Download Estimation of residual urine in normal dogs.

A prospective, randomized, double-blinded study comparing the
efficacy and side effects of terazosin and alfuzosin for treatment of
vesico-urethral reflex dyssynergia in dogs.
Master Research Project Veterinary Medicine
Department of Clinical Sciences of Companion Animals
Céline N. Baaren BSc.
3574113
Supervisors: drs. A.N. Haagsman
September 16th 2013 - February 23th 2014
02-06-2014
Abstract
In this study, nineteen dogs with vesico-urethral reflex dyssynergia (VURD) were included to compare
the efficacy and side effects of alfuzosin and terazosin. The dogs were referred to the Clinic for
Companion Animals of Utrecht University, because of signs of dysuria, stranguria and/or pollakiuria.
Physical examination, urinalysis, ultrasonographic examination and radiographic examination
(retrograde urethrogram) were performed. When mechanical obstruction or spinal trauma was ruled
out, the diagnosis VURD was suspected and these dogs were included in the study. The dogs were
treated randomly, with either alfuzosin or terazosin 0.25 mg/kg twice daily. Information was
obtained from owners, referring veterinarians and the patient data system of the Clinic for
Companion Animals of Utrecht University (Vetware). There was no significant difference in efficacy
between alfuzosin-treated and terazosin-treated dogs (p=0.337). A moderate to good effect was
found in 75% of the dogs treated with alfuzosin and in 71.5% of the dogs treated with terazosin.
There was no significant difference in side effects between both treatment groups (p=0.663).
Five healthy male dogs were catheterized after a 15-minute walk to determine the mean residual
volume in the urinary bladder, as a control group. The measured residual volume in these five dogs
ranged from 1ml to 20 ml (mean 7.4 ml). When residual volume was calculated in relation to body
weight, the volume ranged from 0.03ml/kg – 0.55 ml/kg with a mean residual volume of 0.22 ml/kg.
2
Inhoud
Abstract ................................................................................................................................................... 2
Introduction............................................................................................................................................. 4
Hypothesis ............................................................................................................................................... 5
Abbreviations .......................................................................................................................................... 5
Material and methods ............................................................................................................................. 6
Statistics .............................................................................................................................................. 7
Results ..................................................................................................................................................... 8
Alfuzosin-group ................................................................................................................................... 8
Terazosin-group................................................................................................................................. 10
Alfuzosin versus Terazosin ................................................................................................................ 12
Kaplan-Meier curve of mean survival time ....................................................................................... 13
Kaplan-Meier curve of response to medication ................................................................................ 15
Discussion .............................................................................................................................................. 16
Estimation of residual urine in normal dogs. ........................................................................................ 18
References ............................................................................................................................................. 21
Appendix I .............................................................................................................................................. 23
Appendix II ............................................................................................................................................. 24
3
Introduction
Dysuria is defined as a condition in which voiding is difficult and painful.11,19 Dysuria may be caused
by a lot of different conditions, such as urolithiasis, urinary tract infections, prostatic diseases,
bladder neck neoplasia, urethral trauma, urethral neoplasia and vesico-urethral reflex dyssynergia
(VURD).7,11,12 VURD is a disorder of the voiding phase of micturition.7 Middle-aged male large breed
dogs presumably have a predisposition for this disease.7,8,11 Dysuria in VURD is most often caused by
insufficient relaxation of the internal urethral sphincter during contraction of the m. detrusor in the
bladder wall, during attempted micturition.11,12 Another form of VURD is caused by somatic
dysfunction, which can affect the external urethral sphincter.11 Other clinical symptoms, besides
dysuria, are prolonged attempts to urinate, a reduction of urine flow during micturition and an
abnormal residual bladder volume.8,11
Prior to the diagnosis VURD, all the other causes of dysuria should be excluded by physical
examination and additional research.7,11 Physical examination (including rectal palpation), urinalysis,
ultrasonography of the abdomen and a radiographic contrast study of the bladder and urethra
(urethrocystography) were performed. If no mechanical obstruction was found observed, the
diagnosis VURD was made.11
Until 2011, VURD in dogs was treated in The Netherlands with prazosin, an α1-adrenoreceptor
antagonist, used as a treatment for men with benign prostatic hyperplasia. Prazosin relaxes the
internal urethral sphincter in dogs with VURD. However, due to discontinuation for use in the human
market, it was no longer available in The Netherlands.11 Terazosin, a long acting α1-adrenoreceptor
antagonist, was chosen as an alternative for prazosin. Terazosin was chosen based on previous
studies on bioavailability and efficacy and because it is easily to administer in the currently available
doses (2, 5 and 10 mg tablets).11Terazosin is being used as a temporary treatment of functional signs
of benign prostate hyperplasia in humans awaiting prostatic surgery.11 In dogs with VURD, terazosin
improves the urine flow by blocking α1- adrenoreceptors on the urethra. However, it also reduces
arterial blood pressure by blocking α1-receptor mediated vasoconstriction, whereby reported side
effects in humans include asthenia and dizziness. In dogs several side effects were seen during a sixweek treatment. In particular lethargy was seen after terazosin administration. Nine out of fourteen
dogs (64%) treated with terazosin showed signs of lethargy. The side effects were reversible
immediately after the medication was tapered down.11 Therefore, alfuzosin was suggested as an
alternative. This drug has similar characteristics in efficacy and has little effect on blood pressure in
patients with lower urinary tract symptoms, which may lead to less side effects.5 However, the
efficacy and side effects are not completely known in dogs with VURD.
