Download OVERACTIVE BLADDER

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URINARY
TRACT INFECTION
CONSULTATION INFORMATION
Round Rock: 512-828-5522
North Austin: 512-231-1444
www.urologyteam.com
Westlake: 512-328-1313
rev/asj/03/11
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TABLE OF CONTENTS
Overview………………………………………………………………………………………………………....……………2
The Urinary System……………………………………………………………………………………….…………3 - 4
Factors that Increase Risk of UTIs
Incidence and Definitions…….…………………..……………………………………………………….…...5 - 6
Initial Screening……………………………………………………………………………………………………………7
History and Physical Examination
Urinalysis or Urine Culture
Post Void Residual
Review of Previous Medical Records
Further Evaluation……………………………………………………………………………………………………8 - 9
Voiding Diary
Cystoscopy
Imagery of Kidneys and Ureters
Treatments Options for Recurrent Uncomplicated UTIs ……..…………………………. 10 - 14
Antibiotics
Behavior Therapy
Vaginal Hormone Replacement
Alternative Daily Treatments
Appendices……………………………………………………………………………………………………..............14
A. Application of Estrogen Vaginal Cream
B. Theracran
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OVERVIEW
Your Urinary System
*What are your concerns?
*Factors increasing risks for UTIs
Initial Screening
*History & Physical Examination
*Urinalysis or Urine Culture
*Post Void Residual
*Review of Medical Records
Potential Further Evaluation
*Voiding Diary
*Cystoscopy
*Upper Tract Imaging
Treatment Options
Continue If
Results Are
Satisfactory
*Antibiotics
*Behavior Therapy
*Vaginal Hormone Replacement
*Dietary Supplements
If 3 or less UTIs per
year
If greater than 3 UTIs
per year
*Treat by culture
*Self start antibiotics
*Post-coital Antibiotics
*Continuous Prophylaxis
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THE URINARY SYSTEM
The urinary system is comprised of several muscles, organs, and
nerves which collect, store, and release urine. The kidneys
form urine by filtering waste and extra water from the
bloodstream. The urine is carried through the ureters to the
bladder, a hollow muscular organ shaped like a balloon.
Located in the pelvis, it is held in place by ligaments attached to
other organs and to the pelvic bones. The bladder stores urine
until you are ready to empty it. It swells into a round shape
when it is full and decreases in size as it empties. A healthy
bladder can hold up to 16 ounces (2 cups) of urine comfortably
for two to five hours.
The bladder opens into the urethra, the tube which allows urine
to pass outside the body. Sphincter muscles, circular muscles
at the end of the urethra, close tightly to keep urine from
leaking. Nerves in the bladder signal you when it is time to
empty your bladder. The sensation intensifies as the bladder
continues to fill and reaches its maximum capacity. When you are ready to urinate, the brain
signals the sphincter muscles to relax. At the same time, the brain signals the bladder muscles to
tighten, squeezing urine out. Urine can then leave the bladder through the urethra. When these
signals occur in the correct order, normal urination occurs.
The normal vagina
and is a reservoir
organisms.
of many types of
lactobacillus,
streptococcus, and
and
Klebsiella.
coliform bacteria,
infections (UTIs).
approximately
opens just behind the urethra
for
different
types
of
Normal vaginal flora consists
bacteria
including
staphylococcus
species,
fecal organisms such as E.coli,
These fecal organisms, or
most often cause urinary tract
E.coli is responsible for
85% of uncomplicated UTIs.
These organisms
that live in the vagina often
crawl
or
get
pushed through the short
urethra of women
and get into the bladder. Most
often
these
bacteria are flushed out with
the next void, but sometimes they begin to multiply and an infection develops.
Factors that may make increase the risk for UTI:
Infrequent voiding – The bacteria spends a greater amount of time in the bladder allowing it
time to replicate and take hold.
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Incomplete voiding – An excess amount of urine is left in the bladder and the bacteria is not
completely flushed out with each void.
Personal Hygiene – Perineal contamination with feces increases the risk of coliform bacteria in
the vagina and near the urethra will increase the risk of urinary tract infections.
Sexual Activity – Trauma to the urethra and surrounding tissue may increase susceptibility to
infection and also the bacteria can be mechanically pushed into the urethra.
