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Medical Treatment for Lower Urinary Tract Dysfunction
Hann-Chorng Kuo
Department of Urology
Buddhist Tzu Chi General Hospital Hualien
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Innervation of Lower Urinary Tract
• Bladder-
cholinergic parasympathetic- contraction; beta-adrenergic & NO– relaxation
• Bladder neck – alpha-adrenergic- contration
• Urethral muscles-
cholinergic parasympathetic, NO, cholinergic somatic nerves
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Neuroanatomy of Lower Urinary Tract
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Treatment Goals of Voiding Dysfunction
• To increase bladder capacity – Bladder Hypersensitivity
• To reduce detrusor overactivity – Detrusor overactivity
• To increase urethral resistance – Urethral incompetence
• To reduce urethral resistance -- Bladder outlet obstruction
• To increase bladder contractility – Detrusor underactivity or acontractility
• To improve bladder compliance – Low bladder compliance
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Improved Voiding Efficiency
• Increase detrusor contractility – increase detrusor muscle tone or contractility
• Reduce urethral resistance – bladder neck, urethral sphincter, prostatic urethra
• Improved bladder capacity and compliance
• Combination of all of the above
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Storage of Urine
• Stable bladder
• Good compliance
• Competent urethra- mucosa, submucosa, smooth muscles, striated skeletal muscles (external sphincter)
• Good pressure transmission and hammock effect during stress
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Storage Problems
• Bladder hypersensitivity
• Low bladder compliance
• Detrusor overactivity – neurogenic or idiopathic
• Low urethral resistance
• Bladder outlet obstruction
• Combination of the above
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Detrusor overactivity during Bladder filling phase
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Detrusor Overactivity followed by Valsalva maneuver
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Empty of Urine
• Sustained detrusor contraction- cholinergic parasympathetic fibers
• Relaxation of bladder neck – alpha-adrenergic sympathetic nerves
• Relaxation of external sphincter- cholinergic pudendal nerves
• Patent non-obstructive urethra
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Normal Micturition – relaxation of urethral sphincter
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Empty Problems
• Bladder outlet obstruction – Bladder neck dysfunction, BPH, Urethral stricture, Dysfunctional voiding, DESD
• Bladder hypersensitivity
• Detrusor underactivity or areflexia
• Poor urethral sphincter relaxation
• Combination of the above
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Dysfunctional Voiding in a girl with Bilateral Hydronephrosis
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Low Detrusor Contractility
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Pharmacology of Micturition- Increase storage efficiency
• Reduce detrusor overactivity• Anticholinergic agents- oxybutynine, flavox
ate, imipramine• Ganglion blocker- bentyl• Beta-adrenergic agents• Botulinum toxin• Vanilloid receptor blockers- capsaicin, resin
iferatoxin
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Pharmacology of Micturition- Increase empty efficiency
• Parasympathomimetic agent- Urecholine
• Adrenergic blockers- inhibition of detrusor relaxation (?)
