Interventional procedure overview of botulinum toxin type A injection into the urethral sphincter for idiopathic chronic non-obstructive urinary retention

RCT (NCT01733290)

Taiwan, Helsinki

2012-2014

N=73 patients with DV or DU refractory to medical or behavioural treatment.

(48 in botulinum injection group versus 25 in placebo group)

Mean age 65.2± 15.2 years (range, 28 to 87 years); botulinum injection group 64.7 years versus placebo injection group 66.9 years; p= 0.562.

Sex: overall 66% (48/73) women;

At 1 month, botulinum injection group had 76% (29/38) women, placebo injection group had 76% (19/25) women

Inclusion criteria: patients more than 20 years of age with a 3-month history of medically refractory non-neurogenic voiding dysfunction (DV and DU diagnosed by video-urodynamic studies). DV was diagnosed in patients with an open bladder neck and narrow membranous urethra, a poorly relaxed urethral sphincter, and a normal to-high voiding pressure with a low and/or intermittent urinary flow during voiding. DU was diagnosed in patients with low voiding pressure and low flow rate, a post-void residual volume >300 mL, and a low VE (<33%) and the presence of a relaxed urethral sphincter during voiding.

Exclusion criteria: anatomic bladder outlet obstruction conditions, including benign prostatic obstruction in men, bladder neck obstruction or contracture, and urethral stricture, active UTI, interstitial cystitis, and occult or overt neuropathy (including cerebrovascular accidents, diabetes mellitus, multiple sclerosis, Parkinson's disease, and spinal cord injury).

All injections were done under general anaesthesia through a transurethral route in men and perineal route in women.

Treatment group (n=48) received injections of botulinum (100U diluted was with 5ml saline) into the external urethral sphincter. Men received 10 injections using a 23 gauge needle. Each injection site received 10U of botulinum or 0.5ml of normal saline. Women received 5 urethral sphincter injections of botulnium solution or 1.0ml of normal saline circumferentially into the urethral sphincter using a 27 gauge 1ml syringe needle.

Placebo group (n=25) received normal saline (5ml) injections (10 in men and 5 in women)

After injections, a Foley catheter was inserted overnight in men but not in women. Patients are discharged next day and oral antibiotics are given for a week.

48 in the botulinum group and 25 in placebo group received first injection, and 19 and 13 patients in each group received a second botulinum injection after 1 month.

1 month.

Study was approved by Tzu-Chi General Hospital. No external funding for this study.

Botulinum injection % (n=38)

Placebo injection % (n=24)

P value

Success rate (PPBC>2)

36.8 (14/38)

54.2 (13/24)

0.114

IPSS-V

Baseline

15.2±5.6

14.5±6.7

0.468

0.002

1 month

12.7±7.0*

6.0±6.6*

IPSS-S

Baseline

10.7±4.0

11.0±4.3

0.518

0.074

1 month

8.5±3.8*

7.1±4.2*

IPSS-T

Baseline

25.8±8.2

25.5±8.8

0.776

0.001

1 month

21.2±8.6*

13.1±9.5*

QOL-index

Baseline

4.5±1.9

5.4±0.9

0.024

0.014

1 month

3.0±1.9*

2.4±1.9*

PPBC

Baseline

4.8±1.7

5.0±1.7

0.761

0.066

1 month

3.4±2.0*

2.7±2.1*

CBC (mL)

Baseline

378.9±154.2

397.8±223.5

0.585

0.201

1 month

404.6±182.4

360.0±140.7

Pdet (cmH₂O)

Baseline

22.7±24.7

25.3±24.6

0.444

0.161

1 month

19.2±19.6

30.5±25.1

Qmax (mL/s)

Baseline

5.3±5.7

6.3±5.1

0.344

0.558

1 month

9.8±9.5*

9.5±6.6*

Vol (mL)

Baseline

104.8±112.2

102.4±101.4

0.942

0.627

1 month

170.7±140.5*

148.5±144.7

PVR (mL)

Baseline

295.7±194.1

279.3±246.9

0.965

0.141

1 month

251.7±214.0

146.6±160.5*

VE (%)