Use of spermicidal contraception – The actual spermicide changes the normal flora in the vagina
and more coliform bacteria colonize the area. The presence of these strains of bacteria leads to
a greater risk of a UTI.
Genetics – Certain cells on the vaginal mucosa and the urethra can express receptors that
actually allow certain bacteria to attach and pull themselves into the bladder causing an
increase risk of a UTI. This receptor expression tends to run in families.
Hormonal Status - A lack of estrogen allows for thinning and deficiency of the tissue in the vagina
and urethral that may allow for greater susceptibility to UTIs. This lack of estrogen also changes
the pH of the vagina which allows for colonization with more coliform bacteria and increases the
risk of UTIs.
Diabetes – Persistently high blood sugar levels cause immunosuppression which allows for
greater susceptibility to UTIs. Additionally, transient high blood sugars cause a spilling of sugar
into the urine which acts as food for bacteria and makes it much easier for bacteria to grow and
replicate.
Immunosuppression – There are a variety of causes of immunosupression which decreases a
person’s ability to fight off infections.
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INCIDENCE & DEFINITIONS
Up to 30% of women will experience at least one UTI by the age of 24, and 50% of women will
experience at least one in their lifetime. Once a patient has experienced a UTI, she is much more
likely to develop subsequent infections.
Symptoms of a UTI often consist of burning with urination, urgency and frequency, suprapubic
discomfort, increased incontinence, difficulty emptying, and occasionally gross blood in the urine.
If a urine sample is obtained, there is often a foul odor and cloudiness. At initial diagnosis, a
urinalysis is often performed which may give a good indication of the presence of a bacterial
infection; however, ideally, a urine culture is obtained to identify the bacteria and determine any
resistance patterns that may be present. This begins to become more important as patients have
increased numbers of recurrent UTIs.
Simple, uncomplicated UTIs often respond to short courses of antibiotics. Often these infections
are treated by primary care offices over the phone. If UTIs become recurrent and frequent,
however, providing a urine sample for culture with subsequent symptoms becomes increasingly
important.
Definitions
UTI (Urinary Tract Infection) - An inflammatory process in the bladder or urinary tract, usually
due to the presence of bacteria.
Urinalysis – A simple laboratory test where a dipstick is introduced into the urine sample. Based
on color changes of the stick, the presence of various substances or cellular material can be
detected. The reliability of the test is based on the purity of the sample.
Urine Culture - The urine is actually spread on a dish with bacterial nutrients to allow for growth
and identification of the infecting bacteria.
Bacteriuria – The presence of bacteria in the urine which is not associated with any specific
symptoms and does not require treatment.
Pyuria - The presence of white blood cells in the urine, which may represent an inflammatory
process or infection.
Cystitis – An inflammatory process in the bladder usually associated with symptoms of burning
with urination, frequency, urgency, occasionally suprapubic pain, increased incontinence or
bleeding. This condition may or may not be the result of the presence of bacteria in the bladder.
Coliform Bacteria – Bacteria most abundantly found in the stool. It is named after the shape
of the bacteria and is the most frequent cause of uncomplicated bladder infections.
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Atrophic vaginitis – A lack of the hormone estrogen which allows for thinning and deficiency
of the tissue in the vagina and urethra which may allow for greater susceptibility to UTIs. This
lack of estrogen also changes the pH of the vagina which allows for colonization with more virulent
types of bacteria.
Uncomplicated UTI – A bladder infection found in a healthy patient with a structurally and
functionally normal urinary tract.
Complicated UTI – An infection associated with factors that cause an increased risk of acquiring
an infection or a decreased ability to clear that infection. These factors could include immune
suppression, an inability to empty the bladder, a stone or foreign body within the urinary tract,
or other structural abnormality.
Recurrent UTI – A re-infection describes an event associated with reintroduction of bacteria
into the urinary tract from outside after successful treatment of a previous infection. Often
different organisms are cultured.
Bacterial persistence - A recurrent UTI caused by the same bacteria reemerging from a focus
within the urinary tract, such as an infectious stone or foreign body within the urinary tract. The
same organism repeatedly is cultured.
Prophylactic antimicrobial therapy – This is a regularly scheduled dose of antibiotics over an
extended course of time taken in an attempt to prevent re-infection.
Breakthrough infection – An infection that is contracted despite appropriate use of antibiotic
prophylaxis.
PVR – The measurement of how much urine is left in the bladder after voiding.