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Pharmacology of Micturition- Increase outlet resistance
• Increase smooth muscle tone –
Imipramine, methylephedrine
• Increase striated muscle tone –
Nitric oxide synthase inhibitor
Pelvic floor muscle training
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SUI & Urethral Incompetence induced Detrusor Overactivity
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Pharmacology of Micturition- Decrease outlet resistance
• Decrease bladder neck & urethral resistance
• Alpha-adrenergic blockers- dibenyline, terazosin, tamsulosin, doxazosin
• Nitric oxide donors
• Botulinum toxin
• Polysynaptic blocker – baclofen, diazepam
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Decreased MUCP after Botulinum Toxin Injection
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Reduction of MUCP after Nitric Oxide Donors (NTG)
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Combined Medication- Improved Storage Efficiency
• Detrusor Overactivity- anticholinergics, sympathomimetics, imipramine
• Intrinsic sphincter deficiency- imipramine, sympathomimetics
• DHIC- depends on voiding efficiency and grades of incontinence
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Combination of Medication- Improve Voiding Efficiency
• Increased bladder sensation- intravesical capsaicin, RTX
• Detrusor overactivity- anticholinergic, intravesical RTX, botulinum toxin
• Detrusor underactivity – parasympathomimetics, alpha-blocker, NO donors, striated muscle relaxant, periurethral botulinum toxin injection
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Combined Medication – Improved Voiding Efficiency
Urethral sphincter hypertonicity- alpha-blocker, NO donors, striated skeletal muscle relaxant
• Urethral sphincter overactivity- alpha-blocker, striated muscle relaxant, NO donors, botulinum toxin
• Bladder neck dysfunction- alpha-adrenergic blocker
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Dysfunctional voiding in A woman with Multiple Stroke
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Medication for Detrusor hyperreflexia
• Oxybutynin & anticholinergics
• Imipramine
• Intravesical capsaicin & resiniferatoxin
• Intra- detrusor botulinum toxin
• Multiple medication increases adverse effect especially in elderly with inadequate detrusor contractility (DHIC)
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Anticholinergics Treatment
• Oxybutynin – the most effective and safe drug currently available
• Detrusitol – M3 antagonist, less salivary and GI side effects than Ditropan
• Flavoxate – mild effect on detrusor
• Imipramine – central and anticholinergics
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Tolterodine vs Oxybutynin
• A secondary amine with competitive muscarinic receptor blocking property
• As potent as oxybutynin in inhibiting detrusor contractions
• 8 times less potent in inhibiting salivation than oxybutynin
• 2mg bid tolterodine in comparison to 5mg tid of oxybutynin
• Titration doses from 1-2 mg bid to 4mg bid
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Side effects of Anticholinergic
• Post-synaptic receptors M1 and M2 are widespread in CNS, anticholinergics may have cognitive dysfunction, especially in elderly
• Dry mouth, constipation, blurred vision• Darifenacin has 11-fold higher affinity to M
3 than M2 receptors and a 5-fold lower affinity for M receptors in parotid gland
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Pharmacology of Detrusor Overactivity
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Extended-release system for oxybutynin & tolterodine
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Intravesical Therapy for Detrusor overactivity
• Blocking efferent cholinergic fibers – intravesical oxybutynin, atropine
• Blocking neuromuscular junction – intravesical botulinum A toxin injection
• Blocking afferent fibers that mediate detrusor reflex – intravesical lidocaine
• Blocking C-fiber mediated detrusor contractions – intravesical capsaicin, resiniferatoxin
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Intravesical Capsaicin Therapy
• Patients who are refractory to conventional treatment
• Capsaicin 10 -5 M in 30ml N/S instilled to bladder for 30 minutes
• Resiniferatoxin 10-8 M in 30ml N/S
• A burning sensation or urge at instillation
