Pulmonary arterial hypertension (PAH) or pulmonary hypertension (PH) is a rare
disease that predominately affects young women, although it can be diagnosed in
either sex at any age.
true incidence of PAH is unknown, but it is calculated that one to two new cases
of primary PH per million inhabitants in the general population.
PH is relatively more common, but frequently underdiagnosed. Many patients present
a prolonged interval between onset of symptoms and diagnosis of PH, which delays
their treatment and shortens their prognosis yet further.
associated with P H is extremely elevated. Once diagnosis has been confirmed mean
survival among adults is 2.8 years and less than 1 year among children.
the last few years, advances have been associated with earlier diagnosis and a
greater understanding of the pathophysiological mechanisms involved. We have come
to understand better the association between the degree of vascular compromise
and the clinical manifestations presented. These findings have changed both survival
and quality of life of these patients.
Nevertheless, in the pediatric population
the disease behaves differently. Increased reactivity of pulmonary vessels hinders
us from achieving the prognosis established for adult patients. In contrast, this
increased reactivity may result in better prognosis in the future, in the event
that these patients come to benefit from the clinical use of new drugs (with vasodilatory
and antiproliferative effects).
Definition and classification
hypertension is defined as an increase in the mean pressure of the pulmonary artery
(PmAP) ≥ 25 mmHg (resting) or ≥ 30 mmHg (exercising).
when we use the systolic pulmonary artery pressure, we defined hypertension as
values above 35 mmHg.
Another definition, more adaptable to pediatric practice, takes into account the
relationship between pulmonary artery pressure (PAP) and systemic systolic pressure
(BP). Accordingly the diagnostic criterion for PH is: PAP > 50% of BP.
while exercising are particularly important in pediatrics because in children
the response of the pulmonary vascular bed to exercise and hypoventilation is
Furthermore, it is known that more than 50% of the vascular bed must be affected
(unresponsive or dysfunctional) before symptomology emerges. Nevertheless, during
exercise, particularly in children, this lack of response may be present even
in very initial phases of the disease.
most recent update to the classification of PH drawn up during the World Health
Organization World Symposium on Pulmonary Hypertension (WHO). This classification
was based on advances in the form of histopathological findings, mechanisms involved
in molecular and vascular biology in addition to genetic alterations (Table 1).
Classification of pulmonary hypertension (children and adults) - Venice, 2003
pulmonary hypertension (PPH), also known as idiopathic, has no definite etiology,
is sporadic and has been linked with family-based predisposition (10% of cases).
At the WHO symposium, the term "primary pulmonary hypertension" was
officially modified to "pulmonary arterial hypertension idiopathic,"
reflecting the character of diagnosis by exclusion. Secondary PH is generally
associated with chronic hypoxemia, parenchymatous lung disease, chronic thromboembolic
disease, left chamber heart valve disease, myocardial disease, congenital heart
disease or connective tissue disease.
of the etiology associated with the presence of PH, some of the alterations observed
are in common. Similarly, within a single disease associated with the presence
of PH, we can observe the damage found exhibits a heterogeneous nature.
the newborn infant, biological alterations triggered by PH appear to be: problems
with opening the vascular bed and reduction in the number of arteries backspace.
In infants, hyperplasia of the tunica intima, with occlusion of pulmonary arterioles
and plexiform abnormalities. Adults with PPH exhibits severe plexiform damage,
with abnormalities that are apparently fixed in the pulmonary vascular bed. In
contrast, children with PPH suffer more hypertrophy of the pulmonary vessel tunica
media and less fibrosis of the tunica intima; as a consequence they suffer less
infants appear to exhibit a more reactive pulmonary bed, both during vasoconstriction
and vasodilation, with PH crises being triggered more recently than in adults
and older children. Histopathological findings suggest that the basic mechanism
to be blamed for PH is the presence of vasoconstriction in these patients. Certain
structural and functional abnormalities confirm this theory, but do not explain
up to what point some alterations may be cause or consequence.
earliest pathological alterations affect the function of vascular endothelium,
an important source of local mediators which contribute to the control of vasomotor
tonus and structural remodeling.
alterations on the vascular level include reduced production of vasodilatory and
antiproliferative substances- prostacyclins, nitric oxide (NO) - and increased
production of vasoconstrictive substances and mitogens (endothelin-1).