Baseline

29.6±28.3

34.4±34.2

0.530

0.336

1 month

44.1±35.3*

56.1±36.4*

IPSS-V

Baseline

12.7±6.6

14.1±5.8

17.0±3.8

15.1±8.4

1 month

8.3±7.6*

5.7±5.8*

0.089

16.0±4.3

6.6±8.2*

0.036

IPSS-S

Baseline

11.4±4.3

12.1±4.0

10.1±3.8

9.8±4.5

1 month

8.5±3.7*

6.3±3.9*

0.089

8.5±3.9

8.4±4.5

0.831

IPSS-T

Baseline

24.1±10.3

26.2±7.8

27.1±6.2

24.3±10.7

1 month

16.8±10.4*

12.0±8.0*

0.026

24.4±5.2*

15.0±11.8*

0.002

QoL-I

Baseline

4.4±1.7

5.4±1.0

4.6±2.0

5.4±0.9

1 month

2.8±2.1*

2.4±2.1*

0.089

3.0±1.9*

2.4±1.8*

0.107

PPBC

Baseline

4.8±1.4

5.4±1.4

4.7±1.9

4.4±1.9

1 month

3.3±1.9*

2.5±2.2*

0.085

3.5±2.1*

3.0±1.8*

0.814

CBC (ml)

Baseline

359.0±172.6

334±176

393.9±141

497±262.5

1 month

365.0±154.4

354±125.7

0.860

434.7±199.4

369±169.2

0.042

Pdet (cmH2O)

Baseline

40.3±23.0

35.6±25.1

9.2±16.4

9.1±12.8

1 month

31.6±22.3*

32.1±22.6

0.473

9.8±10.0

27.9±30.0

0.070

Qmax (mL/s)

Baseline

6.4±5.4

7.9±5.2

4.5±6.0

3.4±3.7

1 month

11.1±10.1*

8.9±4.7

0.099

8.8±9.1*

10.6±9.2*

0.445

Vol. (mL)

Baseline

119.9±82.2

136.3±109

93.9±130.9

45.9±54.9

1 month

191.0±140.1*

117.5±63.7

0.020

155.0±142.0

200±219.7

0.182

PVR (mL)

Baseline

225.0±200.7

198±168.2

350.0±174.6

415±304.0

1 month

198.0±179.1

156±160.5

0.770

293.0±233.1

131±169.1*

0.046

VE (%)

Baseline

42.1±27.8

44.9±32.2

20.8±28.5

17.0±31.5

1 month

50.5±34.6

52.8±34.6

0.969

39.4±36.0*

61.6±40.7*

0.094

IPSS-V

−4.0±5.5

−3.4±5.4

0.848

−1.0±4.0

−6.3±7.0*

0.035

IPSS-S

−2.3±3.9

−3.4±3.3*

0.563

−2.1±3.8

−4.5±5.7*

0.250

IPSS-T

−6.3±6.7*

−6.9±3.5*

0.846

−3.0±5.0

−10.7±10.8*

0.051

QOL-index

−1.0±2.2

−2.0±1.5*

0.337

−1.8±1.8*

−3.1±2.2*

0.144

PPBC

−0.9±2.7

−1.7±1.8*

0.502

−0.9±1.6

−1.8±1.7*

0.202

CBC (ml)

60.6±105.5

143.3±143.0*

0.242

32.1±72.8

77.2±148.5

0.381

Pdet (cmH₂0)

−8.1±14.7

−13.4±21.1

0.597.5

2±10.7

3.8±10.0

0.719

Qmax (mL/s)

1.3±5.2

2.6±6.0

0.676

−0.6±3.8

5.4±5.5*

0.008

Vol (mL)

17.9±64.7

29.7±55.8

0.720

−10.3±94.5

57.5±150.5

0.206

PVR (mL)

29.1±104.2

21.3±124.7

0.900

−1.3±174.4

−70.9±179.3

0.367

VE (%)