• Relief of pain and urge in the later days
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Therapeutic Effects of Resiniferatoxin on Detrusor Overactivity
• 10 -5 to 10 -7 M RTX is effective for DH of SCI and DH of CNS origin
• 10 -8 M RTX can significantly improve voiding pattern and pain score in hypersensitive disorders and bladder pain
• RTX is safe for application in humans• Less initial irritative response in RTX treat
ment than capsaicin
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Urodynamic Result after RTX Therapy in a SCI patient
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Urodynamic Changes after RTX in Chronic SCI with DESD
Baseline Post-RTX Stastistics
Cystometric capacity(ml) 102.1±31 236.6±88.6 P<0.001
Bladder compliance
(ml/cmH2O)23.7±12.1 25.9±15.3 P>0.05
Voiding pressure
(Pdet, cmH2O)55.9±23.2 47.5±28.1 P>0.05
Presence of
DESD (n=20)100% 100%
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Intravesical RTX in treatment of Neurogenic Detrusor Overactivity
• C-fiber mediated detrusor reflex does not predominate neurogenic detrusor overactivity in lesion above pons
• Resiniferatoxin in 10-6~-7 M can activate initial excitatory responses
• Therapeutic results are not as satisfactory as that in SCI patients
• An alternative for patients who cannot tolerate or refractory to anticholinergic agents
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Therapeutic Results of RTX in Neurogenic v Non-neurogenic Voiding Dysfunction
• 22/41 patients (53.6%) with detrusor overactivity improved after RTX 10-7M instillation (initial concentration)
• 6/10 (60%) Neurogenic DH, 4/13 (31%) Idiopathic DI, 12/18 (67%) BOO related DI improved
6/7 (86%) type I, 1/3 (33%) type II, 7/16 (44%) type III, 8/15 (53%) type IV
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Urodynamic Changes after RTX in Detrusor Overactivity
Baseline Post-RTX Statistics
Cystometric capacity(ml)
(n=41)216±106 302±133 P=0.000
Qmax (ml/sec) 12.7±7.6 21.8±28.9 P=0.224
Voiding pressure
(Pdet, cmH2O)33.6±11.7 34.1±19.5 P=0.923
Residual urine (ml) 41.1+52.7 49.4+98.9 P=0.725
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Botulinum A toxin Injection
• Inhibition of acetylcholine (Ach) release from presynaptic cholinergic fiber
• Induce paralysis of muscle fibers• Intravesical injection can inhibit detrusor ov
eractivity• Urethral injection can reduce urethral resist
ance and sphincter spasticity• Duration of effect about 3-6 months
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Mechanism of Botulinum A Toxin in Neuromuscular Junction
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Botulinum A Toxin Urethral Injection in Woman
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Cystoscopic Urethral Injection in Men
**
** **
**
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Table 1.The Urodynamic Parameters at Baseline and after Botulinum Toxin in Effective Patients
Baseline Post-Botox Statistics*
Capacity (n=53) 331.4±148.8 333.2±155.4 0.922
Qmax (n=53) 6.7± 6.7 9.4± 5.7 0.003
Voiding pressure (n=53)
62.0± 43.1 45.9±37.8 0.000
MUCP (n=21) 97.1±31.7 51.1±23.2 0.027
FPL (n=21) 3.35±0.59 3.30±0.33 0.773
PVR (n=53) 225.4±174.4 110.1±137.6 0.000
MUCP=maximal urethral closure pressure, FPL=functional profile length,
PVR= postvoid residual volume
*Comparison between baseline and 4weeks after treatment
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Therapeutic Results after Botox Urethral Injection for Voiding Dysfunction
GoodGood ImprovedImproved FailedFailed
Detrusor underactivity (n=27)Detrusor underactivity (n=27)13
(48.2%)
8
(29.6%)
6
(22.2%)
DESD (n=18)DESD (n=18)3
(16.7%)
10
(55.6%)
5
(27.8%)
Dysfunctional voiding (n=18)Dysfunctional voiding (n=18)6
(33.3%)
10
(55.6%)
2
(11%)
Poor relaxation of urethral Poor relaxation of urethral sphincter (n=12)sphincter (n=12)
3
(25%)
7
(58.3%)
2
(16.6%)
TOTAL (n=75)TOTAL (n=75)25
(33.3%)
35
(43.7%)
15
(20%)
DESD=Detrusor external sphincter dyssynergia
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Botulinum Toxin Detrusor Injection for Detrusor Hyperreflexia
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Btulinum A Toxin Detrusor Injection for DH
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Initial Results of BotulinumToxin Detrusor Injection for Incontinence
No Sex / Age Disease DESE Capacity Dysuria Incontinence
