Keywords
suprasacral spinal cord injury - phosphodiesterase 5 inhibitors - lower urinary tract
symptoms - urodynamic parameters
Introduction
Spinal cord injury (SCI) is one of the most debilitating and devastating injuries
to humans. It occurs throughout the world with an annual incidence of 15 to 40 cases
per million.[1] The occurrence of SCI is highest among young persons in the 16 to 30 age group.[2] The most common mode of injury is road traffic accidents. In the Indian subcontinent,
every year there are approximately 20,000 new cases of SCI in trauma victims,[3] with main mode of injury being fall from height.
The sacral spinal cord begins at about spinal column level T12 to L1. Injury above
T12 to L1 qualifies as suprasacral SCI (SSSCI). The patients with SSSCI often develop
lower urinary tract symptoms (LUTS). Failure to properly address the LUTS associated
with SSSCI can lead to significant morbidity and mortality.[4] In the past few decades, survival rates have considerably improved in SCI patients,[5] and hence it has become increasingly important to give these patients better quality
of life.
Urodynamic study is gold standard for evaluation of urinary tract dysfunction in SCI
patients as well as to establish effectiveness of new drugs.[6] Efficacy of phosphodiesterase 5 (PDE5) inhibitors in amelioration of LUTS has gained
attention in recent years. In our knowledge, few studies[7]
[8] done till date have shown that PDE5 inhibitors positively affect urodynamic parameters
in SCI men. These studies included only subjects of the male sex, but in our study
we included patients from both sexes as we assumed that PDE5 receptors would be present
on detrusor muscles and on bladder outflow area equally in both sexes, so females
should also be evaluated for the actions of PDE5 inhibitors.
Materials and Methods
This was a prospective observational hospital-based study carried on a cohort of 31
patients suffering from SSSCI with LUTS in the age group 18 to 65 years who came for
follow-up in the Department of Neurosurgery/Urology from November 2012 to October
2014 in SKIMS, Soura, Srinagar. Institutional ethical clearance was sought before
undertaking the study. After taking proper consent, urodynamic study was performed
in these patients and repeated 2 hours after taking single oral dose of 20 mg tadalafil.
Urodynamics were performed on patient in sitting position, zeroing of device done
every time at the start of procedure. We used normal saline at the rate of 15 mL/s
at temperature of 25° C as filling fluid. Urodynamic parameters such as maximum detrusor
filling pressure (DFP) in cm H2O, maximum detrusor voiding pressure (DVP) in cm H2O, maximum bladder capacity in mL, and bladder compliance in mL/cm H2O before and after tadalafil administration were specifically recorded and analyzed.
Patients with chronic renal and liver disease, diabetes mellitus, proven urinary tract
infection, history of pelvic surgery, and absolute contraindications to tadalafil
were excluded from the study.
In patients with a history of autonomic dysreflexia or whose neurologic level of injury
was D6 or above, blood pressure was monitored during testing. We used Netherlands-made
medication measurement systems (MMS) (medication measurement systems) LIBRA+ 3T urodynamic
system for urodynamic study. Data were analyzed by MMS software ver.7.3t. Data before
and after taking the drug were compared for final results and conclusion. p-Value of < 0.05 was considered statistically significant.
Results
Thirty-one patients were included in our study. Mean age of the study group was 34.5
± 12.6 years, with the youngest patient being 18 years old and oldest patient being
62 years old. Twenty-five patients were males and six were females. Twelve patients
suffered injury at and above D6 spinal cord level and 19 below D6 spinal cord level.
Out of 31 patients, 10 had complete injury and 21 had incomplete injury. Severity
of injury was calculated according to ASIA (American Spinal Injury Association) scale.
Type A was labeled as complete injury and types B and C as incomplete injury, as shown
in [Table 1].
Table 1
Demographic profile of patients
|
Number of patients
|
31
|
|
Mean age
|
34.52 y
|
|
Sex distribution
|
|
|
Male
|
25
|
|
Female
|
6
|
|
Level of injury
|
|
|
At or above D6
|
12
|
|
Below D6
|
19
|
|
Severity of injury
|
|
|
Complete
|
10
|
|
Incomplete
|
12
|
Maximum filling detrusor pressure in cm H2O before administration of drug was 36.03 ± 20.54. It improved after taking drug to
32.90 ±16.47, although results were not statistically significant (p > 0.05).
Maximum voiding detrusor pressure in cm H2O before taking drug was 64.65 ± 33.19. It improved to 58.13± 20.7; however, p-value in this case was > 0.05.
Maximum bladder capacity in mL showed a statistically significant improvement after
single 20-mg dose of tadalafil (p < 0.05) as shown in [Table 2]. The results for males and females are shown in [Tables 3]
[4], respectively. In males, maximum bladder capacity in mL showed a statistically significant
improvement after single 20-mg dose of tadalafil, but in female patients we did not
observe any statistically significant improvement in any of these parameters.