Clean catch specimen – A urine sample obtained by voiding into a cup.
contaminated by vaginal bacteria even after wiping prior to collection.
This is often
Catheterized specimen – A urine sample obtained by placing a small catheter into the bladder.
This is often a more reliable way of obtaining a non-contaminated sample.
Bacterial Resistance – When a bacteria has obtained the ability to multiply and thrive despite
exposure to the appropriate concentration of an antibiotic.
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INITIAL SCREENING
I. History and Physical Examination
Your physician will inquire into your symptoms, past urological and gynecological history, prior
surgeries, and medical conditions such as diabetes or stroke that may predispose the patient to
recurrent bladder infections. A physical examination is then performed, frequently with special
attention to the pelvic examination. A pelvic examination will determine if the bladder and
urethra are normal and whether the vaginal tissue is healthy.
II. Urinalysis or Urine Culture
A clean catch or catheterized urine sample will be collected and analyzed to determine if you have
a urinary tract infection, blood, or other abnormality in your urine. If infection is suspected, the
urine sample will be sent for culture.
III. Post Void Residual
This test is performed to see whether any urine remains in you bladder after you have attempted
to empty it completely. Measurements may be made by catheterization or ultrasound. A normal
post-void residual is less than 100 cc of urine remaining in the bladder.
IV. Review of Previous Medical Records
It is very important to review previous culture results. This helps determine whether true bladder
infections have been present or whether these are re-infections or persistent UTIs. The need for
additional work-up may be dependent on information obtained. Additionally, other urologic
conditions may “mimic” UTI symptoms and treatment might significantly differ.
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FURTHER EVALUATION
I.
Voiding Diary
A voiding diary is an essential part of your
evaluation. It will allow you to communicate clearly
with your physician about the status of your
bladder, including how frequently you urinate
during the day and at night, how much fluid you
drink during the day.
II.
Cystoscopy
Cystoscopy (also called Cysto) is a
test that allows your doctor to look at the interior
lining of the bladder and urethra, areas which
usually do not show up well on x-rays.
A
cystoscope is a thin lighted viewing instrument that
is inserted into the urethra and advanced into the
bladder. Your doctor then examines the inside of
your bladder for stones, tumors, pockets that don’t
empty, and foreign bodies.
Just before the procedure, you will be allowed to
empty your bladder. Cystoscopy is usually performed with local anesthesia; a small
amount of numbing jelly is placed into your urethra to reduce discomfort. After the
anesthetic takes effect, a well-lubricated Cystoscope is inserted into your urethra and
slowly advanced into your bladder. If your urethra has a spot that is too narrow to allow
the scope to pass, other smaller instruments are inserted first to gradually enlarge the
opening.
Once the Cystoscope is inside your bladder, sterile water is instilled through the scope to
expand your bladder creating a clear view. The Cystoscope is usually in your bladder for
only two or three minutes. You may feel a cool sensation, an uncomfortable fullness, or
an urgent need to urinate. Try to relax during the procedure by taking slow, deep breaths.
Most people report that this procedure is not nearly as uncomfortable as they had
expected.
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After the procedure, you may need to urinate frequently, with some burning during and
after urination for a day or two. A pinkish tinge to the urine can be common for several
days after Cystoscopy. Afterwards, you should drink ample fluids to help minimize the
burning and to prevent a urinary tract infection.
Call 512-231-1444 to talk to the Triage nurse or your doctor immediately if:
III.

Your urine remains red or you see blood clots after you have urinated
several times.

You are unable to pass urine 8 hours after the procedure.

You develop a fever, chills, or severe pain in your flank or abdomen after
the procedure.
Imaging of the Kidneys and Ureters
A CT scan or ultrasound of the upper part of the
urinary tract may be appropriate, especially if the
infections have been difficult to treat or have been
associated with fevers, elevated blood counts, or
nausea and vomiting. This indicates potential
involvement of the upper tracts. Additionally,
breakthrough infections or persistent UTIs may
indicate the need for further upper tract evaluation.
Kidney stones or urethral obstruction are
infrequently found.