1 M / 35 DESD 250 U Improved - +
2 F / 10 DI 100 UNo
Change- +++
3 F / 45 DI 200 U Improved - -
4 M / 48 DHIC 200 U Improved - +
5 F / 56 DH 200 U Improved - -
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Medication for Bladder outlet obstruction
• Bladder neck – alpha-adrenergic blocker
• Smooth muscle – Nitric oxide donors (nitroglycerine, isosorbid mononitrate), anticholinergics
• Striated muscle – baclofen, diazepam, dantrolene, calcium channel blocker, NO donors, botulinum A toxin
• Enlarged Prostate – finasteride (Proscar)
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Bladder neck dysfunction in woman
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Spastic urethral sphincter (Dysfunctional voiding)
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Medical Treatment for Female BOO
• Skeletal muscle relaxant – diazepam, baclofen, dantrolene, calcium blocker
• Alpha-adrenergic blocker – dibenylene, terazosin, doxazosin, tamsulosin
• Nitric oxide donor- nitroglycerine, isosorbid mononitrate
• Estrogen• Botulinum A toxin
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Medical Therapy for BPH• Prostatic smooth muscle tension was mediate
d by alpha 1-adrenoreceptors
• Smooth muscle contractions contribute 40% of outflow obstruction
• Alpha 1- blockers can rapidly improve Qmax and relieve LUTS
• Phenoxybenzamine, terazosin, doxazosin have side effect of dizziness and hypotension
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Relation of prostate and urethra
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Bladder Outlet Obstruction due to Benign Prostatic Hyperplasia
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Bladder outlet obstruction due to BPH in Men
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Prostatic specific alpha- adrenoreceptor
• Alpha 1A- AR subtype comprises 70% of all alpha-1 receptors
• Alpha 1A-AR agonist – tamslosin has 13 x more affinity to prostatic smooth muscle than urethral muscle , 10 x than vascular smooth muscle
• Side effects are still reported• Long-acting (once daily) dose
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Hormone based medical therapy
• 5-alpha-reductase catalyzes conversion of testosterone to dihydrotestosterone
• Inhibition of 5-alpha-reductase can arrest prostatic growth and relieve obstruction
• Finasteride can improve symptom score, Qmax, QOL score
• Effective especially in prostatic weight of >40 gm and effective in prostatic hematuria
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Combination therapy with alpha-blocker and finasteride
• Terazosin is effective therapy, finasteride was not, combination was no more effective than terazosin alone (Lepor, N Engl J Med 1996; 335: 533)
• Combined dibenyline and finasteride has an additive effect than dibenyline or finasteride alone in improvement of Qmax and prostatic size
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Nocturia
• A result of excessive amount of urine production at night
• Noctural polyuria >35% daily urine
• Abnormal lower urinary tract function
• A combination of two etiologies
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Desmopressin
• The circardian rhythm of vasopressin was lost in the elderly with nocturnal polyuria
• Atrial natriureteric peptide in the elderly was higher during night time
• Use of arginine vasopressin analogue patients with nocturnal enuresis and nocturnal polyuria become dry
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Therapeutic Effects of Desmopressin in Nocturnal Polyuria
BaselineBaseline PosttreatmentPosttreatmentP ValueP Value
(Paired t Test)(Paired t Test)
Nocturnal frequency Nocturnal frequency (time/night)(time/night)
5.20 ± 1.16 2.24 ± 1.12 <0.0001
Nocturnal urine volume (mL)Nocturnal urine volume (mL) 955.6 ± 255.9 255.8 ± 210.5 <0.0001
Quality of lifeQuality of life 4.47 ± 1.07 1.05 ± 0.91 <0.0001
Urine specific gravityUrine specific gravity 1.012 ± 0.007 1.016 ± 0.005 0.011
Serum Sodiun (mEq/L)Serum Sodiun (mEq/L) 139.5 ± 4.34 139.7 ± 3.84 0.761
Serum Potassium (mEq/L)Serum Potassium (mEq/L) 4.46 ± 0.35 4.31 ± 0.44 0.022
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Combination therapy for geriatric Nocturnal polyuria
• Combined anticholinergics and DDAVP for detrusor overactivity and nocturnal polyuria for DI & NP
