Acta Paediatr 81: 345-50. 1992
Effect of phenylpropanolamine on incontinence in children with neurogenic bladders. A double-blind crossover study P Amark'S2 and 0 Beck2 Departments of Paediatrics' and Clinical Pharmacology2.Karolinska Hospital. S-104 01 Stockholm. Sweden
Amark P, Beck 0. Effect of phenylpropanolamine on incontinence in children with neurogenic bladders. A double-blind crossover study. Acta Pzdiatr 1992;8 1:345-50. Stockholm. ISSN 0803-5253 In children with myelodysplasia and a low-level spinal cord lesion (low lumbar-sacral), detrusor hyperactivity together with dyssynergic urethral function forms the main pathophysiological basis for incontinence. Pharmacological treatment of incontinence due to neurogenic bladder dysfunction has been tried, mainly with anticholinergics and alpha-adrenoceptor antagonists. In this study, the effects of the alpha-adrenoceptor agonist phenylpropanolamine on urodynamic parameters and incontinence were investigated in 10 patients. Effects on incontinence were evaluated in a double-blind crossover trial. Plasma concentrations of phenylpropanolamine were measured by means of gas chromatography-mass spectrometry. Phenylpropanolamine reduced detrusor hyperactivity and improved continence, but the effect was not so pronounced as to make the patients continent. 0 Adrenergic receptor agonist. drug analysis, incontinence, neurogenic bladder, phenylpropanolamine P Amark, Department of Pediatrics, Karolinska Hospital, I04 01 Stockholm, Sweden
Most children with myelodysplasia suffer from inconti- phenylpropanolamine (PPA) on urodynamic paranence. Among these children, those with the upper limit meters and incontinence was evaluated in a group of of the spinal cord lesion at the low lumbar or sacral level children with myelodysplasia and neurogenic bladders. show the same type of lower urinary tract pathophysiology. They have detrusor hyperactivity with waves of increased bladder pressure, often accompanied by a decrease in urethral pressure (1, 2) which results in Material and methods intermittent urinary leakage during the bladder-filling phase. The detrusor hyperactivity may be abolished by Patient material atropine (3) and continence is promoted (4). The The patients were consecutively selected from the ward adrenergic influence on the lower urinary tract in these in the Pediatric Clinic where children with neurogenic patients has also been studied. Beta-adrenergic bladder dysfunction are examined. All patients had influence is presumed to relax the detrusor during myelodysplasia and the upper limit of the spinal cord normal filling, but beta-adrenoceptor agonists do not lesion at the low lumbar or sacral level was judged by influence detrusor hyperactivity (3) or promote conti- clinical examination of motor and sensory functions and nence ( 5 ) . For the contractile function of the bladder reflexes (1 3). All were incontinent and earlier urodynabase and the urethral smooth muscle, alpha-adrenocep- mic studies described below had revealed detrusor tor function is important (6, 7), while in the normal hyperactivity. The patients were not receiving any other detrusor its function (shown in some studies (8, 9) but medication for treatment of incontinence. Informed not others (6, 10)) may be less important. Adrenergic consent for participation in the study was obtained from nerve terminals become more densely distributed within the patients and their parents. The study was approved the detrusor muscle in a state of decentralization of by the Ethics Committee of the hospital. Details of the bladder parasympathetic innervation ( 1 1) and then patients are shown in Table 1. alpha-adrenoceptor function may play a role in the occurrence of detrusor pathophysiology. In an earlier study (1 2) the effects of noradrenaline and phentolamine Urodynamic de3nition.s on the detrusor and the proximal urethra were studied in According to the International Continence Society children with myelodysplasia and detrusor hyperacti- (ICS) terminology (14), the overactive detrusor function vity. Both drugs diminished detrusor hyperactivity. The in these patients is called detrusor hyperreflexia. We proximal urethral pressure decreased with phentola- have chosen to refer to the overactivity in these patients mine and increased with noradrenaline therapy. In this as detrusor hyperactivity. This is defined as detrusor study, the influence of the alpha-adrenoceptor agonist contractionsexceeding 10cmH200veraperiodof > 10s.
346
P Amurk und 0 Beck
ACTA PEDIATR 81 (1992)
Table 1. Patient data.
Sex
Age (years)
Weight (kg)
Independent walker
Clean intermittent catheterization
Urine culture
I
F
7
26
Yes
Yes
Negative
2
F
I1
26
Yes
Yes
3
M
18
70
Yes
No
4
9
27
Yes
14
63
N O
11
34
6
23
14
44
9
M M M M M F
12
34
Yes Yes Yes Yes
No Yes No No No Yes
10
F
12
50
Yes
Yes
Negative (placebo) E. coli lo7 (PPA) Negative (placebo) E. coli lo6 (PPA) Negative Negative Negative Negative Negative Negative (placebo) E. coli lo5 (PPA) E. coli lo5
Patient No.