It appears that a "imbalance" takes place between vasoconstrictor and
vasodilator mediators (increased thromboxane and reduced prostacyclins, increased
endothelin and reduced NO). Other factors which may also be involved are: serotonin,
growth factor-derived platelets, angiotensin and loss of vascular NO and prostacyclin
due to synthesis genetic expression.
the initial endothelial damage results in recruitment of local vasoactive mediators,
provoking a procoagulatory state, leading to consequent vascular obstruction.
Furthermore, defects in pulmonary circulation smooth muscle potassium channels
also appear to be involved in onset and/or progression of PH.
of pulmonary vascular disease can be classified from I to VI:
- Grade I:
- Grade II: cellular intimal thickening;
III: occlusive intimal thickening;
- Grade IV: injuries with vascular dilatation;
Grade V: plexiform injuries;
- Grade VI: acute necrotizing arteritis.
I to III abnormalities are considered plexogenic (reversible). Grades IV to VI
are plexiform (irreversible). Plexiform abnormalities encompass: hypertrophy of
the tunica media of preacinar arteries, muscularization of intra-acinar arteries,
concentric thickening of the preacinar arteries, complex alterations and dilatations
with arteritis and ferrugination
Irrespective of etiology patients with PH do not exhibit
a specific clinical status. Smaller children predominately exhibit symptoms of
low cardiac output (failure to thrive, lethargy, irritability, tachypnea and tachycardia).
Older children describe a certain degree of respiratory distress, fatigue and
headaches (especially from light) and may suffer chest pain (from right ventricular
ischemia), episodes of syncope triggered by exertion and, in certain cases, sudden
death. Invasive anesthetic and sedative procedures are not well-tolerated, and
patients with Eisenmenger syndrome may exhibit episodes of hemoptysis.
syndrome is defined as vascular pulmonary disease related to congenital heart
disease. In these patients vascular disease develops after a hyperkinetic period,
with normal vascular resistance and increased pulmonary blood flow.
patients progress with pale extremities (due to low cardiac output) and cyanosis
(due to low oxygenation) because of intrapulmonary or intracardiac (L-R) shunts
via the foramen ovale.
Some infants may suffer convulsions as a result of
exaggerated pulmonary vasoconstriction, but this is a rare complication. In these
patients, systemic arterial oxygenation may be reduced during sleep (especially
during the first few hours of the morning).
interval between onset of symptoms and diagnosis is significantly shorter in children.
It is rare for the signs of direct heart failure to emerge in children less than
10 years old. In these cases peripheral edema, and acrocyanosis are the signs
of terminal disease.
pediatric patients, cardiovascular auscultation is not as rich, but the pulmonary
component is always more audible. Signs of tricuspid regurgitation may be present,
and even thoracic deformity may be observed, secondary to severe right ventricular
with PH can be classified according to their functional capacity (degree of functional
limitation) (Table 2).
Table 2 -
Functional classification (World Health Organization)
Diagnosis of PH is by exclusion, but there maybe
a high degree of clinical suspicion. Family history should be thoroughly investigated
for: connective tissue disorders, relatives with pH, congenital heart disease,
other congenital malformations and any history of sudden death in the family.
Drug use should also be investigated (especially psychotropics and appetite suppressants)
as should exposure to altitude, repeated respiratory infections, obstructive sleep
apnea (not so rare in children), thromboembolic events (rare in pediatrics) and
can be observed in Table 3, the routine for diagnostic evaluation may include
a series of supplementary tests adapted to the individual clinical requirements
of each patient.
Table 3 -
Diagnostic assessment routine
Echocardiographic examination is an extremely
sensitive and non-invasive diagnostic method which has made it first imaging examination
to be used with patients with a clinical suspicion of PH.
The echocardiogram evaluates right ventricular function, which traces the progressive
damage resulting from the disease, and is of fundamental importance for sequential
monitoring of PH patients.
