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The information
provided in these pages is a general overview of the medical
therapies used in the treatment of pulmonary hypertension.
It is provided for reference only, and should not replace
information or specific instructions given by your G.P or
Consultant.
One of
the main goals of treatment is to prevent and even induce
regression of the disease. Impact on patient quality of life
is also a key consideration. It is desirable that the benefits
outweigh the risks of treatment.
The therapeutic
options will vary as the disease progresses and also depending
on the classification of the disease. The pathology of pulmonary
hypertension has three key elements: Vasoconstriction, vascular
wall changes (remodelling) and clot formation (thrombosis)
Medical
Therapies include:
Surgical
Options:
Anticoagulants
(Also known as blood thinners.)
Pulmonary hypertension is associated with pulmonary arterial
thrombosis and a hypercoagulation. Anticoagulation may reduce
thrombosis and slow progression in some forms of the disease.
Warfarin therapy has been shown to almost double three-year
survival in primary pulmonary hypertension. For the patient,
however, anticoagulation carries the inconvenience of regular
INR testing and the possibility of a number of drug interactions.
Recommendations
All patients with primary or thromboembolic pulmonary hypertension
should be treated lifelong with warfarin .The generally accepted
INR IS 1.5-2.5
Warfarin should be considered in other types of pulmonary
arterial hypertension where there is no contraindication,
such as gastrointestinal haemorrhage, significant haemoptysis
or liver disease with coagulation abnormalities.
There are possible serious side effects of anticoagulation
therapy. The risk of bleeding is of major concern.
Points
to note:
- - observe
for prolonged or unusual bleeding
- -
Bruising for unknown reasons
- -
Fever, diarrhoea, vomiting.
- -
Signs of internal bleeding-swollen or painful abdomen,
- -
Joint pain or stiffness. a severe or long standing head
ache.
- -
Do not take medication-containing aspirin Ibuprofen containing
drugs for example. Advil or Tylenol
- - Avoid
sudden weight loss
- - Inform
all health professionals know that you take warfarin
- -Use
alcohol in moderation
Oxygen:
Hypoxaemia (low levels of oxygen in the blood) causes pulmonary
vasoconstriction and may worsen pulmonary hypertension. Many
patients with pulmonary arterial hypertension show significant
falls in arterial oxygen saturation at night. This can be
corrected with long-term supplemental oxygen therapy (2 litres/min
oxygen from an oxygen concentrator). Some patients will find
the need to use supplemental oxygen during the day or with
activity.
Recommendations
Controlled oxygen therapy may be indicated for those patients
with sustained nocturnal hypoxaemia where arterial oxygen
saturations are below an average of 90% on air and are corrected
on supplemental oxygen.
Your doctor may insist that you use oxygen during air travel;
this is not necessary for all patients.
Remember that oxygen is highly flammable; so keep the tank
and tubing away from any open flame.
It is recommended to keep away from high altitudes.
Diuretics:
Right
heart failure gives rise to fluid retention which is improved
by diuretics which assist the kidneys to eliminate water.
Monitoring of renal function is necessary while taking diuretics
in order to assess electrolyte levels. Disturbance of electrolyte
balance can interfere with normal heart function.
Calcium
Channel blockers:(CCBs)
Calcium antagonists cause pulmonary and systemic vasodilatation.
They are effective in the presence of vasoconstriction
The smooth muscle cells in arteries cannot constrict without
cellular calcium, and calcium channel blockers assist the
arteries in dilating by doing what the name implies.
A positive vasodilator response during heart catheterisation
indicates patients who will respond to calcium channel blockers.
Only 10-20% of patients will fall in to this category of responders.
Long-term use of high dose nifidepine and diltiazem reduces
pulmonary artery pressure and mortality with sustained improvement
of symptoms.
Calcium antagonists cause systemic hypotension and their negative
isotropic effect may be adverse when right ventricular function
is already damaged.
In patients with left ventricular dysfunction diltiazem and
nifidipine may worsen heart failure.
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Prostacyclin:
In people who require more intensive treatment to obtain control
of their disease, the largest collection of literature surrounds
the use of prostacyclin and its analogues. In animal studies
it has demonstrated the ability to remodel the pulmonary vascular.