The exact aetiology of VURD is still unknown. However, sexual excitement by the male sex hormone,
testosterone, is considered a risk factor in inducing this disease.7,11 Castration to eliminate
testosterone, is therefore an important part of the treatment. Surgical castration is preferred over
chemical castration, because of a significant greater survival time in surgically castrated dogs. This
may suggest that a greater positive effect on micturition in surgically castrated dogs can be expected,
in comparison to chemically castrated dogs.11
The aim of this prospective study is to evaluate the efficacy and side effects of alfuzosin in
comparison with terazosin as a treatment for dogs with VURD.
4
Hypothesis
H0: There is no significant difference between the efficacy of alfuzosin in dogs with VURD and the
efficacy of terazosin in dogs with VURD.
H1: There is a significant difference between the efficacy of alfuzosin in dogs with VURD and the
efficacy of terazosin in dogs with VURD.
H0: There is no significant difference in side effects between dogs with VURD administered with
alfuzosin or terazosin.
H1: There is a significant difference in side effects between dogs with VURD, administered with
alfuzosin or terazosin.
Abbreviations
S.G.
Specific gravity
5
Material and methods
This study included dogs with VURD that were referred to Utrecht University during a period of 34
months, from January 2011 until November 2013. It is a double-blinded, prospective randomized
trial, including nineteen male dogs. The dogs were randomly treated with either terazosin or
alfuzosin. The randomization was performed by the pharmacy of the Clinic of Companion Animals at
Utrecht University.
Full physical examination was performed. Furthermore, ultrasonographic examination and
radiographic examination (retrograde urethrogram) were performed to rule out anatomical
abnormalities in the urinary tract. Finally, urine samples were collected by cystocentesis during
ultrasound guidance for urinalysis and bacterial culture were performed. When all diagnostic tests
were negative, the diagnosis VURD was made and these dogs were included in the study. The
inclusion criterium for this study was showing signs of (acute or chronic) dysuria with a complete
diagnostic workup to exclude mechanical obstruction, whereby VURD was presumed to be the most
likely diagnosis. Dogs with mechanical obstruction of the urethra or spinal trauma were excluded
from the study.
Current or usage of prazosin, terazosin or phenoxybenzamin within 4 weeks before referral was an
exclusion criterion as well.
The initial dosage of both alfuzosin and terazosin was 0.25mg/kg twice daily. When the response to
alfuzosin or terazosin dosage was disappointing and there were no remarkable side effects,
carbachol (0.03mg/kg three times daily) or pyridostigmine (0.3 - 1 mg/kg 2 to 3 times daily) was
added (rescue 1). Carbachol is a non-specific muscarinic agonist and enhances contraction of the
bladder wall by activation of the muscarinic pathways. This pathway is suggested to be responsible
for the voiding phase of micturition.6 Pyridostigmine is a reversible cholinesterase inhibitor and
competes with acetylcholine (ACh) to bind acetylcholinesterase (AChE). Both will be hydrolysed,
however the hydrolysis of pyridostigmine proceeds much slower than the hydrolysis of ACh, whereby
successful inhibition of ACh hydrolysis is achieved, which enhances the stimulation of the same
muscarinic pathway.13 After another week without improvement, the dosage of alfuzosin or terazosin
was doubled to 0.5 mg/kg twice daily (rescue 2). When the treatment still did not lead to an
improved micturition diazepam (0.08 – 0.16 mg/kg three times daily) was added to the treatment
(rescue 3). Diazepam is a benzodiazepine drug, which relaxes the external urethral sphincter, but also
has systemic effects.11
If this combination of medication still did not lead to progression terazosin was changed to alfuzosin
or vice versa (rescue 4). When the results were still disappointing after all the other rescues,
phenoxybenzamin (Dibenzyran; 0.25-0.5 mg/kg once or twice daily) was administrated instead of
terazosin/alfuzosin (rescue 5), then this patient was excluded from the study. See Appendix II for the
rescue protocol.
If catheterization was necessary, antibiotics were administered for at least a week. If catheterization
was necessary for a longer period, it was recommended to give antibiotics during the same period.
The prescribed antibiotics were amoxicillin/clavulanic acid (Synulox or Clavubactin).
During the first six weeks of therapy, the owner was contacted weekly. The effects of the medication,
any side effects and the voiding pattern were discussed. The owners also kept a diary, which listed
the following: times per day the dog was walked, a description of the voiding pattern, attempts to
6
urinate without success, times of catheterization when necessary and the residual volume and side
effects when present. However, only five out of nineteen diaries were returned to the clinic. Most of
the information was derived from Vetware, the patient data system of the Clinic for Companion
Animals of Utrecht University. Follow-up information was obtained from owners and referring
veterinarians. The owners received a protocol about the times of catheterization. If the residual
bladder volume of the dog was more than 500ml in one day, the dog should be catheterized at least
3 times a day. Is the residual bladder volume of the dog was less than 500 ml in one day, the dog
should be catheterized at least once a day. If the residual bladder volume of the dog was less than
500 ml in two days, the owners didn’t had to catheterize the dog the next day when the dog urinated
well on his own.
When the owner agreed, surgical castration was performed as soon as possible after starting the
treatment. However, some owners preferred chemical castration. For chemical castration either
Vetadinon (delmadinon acetate, injection) or a Suprelorin implant (deslorelin acetate,
subcutaneous chip) was used. Delmadinon acetate is a progesteron-derivate with a short-term effect
of approximately 4 weeks. Deslorelin acetate is a GnRH-agonist with a long-term effect of
approximately 6 months, however it only starts to be effective six weeks after placement.
Statistics
Data were calculated by using the Statistical Package for Social Sciences (IBM SPSS version 20.0.0.0).
A Fisher's exact test was used to determine differences in side effects between the alfuzosin group
and the terazosin group, between the castrated and non-castrated dogs and between the chemicaland surgical-castrated dogs.
The Fisher's exact test was used to test if there was any difference in effect of the treatment
between the alfuzosin group and the terazosin group, between the castrated and non-castrated dogs
and between the chemical- and surgical-castrated dogs.
