Humana 2010 The Management of Acute Pulmonary Arterial Hypertension PDF

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The Management of Acute Pulmonary Arterial Hypertension

Gan Hui-li
Cardiac Surgery Department, Beijing Anzhen Hospital, Capital Medical University (BAZHCMU), Beijing Institute of Heart, Lung, and Blood Vessel
Disease, Beijing 100029, China
Keywords
Pulmonary arterial hypertension (PAH); Right
heart failure.
Correspondence
Dr. Gan Hui-li, Cardiac Surgery Department,
Beijing Anzhen Hospital, Capital Medical
University (BAZHCMU), Beijing Institute of
Heart, Lung, and Blood Vessel Disease,
Beijing 100029, China.
Tel.: 86-10-64456885;
Fax: 86-10-62244207;
E-mail: ganhuili@hotmail.com
doi: 10.1111/j.1755-5922.2009.00095.x
Acute pulmonary arterial hypertension (PAH), which may complicate the
course of many complex disorders, is always underdiagnosed and its treat-
ment frequently begins only after serious complications have developed. Acute
PAH is distinctive because they differ in their clinical presentation, diagnostic
ndings, and response to treatment from chronic PAH. The acute PAH may
take either the form of acute onset of chronic PAH or acute PAH or surgery-
related PAH. Signicant pathophysiologic differences existed between acute
and chronic PAH. Therapy of acute PAH should generally be aimed at acutely
relieving right ventricular (RV) pressure overload and preventing RV dysfunc-
tion. There are three classes of drugs targeting the correction of abnormalities
in endothelial dysfunction, which have been approved recently for the treat-
ment of PAH: (1) prostanoids; (2) endothelin receptor antagonists; and (3)
phosphodiesterase-5 inhibitors. The efcacy and safety of these compounds
have been conrmed in uncontrolled studies in patients with PAH. Intra-
venous epoprostenol is suggested to serve as the rst-line treatment for the
most severe patients. In the other situations, the rst-line therapy may include
bosentan, sildenal, or a prostacyclin analogue. Recent advances in the man-
agement of PAH have markedly improved prognosis.
Pulmonary arterial hypertension (PAH) is a progressive,
symptomatic, and ultimately fatal disorder for which sub-
stantial advances in treatment have been made during
the past decade [1]. Despite advances in the manage-
ment of PAH, the mortality rate remains excessive. Acute
PAH, which may lead to refractory systemic arterial hy-
potension, severe hypoxemia, right ventricular (RV) dys-
function and failure, and ultimately result in cardiogenic
and/or obstructive shock and death have always been ne-
glected until serious complications have developed. Ef-
fective management requires timely recognition and ac-
curate diagnosis of the disorder and appropriate selection
among therapeutic alternatives. Despite progress in treat-
ment, obstacles remain that impede the achievement of
optimal outcomes [2]. The pathophysiology, monitoring,
and management of the acute pulmonary hypertension
are reviewed in this article to highlight the importance
and due management of it. The article also reviews es-
tablished approaches to evaluation and treatment, with
emphasis on the appropriate application of calcium chan-
nel blockers (CCBs), prostacyclin analogues, endothe-
lin receptor antagonists (ETRAs), and phosphodiesterase
5 inhibitors.
Pathophysiology and Pathogenesis
of Acute PAH
PAH is characterized by elevated pulmonary arterial pres-
sure (PAP) and secondary RV failure. The denition of
PAH used in clinical trials has been a mean pulmonary ar-
terial pressure (mPAP) >25 mmHg at rest or >30 mmHg
with exercise, a pulmonary capillary wedge pressure
(PCWP) of <15 mmHg, and a pulmonary vascular resis-
tance (PVR) of >3 Wood units, which has been attributed
to the criteria for idiopathic PAH established by the Na-
tional Institutes of Health Registry on Primary Pulmonary
Hypertension (PPH) [3,4]. It is considered to be severe
if mPAP >50 mmHg; of moderate severity, if mPAP 30
50 mmHg or mild, if mPAP <30 mmHg. Right heart
failure is the most important consequence of PAH and
remains a frequent cause of death in patients with PAH.
