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Shen YC et al., 2022: Prospective, Randomized, Double-blind, Placebo-controlled, Pilot Study of Extracorporeal Shock Wave Therapy for Detrusor Underactivity/Underactive Bladder

Shen YC, Chen CH, Chancellor MB, Chuang YC.
Department of Urology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Taiwan.
Beaumont Health System, Oakland University-William Beaumont School of Medicine, Royal Oak MI 48073, USA.
Department of Urology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Taiwan; Center for Shock Wave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.

Abstract

Background: Detrusor underactivity/underactive bladder (DU/UAB) is a disease with great unmet needs and no current approved drug treatment. Extracorporeal shock wave therapy (ESWT) has been shown to improve regeneration of tissue and increase detrusor contractility in preclinical studies of DU/UAB.

Objective: To assess ESWT as a treatment of DU/UAB.

Design, setting, and participants: Patients with DU/UAB were enrolled in this phase 2 randomized, double-blind, placebo-controlled, physician-initiated study.

Intervention: The patients were assigned to ESWT (N = 6, 2500 shocks, frequency of four pulses per second, and maximum total energy flow density of 0.25 mJ/mm2) once a week for 6 wk at the suprapubic bladder area or to placebo (N = 5, shock wave setting without energy transmission).

Outcome measurements and statistical analysis: The primary endpoint was the average changes in postvoid residual urine (PVR) from baseline to 4 wk after treatment. Other endpoints included the average changes in 3-d voiding diary, global response assessment of patient satisfaction, Underactive Bladder Questionnaire (UAB-Q) score, and urodynamic evaluation.

Results and limitations: The difference in improvement in PVR was -157.8 ml (95% confidence interval [CI]: -380.1, 64.4) versus -6.6 ml (95% CI: -178.1, 164.9) and -77.5 ml (95% CI: -242.1, 87.1) versus 81.8 ml (95% CI: -137.2, 300.7) for ESWT versus placebo (p = 0.116 and 0.056) at 4 and 12 wk, respectively. The ESWT group exhibited a significant reduction in the UAB-Q score (-4.3; 95% CI: -9.1, 0.4) compared with the placebo group (-0.4; 95% CI: -1.8, 1.0) at 4 wk after treatment (p = 0.025), and the effects were decreased at 12 wk (p = 0.091). This study was limited by small sample size.

Conclusions: ESWT was well tolerated with a statistically significant decrease of DU/UAB symptoms and a trend to decrease PVR versus placebo. These results indicate that ESWT may be a promising treatment for DU/UAB and multicenter studies are needed.

Patient summary: Bladder shock wave therapy was studied in this randomized, double-blind, placebo-controlled study in patients with inadequate bladder emptying (underactive bladder). Bladder shock wave therapy was found to be well tolerated with an improvement in bladder emptying. These results indicate that bladder shock wave therapy may be a promising treatment for patients who cannot empty their bladder adequately.
Eur Urol Focus. 2022 Nov 24;S2405-4569(22)00261-9. doi: 10.1016/j.euf.2022.11.011. Online ahead of print. PMID: 36437222. FREE ARTICLE

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Comments 1

Jens Rassweiler on Monday, 20 February 2023 09:30

This study focuses on a new field of indication for ESWT in Urology. There have been studies on the effect of ESWT on overactive bladder and bladder outlet obstruction, however, this is the first clinical study on detrusor underactivity following positive experiments in the animal model.

Detrusor underactivity (DU) is generally associated with decreased duration and strength of bladder muscle detrusor contraction. DU can result in prolonged and incomplete bladder emptying in the absence of urethral obstruction. Underactive bladder (UAB) is a commonly used term to describe DU. DU/UAB is linked to diabetes mellitus, bladder outlet obstruction, and aging with contribution of neurogenic and myogenic factors. Based on an analysis from bladder biopsies, DU/UAB patients have lower E-cadherin expression and greater apoptotic cells than controls. There was also lower expression of P2X3 receptors, muscarinic receptors (M3 and M2), and endothelial nitric oxide synthase.

Besides catheterization, there is a lack of safe or effective treatment for DU/UAB. In specific cases, the use of bladder pace-makers may be effective. Extracorporeal shock wave therapy (ESWT) has been demonstrated to enhance gene expression related to angiogenesis and proliferation, and improve tissue neovascularization and regeneration, which has clinical utility in the treatment of bone fracture, unhealed wound, myocardial infarction, erectile dysfunction, interstitial cystitis, and stress urinary incontinence.

This study was designed as a physician-initiated randomized, phase II, double-blind, paralleled, controlled trial from a tertiary university medical center. The patients with confirmed DU/UAB were randomly assigned to receive (1) ESWT or (2) placebo in a 1:1 ratio. The diagnosis of DU/UAB was established based on a uro-dynamic evaluation in addition to clinical symptoms. Key exclusion criteria included women pregnant or planning to become pregnant or with a history of spinal cord injury, a history of pelvic organ cancer treated within 12 mo, or pelvic organ prolapse beyond the introitus (eg, cystocele and rectocele).

The electromagnetic shock wave applicator (LITEMED LM ESWT mini system, Taiwan) was gently placed directly on the ultrasound transmission gel over the skin surface of suprapubic region above the urinary bladder once a week for 6 wk, with 2500 shocks, frequency of 4 Hz, and maximum energy flow density of 0.25 mJ/mm2. The placebo treatment was performed with the same therapy head, which was also fitted with a placebo standoff without energy transmission.