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TREATMENT OPTIONS FOR
RECURRENT UNCOMPLICATED UTIs
I. Antibiotics
A. Treat by Culture
This course of therapy is appropriate if patients are getting 3-4 UTIs or less per year and the
patient has had a negative work-up in the past. When symptomatic, the patient leaves a
urine sample for culture and then proceeds to take antibiotics based on the identification and
resistance patterns of the particular strain of bacteria that is infecting the bladder.
A reliable patient can even take culture vials home with instructions on how to obtain the
culture at home and return it to the clinic within a couple of days. Antibiotics can be kept at
home to help minimize the impact on the patient’s lifestyle.
Again, it is very important to obtain the urine culture when treating these recurrent infections.
B. Post-coital Prophylaxis
This type of therapy is appropriate for patients with UTIs that are always associated with
intercourse. A small dose of antibiotics is taken around the time of intercourse to prevent
the onset of symptoms. It is best to take this just prior to activity, but if that is not possible,
as soon as possible after intercourse is acceptable.
C. Continuous Prophylaxis
With this type of therapy, a small dose of antibiotics is taken on a daily basis to prevent
recurrence of UTIs. The dosage is usually very small and should be taken at bedtime.
Generally speaking, the urine is most concentrated overnight and spends the most time in
the bladder, therefore a bedtime dosage is often most effective.
With this treatment, it is very important to take the medication on a routine basis. If doses
are missed or sporadically taken, antibiotic resistance may develop. If this
happens, it not only may affect the ability to treat future UTIs but also other
bacterial infections. This is very important.
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Most commonly used antibiotics for UTIs and possible side effects:
Macrodantin (Macrobid or nitrofurantoin) – This antibiotic is great for urinary tract infections. The
kidneys concentrate the antibiotic so the only place it gets to high enough concentrations to kill
bacteria is in the urinary tract. It does not change the colonic flora, therefore minimizing
complications like diarrhea. Side effects of long-term use may include fibrosis or scarring of the
lungs and peripheral neuropathy. Generally, the medication is considered safe during pregnancy,
except with rare genetic metabolic deficiencies.
Bactrim (Septra or sulfa/TMP) – This drug is made up of two types of antibiotics, trimethoprim
and sulfamethoxazole, which may work better in combination. It is relatively broad-spectrum,
meaning it may interfere with colonic and vaginal flora which may increase the risks of diarrhea
and vaginal yeast infections. Unfortunately, many people have allergic reactions to the sulfa
portion of this medication. This drug should not be taken early during pregnancy and may affect
the effectiveness of oral contraceptives.
Trimethoprim – This antibiotic may be used alone especially for those taking antibiotics for UTI
prophylaxis. It works well on a daily basis. It should not be taken during pregnancy.
Quinolones (Levaquin, Levofloxacin, or Cipro) - This is a class of antibiotics often used to treat
infections of the genitourinary tract. It is also broad spectrum, therefore diarrhea and vaginal
yeast infections may be problematic. Overall, resistance patterns to this class of antibiotics are
increasing in individuals and in the community. A bacteria that is resistant to one drug of the
class, may easily become resistant to the entire class of antibiotics. Besides common side effects
like diarrhea and dizziness, peripheral neuropathy, colitis, and tendon ruptures are severe
potential complications. This drug should not be taken during pregnancy.
Cephalosporin (Keflex) – This class of antibiotics is related to penicillin and also has broad
spectrum coverage. With this antibiotic, changes in bowel patterns and vaginal yeast infections
may be problematic. Resistance patterns may also develop. It is considered safe during
pregnancy and breastfeeding but may affect the effectiveness of oral contraceptives.
Doxycycline – This antibiotic is from the teteracycline class of antibiotics. It works well for some
types of urinary tract infections. The greatest side effect is nausea and sun sensitivity. It is not
safe during pregnancy or breastfeeding, but may have less of an effect on the effectiveness of
oral contraceptives.
Fosfomycin (Monural) – This is a relatively uncommon antibiotic that is taken as a one-time dose
for uncomplicated urinary tract infections. It comes as a packet of crystals to be mixed with
water and may cause diarrhea. It is relatively safe during pregnancy.
Methenamine (Hiprex, Mandelamine, or Urex) – Used primarily for prophylaxis, this drug is more
a urinary antiseptic - not really an antibiotic. It metabolizes into formaldehyde in the urine if the
urine is acidic. It is usually taken in conjunction with Vitamin C for urine acidification and normally
is prescribed twice daily. It is generally very well tolerated.