A Kaplan-Meier curve was used to compare the mean survival time of the two treatment groups. A
log-rank test was used to assess the comparisons. Another Kaplan-Meier curve was used to
determine the moment the dog appears to be free of clinical signs. A log-rank test was used to assess
the comparisons.
7
Results
At first, the study group consisted of thirty dogs. However, eleven dogs were never included in the
results. These dogs were not treated for the full six-week treatment or the medication was not
prescribed randomly by the pharmacy.
In total 19 dogs were included in this study. Dogs included were aged between 2 years and 10 years,
with a mean age of 7.4 years. The body weight ranged from 30.1 to 88.3 kg with mean weight of 42.1
kg. Breeds included 9 Labrador Retrievers , 2 Newfoundlanders, 2 crossbreeds and one each of the
following breeds: Doberman, Mastiff, German Shepherd dog, Dalmatian dog and Golden Retriever.
All of these dogs were admitted at the Clinic for Companion Animals with signs of dysuria, stranguria
and/or pollakiuria. The mean period between start of symptoms and start of treatment is 180 days
(range 0-1096 days).
Alfuzosin-group
Twelve out of nineteen dogs (63.2%) were administered alfuzosin as a treatment for VURD. The
alfuzosin group consisted of six Labrador Retrievers, two crossbreeds and one each of the following
breeds: Golden Retriever, Newfoundlander, German Shepherd dog, Dalmatian dog.
Medication
Four dogs were treated with alfuzosin, the other eight dogs in this group received additional
medication due to disappointing response to alfuzosin (table 1). The following medication was
administered in addition to alfuzosin: carbachol (2 dogs), diazepam (2 dogs), amoxicillin/clavulanic
acid (6 dogs) and enrofloxacin (1 dog).
Breed
Duration
of signs
before
therapy
(days)
Therapy
Labrador
Retriever
200
German
Shepherd
Dalmatian
dog
Castration
during
treatment
period
(Surgical/
chemical)
Response
to therapy
Side
effects
Abnormal
Findings
Follow up
November/De
cember 2013
Alfuzosin
Good
None
Urine pH = 8
60
Alfuzosin
Carbachol
Diazepam
Poor
None
Enlarged
prostate
2
Alfuzosin
Synulox
Carbachol
Diazepam
Poor
Incontinenc
e during
whole
period of
treatment
Suffered from
HNP L3-L4
and HNP
lumbo-sacral
S.G.=1.017
Haemoglobin
uria
Haematuria
Proteinuria
Thick bladder
wall
Free from
clinical signs
and alfuzosin.
Last time
clinical signs on
vacation august
2011.
Death due to
dyssynergia.
Euthanasia 147
days after
starting
treatment.
Death due to
dyssynergia.
Euthanasia 46
days after
treatment.
Chemical:
Vetadinon
8
Labrador
Retriever
547
Alfuzosin
Synulox
Poor
Vomiting
(started
before
treatment)
Urine pH= 8
Glucosuria
Cystitis
Golden
Retriever
2
Alfuzosin
Good
Lethargy
during week
2
Enlarged anal
gland
Enlarged
prostate
Proteinuria
Haemoglobin
uria
Labrador
Retriever
1
Alfuzosin
Moderate
Lethargy
during first
four weeks
Labrador
Retriever
113
Alfuzosin
Good
Lethargy
during first
week
Cross breed
56
Alfuzosin
Moderate
Ataxia
during week
3, 4 and 5
Labrador
Retriever
5
Alfuzosin
Synulox
Clavubactin
Good
None
Labrador
Retriever
14
Alfuzosin
Clavubactin
Surgical
castration
Good
None
Cross breed
7
Alfuzosin
Baytril
Surgical
castration
Good
Haematuria
during week
3
Newfoundl
ander
1096
Alfuzosin
Clavubactin
Moderate
None
Chemical:
Vetadinon
Slightly
narrowed
urethra
Recurrent
cystitis
Thick bladder
wall
S.G. = 1.013
Urine pH=8
Possible
cystitis
Haemoglobin
uria,
Haematuria
Narrowed
urethra pars
prostatica
Urolithiasis
Spondylosis
Arthrosis
stifle
Slightly
narrowed
urethra
caudal of the
os penis
Cystitis
Death due to
dyssynergia.
Euthanasia 267
days after
starting
treatment.
Death due to
another cause.
Euthanasia 571
days after
starting
treatment.
Once every two
years clinical
signs. Goes to
vet for
catheterization
and antibiotics.
Free from
alfuzosin.
Free from
clinical signs
without
alfuzosin.
Since 5 months
free from
alfuzosin.
Occasionally
clinical signs
when he is
stressed.
Free from
clinical signs
and alfuzosin.
Symptoms
recurred,
started again
with alfuzosin.
Recently, free
from clinical
signs.
Free from
clinical signs.
Free from
alfuzosin since
December
2013.
Intermittently
symptoms. Still
on alfuzosin.
Daily
catheterization
required.
Table 1. Dogs in alfuzosin group
9
Castration
Six out of twelve dogs were surgically or chemically castrated before the six-week treatment (table
2). Three dogs were castrated surgically or chemically during the treatment and two dogs were intact
during treatment, but chemically castrated afterwards . One of the twelve dogs was castrated
chemically before and during the treatment and was castrated surgically afterwards. The chemically
castrated dogs were all treated with delmadinon acetate.