By means of this examination we can exclude cardiological causes of PH, such as
right ventricular dysfunction, mitral valve disease and the presence of intracardiac
Doppler echocardiogram is used to estimate systolic pressure in the right ventricle
(RV) by means of tricuspid regurgitation velocity measurements. The sum of right
atrial pressure with peak tricuspid regurgitation flow velocity gives an accurate
figure for peak pulmonary pressure.
This figure offers good correlation with systolic pressure at the pulmonary artery.
However, it is known that RV systolic pressure can be underestimated in patients
whose tricuspid regurgitation velocity is reduced.
catheterization is considered the gold standard for the diagnosis of PH and for
Practically all patients with PH should undergo right cardiac catheterization
for the measurement of PAP (mean, systolic and diastolic), pulmonary capillary
wedge pressure, cardiac output and oxygen saturation and to calculate pulmonary
vascular resistance (PVR) and shunts. Pulmonary vascular resistance, cardiac output,
and central venous saturation are the most important prognostic parameters in
Is examination to evaluate pulmonary vascular response to vasodilators:
a fall in PAP to below 40 mmHg, a drop of more than 20 mmHg, or of more than 20%
of baseline. All are considered as a positive hemodynamic response (response test).
severity of PH is classified as mild (PmAP from 25 to 40 mmHg), moderate
(PmAP from 41 to 55 mmHg) or severe (PmAP > 55 mmHg).
cases of PH secondary to heart disease or chronic lung disease are generally related
to mild to moderate increases in pulmonary pressure. Patients with severe PH are
generally suffering from PPH, connective tissue disease, or chronic thromboembolism.
patients with mild (25-40 mmHg) to moderate PH (41-55 mmHg), secondary to chronic
hypoxemia, pulmonary pathologies or collagen disorders, can be monitored serially
with echocardiograms (every 3 to 6 months) and cardiac catheterization can be
reserved for those cases that pass functional class III on the New York Heart
Association (NYHA) scale.
is particularly indicated to rule out congenital heart disease, occult shunts
and stenosis of the distal pulmonary artery.
The risk-benefit ratio should
always be taken into account when indicating cardiac catheterization for pediatric
patients with. Figure 1 is a diagnostic assessment flow diagram for patients with
Figure 1 -
diagram for diagnostic assessment of pulmonary hypertension
date, there is no cure, or even a therapeutic approach that can be recommended
in a universal manner for all PH patients. However, recent advances in the physiopathogenesis
of PH and the emergence of new pharmaceuticals, with selective vasodilatory effects
on the pulmonary vascular bed, contribute to improving these patients' survival.
investigative procedures are always indicated (before and after any treatment
that is instituted) for patients with PH, with the aim of fine-tuning treatment.
Pulmonary circulation is reduced in patients with PH.
Increased oxygen demand may aggravate PH and diastolic heart failure (DHF), therefore
physical activities are restricted (risk of effort syncope).
with PH have greater pulmonary vascular reactivity than do adults. Respiratory
infections should be treated and prevented (immunization for influenza and pneumococcus).
Emphasis should be given to contraception for patients at fertile ages (pregnancy
and delivery are contraindicated.)
indication of chronic anticoagulation in patients with ph is based on histopathological
studies and post-mortem findings obtained from adults.
Rational anticoagulation usage, with the aim of preventing secondary in situ
thrombosis, is only justified those patients with documented right ventricular
failure and low pulmonary flow (DHF). No indication for chronic anticoagulation
has yet been established for pediatric patients with PH (considering risks/benefits/safety/efficacy.)
In severe cases of DHF, in analogy with adults, anticoagulation is recommended
with warfarin or heparin. Neither aspirin nor dipyridamole are indicated because
their efficacy has not been confirmed in low-flow zones, where the risk of thrombosis
in situ is elevated.
efficacy of pulmonary vasodilator therapy has been limited by the absence of selectivity
and potency. The majority of drugs considered pulmonary vasodilators also have
systemic vasodilator action and their effect on pulmonary circulation is not so
marked. Therefore the apparent benefits may be secondary to reduced preload and
reduced RV work.
channel blockers, digitalis and diuretics have limited indications in pediatric
patients with ph, since the efficacy of these medications has not been confirmed.
