Heart rate variability: an objective measure of autonomic activity and bladder sensations during urodynamics.

AIMS: There are still controversies regarding the reproducibility of cystometric data and no objective measurement of bladder sensations is currently available. Additionally, very little information exists about autonomic activity during standard filling cystometry (FC). The aim of this study was to evaluate the use of heart rate variability (HRV) analysis as a reliable monitor of the autonomic nervous system and objective measure for bladder sensations during FC. METHODS: In a volunteer sample of healthy female subjects a standard FC at 25 ml/min was performed, using an 8 Fr microtip catheter with integrated pressure transducers. During FC, subjects had to indicate first sensation of filling (FSF), first desire to void (FDV) and strong desire to void (SDV). A 3-lead electrocardiogram was continuously recorded. After 5 h all measurements were repeated. Power spectrum analysis was used to analyse HRV, to obtain low frequency (LF) and high frequency (HF) parameters, from which the LF/HF ratio was derived. RESULTS: 12 subjects with a mean age of 23.3 +/- 2.3 years could be included. 11 of 12 subjects completed both measurement sessions. One subjects had to be excluded, due to irritating urethral discomfort following catheterisation. The LF/HF ratio showed a reproducible activation pattern in the healthy subjects with a stable sympathovagal balance until FDV. Before SDV was indicated, the sympathovagal balance started to shift towards sympathetic activation and caused a significant increase in LF/HF. CONCLUSION: HRV analysis seems to be a useful indicator for the general activation pattern of the sympathovagal balance during FC, correlating the intensity of the bladder filling sensation to stress and sympathetic activation.

Does tolterodine extended release affect the bladder electrical perception threshold? A placebo controlled, double-blind study with 4 and 8 mg in healthy volunteers.

PURPOSE: We evaluated the influence of tolterodine extended release on human bladder afferents. The afferents were assessed by determining the bladder electrical perception threshold using endovesical electrical stimulation at different potentially neuroselective frequencies. MATERIALS AND METHODS: A total of 30 healthy female subjects with a mean +/- SD age of 23.6 +/- 2.3 years and a mean body mass index of 20.5 +/- 1.7 kg/m2 were assigned to 3 groups of 10 each in a double-blind manner, including group 1-placebo, group 2-4 mg tolterodine extended release and group 3-8 mg tolterodine extended release. The investigation was performed using an 8Fr catheter for filling and stimulation that was placed at the bladder neck in a 100 ml filled bladder. Bipolar stimulation was performed using 2.5, 5 and 250 Hz stimuli. Subjects were asked to indicate sensation by pressing a button. Electrical perception thresholds were determined using the method of levels. Electrical perception thresholds were determined before and 4 hours after medication. RESULTS: No significant change in the electrical perception threshold after treatment could be found among the groups at 2.5, 5 and 250 Hz (p = 0.178, 0.817 and 0.365, respectively). There was a tendency in the tolterodine extended release groups toward an increased electrical perception threshold at 250 Hz (4 mg less than 8 mg). In most cases electrical stimulation with 2.5 and 5 Hz was described as a slight twinge, tickle or desire to void. Stimulation with 250 Hz was the most uncomfortable one, described as a strong, distinct twinge or burning "like urinary tract infection." CONCLUSIONS: Although a tendency was observed toward an increased electrical perception threshold at 250 Hz, this study showed no significant effect of tolterodine extended release on the bladder electrical perception threshold.

Can the ice-water test predict the outcome of intradetrusor injections of botulinum toxin in patients with neurogenic bladder dysfunction?