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II. Behavior Therapy to Reduce Urinary Tract Infections
A. Drink Additional Fluids
Drinking additional fluids increases the amount of urine produced on
a daily basis. With increased urine production, the bladder is emptied
and flushed out more often. The bacterium that does make it to the
bladder spends less time in the bladder and therefore has less of a
chance to multiply and cause bladder infections.
B. Void after intercourse
Any bacterium that has been manually pushed into the bladder
is flushed from the system before it has a chance to cause urinary
tract infections.
C.
Double void
Double voiding means to return to the bathroom soon after a
previous void and try to empty again. With this second void, the
idea is to attempt to empty the bladder closer to empty. The
further the bladder empties, the less chance the bacteria has to
remain in the bladder, multiply, and cause bladder infections.
D. Change contraception
Spermicide used on either condoms or diaphragms can alter the pH of the vaginal cavity. This
change in pH alters the normal flora in the vagina so more coliform bacteria can colonize the
area. The presence of these strains of bacteria may lead to a greater risk of a UTI.
E. Personal Hygiene
Most urinary tract infections are caused by
bacteria that live in the stool. If stool is sitting
around the vagina or on the perineum, this
will increase the chances of the bacteria
making it to the bladder. Therefore it is
important to maintain good personal hygiene
and cleanliness after bowel movements and
make sure that wiping always occurs from
front to back.
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G. Maintain Bowel Regularity
Constipation and impaction can increase the risk of stool
contamination on the perineum. Eat more fiber! The best way
of adding fiber to the diet is increasing the quantity of fruits
and vegetables that are eaten. This means a minimum of five
servings of fruits or vegetables every day. For many people,
however, the amount of fruits and vegetables that are
necessary may be inconveniently large or may not provide
adequate relief from constipation. In this case, fiber
supplements can be useful. Benefiber, Metamucil, and Citrucel
are common over-the-counter supplements which work well.
Good Diabetic Control
H.
Maintain
If diabetic, it is very important to get the blood
sugars under good control. When blood
sugars are high, glucose spills into the urine
through the kidneys. This provides excellent
food sources for any bacteria present in the
bladder and allows for bacteria to rapidly
multiply. This significantly increases the risks of urinary tract infection. Additionally,
elevated blood sugars long-term can cause immunosuppression which also increases
the risk of UTI.
III.
Vaginal Hormone Replacement
After menopause or a hysterectomy, a woman’s body
produces less of the hormone estrogen. This drop in
estrogen allows for thinning and deficiency of the tissue in
the vagina and urethral that may allow for greater
susceptibility to UTIs. This lack of estrogen also changes
the pH of the vagina which allows for colonization with more
virulent types of bacteria. Applying estrogen in the form of
a vaginal cream, vaginal tablet, or ring may help relieve
some of these symptoms. (See appendix for application
directions.)
Estrogen supplementation is a controversial issue. The amount of estrogen that is absorbed
into the blood stream from this vaginal application is small, just a fraction of the dose that
would be absorbed by oral administration. Generally it is considered safe, however may be
contraindicated in those with a history of some cancers and clotting disorders.
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IV.
Alternative Daily Treatments
A. Cranberry Supplementation
Drinking cranberry juice has long been thought to
prevent and treat urinary tract infections. There have
been several recent scientific studies that have verified this information. It
appears that cranberry supplementation helps prevent specifically E. coli
infections which account for 80 – 85% of common UTIs. It works by preventing the
bacteria from adhering to the bladder walls. It does not prevent the bacteria from entering
the bladder.
Many cranberry juices bought in the grocery store are full of sugar (a source of empty
calories) and have a very low concentration of actual cranberry juice. Therefore it is very
important to read labels if consuming the actual juice. The recommended dosage of juice
is 16 ounces of unsweetened cranberry juice daily.
Another option is to purchase cranberry supplementation in a pill form. Supplementation
is this form should be taken twice daily. These supplements are not regulated by the
FDA, so it is important to choose a reputable company from which to purchase them.
B. Vitamin C supplementation
Vitamin C supplementation is used to acidify the urine creating an
unfriendly environment for the bacteria to multiply and grow. There
is no scientific evidence that this works in preventing urinary tract
infections although in some individuals it may be helpful. If taking
a supplement to acidify the urine, one may be more likely to develop
kidney stones.