Patients with PH accompanied by signs of DHF, with hepatic and systemic congestion,
should obtain some benefit from reduced afterload and a certain inotropic effect,
but great care must be taken because of the risk of concomitant preload reduction,
which would worsen cardiac output.
In adults, less than 20% of patients exhibited a response to chronic calcium channel
blocker s (nifedipine, amlodipine), when assessed with exercise and hemodynamic
testing and according to clinical symptomology.
Among patients who respond to this treatment, less than 7% maintained the beneficial
effect over the long term.
Potential associated side effects are: hypotension, pulmonary edema, RV failure
and risk of death.
use of calcium channel blockers, diuretics and digitalis has not been recommended
as routine in children with PH.
notwithstanding, during exacerbations and crises, it may be necessary to provide
intravenous inotropic support.
Oxygen therapy is recommended for patients
with PH secondary to parenchymatous pulmonary disease. Patients with Eisenmenger
syndrome or PPH do not appear to benefit from this treatment, although nocturnal
oxygen therapy may delay progression of polycythemia in those who have Eisenmenger
Children who exhibit reduced oxygen saturation during the night (in the absence
obstructive disease or apnea) may benefit from the administration of nocturnal
oxygen. During these episodes patients may present with severe crises of dyspnea
and syncope, with or without convulsive hypoxemic crises.
Continuous oxygen may be indicated for children with severe DHF, with hypoxemia
during sleep, and markedly elevated oxygen extraction.
therapy is recommended for patients who will travel by air or have symptomatic
respiratory infections, because of the risk of triggering PH crises.
oxygen therapy is indicated, the objective is to maintain oxygen saturation above
90% (except in those patients who have cyanotic congenital heart disease).
use of prostacyclins (epoprostenol) or prostacyclin analogues for PH treatment
is based on a "imbalance" between thromboxane and prostacyclin metabolites.
induce relaxation of the respiratory vascular musculature, stimulating production
of cyclic adenosine monophosphate (AMP), and inhibit respiratory muscle cell growth
and platelet aggregation.
1996, Barst conducted an open, prospective and randomized study with 81 patients
with P H and NYHA functional class III or IV. Patients were randomized to receive
either conservative treatment in isolation (anticoagulants, diuretics, oral vasodilators
and oxygen), or conventional therapy in combination with continuous intravenous
epoprostenol. After 12 weeks of treatment, the group given epoprostenol showed
improvements in the walking test, reduction in PmAP and PVR, with no deaths. The
group treated with conventional therapy exhibited deterioration in all of these
criteria and eight patients died.
based on the results of this study prostacyclins were approved for the treatment
of patients with (Europe and North America). Although prostacyclins are vasodilators,
it appears that the chronic benefits from their use are associated with an antiproliferative
property. Used with patients with advanced disease (absence of pulmonary vascular
reactivity) confirmed a "rescue" effect on the pulmonary vascular endothelium
restoring normal function.
is administered intravenously and appears to be effective with patients at functional
classes II to IV, with a 6 minute walking test ? 330 m.
Several different follow-up studies of patients with PPH have demonstrated significantly
improved prognosis (5-year survival of 55-28%) in those patients who exhibited
improvements in NYHA functional class and the walking test after 3 months of treatment.
In those patients who did not demonstrate improvement after 3 months of treatment
(1/3 of the patients), prognosis was equal to that of the controls.
drug has demonstrated good results in children with severe PH associated with
congenital heart disease;
patients with PH associated with HIV infection and portal hypertension. However,
it does not appear to influence the mortality of patients with PH secondary to
administration of prostacyclins is complex, because it requires a "fully
implantable" intravenous catheter for continuous infusion. Dosage is variable,
between 21±7 ng/kg/min during the first year and 32±10 ng/kg/min
after 41 months.