The aim of this project was to evaluate the ice-water test as a predictor of the response to intradetrusor botulinum toxin injection in patients with neurogenic detrusor overactivity. We retrospectively evaluated the urodynamic parameters in 22 patients with neurogenic bladder dysfunction and positive ice-water test. Maximum cystometric capacity (MCC), reflex volume (RV), maximum detrusor pressure during voiding (MVP) and bladder compliance (BC) were compared before and after intradetrusor injection of 300 units botulinum toxin and calculated as a quotient. The ice-water test was performed before the injection, and the maximum pressure rise and the time to maximum pressure were measured. Furthermore, the ratio between maximum pressure and time to reach maximum pressure was calculated as the velocity of pressure rise. Correlations between the ice-water test criteria and the quotients of the cystometric data before and after injection were determined by the Spearmen's Rho coefficient. The increase in MCC and RV after botulinum toxin A injection showed a small positive, but insignificant correlation of 0.25 and 0.2 to the velocity of pressure rise of the ice-water test. A small negative, but insignificant correlation was found in change of BC and MVP with -0.17 and -0.2, respectively. Based on our population the ice-water test cannot predict the efficacy of intradetrusor botulinum toxin injections in patients with neurogenic detrusor overactivity.

Facilitatory neuromodulative effect of duloxetine on pudendal motor neurons controlling the urethral pressure: a functional urodynamic study in healthy women.

OBJECTIVE: The aim of this functional urodynamic experiment in healthy women was to study the effect of duloxetine, which is a combined serotonin and norepinephrine (5-HT/NE) reuptake inhibitor, on urethral resting pressure, excitability of pudendal motor neurons, and urethral sphincter contractility. METHODS: In 11 healthy female subjects three baseline urethral pressure profiles (UPPs) were obtained to study resting pressure. Afterward the individual motor threshold (MT) for external urethral sphincter (EUS) contraction in response to transcranial magnetic stimulation (TMS) was determined to study the excitability of pudendal motor neurons. Another three UPPs were recorded while sacral root magnetic stimulation (SMS) was performed to evoke reproducible urethral contractions to study urethral sphincter contractility. Then the women received 40 mg duloxetine and the protocol was repeated 4 h after drug administration. The resting pressure values, MT values following TMS, and the EUS pressure amplitudes in response to SMS obtained at baseline were statistically compared to the corresponding values at follow-up after duloxetine. RESULTS: Oral administration of duloxetine significantly lowered MT for EUS contraction in response to TMS (p=0.013). In addition, duloxetine significantly increased EUS pressure amplitudes in response to SMS (p=0.0007, 5 of 11 subjects evaluated) but did not change urethral resting pressures. CONCLUSIONS: This is the first functional, urodynamic controlled study to show that the combined 5-HT/NE reuptake inhibitor duloxetine has a significant effect on the excitability of pudendal motor neurons and on urethral sphincter contractility in healthy women in vivo but no significant effect on urethral resting tone. Our data confirm a facilitatory neuromodulative effect of duloxetine on sphincter motor neurons in humans.

Conditioning stimulus can influence an external urethral sphincter contraction evoked by a magnetic stimulation.

AIMS: To study the effect of a conditioning stimulus on an external urethral sphincter (EUS)contraction evoked by a magnetic stimulation at different time intervals. METHODS: Seven healthy male volunteers underwent EUS pressure measurement. At baseline, magnetic stimulation of the lumbosacral spinal cord above the motor threshold was performed and evoked EUS pressure responses were recorded. The lumbosacral magnetic stimulation was repeated with same intensity, while a selective electrical dorsal penile nerve stimulation below the bulbocavernosus reflex (BCR) threshold was preceding at five different intervals (10, 20, 30, 50, 100 msec). The protocol was performed with empty and full bladder (BLA), and baseline responses were statistically compared to those with combined stimulation. RESULTS: When the dorsal penile nerve electrical stimulation preceded the lumbosacral magnetic stimulation by 20 msec (P=0.0048), 50 msec (P=0.0039), or 100 msec (P=0.0002), the amplitudes of the EUS pressure response with empty BLA were significantly reduced compared to lumbosacral magnetic stimulation alone. With a filled BLA, the amplitudes of the EUS were significantly reduced only at an interval of 50 msec (P<0.0001). CONCLUSIONS: A conditional sensory pudendal stimulation seems to have the capacity to inhibit the external urethral sphincter contraction induced by a magnetic stimulation. The inhibitory effect seems to depend on the latency between the peripheral and lumbosacral stimulation as well as on the degree of BLA filling. It remains to be proved if the neuromodulative effect of the conditional stimulus occurs at a spinal or supraspinal level.