5
6 7
8
Examination procedure The urodynamic investigation was performed in the following way. The patient was placed in the supine position. The bladder was emptied via a catheter, the amount of urine was measured and a culture was taken. Before removal of the catheter, isotonic saline (50-1 25 ml) was slowly (1-3 min) administered into the bladder. Pressures were then recorded in the bladder and the urethra during normal diuresis using a thin dacron catheter (Millar Instr. Inc.) with two transducers, one at the tip of the catheter and one 4 cm from the tip. The intra-abdominal pressure was recorded by a microtransducer at the end of a catheter placed in the rectum. The pressures were recorded on a Grass model 7D polygraph. The system was calibrated against a water column after each examination. This technique has been described earlier (1, 15). The position of the transducers in the urinary tract was determined by comparing the recordings when the catheter was slowly withdrawn from a location where both transducers were in the bladder. Throughout the examination the patient drank water, usually not more than 500 ml. When continuous detrusor hyperactivity occurred, the pressures in the urethra and the bladder and the number of waves were measured for 15 min. Blood pressure and pulse rate were noted. An oral dose of PPA (50-1 50 mg) was given as a slow-release preparation (Monydrin, Draco, Lund, Sweden). During a continuous urodynamic study, evaluations lasting 15 min were again performed at I , 2 and, in some cases, 3 h after
Medication Trimsulfa prophylaxis Nitrofurantoin
None
None None None None None Nitrofurantoin prophylaxis
Nitrofurantoin prophylaxis
drug administration (Fig. 1) when blood samples were also drawn for analysis of plasma PPA concentrations. Experimental design A randomized double-blind crossover study design was performed. The study was organized in the following way: the patients were evaluated on the ward during three periods of one week with intervals of two weeks between each period. During the first week the initial urodynamic evaluation was made. During all three periods the following were recorded: measurement of incontinence, blood pressure, pulse rate, urinary culture, residual urine volume, subjective assessment and adverse reactions. After the run-in evaluation, medication was given for two weeks, followed by the next inward evaluation. The treatment was then changed during the following two weeks and the study was completed with the last evaluation. The dose of PPA was chosen with the help of the pharmacokinetic studies of Lonnerholm et al. (16) and Fossberg et al. (1 7). PPA plasma level analysis Blood samples were drawn during the urodynamic study and before the morning dose of PPA was given during steady-state treatment. We used a gas chromatographic-mass spectrometric (GCMS) method, a modification of the electron-capture capillary gas chromatographic method described by Crisologo et al. (18) for
Effect of phenylpropanolamine on incontinence
ACTA PRDIATR 81 (1992)
347
cm H,O
B
20 ~~
OL I
I
115
120
130min
125
Fig. 1. Intravesical (A) and urethral (B) pressure recordings before (above) and 2 h after (below) oral administration of PPA (3 mg/kg, plasma level 181 nglml). Each point indicates a wave of hyperactivity ( > 10 cmH2O > 10 s.).
Internal standard
PPA
, t " "
70
,
.h.,
,
.
,
j\, - ,
, ,
,.
,
1 _ .
105
126
RETENTION TIME (seconds) Fig. 2. Chromatogram obtained from the selected ion monitoring analysis of a plasma sample. A volume of 0.5 ml plasma was used and 1/50 of the final extract ( I pl) was injected into the GC-MS system (HP 5890 A and Finnigan Incos 50). T h e monitored ion (m/z 280) represents the loss of one C2FsCOO radical from the respective molecular ions of the dipentafluoropropionyl derivatives of PPA and the internal standard (2amino-3-phenyl-I-propanolol).This sample was found to contain 290 ng/ml.
348
P Rrncirk uncl 0 Beck
A C T A PKDIATR 81 (1992)
plasma analysis of PPA (Fig. 2). The difference was the use of pentafluoropropionic anhydride instead of trifluoroacetic anhydride and the use of mass spectrometric detection. These modifications are not likely to influence significantly the results obtained with this method.
ated. The Wilcoxon signed rank test was used to evaluate changes in incontinence. P < 0.05 was regarded as significant.
Results
Measurement of incontinence Pharmacological eflects on urodynamic parameters During the three evaluation periods, incontinence was During PPA therapy the number of hyperactivity waves measured during three consecutive days. The patients was reduced (12.3f7.3 before and 7 f 7 after 2 h, were hospitalized on the ward during each evaluation p < 0.05, Fig. I). The urethral pressure increased in some period under similar conditions with respect to food and patients, but statistical significance was not reached fluid intake, physical activity and other daily activities. (33.8f 16 before and 41.7f 17 after 2 h). The intravesiWeighed diapers were always used and changed every cal pressure was not changed. Blood pressure and pulse hour in the daytime. A >2-g increase in weight was rate were not significantly altered. The mean dose regarded as due to urinary leakage. During the day, administered was 2.9 mg/kg (range 2.1-3.7 mg/kg). micturition or clean intermittent catheterization was Blood samples were obtained from seven patients. performed every 3 h. Volumes voided and due to leakage Plasma levels of PPA 2 h after drug administration were were noted. The degree of incontinence was also 380 f262 ng/ml. assessed according to the method of Nergdrdh et al. ( 1 9): group A: regularly dry for periods of 3 h; group B: daily dry periods of between 1 and 3 h; group C: occasional Pharmacological eflects on incontinence dry periods of between 1 and 3 h; group D: always wet There were no significant day-to-day differences in fluid intake. Daily urine volumes showed some variations. between micturitions. The mean daytime leakage episodes was calculated for each patient and was significantly lower during active Subjective assessment treatment than with placebo (Table 2). The number of The patients were asked which treatment they preferred 3-h dry periods increased during active treatment (runon the basis of their impression of treatment at home. in = 21, placebo = 20, PPA = 37; p < 0.05). There was a The degree of change in continence was regarded as nil shift towards a lesser degree of incontinence (Table 2). (0), moderate (+) or good (+ +). Side effects were The volumes of residual urine were not altered. Blood samples were obtained from nine patients during treatnoted. ment with PPA. Five patients reported a good or moderate effect of PPA and they showed better results Statistical evaluation when measured objectively; their daily dose was 3.5 mg/ Values are given as mean f S D . The two-tailed Stu- kg (range 1.9-5.8 mg/kg). The plasma level in these dent's t-test for independent or paired observations was patients was 381 f 114 ng/ml, which was significantly used when plasma levels of PPA were compared and higher than the plasma concentration measured in the when changes in urodynamic parameters were evalu- four patients in whom the effect of PPA was weak Tuhle 2. Treatment results.