Several adverse effects have been reported: maxillary pain, headaches, diarrhea,
nausea, leg pains, rubor and complications associated with the infusion system
(risk of severe infections and sepsis: 0.1 to 0.6 case/patient/year).
offering proven functional improvement for patients, epoprostenol is far from
being considered an ideal treatment. In addition to its inaccessible price, administration
is complicated and it is associated with several adverse effects.
is a prostacyclin analogue that can be given in continuous subcutaneous (or intravenous)
infusion. It was developed to avoid the complications resulting from intravenous
catheters. In a randomized and controlled study involving 470 patients with PH
of varying etiology, there were improvements in walking test results and in clinical
symptomology (although not so evident as with intravenous prostacyclin).
Teprostinil has been approved in the USA for use with adults with PH since 2002,
but, because of effects associated with pain resulting from infusion, it is contraindicated
for pediatric use.
is an inhaled prostacyclin analogue. Its particle size (0.5 to 3.0 µm) guarantees
it pulmonary selectivity and improved tolerance.
However, its short half-life (45 minutes) demands frequent administrations (6
to 12 times per day).
A randomized, multicenter study carried out in Europe and involving 207 patients
with PH of varying etiology, assessed response after 12 weeks of treatment with
iloprost, in terms of walking test improvements and NYHA functional class. Against
these criteria, treated patients exhibited improvements in relation to placebo.
The adverse symptoms presented are: coughing and those effect resulting from the
drug's vasodilator effect.
There are no studies that have evaluated its
effects over the long term, and clinical experience with children is still extremely
Inhaled iloprost is licensed for use in Europe and the USA. The dose varies depending
upon the response of each patient. It is administered via a special nebulizer,
and the maximum daily dose is 45 mcg. A small proportion of patients appear to
respond in isolation.
oral prostacyclin analogue (beraprost) has around 50% of the effect of epoprostenol,
with a longer half-life. Its hemodynamic effects over the long term (over 6 months)
have not yet been fully confirmed.
This drug is not yet approved for pediatric use.
In patients with PH, endothelin-1(A) levels
are elevated in plasma, and are inversely correlated with prognosis.
It is known that endothelin-1 is a powerful vasoconstrictor, being involved in
the pathogenesis of PH.
Bosentan is an oral endothelin receptor antagonist. This drug has a discretely
greater affinity for ETa, and its pharmacological action is by means
of vasoconstriction inhibition and the action of mitogenesis and remodeling (activated
by endothelin-1 in pulmonary arteries).
performed a placebo-controlled clinical trial of bosentan with 33 adult patients,
demonstrating improvements in PH functional class (NYHA/WHO) and walking test
Later, Rubin et al., in a similar experiment, with a larger number of patients
(n = 213) (n = 213), demonstrated improvement in functional class is and walking
test and increase in disease progression-free survival (period with no need for
transplantation, atrial septostomy, continuous hospital care or death).
Galiè et al., assessed adult patients treated with bosentan by echocardiogram,
finding increased cardiac index, RV systolic function, and initial diastolic filling
of the left ventricle (LV), leading to a reduction in RV dilatation LV size.
should not be used during pregnancy because of the potential for teratogenesis
(animal experiments). Serial liver function tests should be carried out, because
of the risk of hepatotoxicity in 6% of patients (dose-dependent effect).
for use with adult PH patients was granted in 2001 in the USA, and in 2002 in
More recently, the drug was licensed for use in Brazil (2005).
Data on bosentan
in the pediatric population are limited. Barst et al. performed an open, uncontrolled
study involving 19 patients originally treated at two centers (New York and Colorado).
These patients had functional class II or III and weighed more than 10 kg. A 13%
reduction in PmAP was observed. However, no changes were observed in walking test
results or functional class. Apparently, the pharmacokinetic and hemodynamic effects
of bosentan were similar to those observed ion adult patients. The Food and Drug
Administration (FDA) approved the drug for use with children over 12 years or
with weight > 40 kg on the basis of this study.
et al. performed a retrospective study involving 86 children with PH of varying
etiology. They were given long-term bosentan (14 months), in isolation or concurrently
with prostacyclins. The children were evaluated in terms of hemodynamic variables
and functional class (WHO classification). There were reductions in PmAP (64±3
mmHg to 57±3 mmHg) and PVR (20±2U xm² to 15±2U xm²),
and improvements in functional class in 46% of the patients.
suggested dose is 62.5 mg (twice a day for the first month), followed by progressive
increases until the ideal dose of 125 mg is reached (twice a day), making a total
daily dose of 250 mg.
selective ETa inhibitors, such as sitaxsentan and ambrisentan, are
under investigation for use in PH. These drugs' action is based on a blockade
of the vasoconstrictor effect of ETa receptors, while maintaining vasodilation
and clearance of ETb receptors. The risk of hepatotoxicity is similar
to with bosentan, and so far no license has been granted in the USA.