−7.7±25.8

−1.9±31.8

0.715

−0.2±17.2

19.5±37.1

0.113

IPSS-V

−6.1±4.7*

−4.5±7.1

0.585

−7.0±8.9

−7.8±8.7

0.908

IPSS-S

−5.3±4.4*

−2.9±6.1

0.354

−0.0±3.6

−2.3±5.1

0.498

IPSS-T

−11.4±7.9*

−7.4±12.1

0.419

−7.0±6.3

−10.0±4.5*

0.468

QOL-index

−2.3±2.1*

−1.1±2.5

0.289

−1.75±1.5

−2.5±2.1

0.580

PPBC

−2.4±2.1*

−1.6±3.7

0.578

−1.25±1.0

−2.5±2.1

0.317

CBC (ml)

−10.0±245.7

−29.6±225.9

0.876

−133.5±336.7

−88.5±274.7

0.843

Pdet (cmH₂0)

−3.3±14.1

−8.7±7.9*

0.719

33.8±47.0

10.8±28.8

0.436

Qmax (mL/s)

1.0±5.4

1.6±4.5

0.800

3.8±4.3

2.5±4.1

0.691

Vol (mL)

2.2±123.6

−5.0±88.6

0.893

180.0±260.6

69.5±102.2

0.462

PVR (mL)

−54.0±201.7

−107.6±236.3

0.621

−400.2±309.2

−251.3±296.5

0.513

VE (%)

16.6±27.3

15.5±27.6

0.936

64.5±38.9*

22.3±29.1

0.133

Complications at 1 month

% (n)

De novo urgency urinary incontinence*

4.8 (3/62)

De novo stress urinary incontinence*

n=1

UTI*

4.8 (3/62)

Micturition pain*

3.2 (2/62)

Haematuria*

3.2 (2/62)

Case series

Taiwan

2002-2005

N=27 patients with idiopathic low detrusor contractility

(3 had DV, 5 had low detrusor contractility with PRES 10 had DHIC, and 9 had DU)

Mean age not reported; 81% (22/27) women.

Inclusion criteria: presence of bladder and urethral dysfunction (idiopathic low detrusor contractility confirmed on VUD studies and defined no evident neuropathy, no functional or anatomic bladder outlet obstruction, a low or no Pdet combined with a Qmax of less than 10 mL/s, and a large PVR of more than 150 mL or urinary retention difficult urination, with a hyperactive or poorly relaxed urethral sphincter), patients in whom treatment with conventional medications had failed.

Exclusion criteria: with bladder outlet obstruction.

urethral injection of botulinum (50 units or 100 units) performed under general anaesthesia and cystoscopy guidance, directly into the urethral sphincter in men and periurethrally in women.100 units is diluted with 8ml saline.

More than 1 year

Allergan company provided botulinum injections.

Yes 48% (13/27)

Baseline

233 ± 106

7.4 ± 9.2

4.7 ± 5.6

328 ± 134

After treatment

191 ± 87

24 ± 13.1*

13 ± 6.6*

31 ± 35*

14 ± 7.6

No 52% (14/27)

Baseline

368 ± 132

47 ± 39†

4.8± 4.3

228 ± 122

After treatment

297 ± 121

32 ± 27*

7.0± 3.6

132 ± 71*

4.6 ± 2.5 (p<0.001)

Recovery of detrusor contractility^

Without detrusor contractility recovery^^

Excellent (QOL index improved by >2 and reduction in PVR by >50%)

N=10

N=1

Statistically significantly improved (QOL index improved by >2 and reduction in PVR by <50%)

-

-

Improved (QOL index improved by 1 and improvement of UD parameters)

N=3

N=10

Failed (no improvement in QOL)

-

N=3

Case series

Taiwan

Not reported

N=66 patients with voiding dysfunction treated with botulinum injections into the EUS.

(50 unit injection group [n=33] versus 100 unit injection group [n=33])

(DSD n=6, DV [n=21], PRES [n=11], or DU with non-relaxation of the urethral sphincter [n=28])

Mean age: 64.8 years and 60.0 years in the 50 and 100 units injection groups, (p> 0.05).