Table 2
Pre- and post-tadalafil values in whole study group
|
Variable
|
Pre-tadalafil (mean ± SD)
|
Post-tadalafil (mean ± SD)
|
p-Value
|
|
Abbreviation: SD, standard deviation.
Note: DFP = maximum detrusor filling pressure (cm H2O); DVP = maximum detrusor voiding pressure (cm H2O); CAPACITY = maximum bladder capacity (mL); COMPLIANCE = bladder compliance (mL/cm
H2O).
*Statistically significant value.
|
|
DFP
|
36.03 ± 20.547
|
32.90 ± 16.477
|
0.289
|
|
DVP
|
64.65 ± 33.199
|
58.13 ± 20.760
|
0.416
|
|
CAPACITY
|
268.39 ± 130.036
|
298.55 ± 112.027
|
0.049*
|
|
COMPLIANCE
|
18.68 ± 6.414
|
20.35 ± 7.50
|
0.189
|
Table 3
Pre- and post-tadalafil values in males
|
Variable
|
Pre-tadalafil (mean ± SD)
|
Post-tadalafil (mean ± SD)
|
p-Value
|
|
Abbreviation: SD, standard deviation.
Note: DFP = maximum detrusor filling pressure (cm H2O); DVP = maximum detrusor voiding pressure (cm H2O); CAPACITY = maximum bladder capacity (mL); COMPLIANCE = bladder compliance (mL/cm
H2O).
*Statistically significant value.
|
|
DFP
|
38.32 ± 21.311
|
33.56 ± 17.054
|
0.112
|
|
DVP
|
66.76 ± 35.226
|
55.84 ± 21.33
|
0.143
|
|
CAPACITY
|
246.32 ± 120.123
|
286.36 ± 107.06
|
0.020*
|
|
COMPLIANCE
|
18.69 ± 6.02
|
22.833 ± 11.01
|
0.243
|
Table 4
Pre- and post-tadalafil values in females
|
Variable
|
Pre-tadalafil (mean ± SD)
|
Post-tadalafil (mean ± SD)
|
p-Value
|
|
Abbreviation: SD, standard deviation.
Note: DFP = maximum detrusor filling pressure (cm H2O); DVP = maximum detrusor voiding pressure (cm H2O); CAPACITY = maximum bladder capacity (mL); COMPLIANCE = bladder compliance (mL/cm
H2O).
|
|
DFP
|
26.50 ± 14.76
|
30.17 ± 14.892
|
0.273
|
|
DVP
|
55.83 ± 23.267
|
67.67 ± 16.281
|
0.058
|
|
CAPACITY
|
360.33 ± 140.05
|
349.33 ± 128.20
|
0.752
|
|
COMPLIANCE
|
18.66 ± 8.45
|
22.83 ± 11.01
|
0.136
|
On stratification of data, we observed that patients with injury above D6 level showed
a statistically significant improvement in bladder compliance from 17.01 ± 5.63 to
21.73 ± 6.7 (p < 0.05) and bladder capacity from 263.33 ±123.7 to 302.67 ± 123.44 (p < 0.05), as shown in [Table 5].
Table 5
Pre- and post-tadalafil values in patients with injury above D6
|
Variable
|
Pre-tadalafil (mean ± SD)
|
Post-tadalafil (mean ± SD)
|
p-Value
|
|
Abbreviation: SD, standard deviation.
Note: DFP = maximum detrusor filling pressure (cm H2O); DVP = maximum detrusor voiding pressure (cm H2O); CAPACITY = maximum bladder capacity (mL); COMPLIANCE = bladder compliance (mL/cm
H2O).
*Statistically significant value.
|
|
DFP
|
33.92 ± 17.85
|
34.50 ± 16.98
|
0.683
|
|
DVP
|
58.92 ± 25.86
|
59.08 ± 26.548
|
0.969
|
|
CAPACITY
|
263.33 ± 123.79
|
302.67 ± 123.445
|
0.015*
|
|
COMPLIANCE
|
17.01 ± 5.63
|
21.733 ± 6.73
|
0.017*
|
Discussion
Urogenital diseases have been reported as one of the primary causes of death in SCI
patients.[9]
[10]
[11]
[12] The low compliance neurogenic bladder due to SCI clinically receives special attention
as it causes deterioration of renal function.[13]
[14] SSSCI patients often develop LUTS that manifests as detrusor areflexia and urine
retention initially followed by overactive detrusor and detrusor-sphincter dyssynergia
(DSD). The recovery of lower urinary tract function occurs weeks later, but the voiding
function deteriorates and manifests by hyperreflexia and incomplete voiding secondary
to DSD during voiding[15] and consequent renal damage, if untreated. Urodynamic study is an important part
of the evaluation in SCI patients with LUTS and can provide useful clinical information
about the function of the urinary bladder, sphincteric mechanism, and voiding pattern.[16]
Overactive bladder is the underlying cause of LUTS in SSSCI patients, the impact of
PDE5 inhibitors on improving of SCI-induced LUTS seems valid.[17] PDE5 receptors are normally present in the detrusor muscles, bladder neck, and urethra.