Nitric oxide is an inhaled vasodilator with a selective action
on pulmonary circulation. It activates the guanylyl-cyclase enzyme in pulmonary
smooth muscle vascularization, which increases cyclic guanine monophosphate (GMPc)
and reduces intracellular calcium concentration, resulting in vasodilation.
Administered by inhalation, NO rapidly binds to hemoglobin in pulmonary capillaries,
inactivating it. This makes it a selective pulmonary vasodilator, capable of attenuating
the pulmonary vasoconstriction induced by hypoxia or other vasoconstriction agonists,
without producing significant systemic vasodilation. It is not yet known whether
NO has antiproliferative properties in the pulmonary vascular bed.
use of NO for persistent PH in the neonate
and for the management of congenital heart disease (especially during the immediate
are well-established. Prophylactic use for patients with risk of PH during post-op
for correction of congenital heart disease is controversial.
Similarly, chronic NO use for PH treatment also requires further investigation.
There are reports of tachyphylaxia, in addition to difficulties related with administration
logistics and elevated cost.
same benefits have been reported from NO (antiproliferative and/or platelet antiaggregants)
as are offered by chronic epoprostenol use;
although so far without adequate foundation.
oxide has been used to assess pulmonary vascular reactivity and its in a hemodynamic
study by cardiac catheterization.
Unfortunately, the elevated cost of NO (approximately US$ 100.00/h)
has restricted its use at some centers. Currently, many Latin American
countries no longer make NO routinely available and, even in European
countries, attempts have been made to employ the gas more selectively.
European consensus recommendation is to start at 20 ppm and observe the response
for 10 min. Sequentially increase to 40 ppm and observe the response over a short
period of time, around 30 min (no more than 2 hours). The response criteria are
a reduction in PAP and/or at least a 20% improvement in oxygenation saturation
over baseline. Patients who do not respond to 40 ppm will probably not respond
to 80 ppm either. As soon as a response is observed and the patient stabilized,
it is recommended that NO be reduced to 10 to 5 ppm.
Nitric oxide is a powerful, short-acting pulmonary vasodilator.
Within the smooth muscle it activates the guanylyl-cyclase enzyme, which generates
GMPc, which in turn relaxes smooth muscle. Phosphodiesterase (PDE) is responsible
for degrading GMPc.
Sildenafil is a potent and selective PDE type 5 inhibitor,
better known for its clinical indication to correct male erectile dysfunction.
In addition to its wide distribution across the corpora cavernosa, it also reaches
high concentrations within the pulmonary vascular smooth muscle, the trachea and
appear to accrue added benefits when used together with NO. In this situation,
abrupt withdrawal of the gas can precipitate a sudden elevation in PAP.
The first cases of the clinical application of sildenafil to PH treatment were
conducted by Atz et al., who reported on three patients with diagnoses of total
anomalous pulmonary venous drainage (TAPVD) presenting with PH during the immediate
postoperative period. These patients were effectively controlled with ON, but
presented problems for gas withdrawal. For all three patients (two infants and
a neonate), GMPc assays were performed and, after oral sildenafil was given, levels
rose significantly, allowing the gas to be withdrawn definitively.
reports of the treatment of two adult patients and one child suffering from PH
provided evidence of improved capacity to perform exercise and improved quality
of life, with no evidence of adverse effects associated with the drug.
from the case reports, studies emerged employing animal PH models (induced with
monocrotaline, thromboxane, or by hypoxia). These studies proved capable of demonstrating
improvements in hemodynamic variables, with concomitant elevation of plasma GMPc
levels. These studies also attempted to define the appropriate dose by patient
weight for adults (using three comparative doses), which proved useful for estimation
of the pediatric dose.
study carried out by Kleinsasser et al., with normal pigs (free of PH), assessed
hemodynamic and gaseous exchange parameters with three progressive doses of sildenafil.