Sex: 54% (18/33) and 58% (19/33) women in the 50 and 100 units injection groups, (p>0.05)

Inclusion criteria: presence of bladder and urethral dysfunction (idiopathic low detrusor contractility) confirmed on VUD studies (no anatomic bladder outlet obstruction, difficult urination, and urinary retention or a large PVR volume, and low detrusor pressure with a hyperactive or poorly relaxed urethral sphincter), patients with voiding dysfunction in whom treatment with conventional medications (such as α-blockers and skeletal muscle relaxants) had failed.

Exclusion criteria: with bladder outlet obstruction.

botulinum injections into the urethral sphincter (50 units in 33 patients or 100 units in 33 patients) performed under light intravenous general anaesthesia and cystoscopy guidance transurethrally in men at the 3, 6, 9 and 12 o'clock positions at a depth of about 5 mm and transcutaneously and periurethrally in women at a depth of 15mm.100 units is diluted with 8ml saline.

Both groups received same volume of injection but different doses.

More than 12 months

Allergan company provided botulinum injections. Study was supported by grants from the National Science Council of Taiwan.

50 units injection (n=33)

Baseline

66.6 ± 34.4

3.3 ± 0.5

51.6 ± 40.7

5.6 ± 5.3

285 ± 154

4.1 ± 0.9

After treatment

48.9 ± 27.3

(p<0.001)

3.1 ± 0.3

(p=0.186)

37.5 ± 35.4

(p<0.001)

8.3 ± 5.4

(p=0.016)

120 ± 145 (p<0.001)

1.9 ± 1.2 (p<0.001)

6.4 ± 3.6

100 units injection (n=33)

Baseline

61.9 ± 26.0

3.8 ± 1.0

53.8 ± 38.9

5.8 ± 4.8

261 ± 157

4.0 ± 1.0

After treatment

49.5 ± 21.5

(p=0.049)

4.1 ± 1.0

(p=0.493)

33.0 ± 31.7

(p=0.006)

10.5 ± 5.9

(p<0.001)

114 ± 107

(p<0.001)

2.2 ± 1.2

(p<0.001)

8.4 ± 3.4 (p=0.022)*

50 units of injection % (n=33)

100 units of injection % (n=33)

Excellent (QOL index improved by >2 and 50% reduction in PVR and ≥ 25% reduction in MUCP)

69.7 (23/33)

60.6 (20/33)

Improved (QOL index improved by 1 and improvement of VUD parameters by either a ≥ 50% reduction in PVR or a ≥ 25% reduction in MUCP)

15.2 (5/33)

30.3 (10/33)

Failed (no improvement in QOL regardless of urodynamic improvement)

15.2 (5/33)

9 (3/33)

Overall rate of success

84.9 (28/33)

90.9 (30/33) p=0.452

Excellent %(n)

Improved % (n)

Failed % (n)

p value

Poor relaxation of urethral sphincter (n=11)

0.182

50 units (n=5)

60 (3/5)

40 (2/5)

0

100 units (n=6)

100 (6/6)

0

0

DU (n=28)

0.066

50 units (n=19)

68.4 (13/19)

10..5 (2/19)

21.1 (4/19)

100 units (n=9)

33.3 (3/9)

55.6 (5/9)

11.1 (1/9)

DV (n=21)

0.399

50 units (n=6)

83.3 (5/6)

16.7 (1/6)

0

100 units (n=15)

53.3 (8/15)

33.3 (5/15)

13.3 (2/15)

Retrospective case series

Taiwan

2016

N= 81 women with non-neurogenic DV

Age not reported; 100% women

Inclusion criteria: all women with DV (confirmed on VUD studies) refractory to medical treatment who received urethral botulinum 100 units, evidence of radiographic obstruction at the middle urethra with an open bladder neck and urodynamic findings, with baseline and postoperative urodynamic data were included.

Exclusion criteria: no urethral stricture or anatomic bladder outlet obstruction.

Urethral botulinum injections were done under light intravenous general anaesthesia 100 units reconstituted to 4 ml with normal saline to create a solution equivalent to 25 U/ml. botulinum was injected into the urethral sphincter along the urethral lumen at the 2, 5, 7, 9, and 12 o'clock positions.