Castrated
Chemically
Before treatment
4 out of 12
During treatment
2 out of 12
After treatment
2 out of 12
Total
8 out of 12 (66.67%)
Table 2. Castrated dogs in alfuzosin group
Surgically
2 out of 12
1 out of 12
3 out of 12 (25.0%)
Total
6 out of 12 (50.0%)
3 out of 12 (25.0%)
2 out of 12 (16.67%)
11 out of 12 (91.67%)
Catheterization
In seven out of twelve dogs (58.3%) urethral catheterization was needed. Two out of seven dogs
received a permanent catheter for the first few days of the study. Afterwards, catheterization was
not necessary. However, one of these two dogs suffered from recurrent cystitis.
One dog was catheterized once in week 3 of treatment. One dog was catheterized twice in week 2
and once in week 3 of treatment. One dog needed daily catheterization during week 1 of the
treatment period and this dog suffered from cystitis. One dog needed catheterization once during
week 1, once during week 2, twice during week 4, three times during week 5 and daily
catheterization was necessary during week 6 of treatment. This dog developed cystitis. One dog
needed daily catheterization four times a day for six weeks.
Side effects
Five out of twelve dogs did not reveal any side effects during or after the six-week treatment (table
1). However, in 7 dogs side effects were seen. Three dogs were lethargic. One dog suffered from
ataxia during week 3, 4 and 5 of the treatment. One dog vomited during the first four weeks of
treatment. One dog showed haematuria during week 3. One dog suffered from incontinence before,
during and after the six-week treatment.
Terazosin-group
Seven out of the nineteen dogs (37.8%) were administered terazosin in this trial. The terazosin group
consisted of three Labrador Retrievers and one each of the following breeds: German shepherd dog,
Newfoundlander, Mastiff, and a Dobermann Pinscher.
Medication
One dog was only treated with terazosin, the other six dogs in this group received additional
medication (table 3). The following medication was administered in addition to terazosin during the
six-week period: pyridostigmine (2 dogs), carbachol (2 dogs), diazepam (1 dog), amoxicillin/clavulanic
acid (2 dogs), augmentin (1 dog), rimadyl (1 dog), metoclopramide (1 dog) and ranitidine (1 dog).
Breed
Duration
of signs
before
therapy
(days)
Therapy
Castration
during
treatment
period
(surgical/
chemical)
Response
to therapy
Side
effects
Abnormal
findings
Follow up
November/Dec
ember 2013
10
Labrador
Retriever
11
Terazosin
Poor
Lethargy
in week 3
S.G.=1.012
Haemoglobi
nuria
German
Shepherd
1
Terazosin
Augmentin
Rimadyl
Metoclopramid
Ranitidine
Good
Sleepy in
week 1
Bladder
rupture
Enlarged
prostate
Newfoundl
ander
912
Terazosin
Clavubactin
Mestinon
Good
None
Cystitis
Urine pH=9
Labrador
Retriever
60
Terazosin
Synulox
Carbachol
Chemical:
Vetadinon
Moderate
None
Haemoglobi
nuria
Haematuria
Labrador
Retriever
210
Terazosin
Mestinon
Chemical:
Suprelorin
Moderate
Lethargy
during
week 3
S.G.=1.013
Haematuria
Mastiff
6
Terazosin
Carbachol
Diazepam
Alfuzosin
Surgical
castration
Poor
Lethargy
during the
whole
period of
treatment
Tendinitis
biceps
muscle at
the level of
the elbow
joint, left
forepaw
Dobermann
Pinscher
125
Terazosin
Chemical:
Vetadinon
Suprelorin
Moderate
None
Haematuria
Urine pH=9
Chemical:
Vetadinon
Suprelorin
Death due to
dyssynergia.
Euthanasia 101
days after starting
treatment.
Death due to
another cause.
Euthanasia 528
days after starting
treatment.
Treated with
terazosin until
euthanasia.
Free from clinical
signs. Since April
2013 free from
terazosin.
Ups and downs.
Still on terazosin.
Free from clinical
signs. Still on
terazosin and
Mestinon.
Daily
catheterization
necessary. No
terazosin/
alfuzosin
treatment. Tried
Dibenzyran for
VURD, also gave
side effects.
Intermittently
symptoms of
dysuria. Still on
terazosin.
Table 3. Dogs in terazosin group
Castration
One dog was castrated prior to the treatment. Four dogs were castrated during the six-week
treatment. One dog was intact during the treatment period, however castrated after the six-week
treatment (table 4). One of the seven dogs was castrated chemically during and after the treatment.
Of the chemically castrated dogs in this group, one dog was treated with delmadinon acetate. One
dog was treated with deslorelin acetate. Two dogs were treated with both delmadinon acetate and
deslorelin acetate.
Castrated
Chemically
Before treatment
During treatment
3 out of 7
After treatment
1 out of 7
Total
4 out of 7 (57.1%)
Table 4. Castrated dogs in terazosin group
Surgically
1 out of 7
1 out of 7
2 out of 7 (28.6%)
Total
1 out of 7 (14.3%)
4 out of 7 (57.1%)
1 out of 7 (14.3%)
6 out of 7 (85.7%)
Catheterization
In five out of seven dogs (71.4%) catheterization was necessary. One dog had a permanent urine
catheter during the first few days of treatment. Catheterization afterwards was not necessary. Three
11
dogs needed intermittent catheterization. For one dog catheterization was necessary once, twice or
three times daily during the whole treatment period.
Side effects
Three out of seven dogs did not reveal any side effects during or after the six-week treatment (table
3). Three out of seven dogs were lethargic during the study. Two dogs were lethargic during one
week of the treatment. The other dog was lethargic during the whole period of treatment. However,
after tapering down the medication, the lethargy disappeared. One dog was slightly lethargic during
the first week of the therapy.
Alfuzosin versus Terazosin
Effects of treatment
The dogs were divided in three groups concerning the effects of the treatment (table 5). Additional
information about the distribution, see Appendix I.