The authors demonstrated that the reduction in PVR is dose-dependent and makes
ventilation/perfusion more heterogeneous (with increased R-L intrapulmonary shunt)
and can lead to reduced arterial oxygen saturation. This effect was not observed
with low doses, but at intermediate and high dosages.
consensus of specialists agreed on the use of sildenafil with patients suffering
from cardiovascular disease in 1999. They reported it as safe as a result of its
PDE5 selectivity (in preference to PDE3), without causing significant inotropic
studies of the pharmokinetics of sildenafil, carried out with healthy volunteers,
demonstrated good enteral absorption (peak plasma levels 30-120 minutes after
administration), with a half-life of 4 h.
Patients using nitrates concurrently may present hypotension.
In terms of its presentation for clinical use, it is available in inhaled, oral
and intravenous formulations.
is no information on interactions with other PDE
inhibitors (milrinone, amrinone, enoximone or vesnarinone). Similarly, there is
no information on its use in association with platelet antiaggregants (dipyridamole,
clopidogrel or ticlopidine). No pharmacokinetic interactions were observed when
sildenafil was given in association with acetylsalicylic acid,.
medical literature contains few controlled clinical trials assessing the efficacy
and safety of sildenafil (oral, inhaled or intravenous) for PH, in comparison
with other pulmonary vasodilators (NO, prostacyclins and bosentan). Some studies
carried out with experimental models of PH have been published.
relation to the pediatric population, there are only case reports that demonstrate
possible clinical benefits from the use of sildenafil for PH.
A recent systematic literature review by Cochrane, drawing on material from several
databases (MEDLINE, EMBASE and CINAHL), selected just four controlled clinical
trials, involving 77 patients (adults and children). Two of these studies assessed
the acute effects of sildenafil, while the other two assessed effects over the
Many questions therefore remain about the true efficacy of sildenafil for the
treatment (chronic and acute) of patients with PH, and it is still necessary to
define dosage, intervals and safety for pediatric patients.
Wilkens et al.
studied five patients with PPH, comparing the prescription of inhaled prostacyclin
in isolation (iloprost) with oral sildenafil and with both drugs in combination.
They observed acute reductions in PmAP in all groups, with the least response
being to sildenafil alone and the greatest to the combined treatment.
et al. assessed a group of 10 patients with PPH, comparing NO, iloprost and oral
sildenafil. Both drugs caused an acute reduction in PAP, a reduction in PVR and
an increase in cardiac output; iloprost provoked the best response (20% reduction
et al. assessed long term effects of sildenafil on 11 patients with PPH, with
clinical deterioration despite chronic prostacyclin use. These patients exhibited
improved walking tests, PH functional class and echocardiographic measurements
(reduced RV diameter and LV diastolic index).
et al., in an uncontrolled clinical trial, assessed the effects of sildenafil
prescribed in isolation, for 4 weeks, on 15 adults with PPH. The majority of these
patients (80%) exhibited improved functional class, Borg dyspnea index, walking
test and PAP (evaluated by echocardiography). Therapeutic failure was observed
in 20% of the patients, even when the drug dose was increased.
recently, two new clinical trials were performed with adult populations. They
compared sildenafil with oral prostacyclin (beraprost) and intravenous prostacyclin
(epoprostenol). Kataoka et al. assessed the long-term effects on 20 adult patients
with PPH refractory to treatment with epoprostenol. They observed improvement
in hemodynamic variables (PVR, PAP and RA diameter), tolerance of exercise and
Ikeda et al. assessed, acutely, six adult patients with PH of varying etiology
by means of hemodynamic studies. They observed reductions in PAP and PVR, with
the change being greatest when sildenafil was combined with beraprost.