Increased RV afterload leads to RV dilatation in most
Cardiovascular Therapeutics 29 (2011) 153175 c 2010 Blackwell Publishing Ltd 153
The Management of Acute Pulmonary Hypertension G. Hui-li
acute cases of PAH when there is not enough time for
adaptive mechanisms (e.g., RV hypertrophy) to develop.
Thus, RV dilatation or RV hypertrophy are the main fea-
tures of the acute and chronic PAH, respectively.
The mechanisms of arterial PAH include vascu-
lar thromboembolism, endothelial dysfunction, hy-
poxic vasoconstriction, pulmonary vascular remodeling,
smooth muscle proliferation with or without neointimal
formation, and in situ thrombosis [4]. Endothelial dys-
function with an imbalance between vasodilation and
vasoconstriction, and between apoptosis and prolifera-
tion is thought to play a pivotal role in the develop-
ment of chronic progressive PAH. Hypoxemic pulmonary
vasoconstriction is an important determinant of arterial
PAH in patients with respiratory disorders [4]. In many
types of PAH, production of endogenous vasodilators (ni-
tric oxide [NO] and prostacyclin) is impaired and produc-
tion of vasoconstrictors [5] (endothelin-1) is increased
[4]. This forms the pathophysiologic basis of common
treatment strategies for arterial PAH, which attempt to
achieve balance in key molecular pathways by increasing
available NO and prostacyclin, or reducing the effects of
endothelin-1.
Acute arterial PAH is characterized by a sudden in-
crease in PAP. Mechanical obstruction with subsequent
vasoconstriction characterizes acute PAH in pulmonary
embolism (PE). In acute lung injury (ALI)/acute res-
piratory distress syndrome (ARDS), both hypoxic pul-
monary vasoconstriction and accumulation of intravas-
cular brin and cellular debris contribute to subsequent
vascular obliteration and PAH [6]. Endotoxin plays a sig-
nicant role in the development of PAH during sepsis.
Multiple animal studies have shown that endotoxin can
cause not only systemic hypotension, but also pulmonary
biphasic hypertension, along with a decrease in compli-
ance and an increase in resistance of respiratory system
[7]. Endotoxin-dependent hemodynamic and respiratory
effects are mediated by excessive release of inamma-
tory mediators and imbalances in production of NO,
prostanoids, and endothelin-1 (ET-1) [8]. PAH in endo-
toxemia is characterized by constriction of proximal pul-
monary arteries during the early phase followed by de-
creased compliance of the distal pulmonary vasculature
[9].
Neurohormonal activation is an important factor in
both acute and chronic RV failure. The consequence of
sympathetic hyperactivity is an increase in PVR with
impedance of ow, causing RV strain that impairs lling
and causes RV volume and pressure overload. The RV di-
lates (and eventually hypertrophy can develop in chronic
gradual pulmonary hypertension), encroaching on the
left ventricle and decreasing preload, cardiac output, and
coronary perfusion. Increased RV wall stress results in RV
ischemia [10]. Tricuspid regurgitation develops as a result
of RV dysfunction and portends a poor prognosis [11].
RV systolic dysfunction, severe tricuspid regurgitation,
arrhythmias, and left ventricular dysfunction caused by
ventricular interdependence may contribute to low car-
diac output and hypotension in patients with pulmonary
hypertension. Regardless of the underlying cause of PAH,
the nal common pathway for hemodynamic deteriora-
tion and death is cor pulmonale and RV failure. Among
other clinically important adverse effects of right heart
failure is the development of systemic venous hyperten-
sion leading to concomitant visceral organ congestion and
dysfunction such as renal function impairment. The nor-
mal RV can acutely adapt to high ow, but is not able
to tolerate any but very short acute high pressure load
[12]. The normal RV cannot acutely increase and sustain
mean PAP >40 mmHg for more than a brief period of
time [13].