For the statistical analysis, the dogs were divided into two groups concerning the effect, 'good' or
'poor’. The dogs which responded good, are placed in the group 'good' and the dogs which
responded moderate and poor, are placed in the group 'not good'. There is no significant difference
in respect to the effect between the alfuzosin-treated and terazosin-treated dogs (p=0.337). Dogs
that were castrated before therapy are placed in the group 'castrated'. Dogs that were castrated
during or after the six-week treatment are placed in the group 'non-castrated'. There is no significant
difference in respect to the effect between the castrated and non-castrated dogs (p=0.449). There is
no significant difference in respect to the effect between the chemically and surgically castrated dogs
(p=0.395).
Side effects
There are no significant differences in respect to side effects between the two treatment groups
(p=0.663). There is no significant difference in respect to side effects between the castrated and noncastrated dogs (p=0.551). There is no significant difference in respect to side effects between
chemically and surgically castrated dogs (p=0.115)
Participants
% side effects
Respons therapy % Good
Response therapy % Moderate
Response therapy % Poor
Death due to dyssynergia
Death due to another cause
Alive
Alfuzosin
Terazosin
12
58.33% (7 out of 12)
50.00% (6 out of 12)
25.00% (3 out of 12)
25.00% (3 out of 12)
25.00% (3 out of 12)
8.333% (1 out of 12)
66.77% (8 out of 12)
7
57.1% (4 out of 7)
28.6% (2 out of 7)
42.9% (3 out of 7)
28.6% (2 out of 7)
14.3% (1 out of 7)
14.3% (1 out of 7)
71.4% (5 out of 7)
Table 5. Alfuzosin versus terazosin
Follow-up
At the end of the study (January 2014) four dogs were euthanized in the alfuzosin group, three dogs
due to dyssynergia and one dog due to another cause (table 5). In March 2014 six dogs were still free
from clinical signs of dyssynergia, whereby five dogs are not treated with alfuzosin and one dog is
daily treated with alfuzosin.
In the terazosin group two dogs were euthanized, one dog was euthanized due to dyssynergia and
12
one dog due to another cause and this dog was free from clinical signs without terazosin until
euthanasia (table 5). Up to now, two dogs are free from clinical signs. One of the two dogs is still
treated with terazosin and mestinon. The other dog is free from terazosin.
Kaplan-Meier curve of mean survival time
All thirty dogs, which started treatment, were used to determine the mean survival time of the
alfuzosin- and terazosin-treated dogs. The Kaplan-Meier curve was based on the time the dogs were
included in the study and the end of the study (January 2014). There is no significant difference in
survival time between both treatment groups (p = 0.765). 24 out of 30 dogs are censored. A small
number of dogs died due to another cause than dyssynergia (3 dogs). 21 dogs are still alive and
therefore, these dogs were censored.
Figure 1. Kaplan-Meier curve, survival time: Alfuzosin (blue line) versus terazosin (green line)
Kaplan-Meier curve survival time breeds
The nineteen dogs, which did fore fill the full six-week treatment period, were used for this KaplanMeier curve. The mean survival time of Labrador Retrievers is not significant different from the mean
survival time of other breeds (p=0.172).
13
Figure 2. Kaplan-Meier curve, survival time: Labrador Retrievers (green line 1), other breeds (blue line 0)
Kaplan-Meier curve survival time castrated and non-castrated dogs
The nineteen dogs, which did fore fill the full six-week treatment period were used for this KaplanMeier curve. Dogs which were castrated prior to the treatment seem to have a greater survival time
than the dogs which were castrated during or after the treatment. However, there is no significant
difference between both groups (p=0.077).
Figure 3. Kaplan-Meier curve, survival time: Castrated prior to treatment (blue line 0), castrated during after
treatment (green line 1)
14
Kaplan-Meier curve survival time chemical- and surgical-castrated dogs
The nineteen dogs, which did fore fill the full six-week treatment period ,were used for this KaplanMeier curve. There is no significant difference in survival time between the two groups (p=0,386).
Figure 4. Kaplan-Meier curve, survival time: Chemical-castrated (blue line 0), surgical-castrated (green line 1)
Kaplan-Meier curve of response to medication
All thirty dogs were used to determine the moment dogs are free from clinical signs, and therefore it
shows the response to the medication. The dogs in the alfuzosin treated group appear to respond
faster to the treatment than the dogs in the terazosin treated group. However, there is no significant
difference between both treatment groups (p=0.451).
Figure 5. Kaplan-Meier curve, free from clinical signs: Alfuzosin (blue line A) versus terazosin (green line T)
15
Discussion
The aim of this study was to compare alfuzosin and terazosin for treatment of VURD in dogs, with
respect to efficacy and side effects.
The efficacy of both alfuzosin and terazosin was comparable. Seventy-five percent of the dogs
treated with alfuzosin and 71.5% of the dogs treated with terazosin responded moderate to good to
the medication. Alfuzosin and terazosin appear to have a better efficacy in this study than terazosin
in a previous study, reported by Haagsman (12/19, 63%).11 However, the efficacy and side effects
were determined based on the owners opinion during weekly phone calls with a veterinarian or a
research student. These observations may be very subjective. To obtain more reliable results, the
same questions should be asked to all owners. A questionnaire could support the veterinarian and
research student to work systematically and consistently during the conversation with the owners. In
addition, it is important to document these conversations very carefully in the patient’s card, so the
information may be used properly for research later on.
There was no significant difference in side effects between the alfuzosin-treated and the terazosintreated dogs. Multiple side effects were detected in the alfuzosin-group, including lethargy, ataxia,
vomiting, incontinence and haematuria. The dog that vomited already started vomiting before the six
-week treatment period started. Therefore, the reason for vomiting might be another underlying
disease. Furthermore, the dog with urine incontinence suffered besides VURD from a hernia nuclei
pulposis (HNP) L3-L4 and a severe hernia nuclei pulposis lumbosacral, what might explain the urine
incontinence. The dog with haematuria was diagnosed with a urolithiasis (an urolith of 2 cm
circumference in the bladder) in week 5 of the six-week treatment. After cystotomy and removal of
the urolith the dog was free from clinical signs. With this in consideration, only two dogs in the
alfuzosin group had lethargy what can't be related to another disease and one dog suffered from
difficulty walking.