et al., in a retrospective study, reported on eight adult patients with PH (heart
surgery post-op) who were given oral sildenafil as an adjuvant therapy when weaning
them from other pulmonary vasodilators (sodium nitroprusside, nitroglycerine and
NO). They observed PAP reduce (a fall of 20% from baseline), allowing sequential
weaning from all the other drugs after the first dose of sildenafil.
largest patient sample used to assess the effects of sildenafil on pediatric patients
was reported on by Schulze-Neick et al. The sample comprised 24 children with
PH secondary to congenital heart disease. This study, controlled with inhaled
NO, assessed 12 children by cardiac catheterization and 12 by hemodynamic monitoring
during the immediate postoperative period. Intravenous sildenafil was more effective
for reducing PVR than was ON. It caused am increase in GMPc 2 to 2.4 times greater
than with NO in isolation. The selective pulmonary vasodilator effect of sildenafil
with associated with increased intrapulmonary shunt, which was not clinically
significant in this study, but which could represent an undesirable effect if
we consider patients in the postoperative period of congenital heart disease surgery.
Brazil, Bentlin et al. reported on the use of sildenafil with a neonate in the
immediate postoperative period of heart surgery. The patient exhibited good tolerance
and response, despite not having responded to inhaled NO previously.
arte few adverse effects described in pediatric patients: penile pain and erections
were observed in normal patients after accidental consumption of elevated doses
of sildenafil (5 mg/kg).
In a neonatal study, Marsh suggested that retinopathy of prematurity may be exacerbated
after sildenafil use. This report, however, involved an extremely premature patient,
using oxygen at high concentrations and for a prolonged period, which, by themselves,
would already explain this occurrence.
recent study carried out by our research team, involving 26 pediatric patients
with PH (varying etiology), demonstrated an acute reduction in PmAP of 20% of
baseline. Patients were divided into two groups: one assessed echocardiographically
and the other hemodynamically by invasive monitoring during the postoperative
period of heart surgery. This reduction was accompanied by a reduction in central
venous pressure (CVP), elevation in oxygen saturation and reduction in heart rate,
with those patients with postoperative PH tending to elevated PAM. The group assessed
by echocardiogram was placebo-controlled and also exhibited reduced PAP, with
no repercussions on other variables.
true role of this drug for patients with PH has not yet been established, but
it appears to be a useful alternative for weaning from NO and during acute PH
The combined use of drugs
which have different sites of action appears to be promising for PH treatment.
Adjuvant use of bosentan and sildenafil with patients already on prostacyclin
(oral, inhaled or intravenous) improved the variables under analysis.
Further studies are needed to determine the true combined effects of these drugs,
particularly in the pediatric population.
Surgical options (and transplantation)
with frequent syncope and DHF have poor prognosis. Effort-induced syncope occurs
because of an inability to increase cardiac output to maintain cerebral blood
flow. A patent foramen ovale is capable of increasing these patients' survival.
Systemic arterial oxygen saturation declines, but cardiac output and oxygen supply
to tissues improve, through the shunt. Despite experience with more than 100 patients
with atrial septostomies for PH, the procedure is still considered investigative.
or just pulmonary (unilateral or bilateral) transplantation has been indicated
for patients with PH since 1981. Currently, combined transplantation is only indicated
in cases of anatomical cardiac defects, with no possibility of surgical correction,
since morbidity and mortality are higher. Overall surgical mortality for lung
transplantation is 16 to 29%. Pediatric data from the International Society for
Heart and Lung Transplantation demonstrate 2-year survival of 65% and 5-year survival
is not the perfect treatment for PH, being linked with greater post-transplantation
morbidity and mortality than among those patients whose indication is a different
disease. Currently, transplantation is recommended for a specific group of patients,
who do not respond to vasodilatador therapy, or who exhibit clinical/hemodynamic
deterioration during vasodilator therapy (isolated or combined drug use).
management of PH is a challenge, even to more experienced clinicians. Recent advances
in understanding the pathophysiologic mechanisms involved indicate that there
are differences in disease presentation in the pediatric population. New drugs
have emerged and opened up fresh prospects for medium and long-term prognosis.
2 is our suggestion for the therapeutic management of patients with PH in the
form of a flow-diagram.
Figure 2 -
diagram of current treatment for pulmonary hypertension