This agent
is FDA approved and indicated for clinical use in the long-term
intravenous treatment of primary pulmonary hypertension in
New York Heart Association (NYHA) functional class III and
Class IV PPH or PAH associated with collagen vascular disease
(the Scleroderma spectrum of patients).
Mode
of action:
This is a potent pulmonary and systemic vasodilator,
which prevents platelet aggregation. (Clotting). In animal
studies it has demonstrated the ability to remodel the pulmonary
vascular bed and subsequently reduce damage to the cells lining
the blood vessels. All prostaglandins are inactivated by Gastric
Ph, hence require administration by intravenous infusion.
There
are several prostaglandin's available for treatment of pulmonary
arterial hypertension. The only prostaglandin to currently
hold a license is epoprostenol (flolan). This agent
increases cardiac output and reduces pulmonary vascular resistance
during long-term therapy.
 Mode
of administration:
Epoprostenol (flolan) has a half life of 2-3 minutes
so it has to be administered by continuous infusion through
a permanent central venous catheter, usually a Hickman line.
This procedure is carried out in theatre, and requires a general
anaesthetic.
Side
effects :
Hypotension: (low blood pressure) can occur during
administration of the drug
Tachycardia: (increase in heart rate)or bradycardia
(slow Heart rate can occur )
Bradycardia: accompanied by pallor,nausea,sweating
and occasionally abdominal discomfort
Facial flushing is commonly reported, Headache, Lassitude,
Nausea, vomiting, Abdominal colic, Jaw pain, Dry mouth, Chest
pain and tightness
Flolan can potentiate the risk of bleeding, Observe
for bruising, unusual /prolonged bleeding, Local line infection
/sepsis, Occlusion of hickman line, Displacement of hickman
line
Points
to Remember: Abrupt withdrawal of flolan or sudden reduction
in infusion should be avoided, as the patient will experience
rebound pulmonary hypertension symptoms, which could prove
fatal.
Except
in life threatening situations (Eg.unconsciousness, collapse)
infusion rates should be adjusted only under the direction
of a physician.
Iloprost:
This drug is currently available and indicated for clinical
use in severe primary pulmonary hypertension but is not yet
licensed in the UK or Ireland.
 Mode
of action: Iloprost is a potent systemic and pulmonary
vasodilator that inhibits platelet aggregation. It is more
potent than epoprostenol and only half the dose is required
to produce the same long-term effects.
Mode
of administration: Iloprost is administered by
continuous intravenous infusion through a permanent central
venous catheter using a portable infusion pump .It can also
be administered through inhalation using a nebuliser.
Side
effects: Nausea, Jaw pain, Leg pain, Diarrhoea, Hypotension,
Bradycardia, Pallor
Points
to Remember: The systemic side effects are avoided with the
use of inhaled prostanoids like iloprost. Using the
inhalation technique can be time consuming, as it requires
6-9 Inhalations per day.
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Tracleer (Bosentan)
This drug is FDA approved and indicated for clinical use in
the treatment of pulmonary arterial hypertension in patients
with NYHA Class III or IV symptoms, following two randomised,
placebo controlled, double blind studies that both showed
marked improvement in exercise capacity after treatment, to
improve exercise ability and decrease the rate of clinical
worsening.
Mode
of action: Bosentan is classified as the first oral active
non peptide antagonist of both endothelin receptor subtypes
(ETa and ETb)
Mode
of administration: This medication is in tablet form .It
should be initiated at a dose of 62.5mg bd(twice daily) for
four weeks and then increased to a maintenance dose of 125mg
bd.This dose increase is dependent on tolerability and liver
function results.
Side
effects: There is the Potential for serious liver injury.
Elevation of liver enzymes (AST and ALT) appears to be dose
dependent, occurs at any stage in treatment, usually progresses
slowly and patients are usually asymptomatic.To date this
effect has been reversible after treatment interruption or
cessation.
Haematological
changes: Treatment with bosentan can cause a dose related
decrease in haemoglobin and haematocrit.