Patient No. 1
2 3
4"
5 6 1
8 9 10 a
Daily dose of PPA (mg)
Plasma level PPA (ngiml)
100 100
48 1 221 310
200 I00 200 100 100 200 200 200
-
496 I39 206 212 393 147
Degree of incontinenceb Subjective assessment
++ + + 0 ++ 0 0 0
+ 0
Number of 3-h dry periods during three consecutive days
Number of leakage episodes (mean/day)
Run-in
Placebo
PPA
Run-in
Placebo
PPA
Run-in
Placebo
PPA
B B D D C C C B B B
C A D D C C D C B B
A A C D A B C B A B
I 9 0 0 0 I 0 4 3 3
0 9 0 0 0 I 0 I 5
4
6
9 1
2 13 13
II 2
6 1
14
13 12 6 9 9 11 6 9
4
0 7
2 2 3 6 3
10 10
II 8 8 9
A blood sample could not be obtained from patient No. 4; degree of incontinence (A-D) is explained in the text.
12 II 12 II 12 8 7
ACTA PADIATR 81 (1992)
(176 f38 ng/ml) and who were given a daily dose of 4.0 mg/kg (range 2.9-4.5 mg/kg).
Effect of phenylpropanolamine on incontinence
349
the detrusor and the urethra by the alpha-adrenoceptor antagonists. Alpha-adrenoceptor agonists, on the other hand, have been used to increase urethral pressure in order to treat stress incontinence in otherwise healthy Aduerse reactions women ( 1 7, 27). Such treatment has also been used 'for In two patients a slight increase in systolic blood nocturnal enuresis in childhood (28). The rationale for pressure was noted during active treatment. Three this treatment is the effect of alpha-adrenoceptors on patients reported fatigue, mood changes and sleep urethral smooth muscle-mediating contraction (6, 7).' disturbances. However, these reactions were tolerated However, the use of alpha-adrenoceptor agonists to by two patients; in the third patient the dose was reduced improve continence in children with neurogenic bladfrom 100 to 50 mg twice daily, and the side effects ders has not been evaluated. disappeared and treatment was continued. Fossberg et al. (17) concluded that plasma levels of PPA above 150 ng/ml were needed to improve continence, while there was no correlation between plasma Subjective assessment levels and increased urethral resistance. Collste & Increase in incontinence was never reported. All patients Lindskog (27) found no correlation between plasma reported that the placebo had no effect on incontinence levels and subjective or objective improvement. In our and caused no side effects. Active treatment was study the plasma levels were higher than in the two regarded as ineffective by five patients and of moderate above-mentioned studies, probably because of the value (+) by three patients, while two reported a good higher doses given. In both these studies plasma levels were measured a few hours after the last dose of PPA ( + +) effect. was given and not just before drug administration. It also appears that plasma levels higher than in the abovementioned studies are needed to improve continence in Discussion our patients. The effect on the circulation was weak, even when high plasma levels were reached. Treatment In this study the effects of phenylpropanolamine, an alpha-adrenoceptor agonist, on the pathophysiology of with phenylpropanolamine in this particular group of the lower urinary tract and on incontinence in a group of patients may improve continence, but we conclude that children with neurogenic bladders were evaluated. the effect is not good enough to recommend treatment, Detrusor hyperactivity was reduced while urethral and except in well selected cases. intravesical pressures were not significantly changed. In AcknoM'/edge~ienls.-This study was supported by grants from the the double-blind crossover study, PPA treatment Norrbacka-Eugenia Foundation and Sallskapet BarnavArd. The improved continence in half of the patients. Placebo skilful assistance of Ms Ebba Nilsson in evaluating continence is gratefully acknowledged as is her assistance and that of Head Nurse treatment produced no effects. Maj-Britt Pettersson in carrying out the urodynamic examinations. Problems arise in evaluating the effect of treatment Ms Inger Unnerstad provided valuable help in preparing figures and for incontinence. There may be day-to-day variations in tables. The authors thank Draco Lakemedel AB for PPA and placebo the severity of symptoms which are influenced by factors tablets. such as psychological stress, physical activity, food and fluid intake and compliance with schedules for regular bladder emptying. In this study incontinence was evalu- References ated under conditions as controlled and similar as 1. Naglo A-S, Nerghrdh A. Diagnosis of detrusor hyperactivity in possible regarding the above-mentioned factors during children with neurogenic bladder. Scand J Urol Nephrol three different periods of evalution, thus ensuring a I98 I; I5:91-6 good basis for comparison of placebo versus active 2. NergArdh A, Naglo A-S. Observations on the internal sphincter mechanism