In the terazosin-group four out of seven dogs revealed signs of lethargy. Lethargy as the main side
effect of terazosin was also seen in a previous study.11
At first, the group contained thirty dogs, however eleven dogs were excluded from the study during
the treatment period because they did not fore fill the six-week treatment period. Just a small
number of dogs remained in the study group. Some of the revealed side effects might be an
inconvenient coincidence and may affect the outcome of this study.
Thereby, the distribution of dogs in the two treatment groups was unequal. This was due to the fact
that more dogs with terazosin were excluded. If all thirty dogs are taken into account, still no
significant difference in side effects between the two groups is measured (p=0.261).
There is no significant difference in survival time between the both treatment groups (figure 1).
However, a lot of dogs were censored because of several reasons. With a larger group the ratio of
censored dogs and useful dogs would be more representative and the survival time might be more
reliable. However, VURD is an infrequent disease. Only a small number of dogs with presumably this
disease are being referred to the Clinic for Companion Animals. Furthermore, owners should spend a
lot of money on diagnostic tests, before the diagnosis VURD can be made. Some owners prefer to try
treatment for VURD rather then excluding all other causes of stranguria, dysurai and pollakiuria.
Therefore, it is almost infeasible to get a larger study group in three years. A new study should last
longer or researchers should settle with a small study group.
16
Remarkable more Labrador Retrievers were included in this study (9/19 (47%)). The comparison with
the reported numbers by Haagsman is striking, where also nine out of nineteen dogs (47%) were
Labrador Retriever dogs.11 This suggests a possible genetically predisposition of VURD in Labrador
Retrievers. However, at the moment no literature was found to confirm this. More research is
required to confirm this assumption. Haagsman suggested a better survival for Labrador Retrievers in
comparison to other breeds.11 However, in this study there was no difference in survival time
(p=0.172) (figure 2).
Although there is no significant difference (p=0.077), surgical castration does seems to lead to a
longer survival time (figure 3). Dogs castrated prior to the six-week treatment have a better survival
than dogs castrated during or after the six-week treatment period.
Notable is that there is no significant difference between chemical and surgical castrated dogs in
respect to the efficacy of the treatment and in respect to the survival (figure 4). Remarkable is that
the chemically castrated dogs possibly even have a longer survival time than the surgically castrated
dogs. This is in contrast with the outcome of a previous study, where surgical-castrated dogs had a
significant better survival (p<0.01).11
The most important findings in this study are that there is no significant difference in efficacy
between alfuzosin and terazosin, wherein both are effective in dogs with VURD. There was a
moderate to good effect in 75% of the dogs treated with alfuzosin and in 71.5% of the dogs treated
with terazosin. Furthermore, there is no significant difference in side effects, whereby both drugs can
cause lethargia. However, additional research is required to be able to give a final conclusion more
information concerning both the efficacy and the side effects. Reason for this is the subjective
aspects of this study and the small amount of dogs that participated in this study.
17
Estimation of residual urine in normal dogs.
Normal micturition can be divided into two different phases: a storage phase and an emptying phase.
The storage phase is dominated by sympathetic innervation. The ß-adrenergic stimulation results in
the relaxation of the detrusor muscle. Simultaneously, the internal urethral sphincter is contracted
by α-adrenergic stimulation to maintain continence.10,15 The external urethral sphincter is innervated
by the somatic system. The voiding phase is controlled by parasympathetic activity; the detrusor
muscle contracts and the sympathetic stimulation to the internal urethral sphincter is inhibited.10
Residual urine can be defined as the volume of fluid remaining in the bladder immediately after the
completion of micturition. It can be used as an index of the capacity of the bladder to empty.3 An
abnormal amount of residual urine may be a sign of incomplete voiding and may result from
neurological or obstructive diseases, like functional obstruction of urine outflow. 3,15 When excessive
residual volume is present in the urinary bladder this might predispose for bacterial cystitis.3,16 The
urethra is colonized with bacteria, which are derived from the skin and gastro-intestinal tract. These
bacteria may ascend to the bladder and lead to a urinary tract infection. However, host defences are
able to eliminate the bacteria or to prevent them to multiply. The most important defence
mechanism is the frequent and complete voiding of urine, the so called 'bladder wash out'. 4 Which
does not work efficiently in dogs with VURD..
What is the amount of residual urine in the urinary bladder in normal, healthy dogs after
completing micturition?