Potential damage to the foetus
Contra indicated with cyclosporine
Facial flushing
Headaches
Points
to Remember:Treatment Should not be initiated by the prescriber
until a urine or serum pregnancy test provides a negative
result. The patient must be advised that if there is any change
in menses or any reason to suspect a potential pregnancy,
the physician must be notified immediately. Follow up urine
or serum pregnancy tests should be obtained monthly on women
of child bearing years. If elevated aminotransferase levels
are seen, reduction in dosage must be initiated.
If elevation
in liver aminotransferase is accompanied by clinical symptoms
of liver injury (nausea, fever, abdominal pain, jaundice)
or increase in billirubin by >2 x UNL treatment should
be stopped.
Bosentan
should be avoided in patients with pre existing mild /moderate
liver impairment.
Monthly
liver function testing, two weekly if indicated.
Haemoglobin
monitored 1 month and 3 months after treatment commencement
and every 3 months thereafter.
It may
reduce plasma concentrations of oral hypoglycaemic agents,
the possibility of poor glucose control in these people should
be considered.
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Remodulin (treprostenol):
This agent is an investigational subcutaneous prostacyclin analogue
also referred to as UT-15 indicated for clinical use in patients
with modified NYHA functional Class II,III or IV PAH.
The FDA
has approved its use in the USA, however, it remains unlicensed
in the UK and Ireland and currently usage is relatively small.
Mode
of action: a potent systemic and pulmonary
vasodilator.
Mode of administration: Remodulin is administered
by continuous subcutaneous infusion through a fine bore catheter
in to the subcutaneous tissue. A small needle (cannulae) is
inserted into the tissue and connected to the infusion line.
The 'Sof-serter'
automatically inserts a this needle with the push of a button,
giving a simple, quick and virtually painless insertion. Hold
the Sof-serter perpendicular and against the surface of the
skin (leaner patients may wish to pinch a fold of skin). Gently
push the activation button to insert the needle. It is then
secured with a dressing.
It comes
in premixed prefilled 2ml syringes and therefore patients
need only to replace the syringe in the pump. The minimed
pump is about the size of a pager, and can be concealed easily
Side
effects: Hypotension, Bradycardia, Tachycardia, Pallor,
Clammy, Facial flushing, Headache, Nausea, vomiting, Diarrhoea,
Abdominal discomfort, Infusion Site pain, Infusion site erythema,
Jaw pain
Points
to Remember: The half life of the drug is 3 hours,
because of this interruptions of drug dose due to dislodgment
of the catheter or due to pump malfunction are less serious
than with epoprostenol
The nemesis
of remodulin has been pain and erythema at the infusion site.
This does not seem to be dose related. Hot or cold packs,
topicall analgesia and anti-inflammatory agents have been
variable effective.
More
recently a pharmaceutical transdermal cream known as Pluronic
Lecithin Organogel (PLO GEL), has been compounded with a variety
of analgesic and anaesthetic therapies for application to
the site. Initial observations appear promising, although
the therapy has yet to be studied in a controlled fashion.
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Beraprost
sodium:
This agent is an oral prostacyclin analogue
Mode
of action:
Mode of administration: This agent is administered
in tablet form, dosing is three to four times daily
Side effects:
Headache, Flushing, Jaw pain, Diarrhoea, Leg pain,
Nausea, Abdominal discomfort
Points
to Remember: Side effects can be minimised when the medication
is taken with alcohol. Usage of this drug is limited. It was
primarily developed and used in Japan. Trials are now ongoing
in Europe and the USA.
- Once
a referral has been set up by your GP or referring Consultant
to the Unit, The Nurse Specialist will confirm the appointment
date and time in writing.
- On
the Clinic visit the patient will be reviewed by the Physician
.A full medical history and examination will take place.
- Pulmonary
Function tests, six-minute walk and echo will be carried
out if not already performed.
- The
patient will have a consultation with the Nurse specialist
regarding further investigations, and future appointments.
- This
will also be an opportunity for the patient and family members
to voice any queries pertaining to the disease and available
treatments.
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Surgical
Options
Atrial septostomy
This is a palliative surgical procedure, which allows an opening
to be made through the atrial septum (the muscular wall separating
the right and left chambers of the heart). This creates a
safety valve, which alleviates the high pressure to which
the right heart is subjected in severe disease.