Sleep-related painful erections.

BACKGROUND: A 45-year-old man presented with repeated awakenings at night caused by nocturnal painful erections, in sharp contrast with normal erections at other times, 2 years after surgical removal of a thoracic (Th6-7) ependymoma. INVESTIGATIONS: Physical examination, pharmaco-sensitized penile Doppler ultrasound, spinal and brain MRI, neurophysiological work-up (tibial and perineal somatosensory-evoked potential; hand, foot and perineal sympathetic skin response assessment), polysomnography with recording of nocturnal penile tumescence. DIAGNOSIS: Sleep-related painful erections, characterized by penile pain during nocturnal erection, typically during rapid eye movement sleep, in the presence of a residual thoracic spinal cord syndrome. MANAGEMENT: Amitriptyline, an antidepressant that suppresses rapid eye movement sleep, was ineffective. Treatments with other antidepressants, clozapine and beta-blockers were suggested, but the patient declined because of potential severe side effects.

The effect of tamsulosin on the resting tone and the contractile behaviour of the female urethra: a functional urodynamic study in healthy women.

AIMS: The aim of this functional urodynamic experiment was to study the effect of the selective alpha1(A)-blocker tamsulosin on the urethral pressure in healthy human females and assessed first the resting urethral pressure and second the urethral contractility in response to magnetic stimulation of the sacral roots. METHODS: 11 healthy female subjects gave their written informed consent and were included. A microtip pressure transducer catheter was inserted into the bladder and three baseline urethral pressure profiles were obtained. Another three urethral pressure profiles were recorded while magnetic single pulse stimulation of the sacral roots was performed above the motor threshold of the pelvic floor to evoke reproducible urethral contractions. Then the subjects received 0.4 mg of tamsulosin and the entire protocol was repeated 6 hours after drug administration. Cardiovascular monitoring was obtained during the baseline and follow-up measurements. Mean and maximal urethral pressure values calculated over the entire urethra, mean pressure values calculated over the proximal, middle and distal third of the urethra and the pressure amplitudes to magnetic stimulation at baseline were statistically compared to the follow-up measurements with tamsulosin. RESULTS: The oral administration of tamsulosin did not change the systemic blood pressure, but did significantly reduce the mean and maximal urethral pressure acquired over the entire urethra. When the proximal, middle and distal third of the urethra were analysed separately, there was a significant pressure reduction in all three segments. Amplitudes of the urethral contractions evoked by sacral magnetic stimulation remained unchanged after tamsulosin. CONCLUSIONS: These data show a significant relaxing effect of tamsulosin on the resting urethral tone in healthy females in vivo. These results may suggest tamsulosin as a new pharmacological approach to treat urinary retention due to overactive or non-relaxing urethra in women.

Oral nitric oxide donors: a new pharmacological approach to detrusor-sphincter dyssynergia in spinal cord injured patients?