during the filling phase in children with hyperactive treatment. neurogenic bladder. Scand J Urol Nephrol 1982;16205-9 The side effects on mood may be attributed to the 3. Naglo A-S, NergArdh A, Bortus LO. Influence of atropine and central effects of PPA. Such adverse reactions have been isoprenaline on detrusor hyperactivityin children with neurogenic reported to be commoner in children than in adults (20). bladder. Scand J Urol Nephrol 198 I ;15:97- 102 4. Naglo A-S. Continence training of children with neurogenic Earlier reports (3, 4) showed that anticholinergic bladders and hyperactivity of the detrusor: Effect of atropine. treatment reduces detrusor hyperactivity and improves Scand J Urol Nephrol 1982;16:211-17 continence. Alpha-adrenoceptor antagonists have been 5 . Naglo A-S, Bortus L-0,Hellstrom B, NergArdh A. Is betaused for the treatment of incontinence due to neurogenic receptor blockade of value in continence training of children? Scand J Rehabil Med 1979;I 1:63-6 bladder dysfunction (21, 22). Both non-selective alpha6. NergArdh A, Boreus L-0. Autonomic receptor function in the antagonists, such as phenoxybenzamine ( 1 1, 23, 24), lower urinary tract of man and cat. Scand J Urol Nephrol and alphal-selective antagonists, such as prazosin (7,25) 1972;632-6 or indoramine (26) have been used. The fact that bladder 7. Andersson K-E, Ek A, Hedlund H, Mattiasson A. Effects of capacity improved as did bladder emptying with deprazosin on isolated human urethra and in patients with lower motor neuron lesions. Invest Urol 1981;19:39-42 creased residual urine volumes, indicates effects on both
350
P Amark and 0 Beck
8. Awad SA, Bruce AW, Carro-Ciampi G, Downie JW, Lin M. Distribution of alpha- and beta-adrenoceptors in human urinary bladder. Br J Pharmacol 1974;50525-9 9. h a r k P, Nergirdh A, Kinn A-C. The effect of noradrenaline on the contractile response of the urinary bladder. Scand J Urol Nephrol 1986;20:203-7 10. Kullendorff CM, ElmCr M, Alm P. Urinary bladder innervation in children. J Pediatr Surg 1987;22:240-2 I I. Sundin T, Dahlstrom A, Norlen L, Svedmyr N. The sympathetic innervation and adrenoceptor function of the human lower urinary tract in the normal state and after parasympathetic denervation. Invest Urol 1977;14:322-8 12. Amark P, Nergirdh A. Influence of adrenergic agonists and antagonists on urethral pressure, bladder pressure and detrusor hyperactivity in children with myelodysplasia. Acta Paediatr Scand 1991;80:824-33 13. Ericsson NO, Hellstrom B, Nergirdh A, Rudhe U. Factors promoting urinary and anal continence in children with myelomeningocele. Acta Paediatr Scand 1970;59:491-6 14. Abrams P, Blaivas JG, Stanton SL, Andersen J. The standardisation of terminology of lower urinary tract function. International Continence Society Committee on Standardisation of Terminology. Scand J Urol Nephrol 1988;(suppl 114):5-19 15. Asmussen M, Ulmsten U. Simultaneous urethrocystometry with a new technique. Scand J Urol Nephrol 1976;107-11 16. Lonnerholm G, Grahnen A, Lindstrom B. Steady-state kinetics of sustained-release phenylpropanolamine. Int J Clin Pharmacol Ther Toxicol 198422:39+ I 17. Fossberg E, Beisland HO, Lundgren RA. Stress incontinence in females: Treatment with -phenylprooanolamine. Urol Int - _ 1983;38:293-9 18. Crisologo N, Dye D, Bayne WF. Electroncapture capillary gas
ACTA PEDIATR 81 (1992)
chromatographic determination of phenylpropanolamine in human plasma following derivatization with trifluoroacetic anhydride. J Pharm Sci 1984;73:1553-6 19. Nergirdh A, von Hedenberg C, Hellstrom B, Ericsson NO. Continence training of children with neurogenic bladder dysfunction. Dev Med Child Neurol 1974;16:47-53 20. Norvenius G, Widerlov E, Lonnerholm G. Phenylpropanolamine and mental disturbances. Lancet 1979;2: 1367-8 21. Hilwa N, Perlmutter A. The role of adjunctive drug therapy for intermittent catheterization and selfcatheterization in children with vesical dysfunction. J Urol 1978;119:551-5 22. De Voogt HJ, van der Sluis C. Preliminary evaluation of alphaadrenergic blocking agents in children with neurogenic bladder due to myelomeningocele. Dev Med Child Neurol 1976;I8(suppl 37):82-8 23. Mobley DF. Phenoxybenzamine in the management of neurogenic vesical dysfunction. J Urol 1976;116:737-8 24. Seifert J. Types of neurogenic bladder in children with spina bifida, and response to treatment with phenoxybenzamine. Dev Med Child Neurol 1976;18(suppl 37): 94-7 25. Jensen D. Uninhibited neurogenic bladder treated with prazosin. Scand J Urol Nephrol 1981;15:229-33 26. Vaidyanathan S, Rao MS, Sharma PL, Sachdeva NK. Significance of alpha-] adrenergic innervation of the urinary bladder in human neurogenic vesical dysfunction. Indian J Med Res I983;77:529-33 27. Collste L, Lindskog M. Phenylpropanolamine in treatment of female stress urinary incontinence. Urology 1987;30:398-403 28. Penders L, deLeval J, Petit R. Enuresis and urethral instability. Eur Urol 1984;10:317-22 Received Feb. 19, 1991. Accepted June 12, 1991