In selected patients it results in an immediate fall in right
ventricular end diastolic pressure and systemic oxygen saturations,
and is accompanied by an increase in cardiac output.
It may improve survival while awaiting lung transplantation.
It is well tolerated despite the fall in systemic oxygen saturations,
but it carries a high mortality in critically ill patients.
Recommendations
Atrial septostomy may be considered in severe pulmonary hypertension
unchanged by prostaglandin therapy particularly if it is associated
by recurrent syncope.
Physicians should only perform Atrial septostomy with experience
in performing this procedure and in a specialised pulmonary
hypertension centre.
Pulmonary Thromboendartrectomy
A pulmonary
Thromboendartrectomy is a cardio thoracic surgical procedure,
which removes organised thrombus (clot) formation from the
pulmonary arteries.
What
is the Length of hospital stay?
The average duration of hospital stay is 2-3 weeks: this includes
2-3 days of evaluative testing where the cardio thoracic surgeon
reviews the patient history, and the various diagnostic scans.
A period of 2-5 days will be spent in the surgical intensive
care unit; of course this will depend on the patient's progress.
The patient will remain on the pulmonary ward for 7-10 days
for further monitoring. Of course, with complications, the
postoperative course can be longer.
What should I expect following surgery?
This is variable for each patient, as the functional improvement
postoperatively is related to the amount of pulmonary vascular
bed reopened, and to the amount of clot successfully removed.
In the vast majority of patients, within several weeks to
two months postoperatively there is a dramatic decline in
dyspnoea (breathlessness) related to exertion, and an improvement
in functional class.
Common symptoms such as chest discomfort, palpations and fluid
retention disappear.
Progress will also depend on the condition of the patient
before surgery, obviously in
sicker patients recovery may take longer. If there is additional
heart or lung damage related to another disease process then
some functional limitations may remain
.
How am I referred for surgery?
The Patient is reviewed in the pulmonary hypertension unit
and following a series of investigations a diagnosis of pulmonary
hypertension associated with chronic thromboembolic disease
is confirmed.
The consultant will then write a letter of referral, sending
copies of the various scans, along with a patient history
to a specialist centre, to determine if the clots are accessible
through a surgical route.
If it is believed to be a possibility, then the patient will
travel over to the centre in question and under go possible
further evaluation and potentially surgery.
The provision of financial support has to be obtained from
the relevant health authority before travel can take place.
Lung or heart lung transplantation
Lung or heart lung transplantation improves quality of life
and survival in patients with pulmonary hypertension. Rapid
expansion of this treatment has been limited by scarcity of
donor organs and is limited to approximately 10 pulmonary
hypertension patients per annum in the UK.
Pulmonary hypertension accounts for 23.3%of all lung transplants
in the USA. The choice of the transplant procedure depends
on the underlying disease and on the operating teams experience.
Heart lung transplantation may be indicated for patients with
primary pulmonary hypertension, valvar heart disease, Eisomengers
syndrome with complex cardiac abnormalities, and complex pulmonary
Artesia. Survival after transplantation is 83% at one year,
70% at three years, and 54% at five years. The main cause
of death in the long term remains obliterative bronchiolitis.
Pre treatment with prostaglandins improves postoperative survival.
Recommendations
Lung or heart lung transplantation is indicated in patients
with pulmonary hypertension with symptomatic progressive disease,
which, despite optimal medical and/or surgical treatment,
leaves the patient in modified functional classes III or IV.
The six-minute walk is a useful tool in the assessment of
when to list patients for transplantation. Candidates should
meet the internationally recognised guidelines for transplantation.
Pulmonary
hypertension without congenital heart disease:
All candidates should be evaluated for vasodilator therapy
(including prostaglandin's) and other medical or surgical
interventions before transplant consideration. It should be
considered when treatment with epoprostenol is initiated or
failing or is causing intolerable side effects .
Pulmonary
Hypertension secondary to congenital heart disease.
Since predictors of survival are least reliable in this group,
the health of patients should have reached an unacceptable
level from the patient's perspective or there should be clear
evidence of right heart failure
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