladder capacity in the continent patients was unchanged, compared to that for all 3 stages of incontinence when a slight rise in bladder of 2 to 10 per cent was recorded. The maximum pressure amplitude increased after midodrine in. all 4 groups by 22 to 35 per cent (fig. 3). Before midodrine treatment was reduced heavily with minimum values for stage Ill incontinence. After midodrine the compliance decreased in the individual groups by 19 to 23 per cent (fig. 4). Cystourethrometry. After midodrine therapy a rise of more than 10 per cent in the urethral occlusion pressure was noted

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in the continent patients and for incontinence in stages I and II this increase was 30 and 25 per cent, respectively. The angle of rise of the pressure curve was 8 per cent above the initial value for continence and 6 per cent for stages I and H incontinence. In stage HI the percentage change in both parameters was insignificant (fig. 5, A). The mean values for urethral occlusion pressure of the functional urethra subdi.vided into 5 portions before and after midodrine treatm.ent showed the maximum pressure rise in the third-fifth distal to the bladder outlet with the exception of stage I incontinence. As was expected, the general level of the pressure curves was above the initial curve, particularly in the continent uaueiu,, and also in stage H incontinence, while in stage HI nc important pressure gain was seen (fig. 5, B).

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20

gations. Also, as indicated herein midodrine appears to be effective in the treatment of postoperative incontinence (for example after total prostatectomy), neurogenic incontinence (with or without residual urine) and disturbances in ejaculation (for example after retroperitoneal lymphadenectomy for teratomatous testicular tumors).

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Fm. 5. A, mean values of urethral occlusion pressure and increased angle of pressure curve. B, mean urethra pressure profile before(--) and after (e-e) 10-day midodrine treatment.

Clinical results. With this treatment 83 per cent of the patients in stage I and 63 per cent in stage II became continent. In stage II 18 per cent showed improvement. In stage III no decisive therapeutic success was recorded (table 1). At the same time the pulse rate decreased by 8 per cent and the systolic and diastolic pressures increased by 9 to 10 per cent (table 2). DISCUSSION

The urethral occlusion pressure, which is diminished in stress incontinent female subjects as a result of the atony of the musculature of the pelvic floor, can be influenced by midodrine. Alpha-adrenergic stimulation leads in the smooth musculature of the bladder and urethra not only to a distinct rise in urethral resistance but, at the same time, to a rise in the detrusor pressure without impairing bladder capacity. Therefore, the recommended treatment with midodrine in stages I and II incontinence should take precedence over the competing surgical procedures. The rise in the systolic and diastolic pressures and also the slight decrease of reflex origin in the heart rate are, as an effect of alpha-adrenergic stimulation of the vascular system, mostly unavoidable in the treatment of female stress incontinence with midodrine. This circulatory effect for the dose used in this study (5 mg. 3 times a day) or an attenuated effect for a reduced dose (2.5 mg. 3 times a day) in the treatment of constitutional hypotension has been confirmed by numerous investigations. &-1 1 It is noteworthy that in normotensive subjects between 15 and 53 years old no significant change in the circulatory situation was observed. 12 Thus, the indication for midodrine in hypotensive and normotensive stress incontinent female subjects under regular circulatory control appears justified. However, hypertension is an absolute contraindication. Decisive evidence for the effectiveness of midodrine as compared with other sympathomimetics is its sustained activity even in oral use (fig. 1). Ephedrine administered via the same route and used primarily in cases of neurogenic incontinence4 is considered second-rate compared to midodrine. A guaranteed effect of synephrine in stress incontinence3 is doubtful because of the results of the aforementioned investi-

REFERENCES

1. Elbadawi, A. and Schenk, E. A.: A new theory of the innervation of bladder musculature. Part 3. Postganglionic synapses in uretero-vesico-urethral autonomic pathways. J. Urol., 105: 372, 1971. 2. Donker, P. J., lvanovici, F. and Noach, E. L.: Analyses of the urethral pressure profile by means of electromyography and the administration of drugs. Brit. J. Urol., 44: 180, 1972. 3. Stockamp, K. and Schreiter, F.: Beeinflussung von Harninkontinenz und neurogener Harnentleerungsstorung iiber das sympathische Nervensystem. Akt. Urol., 4: 75, 1973. 4. Schrott, K. M. and Sigel, A.: Neue Aspekte der Pharmakotherapie der neurogenen Blase. Verh. Dtsch. Ges. Urol., 27: 142, 1975. 5. Pittner, H.: Vergleichende Untersuchung zur Kreislaufwirksamkeit von Alpha Sympathomimetica. Personal communication, 1976. 6. lngelman-Sundberg, A.: Gynakologische Urologie. In: Gynakologie und Geburtshilfe. Edited by 0. Kaser, V. Friedberg, K. G. Ober, K. Thomsen and J. Zander. Stuttgart: G. Thieme Verlag, Band III, Spezielle Gynaekologie, 1972. 7. Heidenreich, J. and Beck, L.: Simultane Druckmessung in Harnblase und Harnriihre zur Diagnostik der Harninkontinenz. Arch. fur Gynaekologie, 211: 325, 1971. 8. Schramek, G., von and Wolkerstorfer, H.: Zur Therapie der konstitutionellen Hypotonie. Wien. med. Wschr., 123: 571, 1973. 9. Paumgartner, G., Pokorny, D. and Grabner, G.: Experimentelle und klinische Erfahrung mit einer neuen blutdrucksteigernden Substanz (2'; 5' -dimethoxyphenyl-2-glycinamidoathanol1-hydrochloride). Wien. Klin. Wschr., 82: 490, 1970. 10. Lachner, 0., von, Lillie, C. and Roth, H.: Pharmakologie von Midodrin sowie dessen klinische Austestung bei hypotoner Regulationsstiirung des Kreislaufes. Wien. Klin. Wschr., 86: 344, 1974. 11. Engel, K., von, Havelec, L., Klausgraber, F. and Pramer, I.: Vergleichende Untersuchungen und Beurteilung der therapeutischen Verwendungsmiiglichkeit von Midodrin (Gutron) beim Hypotoniesyndrom. Wien. med. Wschr., 124: 501, 1974. 12. Steinbach, K., von and Weidinger, P.: Der Einflu58 von Midodrin auf die Orthostase. Wien. Klin. Wschr., 85: 621, 1973. COMMENT The aforementioned alpha-adrenergic stimulating agent may prove superior to ephedrine in the management of female stress incontinence. This study adds another adrenergic agent to a growing armamentarium for the uropharmacology of urinary incontinence. WEB.