Effect of phenylpropanolamine on incontinence in children with neurogenic bladders. A double-blind crossover study P Amark'S2 and 0 Beck2 Departments of Paediatrics' and Clinical Pharmacology2.Karolinska Hospital. S-104 01 Stockholm. Sweden
Amark P, Beck 0. Effect of phenylpropanolamine on incontinence in children with neurogenic bladders. A double-blind crossover study. Acta Pzdiatr 1992;8 1:345-50. Stockholm. ISSN 0803-5253 In children with myelodysplasia and a low-level spinal cord lesion (low lumbar-sacral), detrusor hyperactivity together with dyssynergic urethral function forms the main pathophysiological basis for incontinence. Pharmacological treatment of incontinence due to neurogenic bladder dysfunction has been tried, mainly with anticholinergics and alpha-adrenoceptor antagonists. In this study, the effects of the alpha-adrenoceptor agonist phenylpropanolamine on urodynamic parameters and incontinence were investigated in 10 patients. Effects on incontinence were evaluated in a double-blind crossover trial. Plasma concentrations of phenylpropanolamine were measured by means of gas chromatography-mass spectrometry. Phenylpropanolamine reduced detrusor hyperactivity and improved continence, but the effect was not so pronounced as to make the patients continent. 0 Adrenergic receptor agonist. drug analysis, incontinence, neurogenic bladder, phenylpropanolamine P Amark, Department of Pediatrics, Karolinska Hospital, I04 01 Stockholm, Sweden
Most children with myelodysplasia suffer from inconti- phenylpropanolamine (PPA) on urodynamic paranence. Among these children, those with the upper limit meters and incontinence was evaluated in a group of of the spinal cord lesion at the low lumbar or sacral level children with myelodysplasia and neurogenic bladders. show the same type of lower urinary tract pathophysiology. They have detrusor hyperactivity with waves of increased bladder pressure, often accompanied by a decrease in urethral pressure (1, 2) which results in Material and methods intermittent urinary leakage during the bladder-filling phase. The detrusor hyperactivity may be abolished by Patient material atropine (3) and continence is promoted (4). The The patients were consecutively selected from the ward adrenergic influence on the lower urinary tract in these in the Pediatric Clinic where children with neurogenic patients has also been studied. Beta-adrenergic bladder dysfunction are examined. All patients had influence is presumed to relax the detrusor during myelodysplasia and the upper limit of the spinal cord normal filling, but beta-adrenoceptor agonists do not lesion at the low lumbar or sacral level was judged by influence detrusor hyperactivity (3) or promote conti- clinical examination of motor and sensory functions and nence ( 5 ) . For the contractile function of the bladder reflexes (1 3). All were incontinent and earlier urodynabase and the urethral smooth muscle, alpha-adrenocep- mic studies described below had revealed detrusor tor function is important (6, 7), while in the normal hyperactivity. The patients were not receiving any other detrusor its function (shown in some studies (8, 9) but medication for treatment of incontinence. Informed not others (6, 10)) may be less important. Adrenergic consent for participation in the study was obtained from nerve terminals become more densely distributed within the patients and their parents. The study was approved the detrusor muscle in a state of decentralization of by the Ethics Committee of the hospital. Details of the bladder parasympathetic innervation ( 1 1) and then patients are shown in Table 1. alpha-adrenoceptor function may play a role in the occurrence of detrusor pathophysiology. In an earlier study (1 2) the effects of noradrenaline and phentolamine Urodynamic de3nition.s on the detrusor and the proximal urethra were studied in According to the International Continence Society children with myelodysplasia and detrusor hyperacti- (ICS) terminology (14), the overactive detrusor function vity. Both drugs diminished detrusor hyperactivity. The in these patients is called detrusor hyperreflexia. We proximal urethral pressure decreased with phentola- have chosen to refer to the overactivity in these patients mine and increased with noradrenaline therapy. In this as detrusor hyperactivity. This is defined as detrusor study, the influence of the alpha-adrenoceptor agonist contractionsexceeding 10cmH200veraperiodof > 10s.
346
P Amurk und 0 Beck
ACTA PEDIATR 81 (1992)
Table 1. Patient data.