3 months

None

Treatment successful^ % (n)

Treatment failure % (n)

67.9 (55/81)

32.1 (26/81)

Baseline

Follow-up

Baseline

Follow-up

P value

First sensation filling (ml)

152.3 ± 79.5

150.4 ± 94.3

119.2 ± 52.4

131.7 ± 105.6

0.652

Full sensation (ml)

225.2 ± 97.0

206.9 ± 102.8

195.4 ± 67.7

173.1 ± 125.9

0.910

Urge sensation (ml)

257.8 ± 107.6

232.1 ± 119.9

226.0 ± 82.6

192.8 ± 136.3

0.839

Pdet (cmH₂O)

59.9 ± 38.8

44.4 ± 33.6*

51.2 ± 36.0

36.2 ± 35.7

0.959

Compliance

60.9 ± 52.8

64.2 ± 63.8

69.6 ± 84.7

57.3 ± 61.2

0.526

Qmax (mL/s)

8.51 ± 6.21

8.83 ± 8.19

7.53 ± 4.72

4.85 ± 4.33

0.254

Volume (ml)

146.2 ± 108.2

160.1 ± 140.7

126.5 ± 87.1

82.9 ± 73.4

0.185

PVR (mL)

206.0 ± 137.5

132.6 ± 156.1*

195.3 ± 101.6

243.3 ± 239.2

0.032

CBC (ml)

352.2 ± 145.2

292.6 ± 136.9 *

321.9 ± 116.6

326.2 ± 215.4

0.185

VE

42.7 ± 28.3

58.2 ± 36.8 *

40.3 ± 27.4

34.3 ± 32.4

0.057

Bladder outlet obstruction index

42.9 ± 41.8

26.7 ± 39.5 *

36.1 ± 37.4

26.5 ± 32.8

0.630

Lower urinary tract symptoms

Total % (n=81)^^

Bladder neck dysfunction and DV 8.6% (7/81)

Midurethral DV

67.9% (55/81)

Distal urethral DV 23.5% (19/81)

Baseline

Follow-up^^

Baseline

Follow-up

Baseline

Follow-up

Baseline

Follow-up

Storage symptoms

70.4 (57/81)

50.6 (41/81)

71.4 (5/7)

42.9 (3/7)

72.7 (40/55)

54.5 (30/55)

63.2 (12/19)

42.1 (8/19)

Frequency/urgency/nocturia

19

17

1

1

10

10

8

6

Urge incontinence

38

24

4

2

30

20

4

2

Voiding symptoms

87.7 (71/81)

42 (34/81)

85.7 (6/7)

28.6 (2/7)

87.3 (48/55)

38.2 (21/55)

89.5 (17/19)

57.9 (11/19)

Difficulty urination

67

34

5

2

45

21

17

11

Urinary retention

4

0

1

0

3

0

0

0

Painful symptoms

13.6 (11/81)

4.9 (4/81)

14.3 (1/7)

0

9.1 (5/55)

3.6 (2/55)

0

0

Bladder pain

6

2

1

0

5

2

0

0

Micturition pain

5

2

2

1

3

1

0

0

% (n)

Haematuria (mild, resolved in 3 days)

6.2 (5/81)

Difficulty in urination (mild resolved in 3 days after treatment)

8.6 (7/81)

Case series

UK

2009-2012

N= 10 women with a primary disorder of urethral sphincter relaxation (Fowler's syndrome) with impaired voiding (n=5) or complete urinary retention (n=5)

mean age 40 (25–65) years, all women

Inclusion criteria: patients with a diagnosis of Fowler's syndrome (elevated UPP, sphincter volume, and abnormal EMG)

Exclusion criteria: urological and neurological causes for voiding dysfunction; a history of previous urethral surgery, neurological disease, pregnancy, current UTI, and those taking anticoagulants.

After 2% lidocaine injection, 100 units of botulinum (dissolved in 2ml saline) was injected into the external urethral sphincter on either side under EMG guidance.

This was done as an outpatient procedure.