Overall, it is suggested that normal residual volume in the urinary bladder of a normal dog after
complete voiding is 0.2 – 0.4 ml/kg or less than 10 ml (table 6).3,9,14-19 A recent study by Atalan et al.3
showed that the residual volume in the bladder of healthy dogs varies from 0.1 – 3.4 ml/kg body
weight with a median of 0.2 ml/kg body weight. This shows a wide range of variation. Forty-eight
normal dogs were used in this study of which 33 male dogs and 15 female dogs. Male dogs had a
smaller range (0.1 – 2.4 ml/kg body weight) than female dogs (0.1 – 3.4 ml/kg body weight). In this
study ultrasound was used to measure the residual urine volume.3 Breed, age and body weight of
each dog were recorded. The dogs were positioned in dorsal recumbency while they were under
general anaesthesia. An ultrasound scanner with a 5- or 7,5MHz mechanical sector transducer was
used to perform the transabdominal ultrasonography. Longitudinal sections were made to determine
the maximal length of the bladder (measured from the cranial pole to the bladder neck) and the
maximal depth on longitudinal ultrasonography (DL; from ventral to dorsal walls). Transverse
sections were made to determine maximal width and maximal depth on transverse ultrasonography
(DT). Six different formulas were compared and the following formula gave the most accurate
bladder volume, compared to the estimated bladder volume by catheterization: 1
Bladder volume (ml) =
L x W x (DL+DT)x 0,625
2
where L = length on longitudinal ultrasonography, W = width on transverse ultrasonography, DL =
depth on longitudinal ultrasonography, DT = depth on transverse ultrasonography. 1
Using this formula, the total bladder volume was estimated for each dog. Subsequently, the dogs
were taken outside for a 10-minute walk. During this 10-minute walk, the number of attempts to
void were recorded as well as the successful attempts. After the 10-minute walk, ultrasonography
18
was immediately repeated and the urine volume after urination was calculated. Residual volume was
calculated as a volume and as a percentage of the bladder volume before micturition. It was also
calculated in relation to body weight of the dogs as ml residual urine/kg body weight.3
The residual volume of 48 healthy dogs was compared to the residual volume of 51 dogs with
neurogenic or obstructive diseases in this study. The residual volume of healthy dogs was
significantly lower than the residual volume of dogs with neurogenic or obstructive diseases.3
Atalan3
Grauer9
Labato14
Moreau15
Oliver16
Oliver17
Sharp and Gookin18
Stone and Barsanti19
0.2 – 0.4 ml/kg or less than 10 ml OR less than 10 percent of
normal volume
Study: 0.1 – 3.4 ml/kg (median 0.2 ml/kg)
Approximately 0.2 – 0.4 ml/kg
Less than 0.4 ml/kg
0.2 – 0.4 ml/kg
10 ml or less than 10 percent of the normal volume
Less than 10 percent of normal volume, will be less than 10 ml in
most animals
0.2 – 0.4 ml/kg
Less than 10 ml
Table 6. Survey of residual bladder volumes after micturition in literature. 3,9,14-19
How to measure the residual bladder volume in dogs?
Residual bladder volume can be measured by urethral catheterization after a 15-minute walk.9
However, there are risks associated with using urinary catheters for the use of residual volume
estimation, such as direct physical injury of the urinary tract and the introduction of bacteria in the
urinary tract causing urinary tract infection. Another, less-invasive method is to measure residual
bladder volume by ultrasound.1,3 However, this technique may be less invasive, ultrasonography has
its disadvantages. Ultrasonographic equipment may not always be available in small animal
veterinary clinics.2 Furthermore, not every veterinarian is specialised in ultrasonography. Estimation
of bladder volume by using ultrasonography should be performed by a specialist because it is not a
routinely technique to determine bladder volumes. Finally, dogs have to undergo general
anaesthesia, which is not preferable.1 Other disadvantages are the various shapes of bladders and
imprecise organ boundaries, which are limiting factors to make this an accurate technique to
determine bladder volumes.1
Study residual volume normal male dogs as a control group.
The aim of the study was to determine the residual volume in the urinary bladder of normal male
dogs as a control group.
Hypothesis
The residual volume in the urinary bladder of normal dogs is 0.2 – 0.4 ml/kg body weight.
Material and methods
The dogs were catheterized after a 15-minute walk. Catheterization had been performed under
sterile conditions with a 2.0mm or 2.6mm sterile urinary dog catheter and Optilube lubricating
jelly. Residual volume was estimated with 50ml syringes.
19
Results
The control group contains five male dogs between 6 years and 10 months and 12 years and 3
months old (mean age 9.2 years). Their mean weight was 30.9 kg (22.0 kg – 38.0 kg). These dogs did
not had any underlying conditions. Three dogs were neutered and two dogs were intact.
Breed
Weight (kg)
Age
11 years
12 years
6 years
Residual
volume (ml)
20
2
8
Castrated
(yes/no)
no
yes
no
Residual volume
(ml/kg BW)
0.55
0.09
0.21
Crossbreed
Crossbreed
Golden
Retriever
Labrador
Retriever
Stabyhoun
36.5
22
38
31
8 years
1
yes
0.03
27
7 years
6
yes
0.22
Table 7. Data of dogs in control group
The measured residual volume in these five dogs was ranged from 1ml to 20 ml (mean 7.4ml). When
residual volume was calculated in relation to body weight, it ranged from 0.03ml/kg – 0.55 ml/kg
with a mean residual volume of 0.22 ml/kg.
Discussion
The aim of this control study was to determine the residual volume in the urinary bladder of normal
male dogs. The measured mean residual volume matches the reference, however two dogs had a
much lower residual volume (0.03ml/kg and 0.09 ml/kg) and one dog had a higher residual volume
than the before mentioned reference value (0.55ml/kg). These individual differences have to be
taken into account in daily practice.
To accept the hypothesis more dogs should be included in a study. It is possible that not all of the
residual urine was collected by catheterization, this can influence the results.
A previous study indicates a median residual volume of 0.2 ml/kg, with a range from 0.1 to 3.4 ml.3 In
this study, the mean residual volume per kg body weight is measured and is therefore not completely
comparable to the median residual volume in the previous study. However, the median residual
volume in this study would be 0.21 ml/kg, which matches the suggested median residual volume in
the previous study. One must pay attention to the difference between mean and median residual
volume.
In addition, catheterization is a minimally invasive technique but not very comfortable for a dog. As
seen in the introduction above-mentioned, measuring residual volume by ultrasound would be a less
invasive method to calculate residual volumes. However, the described technique is very time
consuming and am experienced veterinarian or even a specialist should perform the measurements.
Conclusion
The measured urine residual volume per kg body weight corresponds with the reported volume in
literature. However, a larger control group is required to confirm these findings.