Sex
Age (years)
Weight (kg)
Independent walker
Clean intermittent catheterization
Urine culture
I
F
7
26
Yes
Yes
Negative
2
F
I1
26
Yes
Yes
3
M
18
70
Yes
No
4
9
27
Yes
14
63
N O
11
34
6
23
14
44
9
M M M M M F
12
34
Yes Yes Yes Yes
No Yes No No No Yes
10
F
12
50
Yes
Yes
Negative (placebo) E. coli lo7 (PPA) Negative (placebo) E. coli lo6 (PPA) Negative Negative Negative Negative Negative Negative (placebo) E. coli lo5 (PPA) E. coli lo5
Patient No.
5
6 7
8
Examination procedure The urodynamic investigation was performed in the following way. The patient was placed in the supine position. The bladder was emptied via a catheter, the amount of urine was measured and a culture was taken. Before removal of the catheter, isotonic saline (50-1 25 ml) was slowly (1-3 min) administered into the bladder. Pressures were then recorded in the bladder and the urethra during normal diuresis using a thin dacron catheter (Millar Instr. Inc.) with two transducers, one at the tip of the catheter and one 4 cm from the tip. The intra-abdominal pressure was recorded by a microtransducer at the end of a catheter placed in the rectum. The pressures were recorded on a Grass model 7D polygraph. The system was calibrated against a water column after each examination. This technique has been described earlier (1, 15). The position of the transducers in the urinary tract was determined by comparing the recordings when the catheter was slowly withdrawn from a location where both transducers were in the bladder. Throughout the examination the patient drank water, usually not more than 500 ml. When continuous detrusor hyperactivity occurred, the pressures in the urethra and the bladder and the number of waves were measured for 15 min. Blood pressure and pulse rate were noted. An oral dose of PPA (50-1 50 mg) was given as a slow-release preparation (Monydrin, Draco, Lund, Sweden). During a continuous urodynamic study, evaluations lasting 15 min were again performed at I , 2 and, in some cases, 3 h after
Medication Trimsulfa prophylaxis Nitrofurantoin
None
None None None None None Nitrofurantoin prophylaxis
Nitrofurantoin prophylaxis
drug administration (Fig. 1) when blood samples were also drawn for analysis of plasma PPA concentrations. Experimental design A randomized double-blind crossover study design was performed. The study was organized in the following way: the patients were evaluated on the ward during three periods of one week with intervals of two weeks between each period. During the first week the initial urodynamic evaluation was made. During all three periods the following were recorded: measurement of incontinence, blood pressure, pulse rate, urinary culture, residual urine volume, subjective assessment and adverse reactions. After the run-in evaluation, medication was given for two weeks, followed by the next inward evaluation. The treatment was then changed during the following two weeks and the study was completed with the last evaluation. The dose of PPA was chosen with the help of the pharmacokinetic studies of Lonnerholm et al. (16) and Fossberg et al. (1 7). PPA plasma level analysis Blood samples were drawn during the urodynamic study and before the morning dose of PPA was given during steady-state treatment. We used a gas chromatographic-mass spectrometric (GCMS) method, a modification of the electron-capture capillary gas chromatographic method described by Crisologo et al. (18) for
Effect of phenylpropanolamine on incontinence
ACTA PRDIATR 81 (1992)
347
cm H,O
B
20 ~~
OL I
I
115
120
130min
125
Fig. 1. Intravesical (A) and urethral (B) pressure recordings before (above) and 2 h after (below) oral administration of PPA (3 mg/kg, plasma level 181 nglml). Each point indicates a wave of hyperactivity ( > 10 cmH2O > 10 s.).
Internal standard
PPA
, t " "
70
,
.h.,
,
.
,
j\, - ,
, ,
,.
,
1 _ .
105
126
RETENTION TIME (seconds) Fig. 2. Chromatogram obtained from the selected ion monitoring analysis of a plasma sample. A volume of 0.5 ml plasma was used and 1/50 of the final extract ( I pl) was injected into the GC-MS system (HP 5890 A and Finnigan Incos 50). T h e monitored ion (m/z 280) represents the loss of one C2FsCOO radical from the respective molecular ions of the dipentafluoropropionyl derivatives of PPA and the internal standard (2amino-3-phenyl-I-propanolol).This sample was found to contain 290 ng/ml.
348
P Rrncirk uncl 0 Beck
A C T A PKDIATR 81 (1992)
plasma analysis of PPA (Fig. 2). The difference was the use of pentafluoropropionic anhydride instead of trifluoroacetic anhydride and the use of mass spectrometric detection. These modifications are not likely to influence significantly the results obtained with this method.
ated. The Wilcoxon signed rank test was used to evaluate changes in incontinence. P < 0.05 was regarded as significant.
