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Management
Although the etiology and natural history of PPH and ES
are dif-ferent, the histopathologic changes are virtually
identical. This has prompted adaptation of some of the
treatment strategies for PPH for ES patients.
Supplemental oxygen: Supplemental oxygen
therapy should be considered for patients with ES. Although
recent data from one small study demonstrated that supplemental
oxygen did not offer a survival benefit for adult patients
with ES,13 previ-ous studies have demonstrated that the
use of supplemental oxygen in children with pulmonary
vascular disease during sleep may slow the progression
of polycythemia.14 There is also evidence that desaturation
may occur in the supine position because of VQ mismatch
15 and that the use of supplemental oxygen attenuates
these changes.
In addition, patients who have significant desaturation
with activity during exacerbations of heart failure, infections,
or air travel because of increased oxygen extraction,
in the setting of fixed oxygen delivery, may benefit from
supplemental oxygen during exercise.
Digitalis and diuretics: The
efficacy of inotropic agents for right-heart failure remains
controversial. There have been reports of increased cardiac
output with the use of digitalis in patients with PPH.16
Thus, there may be a role for digitalis for ES patients
with diminished right ventricular function.
Diuretics may be useful for patients with ES and severe
right-heart failure to relieve hepatic congestion and/or
increased intravascular volume.
Anticoagulation: Patients with
ES are at risk for throm-boembolic events and even a small
pulmonary embolus can be life-threatening in patients
who cannot vasodilate or recruit additional pulmonary
vessels normally. Although there have been no adequate
studies to demonstrate the efficacy of anti-coagulation
for patients with ES, most experts recommend anti-coagulation;
however, the risk of bleeding, particularly hemopt-ysis,
needs consideration. If warfarin is used, the aim is to
maintain the international normalized ratio (INR) at 1.5
to 2.0 for most patients, with a higher INR for patients
who are hyper-coagulable.
Phlebotomy: Phlebotomy with
replacement of fluid may be helpful for cyanotic CHD beyond
infancy in which severe hypoxemia has led to a large increase
in red cell mass. When a hematocrit reaches the 65% to
70% range, or if the patient is symp-tomatic with a lower
hematocrit, eg, blurry vision or headaches, exchange transfusion
with plasma or crystalloid is indicated to lower the hematocrit
to the 50% to 60% range. This must be done carefully since
simply removing blood can decrease sys-temic vascular
resistance and result in a sudden hypoxic event. Fortunately,
many patients with ES tend to stabilize their hema-tocrit
in the 60% to 65% range for many years or even decades,
and no longer require phlebotomy. One must also follow
iron stores, which often become depleted, leading to a
decrease in the circulating blood volume and increased
viscosity.17 Supplemental iron therapy is indicated for
iron deficiency even if a patient is polycythemic to avoid
a hyperviscosity syndrome related to iron deficiency in
the setting of polycythemia.
Vasodilator/antiproliferative therapies:
Pulmonary vasodila-tor therapy has been used for the treatment
of PPH based on the premise that pulmonary vasoconstriction
plays a role in the development of the pulmonary vascular
disease. Patients with ES may also benefit from vasodilator/antiproliferative
therapies such as intravenous epoprostenol, previously
reserved only for PPH patients 18 (Table).
In our center, prior to initiation of pulmonary vasodilator
therapy, ES patients undergo cardiac catheterization with
acute pulmonary vasodilator testing. If patients respond
to acute vasodilator testing with a fall in pulmonary
vascular resistance of >30% following the administration
of inhaled nitric oxide (80 ppm) or intravenous epoprostenol,
and demonstrates a sim-ilar response to acute testing
with sublingual calcium channel blockade, they can be
offered treatment with long-term oral cal-cium channel
blockade, if they are not in significant right-heart failure
(mean RAP > 15 mmHg, C.I.<1.5 L/min/m 2 ). This is based
on previous studies of patients with PPH that demon-strate
acute pulmonary vasoreactivity and subsequent clinical
and hemodynamic improvement, as well as increased survival
with long-term oral calcium channel blockade.19 It should
be noted that our experience has demonstrated significantly
lower acute response rates for ES patients than for patients
with PPH. In a small study from our institution, only
7% of 94 patients (including 27 adult patients) with PAH
associated with CHD responded to acute vasodilator testing.20
None of the “respon-ders” were adult patients. For those
symptomatic patients with ES who do not respond to acute
vasodilator testing, treatment options include long-term
intravenous epoprostenol therapy or lung or heart-lung
transplantation.
Continuous intravenous epoprostenol therapy has been
used successfully in patients with PAH and associated
CHD. In a report from our institution of 20 patients (including
6 adult patients) with PAH associated with CHD (10 operated
and 10 with residual shunts), who were not responsive
to acute vasodilator testing, there were improved hemody-namics,
and quality of life following one year of treat-ment with
continuous intravenous epoprostenol.18 Notably, in patients
with residual shunts, we did not see an increase in right-to-left
shunting, nor did we see a fall in systemic arterial blood
pressure with long-term epoprostenol. These 10 patients
with residual shunts had a significant improvement in
oxygen delivery while receiving long-term epoprostenol.18
McLaughlin et al, also reported improved hemodynamics
with continuous intravenous epoprostenol in a study of
patients with PAH that included 7 patients with CHD.21
Unfortunately, the use of continuous intravenous prostacyclin
has several associated risks, including the risk of thromboembolic
events to the systemic circulation in the setting of ongoing
pulmonary-to-systemic shunting. Although the data are
limited, for patients with CHD, an alter-native to continuous
intravenous epoprostenol is the use of a subcutaneous
prostacyclin analogue, such as treprostinil,22 which avoids
the risks associated with a central venous catheter.