• Combined alpha-blocker and DDAVP for BOO and NP
• Combined alpha-blocker and anti-cholinergics and DDAVP for BOO & DI & NP
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Difficult urination due to A Spastic Urethral Sphincter
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Treatment of spastic urethral sphincter
• Behavioral therapy: hydration, laxatives, time voiding, changing voiding posture
• Physiotherapy: pelvic floor muscle exercises• Electric stimulation : interferential current stimulat
ion• Biofeedback: visual or Uroflowmetry & EMG• Medication: baclofen, alpha-adrenergic blockers, e
strogen, combination therapy• Urethral injection of botulinum A toxin
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Therapeutic results of baclofen and terazosin in treatment of spastic urethral sphincter
IPSS Qmax Residual urine
Baseline Trated Baseline Treated Baseline Treated
Baclofen (n=73) 15.2±6.7 10.4±5.7 14.3±9.7 16.7±8.1 65.7±33.9 37.5±21.7
% of change 31.6±21.5 16.87±12.7 42.9±34.1
Baclofen plus 12.7±7.9 6.1.±4.5 14.8±11.0 22.677.5 58.1±21.8 31.01±31.2
Terazosin (n=64)
% of change 51.7±27.4 52.7±31.1 46.5±29.3
Statistics* P<0.05 P<0.05 NS
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Medication for Dysfunctional voiding
• Oxybutynin – effective in reducing detrusor overactivity, side effects of mucosal dryness & constipation
• Ditropan XL – elimination of peak drug effect and reduce adverse effects
• Tolterodine – M3 anticholinergic• Alpha-adrenergic blocker to reduce urethral resista
nce• Phenylpropanolamine, pseudoephedrine – in ISD
with incontinence ready for CIC
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Treatment of Nocturnal Enuresis
• Conditioning therapy: Alarm system or dry-bed training,effective in about 30-80%
• Medcal therapy: (1) Tricyclic antidepressant (TCA), imipramine, amitriptyline effective in 10-50% (author 24%)
(2) anti-cholinergics (3) desmopressin (DDAVP)• Side effect in combination medical therapy
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DDAVP Therapy in Nocturnal Enuresis in Children
• DDAVP in dose of 10-20 ug intranasally is effective in 70% of children with PNE
• After discontinuing DDAVP for 3months, 21% remained dry without medication
• 20 ug is adequate in treating PNE, in children not responded to 20ug, 40ug did not effective
• No serious adverse effect
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Treatment of Adult Nocturnal Enuresis
• DDAVP in patients proven to have nocturnal polyuria (nocturnal urine volume > 35% daily urine volume, or >900ml/N)
• Oxybutynine in patients proven to have DI• Imipramine or methylephedrine in patients s
uspicious to have urethral incompetence• Pelvic floor muscle exercises or functional
electrostimulation might be helpful
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Medical treatment of Interstitial Cystitis
• Cyclosporine• Methotrexate• Tice strain BCG– 60% response rate vs 27
% in placebo• Elmiron (PPS 100mg tid) – 6.2% to 18.7% r
esponse rate• Electromotive administration of intravesical
lidocaine & dexamethasone – 62% effective
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Inravesical Heparin therapy
• Patients with urgency frequency and a positive potassium test
• Intravesical Heparin 25000u/10ml saline and holding for 2 hours
• 2x or 3x per week for 12 weeks
• 67% patients have improvement in symptoms and increase in bladder capacity
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Urodynamic finding before and after Heparin
Therapy
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The changes of urodynamic parameters before and after
heparin treatment
Baseline 3 months Statistics
P value
FSF(ml) 96.5±46.4
146.1±55.4 0.001
US(ml) 225.4±96.2
264.9±84.2 0.009
Cystometric capacity(ml)
262.0±89.8
304.3±84.8 0.002
PdetQmax(cmH2O) 25.7±9.1 28.3±9.3 0.07Qmax (ml/sec) 12.9±5.7 15.1±7.7 0.063Residual urine(ml)
29.4±38.4
14.5±25.7 0.096
IPSS (points) 19.5±4.6 9.0±4.0 0
Nocturia (times/night)
5.7±2.0 2.3±1.1 0
Pain scale of KCl (points)
3.2±0.5 0.7±0.7 0
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Thank you for your attention
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Low contractility
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Detrusor Overactivity and Contracted Bladder
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