Results
Measurement of incontinence Pharmacological eflects on urodynamic parameters During the three evaluation periods, incontinence was During PPA therapy the number of hyperactivity waves measured during three consecutive days. The patients was reduced (12.3f7.3 before and 7 f 7 after 2 h, were hospitalized on the ward during each evaluation p < 0.05, Fig. I). The urethral pressure increased in some period under similar conditions with respect to food and patients, but statistical significance was not reached fluid intake, physical activity and other daily activities. (33.8f 16 before and 41.7f 17 after 2 h). The intravesiWeighed diapers were always used and changed every cal pressure was not changed. Blood pressure and pulse hour in the daytime. A >2-g increase in weight was rate were not significantly altered. The mean dose regarded as due to urinary leakage. During the day, administered was 2.9 mg/kg (range 2.1-3.7 mg/kg). micturition or clean intermittent catheterization was Blood samples were obtained from seven patients. performed every 3 h. Volumes voided and due to leakage Plasma levels of PPA 2 h after drug administration were were noted. The degree of incontinence was also 380 f262 ng/ml. assessed according to the method of Nergdrdh et al. ( 1 9): group A: regularly dry for periods of 3 h; group B: daily dry periods of between 1 and 3 h; group C: occasional Pharmacological eflects on incontinence dry periods of between 1 and 3 h; group D: always wet There were no significant day-to-day differences in fluid intake. Daily urine volumes showed some variations. between micturitions. The mean daytime leakage episodes was calculated for each patient and was significantly lower during active Subjective assessment treatment than with placebo (Table 2). The number of The patients were asked which treatment they preferred 3-h dry periods increased during active treatment (runon the basis of their impression of treatment at home. in = 21, placebo = 20, PPA = 37; p < 0.05). There was a The degree of change in continence was regarded as nil shift towards a lesser degree of incontinence (Table 2). (0), moderate (+) or good (+ +). Side effects were The volumes of residual urine were not altered. Blood samples were obtained from nine patients during treatnoted. ment with PPA. Five patients reported a good or moderate effect of PPA and they showed better results Statistical evaluation when measured objectively; their daily dose was 3.5 mg/ Values are given as mean f S D . The two-tailed Stu- kg (range 1.9-5.8 mg/kg). The plasma level in these dent's t-test for independent or paired observations was patients was 381 f 114 ng/ml, which was significantly used when plasma levels of PPA were compared and higher than the plasma concentration measured in the when changes in urodynamic parameters were evalu- four patients in whom the effect of PPA was weak Tuhle 2. Treatment results.
Patient No. 1
2 3
4"
5 6 1
8 9 10 a
Daily dose of PPA (mg)
Plasma level PPA (ngiml)
100 100
48 1 221 310
200 I00 200 100 100 200 200 200
-
496 I39 206 212 393 147
Degree of incontinenceb Subjective assessment
++ + + 0 ++ 0 0 0
+ 0
Number of 3-h dry periods during three consecutive days
Number of leakage episodes (mean/day)
Run-in
Placebo
PPA
Run-in
Placebo
PPA
Run-in
Placebo
PPA
B B D D C C C B B B
C A D D C C D C B B
A A C D A B C B A B
I 9 0 0 0 I 0 4 3 3
0 9 0 0 0 I 0 I 5
4
6
9 1
2 13 13
II 2
6 1
14
13 12 6 9 9 11 6 9
4
0 7
2 2 3 6 3
10 10
II 8 8 9
A blood sample could not be obtained from patient No. 4; degree of incontinence (A-D) is explained in the text.
12 II 12 II 12 8 7
ACTA PADIATR 81 (1992)
(176 f38 ng/ml) and who were given a daily dose of 4.0 mg/kg (range 2.9-4.5 mg/kg).
Effect of phenylpropanolamine on incontinence
349
the detrusor and the urethra by the alpha-adrenoceptor antagonists. Alpha-adrenoceptor agonists, on the other hand, have been used to increase urethral pressure in order to treat stress incontinence in otherwise healthy Aduerse reactions women ( 1 7, 27). Such treatment has also been used 'for In two patients a slight increase in systolic blood nocturnal enuresis in childhood (28). The rationale for pressure was noted during active treatment. Three this treatment is the effect of alpha-adrenoceptors on patients reported fatigue, mood changes and sleep urethral smooth muscle-mediating contraction (6, 7).' disturbances. However, these reactions were tolerated However, the use of alpha-adrenoceptor agonists to by two patients; in the third patient the dose was reduced improve continence in children with neurogenic bladfrom 100 to 50 mg twice daily, and the side effects ders has not been evaluated. disappeared and treatment was continued. Fossberg et al. (17) concluded that plasma levels of PPA above 150 ng/ml were needed to improve continence, while there was no correlation between plasma Subjective assessment levels and increased urethral resistance. Collste & Increase in incontinence was never reported. All patients Lindskog (27) found no correlation between plasma reported that the placebo had no effect on incontinence levels and subjective or objective improvement. In our and caused no side effects. Active treatment was study the plasma levels were higher than in the two regarded as ineffective by five patients and of moderate above-mentioned studies, probably because of the value (+) by three patients, while two reported a good higher doses given. In both these studies plasma levels were measured a few hours after the last dose of PPA ( + +) effect. was given and not just before drug administration. It also appears that plasma levels higher than in the abovementioned studies are needed to improve continence in Discussion our patients. The effect on the circulation was weak, even when high plasma levels were reached. Treatment In this study the effects of phenylpropanolamine, an alpha-adrenoceptor agonist, on the pathophysiology of with phenylpropanolamine in this particular group of the lower urinary tract and on incontinence in a group of patients may improve continence, but we conclude that children with neurogenic bladders were evaluated. the effect is not good enough to recommend treatment, Detrusor hyperactivity was reduced while urethral and except in well selected cases. intravesical pressures were not significantly changed. In AcknoM'/edge~ienls.-This study was supported by grants from the the double-blind crossover study, PPA treatment Norrbacka-Eugenia Foundation and Sallskapet BarnavArd. The improved continence in half of the patients. Placebo skilful assistance of Ms Ebba Nilsson in evaluating continence is gratefully acknowledged as is her assistance and that of Head Nurse treatment produced no effects. Maj-Britt Pettersson in carrying out the urodynamic examinations. Problems arise in evaluating the effect of treatment Ms Inger Unnerstad provided valuable help in preparing figures and for incontinence. There may be day-to-day variations in tables. The authors thank Draco Lakemedel AB for PPA and placebo the severity of symptoms which are influenced by factors tablets. such as psychological stress, physical activity, food and fluid intake and compliance with schedules for regular bladder emptying. In this study incontinence was evalu- References ated under conditions as controlled and similar as 1. Naglo A-S, Nerghrdh A. Diagnosis of detrusor hyperactivity in possible regarding the above-mentioned factors during children with neurogenic bladder. Scand J Urol Nephrol three different periods of evalution, thus ensuring a I98 I; I5:91-6 good basis for comparison of placebo versus active 2. NergArdh A, Naglo A-S. Observations on the internal sphincter mechanism during the filling phase in children with hyperactive treatment. neurogenic bladder. Scand J Urol Nephrol 1982;16205-9 The side effects on mood may be attributed to the 3. Naglo A-S, NergArdh A, Bortus LO. Influence of atropine and central effects of PPA. Such adverse reactions have been isoprenaline on detrusor hyperactivityin children with neurogenic reported to be commoner in children than in adults (20). bladder. Scand J Urol Nephrol 198 I ;15:97- 102 4. Naglo A-S. Continence training of children with neurogenic Earlier reports (3, 4) showed that anticholinergic bladders and hyperactivity of the detrusor: Effect of atropine. treatment reduces detrusor hyperactivity and improves Scand J Urol Nephrol 1982;16:211-17 continence. Alpha-adrenoceptor antagonists have been 5 . Naglo A-S, Bortus L-0,Hellstrom B, NergArdh A. Is betaused for the treatment of incontinence due to neurogenic receptor blockade of value in continence training of children? Scand J Rehabil Med 1979;I 1:63-6 bladder dysfunction (21, 22). Both non-selective alpha6. NergArdh A, Boreus L-0. Autonomic receptor function in the antagonists, such as phenoxybenzamine ( 1 1, 23, 24), lower urinary tract of man and cat. Scand J Urol Nephrol and alphal-selective antagonists, such as prazosin (7,25) 1972;632-6 or indoramine (26) have been used. The fact that bladder 7. Andersson K-E, Ek A, Hedlund H, Mattiasson A. Effects of capacity improved as did bladder emptying with deprazosin on isolated human urethra and in patients with lower motor neuron lesions. Invest Urol 1981;19:39-42 creased residual urine volumes, indicates effects on both
350
P Amark and 0 Beck
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ACTA PEDIATR 81 (1992)
chromatographic determination of phenylpropanolamine in human plasma following derivatization with trifluoroacetic anhydride. J Pharm Sci 1984;73:1553-6 19. Nergirdh A, von Hedenberg C, Hellstrom B, Ericsson NO. Continence training of children with neurogenic bladder dysfunction. Dev Med Child Neurol 1974;16:47-53 20. Norvenius G, Widerlov E, Lonnerholm G. Phenylpropanolamine and mental disturbances. Lancet 1979;2: 1367-8 21. Hilwa N, Perlmutter A. The role of adjunctive drug therapy for intermittent catheterization and selfcatheterization in children with vesical dysfunction. J Urol 1978;119:551-5 22. De Voogt HJ, van der Sluis C. Preliminary evaluation of alphaadrenergic blocking agents in children with neurogenic bladder due to myelomeningocele. Dev Med Child Neurol 1976;I8(suppl 37):82-8 23. Mobley DF. Phenoxybenzamine in the management of neurogenic vesical dysfunction. J Urol 1976;116:737-8 24. Seifert J. Types of neurogenic bladder in children with spina bifida, and response to treatment with phenoxybenzamine. Dev Med Child Neurol 1976;18(suppl 37): 94-7 25. Jensen D. Uninhibited neurogenic bladder treated with prazosin. Scand J Urol Nephrol 1981;15:229-33 26. Vaidyanathan S, Rao MS, Sharma PL, Sachdeva NK. Significance of alpha-] adrenergic innervation of the urinary bladder in human neurogenic vesical dysfunction. Indian J Med Res I983;77:529-33 27. Collste L, Lindskog M. Phenylpropanolamine in treatment of female stress urinary incontinence. Urology 1987;30:398-403 28. Penders L, deLeval J, Petit R. Enuresis and urethral instability. Eur Urol 1984;10:317-22 Received Feb. 19, 1991. Accepted June 12, 1991