Transplantation
While successful heart-lung transplantation and lung trans-plantation
with repair of CHD have been available for over 20 years,
there are several limitations to these procedures. Patients
with ES have the highest perioperative mortality and the
lowest 1-month survival rates among all lung transplant
recipients.23 In addition, a limited number of centers
can perform the pro-cedures and care for the patients
following transplantation, and the availability of suitable
donors is limited. Further, the high incidence of bronchiolitis
obliterans in the transplanted organs of these patients
(25 to 40%) is of great concern.23 For at least 5 years,
single and bilateral lung transplantations have been performed
increasingly in patients with pulmonary vascular obstructive
disease including patients with severe right ventric-ular
failure.2 Thus, lung transplantation with repair of the
CHD appears to be the surgical procedure of choice for
virtually all patients in whom left ventricular function
is maintained despite severe right ventricular failure.
Currently, the overall 1-year, 5- year, and long-term
(9-year) survival for lung transplantation for recipients
with all forms of lung disease is 71%, 49%, and 20%, respectively.
For patients with ES, the 1-year and 5-year survival following
lung transplantation is worse, 52% and 39% respectively.23
Recent data suggest that patients with ventricu-lar septal
defects have the best prognosis and that, for patients
with ES secondary to a ventricular septal defect, heart-lung
transplantation may offer a survival benefit.24 For patients
with ES, we often defer transplantation for many years
based on overall risk-benefit considerations. For ES patients,
we general-ly reserve transplantation for those patients
who are very symp-tomatic despite optimal medical management,
in whom long-term survival is unlikely, ie, patients in
whom likeli-hood of 2-year survival is less than 50%.
General Measures
Adults with ES must be advised to avoid situations that
could exacerbate their pulmonary vascular dis-ease. For
example, exercise should be guided by symptoms, with self-limits
placed. Avoidance of travel to high altitudes should be
advised. In addi-tion, because flight cabins are not usually
pressur-ized to sea level, we recommend the use of supple-mental
oxygen during air flight to avoid exacerba-tion of pulmonary
hypertension. Pregnancy, oral contraceptives, hormone
replacement therapies, and appetite suppressants should
be avoided. Pregnancy can be fatal for patients with ES
both in the course of delivery and in the postpartum period.
During pregnancy, the SVR can fall considerably and lead
to increased right-to-left shunting with worsening hypoxemia,
which can be dangerous for both the mother and fetus.
Similarly, hemorrhage and anesthetic agents may have the
same effects on SVR during the peripartum peri-od. Thromboembolic
events have also been associated with up to 43% of all
maternal deaths in ES.25 The practice at our insti-tution
is to firmly advise against pregnancy, as the risk for
maternal death is approximately 30% to 50% in the peripartum
period.25 In addition, because of the increased risk of
throm-boembolic events, which may be associated with oral
contra-ceptives and hormone replacement therapies, we
advise against oral contraceptive therapies for all of
our ES patients and sug-gest barrier methods or tubal
ligation as alternatives.
Future Directions
There are several novel therapeutic agents that are currently
being evaluated and/or considered for clinical investigation
for patients with PAH, alone as well as in combination.
These include endothelin-receptor antagonists, prostacyclin
ana-logues, elastase inhibitors, inhaled nitric oxide,
phosphodi-esterase- 5 inhibitors, eg, sildenafil, and
angiotensin-converting enzyme inhibitors.
Endothelin Receptor Antagonists
Endothelin-1 (ET-1), a very potent vasoconstrictor, is
elevated in patients with PPH, and correlates inversely
with prognosis.26 Plasma ET-1 levels are also elevated
in patients with ES.27 The endothelin-receptor antagonists
bosentan and sitaxsentan have been shown to improve exercise
capacity, hemodynamics, and WHO functional classification
in patients with PPH, PAH asso-ciated with collagen vascular
disorders, and PAH with associat-ed CHD.28-32 Future prospective
studies, which will include a greater number of patients
with CHD, will be critical for deter-mining whether this
class of drug is also effective for patients with ES.
Other novel therapeutic agents: Other
novel therapeutic agents, including oral and inhaled prostacyclin
analogues, elas-tase inhibitors, inhaled nitric oxide,
phosphodiesterase inhibitors, and angiotensin-converting
enzyme inhibitors, are being investigated in patients
with PAH and may show promise for the long–term management
of ES.
While there have recently been many advances in the under-standing
of the pathobiology and management of adults with ES,
there is still no cure for this disease. By furthering
our understanding of the disease, we anticipate that more
advances will continue for patients with ES, thereby improving
the long-term outlook for these patients.
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