PURPOSE: Detrusor-sphincter dyssynergia is a common cause of bladder outlet obstruction in spinal cord injured patients and leads to poor bladder emptying and high bladder pressures, which if left untreated might cause renal failure. In this study, we tested the recently published hypothesis that oral administration of a nitric oxide donor could be a new pharmacological approach to treat detrusor-sphincter dyssynergia in humans with spinal cord injury. METHODS: 12 male spinal cord injured patients presenting with neurogenic detrusor overactivity and detrusor-sphincter dyssynergia were studied. 6 performed clean intermittent catheterisation and 6 used suprapubic tapping for bladder emptying. During cystometry the bladder was filled until the first overactive bladder contraction accompanied by detrusor-sphincter dyssynergia occurred while bladder and external urethral sphincter pressures were continuously recorded. Then the bladder was emptied and the patients received 10 mg of isosorbide dinitrate sublingually. Resting pressures were recorded and cystometry was repeated starting 15 min after drug administration. Maximal and mean values for bladder and external urethral sphincter pressures were calculated in both fillings and statistically compared by analysis of variance for repeated measurements (level of significance p < 0.05). RESULTS: Nitric oxide significantly reduced external urethral sphincter pressures at rest (p < 0.05) and during dyssynergic contraction (p < 0.05) while bladder pressures at rest and during contraction as well as the reflex volume remained unchanged. In the patients who used suprapubic tapping for bladder emptying the mean post triggering residual volume was significantly reduced (p < 0.05). CONCLUSIONS: Oral administration of nitric oxide donors significantly reduced bladder outlet obstruction due to detrusor-sphincter dyssynergia suggesting a role for nitric oxide in inhibitory neurotransmission to the urethral sphincter. This new approach could offer a potential pharmacological option to treat detrusor-sphincter dyssynergia in spinal cord injured patients.

The effect of nitric oxide on the resting tone and the contractile behaviour of the external urethral sphincter: a functional urodynamic study in healthy humans.

AIMS: This functional urodynamic study assessed the effect of the nitric oxide donor isosorbide dinitrate on the external urethral sphincter and hypothesised first that nitric oxide could lower the resting sphincter pressure, second that nitric oxide could influence the sphincter contractility during magnetic stimulation, and third that nitric oxide could induce a faster external urethral sphincter fatigue during continuous magnetic stimulation. METHODS: Eight healthy males gave their written informed consent and were included. A 2-channel microtip pressure transducer catheter was inserted into the urethra measuring the bladder and the external urethral sphincter pressure. Magnetic stimulation of the sacral roots was performed to evoke reproducible contractions of the external urethral sphincter. The baseline protocol included six single pulse stimulations and three stimulations 10sec in duration each for two frequencies 5Hz and 50Hz with intensities at the motor threshold of the pelvic floor. Then the subjects received 10 mg of isosorbide nitrate sublingually and the protocol was repeated 5min, 20min, 40min and 60min after drug administration. RESULTS: The sublingual administration of isosorbide dinitrate could significantly reduce the resting pressure of the external urethral sphincter for at least one hour. The maximal contractile strength measured as the maximal urethral pressure during single pulse and continuous magnetic stimulation of the sacral roots also decreased significantly. Nitric oxide did not induce a significantly faster fatigue of the external urethral sphincter during continuous magnetic stimulation of the sacral roots. CONCLUSIONS: This study shows a functionally relevant effect of nitric oxide on the resting tone and the contractile behaviour of the human external urethral sphincter in vivo while the fatigue properties did not changed significantly. Nitric oxide donors could offer a new pharmacological approach to treat urinary retention due to overactive or non-relaxing external urethral sphincter.

Functional magnetic stimulation of the spinal cord--a urodynamic study in healthy humans.

AIMS: To study the effects of functional magnetic stimulation of the spinal cord in healthy subjects on somatic and autonomic pathways innervating the anal and the external urethral sphincter, bladder, bladder neck, and rectum. METHODS: Eight healthy male volunteers gave their written informed consent and underwent functional magnetic stimulation of the thoracolumbar and sacral spinal cord. A two-channel microtip pressure transducer catheter was placed rectally measuring the abdominal and anal sphincter pressure. A three-channel microtip pressure transducer catheter was inserted into the urethra measuring the bladder, the bladder neck, and the external urethral sphincter pressure. A comprehensive protocol of single and repetitive magnetic stimulations was performed. Frequency, location, and duration of stimulation were varied while the intensity of stimulation was adapted to the maximum the subjects could tolerate. In four subjects, the degree of bladder filling was changed and the protocol was repeated when the subjects reported a full bladder and desire to void. RESULTS: Continuous magnetic stimulation of the thoracolumbar spinal cord and the sacral roots applied with different frequencies (5, 15, 30, 60, 100 Hz) and different duration of stimulation (10, 30, 120 sec) evoked sphincter contraction of both anal and urethral sphincters. The stimulation could not evoke contractions of the bladder, the bladder neck, or the rectum. Also with filled bladder and present desire to void, the magnetic stimulation could not activate autonomic pathways innervating these structures. CONCLUSIONS: Considering our results, we suggest that in individuals with preserved sensibility magnetic stimulation of the spinal cord with intensities below the pain threshold is ineffective in activating autonomic nerve fibres innervating bladder, bladder neck, and rectum.