10 weeks

No conflicts of interest. Study partly funded from National Institute for Health Research (NIHR), Urology foundation, and In Comb project. Allergan provided botulinum injections.

Baseline

10 weeks

Mean IPSS score

25.6

14.1

Mean 'bother' score on IPSS

6.1

3.5

Mean Qmax (mL/s) in people who could void

8.12

15.8

Mean Qmax in people with complete retention who could void spontaneously

14.3

Mean PVR (mL)

260

89

Mean static UPP (cmH₂O)

113

90 (p=0.037)

Unable to void (at week 10, continued with CSIC)

1

UTI (in those with history of recurrent UTI)

3

Case series

Taiwan

2002-2019

N= 106 women receiving sphincteric botulinum-A injections for refractory EUS dysfunction.

Indications:

N=56 idiopathic EUS dysfunction (23 DV and 33 PRES)

N=50 neurogenic EUS dysfunction (20 DSD, and 30 PRES)

mean age 61.8 ± 19.7 years; all women

Inclusion criteria: women who had received urethral sphincteric botulinum injections due to refractory voiding dysfunction caused by EUS dysfunction (diagnosed using image characteristics of VUDS during voiding phase) were retrospectively reviewed..

Exclusion criteria: patients with complicated clinical conditions such as a history of lower urinary tract reconstruction or urethra stenosis were excluded.

botulinum-A injection (100 units) diluted in 5 mL of normal saline was injected into the urethral sphincter (5 injections were done circumferentially via a perineal route under general anaesthesia).

1 month

No conflicts of interest. Study was supported by grants from the National Cheng Kung University Hospital.

DV % (n=23)

PRES % (n=33)

P value

Good subjective outcome

65 (15/23)

64 (21/33)

0.903

Good objective outcome

74 (17/23)

67 (22/33)

0.562

Urinary flow parameters

Qmax

Baseline

7.3±3.2

7.4±5.4

0.980

Follow-up

10.2 ** ±5.7

10.2 * ±7.7

VV

Baseline

139.7 ±94.3

130.5 ±125.6

0.559

Follow-up

174.7 ±104.7

190.9 ±124.6

PVR

Baseline

160.8 ±98.5

188.1 ±147.5

0.657

Follow-up

134.1 ±99.4

171.0 ±221.8

CBC

Baseline

300.4 ±135.4

318.7 ±127.8

0.328

Follow-up

308.8 ±118.9

360.4 ±203.5

VE

Baseline

0.47 ±0.23

0.43 ±0.32

0.616

Follow-up

0.59 ** ±0.30

0.60 ** ±0.32

VUDs parameters

First sensation of filling

Baseline

117.7 ±89.6

164.4 ±74.3

0.086

Follow-up

110.4 ±69.8

151.8 ± 72.4

Full sensation

Baseline

191.7 ±90.9

250.3 ± 108.3

0.023

Follow-up

163.3 ±77.4

251.7 ± 109.8

Urge sensation

Baseline

228.9 ±111.9

286.3 ± 127.0

0.004

Follow-up

180.3 ±83.4

293.8 ±114.1

Compliance

Baseline

92.4 ±125.4

74.4 ±87.5

0.194

Follow-up

44.5 ±35.6

65.5 ±66.4

Pdet

Baseline

53.6 ±29.0

13.0 ±11.9

0.136

Follow-up

51.1 ±31.2

11.9 ±15.4

Qmax

Baseline

5.8 ±2.5

4.2 ±5.4

0.334

Follow-up

6.3 ±4.3 6.7 ±6.6

6.7 ±6.6

BOOI

Baseline

41.9 ±30.8

4.6 ±11.3

0.116

Follow-up

38.5 ±33.0

-1.5 ±15.9

PVR

Baseline

217.2 ±128.2

314.3 ±248.6

0.118

Follow-up

174.4 ±135.9

305.2 ±263.1

CBC

Baseline

340.5 ±126.7

402.8 ±237.1

0.044

Follow-up

303.9 ±141.6

430.0 ±198.3

VE

Baseline

0.40 ±0.22

0.22 ±0.27

0.769

Follow-up

0.47 ±0.33

0.39 ±0.38