20
References
1. Atalan G, Barr FJ, Holt PE. Assessment of urinary bladder volume in dogs by use of linear
ultrasonographic measurements. Am J Vet Res. 1998 Jan;59(1):10-15.
2. Atalan G, Barr FJ, Holt PE. Comparison of ultrasonographic and radiographic measurements of
bladder dimensions and volume determinations. Res Vet Sci 1999 6;66(3):175-177.
3. Atalan G, Barr FJ, Holt PE. Frequency of urination and ultrasonographic estimation of residual urine
in normal and dysuric dogs. Research in Veterinary Science. 1999;68:295-299.
http://www.sciencedirect.com.proxy.library.uu.nl/science/article/pii/S0034528899903363
4. Bush BM. Chapter 17 The urinary system. In: Chandler EA, Thompson DJ, Sutton JB, Price CJ,
editors. Canine medicine and therapeutics. Third edition. Oxford: Blackwell scientific
publications:1991. pp. 601-658.
5. Chapple CR. A comparison of varying alpha-blockers and other pharmacotherapy options for lower
urinary tract symptoms. Rev Urol. 2005;7(4):S22-S20.
6. Coit VA, Gibson IF, Evans NP, Dowell FJ. Neutering affects urinary bladder function by different
mechanisms in male and female dogs. European Journal of Pharmacology 2007;584(1):153-158.
7. Diaz Espineira MM, Viehoff FW, Nickel RF. Idiopathic detrusor-urethral dyssynergia in dogs: a
retrospective analysis of 22 cases. Journal of Small Animal Practice 1998;39:264-270.
8. Gookin JL, Bunch SE. Detrusor-striated sphincter dyssynergia in a dog. Journal of Veterinary
Internal Medicine 1996;10(5):339-344.
9. Grauer GF. Urinary Tract Disorders. Chapter 41 Clinical manifestations of Urinary Disorders. In:
Nelson RW, Guillermo Couto C, editors. Small animal internal medicine. Fourth edition. USA: Mosby;
2010. pp. 607-622.
10. Grauer GF. Urinary Tract Disorders. Chapter 48 Disorders of micturition. In: Nelson RW, Guillermo
Couto C, editors. Small animal internal medicine. Fourth edition. USA: Mosby; 2010. pp. 684-693.
11. Haagsman AN, Kummeling A, Moes ME, Mesu SJ, Kirpensteijn J. Veterinary record 2013 Jul
13;173(2):4. doi: 10.1136/vr.101326.
12. Holt P. Dysuria in the dog. Part 2: Differential diagnosis of dysuria. In Practice. 1990;12:147-153.
13. Kluwe WM, Page JG, Toft JD, Ridder WE, Chung H. Pharmacological and toxicological evaluation
of orally administered pyridostigmine in dogs. Fundamental and Applied Toxicology 1990 1;14(1):4053.
14. Labato MA. Disorders of micturition. In: Birchard SJ, Sherding RG, editors. Saunders manual of
small animal practice. Third edition. Saunders;2006. pp. 940-948.
15. Moreau PM. Neurogenic disorders of micturition in the dog and cat. Comp Cont ED Pract Vet.
1982; 4(1):12-22.
21
16. Oliver JE. Disorders of micturition. In: Hoerlein BJ, editor. Canine Neurology: diagnosis and
treatment. Third edition. Philadelphia: WB Saunders Company; 1978. pp. 461-469.
17. Oliver JE. Disorders of micturition. In: Oliver JE, Hoerlein BF, Mayhew IG, editors. Veterinary
Neurology. Philadelphia: WB Saunders Company; 1987. pp. 342-352.
18. Sharp NJH, Gookin JL. Chapter Twelve Visceral and bladder dysfunction dysautonomia. In:
Wheeler SJ, editor. BSAVA Manual of small animal neurology. Second Edition. 1995. pp. 179-188.
19. Stone EA, Barsanti JA. Urologic surgery of the dog and cat. Philadelphia: Lea & Febiger ; 1992.
Chapter 1, Abnormal urine output and voiding; p. 5-15.
22
Appendix I
Division of response:
Good:
- Dogs which are able to void with normal flow with or without alfuzosin/terazosin
Moderate:
- Dogs, with or without alfuzosin/terazosin, with periods of voiding with normal flow and periods
with decreased flow
- Dogs which need(ed) extra medication (Carbachol/Mestinon/etc.) to improve voiding
Poor:
- Dogs which had to be euthanized due to the dyssynergia
- Dogs without any improvement of voiding despite of the medication
- Dogs which need(ed) catheterization more than once a day despite of the medication
23
Appendix II Protocol Dysuria: Terazosine vs Alfuzosine
A.N.Haagsman
Juni 2013
Dysuria
Clinical examination
Rectal toucher
Urine-examination + culture
Ultrasound
Mechanical
Obstruction
Radiographic Retrograde
Contrast study
Functional
Obstruction
Solve obstruction
Castration
+ TESTmedication
(+ Antibiotic)
terazosine/alfuzosine
IF catheterization needed
(>3days)
0.25 mg/kg 2dd
Chemical
Mechanical
- Tardak/Vetadinon
(delmadinonacetaat)
(Surgery)
RESCUE 1
(if after 7 days no effect)
- OR GnRH-chip
RESCUE 2
(Suprelorin)
(if after 7 days no effect)
* in consultation with the Urology Department
RESCUE 3
Mestinon®/
Carbachol
Tera/Alfu 0.5
mg/kg
Valium®
(if after 7 days no effect)
RESCUE 4
Cross-over
(Terazosine OR
Alfuzosine)
(if after 7 days no effect)
RESCUE 5
(if after 7 days no effect)
24
Dibenzyran®
(+valium)*