C. D-mannose
D-mannose is a naturally occurring sugar. Supplementation with
d-mannose may decrease the risk of urinary tract infections caused
by E. coli, which cause 80-85% of all bladder infections. It works
by preventing bacterial adherence to the bladder wall.
D. Probiotics
Adding probiotics to your diet essentially is adding
good, live bacteria to your colon. These supplements
usually contain Lactobacillus acidophilus and bifid
bacterium. This good bacterium colonizes the colon and
vagina and basically crowds out the other organisms like
coliform bacteria. If the coliform bacterium is not present near the urethra, urinary tract
infections are less likely. They can be taken in a pill form, or can be found in a variety of
foods now, mostly commonly yogurt.
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APPENDICES
A. Application of Estrogen Vaginal Cream
B. Theralogix Cranberry Supplementation
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Appendix A
Fingertip Application Method
For Estrogen Vaginal Cream
1. Wash your hands with soap and
water. Dry thoroughly.
2. Squeeze out enough cream from
the tube to cover 1/2 of your index
finger. (See figure 1.)
3. Locate the vaginal opening. (See
figure 2). Immediately above the
vagina is the urethra (a small
opening where urine is eliminated
from your body). The urethra may
not be as easily identified as the
vagina because the opening is
much smaller; however, use the
diagram
to
determine
its
approximate location.
4. Carefully spread the cream onto
the external vaginal/urethral area
(see figure 2, boxed area). As the
cream is spread, some may be
gently inserted into the vagina;
however, it is not necessary to
push the cream high into your
vagina.
This instruction sheet is provided to help your practitioner explain his/her preferred method for applying vaginal estrogen
cream. Your doctor or nurse will likely use this sheet to assist in their patient education activities. Please note that this
information is not intended to replace your practitioner's instructions; always follow your doctor's specific directions
regarding the use of any prescription medication.
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Appendix B
Theralogix Cranberry Supplementation
TheraCran is a standardized, high-quality, high-potency cranberry supplement
formulated to support and maintain normal urinary tract health.* The formulation
of TheraCran is overseen by an advisory board of leading academic physicians and
scientists.
How is TheraCran different?
TheraCran is the first and only cranberry supplement that has been independently tested and
certified for proanthocyanidin (PAC) and other flavonoid content. PACs are the compounds that
researchers have determined to be the active component of cranberries. For a cranberry
supplement to be effective in reducing the risk of urinary tract infections, it must provide an
adequate dose of these PACs. Research indicates that 30–35 mg PACs per day is needed for
urinary tract health.
TheraCran is the first cranberry supplement to use a new high-potency cranberry powder
containing at least 2.5% PACs. Most supplements on the market contain cranberry powder
with only 1% PACs. As a result, it may take up to six capsules per day of these other supplements
to get the recommended amount of active ingredients. Because TheraCran provides a more
concentrated dose of PACs, only two capsules per day are needed: one in the
morning and one in the evening. TheraCran contains no cellulose or other agents that can bind
to PACs, dramatically reducing their effectiveness. Most other cranberry products do contain
cellulose binders and are not effective.
Q. How is TheraCran different from drinking cranberry juice?
Two TheraCran capsules per day have almost no calories but provide the same bioactivity as
drinking 10-12 ounces of 27% cranberry juice cocktail every day. While TheraCran capsules are
virtually calorie and sugar free, 10 ounces of juice contains approximately 175 calories and lots
of sugar. Taking in the extra calories and sugar every day can add up over time, and can result
in weight gain. In addition, people with diabetes can safely take TheraCran, and it will not
affect their blood sugar levels as sugary juice will. Patients watching their weight or their blood
sugar levels will benefit from choosing TheraCran over cranberry juice.
Q. Are there any side effects from taking TheraCran?
No, taken at the recommended dosage of two capsules per day, no side effects should occur.
Q. Will TheraCran interact with my medications or other dietary supplements?
There are no known dietary supplement interactions with TheraCran. It is safe to take with
other dietary supplements. When taken at the recommended dosage, TheraCran is not likely to
interact with any prescription medications. It used to be thought that cranberry juice or
cranberry supplements would increase the effect of warfarin (Coumadin), a blood thinner.
Recent studies have proven that there is no significant interaction, and cranberry is safe to take
(the recommended dose -1 capsule, twice a day) while taking Coumadin.