Afferent fibers of the pudendal nerve modulate sympathetic neurons controlling the bladder neck.

AIMS: Pudendal nerve stimulation is known to have a potential modulative effect on bladder function. However, even if its efficiency has been established for various neurogenic and non-neurogenic bladder dysfunctions, the underlying neuronal mechanism, and the involved pathways in humans remain unknown. In this prospective study we focused on the effects of pudendal nerve stimulation in complete spinal cord injured patients to identify neuromodulative processes that occur on spinal level. METHODS: Twenty complete spinal male presenting with upper motor neuron lesion and neurogenic incontinence underwent pudendal nerve stimulation. Bladder, bladder neck (BN), and external urethral sphincter (EUS) pressures were continuously recorded with a three channel microtip pressure transducer catheter. Fifty six pudendal stimulations using biphasic rectangular impulses (0.2 ms, 10 Hz) with intensities up to 100 mA were applied to the dorsal penile nerve. In six patients, 18 stimulations were repeated after intravenous (i.v.) administration of 7 mg phentolamine. RESULTS: Mean BN and EUS pressure increased during stimulation significantly (P < 0.001). The latencies to the EUS responses range between 27 and 41 ms and those to the BN responses between 188 and 412 ms. Phentolamine decreased initial BN pressure and reduced the pressure rise during stimulation significantly (P < 0.05). CONCLUSIONS: Pudendal nerve stimulation evoked somatic responses in the EUS and autonomic responses in the smooth muscle sphincter controlling the BN. Longer latencies of the BN responses and the sensitivity to the alpha-blocking agent phentolamine suggest that sympathetic alpha-adrenergic fibers are involved. Somatic afferent fibers of the pudendal nerve are supposed to project on sympathetic thoracolumbar neurons to the BN and modulate their function. This neuromodulative effect works exclusively at the spinal level and appears to be at least partly responsible for BN competence and at least continence.

Sympathetic sudomotor skin activity in human after complete spinal cord injury.

Spinal cord injury (SCI) causes serious disturbances in autonomic innervation and malfunction of the sympathetic nervous system that controls the pelvic organs, blood pressure, skin temperature and sweating. We studied sympathetic sudomotor pathways in 6 healthy subjects and 14 patients with sensory and motor complete SCI on cervical, thoracic and lumbar level. Sympathetic skin responses (SSRs) were provoked by auditory bursts and electrical stimulation of median, pudendal and tibial nerve and recorded from the palmar and plantar skin. The SSRs in healthy subjects occurred generally with the same pattern and with similar latencies suggesting a common sudomotor pathway mediating the SSR. Appearance or absence of the SSRs in SCI following stimulation above the lesion depend on the spinal level of lesion and on the location of stimulation. Lesions below T3 show palmar and lesions below T12 palmar and plantar SSR. Pudendal nerve stimulation evoked plantar SSRs in patients with complete cervical and thoracic SCI. No SSRs were obtained in patients with lesions at L1 and more caudal. SSRs following pudendal nerve stimulation in complete SCI above the level L1 are mediated by sacral somatic afferents and a sympathetic pathway originating at the upper lumbar level. The underlying sacro-lumbar reflex circuit is organized on spinal level and requires intact lumbar segments. Tibial nerve stimulation was not found to elicit SSRs below a SCI lesion and we suppose that this type of electrical stimulation cannot activate the spinal sudomotor reflex circuit.