Human bladder expresses the PDE5 gene on quantitative reverse transcriptase-polymerase chain reaction and protein
on immunohistochemistry and Western blot as well as PDE5 enzymatic activity.[18]
[19] The cyclic guanosine monophosphate (cGMP) represents an important mediator in the
control of the outflow region (bladder, urethra). Use of PDE inhibitors such as sildenafil,
tadalafil, vardenafil, avanafil, or udenafil known to restrain the degradation of
the second messenger cGMP can produce significant relaxation of the aforementioned
tissues offering great opportunities in the treatment of lower urinary tract dysfunction.[20] Major mechanisms in SCI patients that contribute to LUTS include reduced nitric
oxide/cGMP signaling, increased RhoA kinase pathway activity, autonomic over activity,
increased bladder afferent activity, and pelvic ischemia.[21] The probable mechanism by which PDE5 inhibitors decrease these LUTS is that nitric
oxide enters the smooth muscles and stimulates guanosinecyclase that converts cyclic
guanosine three phosphate to cGMP, which in turn decreases intracellular calcium concentration
and consequently causes muscle relaxation.[21]
[22] Latest evidence on pathophysiology of LUTS has provided the rationale for use of
PDE5 for (1) improvement of lower urinary tract oxygenation, (2) negative regulation
of proliferation and trans-differentiation of lower urinary tract stroma,(3) reduction
in bladder afferent nerve activity, and (4) downregulation of prostate inflammation
Tadalafil and other PDE5 inhibitors have demonstrated beneficial effects on smooth
muscle relaxation, endothelial cell proliferation, nerve activity, and tissue perfusion
that may impact LUTS in men.[21] A 20-mg once-daily dose of PDE5 inhibitor such as tadalafil is well tolerated and
has shown clinically meaningful and statistically significant efficacy in men with
benign prostatic hyperplasia (BPH) and LUTS. Tadalafil, the drug we used in our study,
has half-life of 17.5 hours. Peak plasma concentration is reached within 2 hours,
with steady-state plasma concentrations achieved after 5 days of once-daily dosing.[23] Tadalafil 20 mg is an effective and well-tolerated treatment for erectile dysfunction
that has a period of responsiveness of up to 36 hours.[24]
Few studies have been conducted so far that have demonstrated the effect of PDE5 inhibitors
on SCI patients. One study[8] demonstrated that a single 20 mg vardenafil administration allows significant improvement
in urodynamic parameters, including maximum detrusor pressure (MDP), maximum cystometric
capacity (MCC), and detrusor over activity volume (DVO) in 25 male patients. Placebo
administration did not affect urodynamic parameters in these patients. In seven SCI
patients above D6, they observed the most significant improvement in the evaluated
urodynamic items, including MDP (p = 0.039), MCC (p = 0.004), and DVO (p = 0.003). Another study[7] conducted on 20 male patients showed that following administration of 20 mg oral
tadalafil, there was an increase in the bladder compliance, bladder capacity, maximum
voiding detrusor pressure, and maximum detrusor filling pressure.
We conducted our study on 31 patients and included both sexes unlike the previous
studies,[7]
[8] which were confined only to male patients. In our study, mean bladder capacity in
mL showed a statistically significant improvement after single 20-mg dose of tadalafil,
especially in male patients. This is an important finding and suggests a positive
role of PDE inhibitors in improving bladder capacity in SCI patients. This increase
in maximum bladder capacity will decrease daily urinary frequency and incontinence,
leading to an extra period of urinary storage. This may increase the quality of life
in these patients. Our assumption was that because PDE5 receptors are present on smooth
muscles of the bladder neck, it should be equally effective in both sexes. However,
our results failed to demonstrate any positive effect in female patients. Because
of the small sample size of female patients in our study, we suggest further work
be done in this population group with larger sample size to draw final conclusions.
We observed that the patients with injury above D6 level showed statistically significant
improvement in bladder compliance and bladder capacity (p < 0.05). Increase in bladder compliance will help patients in accommodating more
urine at same detrusor pressures, which will lead to a lessening of urinary leakage
leading to physical and social well-being. In patients with injury below D6, no statistically
significant change in urodynamic parameters could be established. This observation
points out the further need of research in this field.
Limitation of our study includes limited sample size in women population and relatively
old urodynamic machine. However, to the best of our knowledge, very limited literature
is available on the topic and there is need to research in this field to explore new
possibilities and use of these drugs in SCI patients.
Conclusion
Our study has been an important step forward in finding the role of PDE inhibitors
in SCI patients. Improvement in bladder capacity and compliance will allow patients
to store more urine at same pressures, decreasing daily urinary frequency and avoiding
leakage and hence providing a better quality of life. However, we recommend further
work should be done on the role of PDE inhibitors in improvement of urodynamic parameters
in SCI patients so that these drugs can become a future treatment modality in these
patients.