The bladder capacity decreased from 417 ml to 315 ml after ESWT within three months, whereas it remained unchanged (vs. 325 ml to 331ml) in the placebo group. Detrusor muscle activity (PdetQmax) increased in the ESWT group (10.3 to 14.5 cm H2O), whereas it decreased in the placebo group (16.2 to 11.5 cm H2O). Residual urine decreased in the ESWT group (380 ml to 302 ml), whereas it increased in the Placebo-group (207 ml t0 290 ml) after three months.

FBC, frequency, and nocturia were not significantly different after treatment in both groups. There were decreases in first desire, urgency, and total bladder capacity from baseline to 12 weeks after treatment in the ESWT group,

The results of this interesting RCT revealed that ESWT was effective in reducing UAB score observed at 4 wk after treatment, and the beneficial effects were persistent at 3 months after treatment. They did not find any change in the placebo group. The findings are limited by the fact that despite the 1:1 randomization, the baseline UAB score was higher in the ESWT group. It has also to be mentioned, that they were not able to completely cure the patients, reflected by the still high residual volume. Nevertheless, the treatment was well tolerated and is in accordance to previous animal studies, were ESWT was able to induce partial recovery in the contractility of a cryoinjury-induced DU/UAB rat model, with a reduction in bladder inflammation and an increase of ki-67–positive cells and reduction of COX-2 expression.

I agree with the authors, that larger prospective studies with a greater number of patients are needed to confirm these interesting results. There are other examples in the literature, that were able to demonstrate even stem-cell proliferation at the urinary sphincter or skin. So such results are very interesting to follow, because the actual ability to cure or improve such diseases are very limited.

Jens Rassweiler


This study focuses on a new field of indication for ESWT in Urology. There have been studies on the effect of ESWT on overactive bladder and bladder outlet obstruction, however, this is the first clinical study on detrusor underactivity following positive experiments in the animal model. Detrusor underactivity (DU) is generally associated with decreased duration and strength of bladder muscle detrusor contraction. DU can result in prolonged and incomplete bladder emptying in the absence of urethral obstruction. Underactive bladder (UAB) is a commonly used term to describe DU. DU/UAB is linked to diabetes mellitus, bladder outlet obstruction, and aging with contribution of neurogenic and myogenic factors. Based on an analysis from bladder biopsies, DU/UAB patients have lower E-cadherin expression and greater apoptotic cells than controls. There was also lower expression of P2X3 receptors, muscarinic receptors (M3 and M2), and endothelial nitric oxide synthase. Besides catheterization, there is a lack of safe or effective treatment for DU/UAB. In specific cases, the use of bladder pace-makers may be effective. Extracorporeal shock wave therapy (ESWT) has been demonstrated to enhance gene expression related to angiogenesis and proliferation, and improve tissue neovascularization and regeneration, which has clinical utility in the treatment of bone fracture, unhealed wound, myocardial infarction, erectile dysfunction, interstitial cystitis, and stress urinary incontinence. This study was designed as a physician-initiated randomized, phase II, double-blind, paralleled, controlled trial from a tertiary university medical center. The patients with confirmed DU/UAB were randomly assigned to receive (1) ESWT or (2) placebo in a 1:1 ratio. The diagnosis of DU/UAB was established based on a uro-dynamic evaluation in addition to clinical symptoms. Key exclusion criteria included women pregnant or planning to become pregnant or with a history of spinal cord injury, a history of pelvic organ cancer treated within 12 mo, or pelvic organ prolapse beyond the introitus (eg, cystocele and rectocele). The electromagnetic shock wave applicator (LITEMED LM ESWT mini system, Taiwan) was gently placed directly on the ultrasound transmission gel over the skin surface of suprapubic region above the urinary bladder once a week for 6 wk, with 2500 shocks, frequency of 4 Hz, and maximum energy flow density of 0.25 mJ/mm2. The placebo treatment was performed with the same therapy head, which was also fitted with a placebo standoff without energy transmission. The bladder capacity decreased from 417 ml to 315 ml after ESWT within three months, whereas it remained unchanged (vs. 325 ml to 331ml) in the placebo group. Detrusor muscle activity (PdetQmax) increased in the ESWT group (10.3 to 14.5 cm H2O), whereas it decreased in the placebo group (16.2 to 11.5 cm H2O). Residual urine decreased in the ESWT group (380 ml to 302 ml), whereas it increased in the Placebo-group (207 ml t0 290 ml) after three months. FBC, frequency, and nocturia were not significantly different after treatment in both groups. There were decreases in first desire, urgency, and total bladder capacity from baseline to 12 weeks after treatment in the ESWT group, The results of this interesting RCT revealed that ESWT was effective in reducing UAB score observed at 4 wk after treatment, and the beneficial effects were persistent at 3 months after treatment. They did not find any change in the placebo group. The findings are limited by the fact that despite the 1:1 randomization, the baseline UAB score was higher in the ESWT group. It has also to be mentioned, that they were not able to completely cure the patients, reflected by the still high residual volume. Nevertheless, the treatment was well tolerated and is in accordance to previous animal studies, were ESWT was able to induce partial recovery in the contractility of a cryoinjury-induced DU/UAB rat model, with a reduction in bladder inflammation and an increase of ki-67–positive cells and reduction of COX-2 expression. I agree with the authors, that larger prospective studies with a greater number of patients are needed to confirm these interesting results. There are other examples in the literature, that were able to demonstrate even stem-cell proliferation at the urinary sphincter or skin. So such results are very interesting to follow, because the actual ability to cure or improve such diseases are very limited. Jens Rassweiler
Monday, 20 May 2024