The Causes of Arterial Pulmonary
Hypertension
Multifactorial impairment of the physiologic balance can
lead to vasoconstriction, vascular smooth muscle cell and
endothelial cell proliferation/brosis, inammation, re-
modeling, and in situ thrombosis. These are the likely
mechanisms that lead to narrowing of the vessel followed
by progressive increase in PVR and the clinical manifes-
tations of PAH. The etiology of acute PAH is different
from what of chronic (or persistent) PAH, but the patho-
genesis of acute PAH is the same as of chronic (or per-
sistent) PAH, which also includes endothelial injury in
the pulmonary arterioles, vasoconstriction caused by re-
duced production of endogenous NO by the pulmonary
endothelium, and thrombosis [14]. Subsequently, major
goal of the therapy is to avoid acute pulmonary vasocon-
striction, halt the progression of vascular remodeling, and
reverse the early vascular remodeling if possible.
Almost all diseases manifested as PAH can cause right
heart failure: either as an acute condition, if the PAH de-
velops acutely (as with sepsis/acute lung injury (ALI),
PE, cardiac surgery, drug induced, etc.), or as a chronic
condition, if arterial pulmonary hypertension is mainly
chronic (as in chronic obstructive pulmonary disease
(COPD), interstitial lung disease , sleep disorder breath-
ing, chronic hypoventilation, PAH, chronic thromboem-
bolic pulmonary hypertension(CTEPH), portopulmonary
hypertension, etc.). PAH associated with various noncar-
diac etiological diseases (connective-tissue diseases, por-
tal hypertension, HIV infection, consumption of anorectic
agents) account for approximately 50% of cases of PAH.
154 Cardiovascular Therapeutics 29 (2011) 153175 c 2010 Blackwell Publishing Ltd
G. Hui-li The Management of Acute Pulmonary Hypertension
The acute PAH may take either the form of acute onset of
chronic PAH or acute PAH or surgery-related PAH.
Acute Onset of Chronic Arterial PAH
Patients with preexisting PAH are particularly vulnerable
to acute illnesses, which commonly result in rapid dete-
rioration and even death [15]. Besides idiopathic PAH,
interstitial lung diseases, COPD, chronic hypoventilation
and sleep disorder breathing, portopulmonary hyperten-
sion and chronic pulmonary thromboembolism are al-
ways accompany with chronic arterial PAH. On the ba-
sis of above-mentioned morbidities, multiple noncardiac
predisposing factors can precipitate acute PAH onset and
right heart failure, even leading to adverse outcome.
These predisposing factors belong to several categories.
In the pulmonary category, there are chronic hypoxia,
and restrictive lung disease (with or w/o COPD), and de-
creased DLCO, and decreased pulmonary compensatory
capacity. In the infection category, these are using of im-
munosuppressive, and disease modifying drugs for un-
derlying disease, and malnutrition and overall decreased
functional reserve. Patients with chronic PAH can rapidly
deteriorate and usually die from progressive RV failure
(49%), progressive respiratory failure (18%), or sudden
cardiac death (17%).
Acute PAH
Massive PE, sepsis, and ALI are the main causes of acute
arterial PAH in the adult patient population [16]. The on-
set of acute right heart failure as a complication of ALI
and its more severe form ARDS is more gradual than in
patients with massive PE. It usually occurs at least 48 h
after the beginning of respiratory support [15]. Evalua-
tion of RV function by transesophageal echocardiography
(TEE) in a group of 75 ARDS patients submitted to pro-
tective ventilation demonstrated 25% incidence of acute
RV dysfuncion, with detrimental hemodynamic conse-
quences associated with tachycardia. However, those
changes in heart function were reversible in patients who
recovered and did not increase mortality [15]. Although
the initial magnitude of pulmonary hypertension was not
an indicator of mortality, PAP further increased in non-
survivors, but not in survivors when followed for 7 days
[17]. Thus, development of PAH in ARDS patients seems
to be a sign of poor prognosis. In a cohort of 352 ARDS
patients, both mortality rate and incidence of right heart
failure were related to the level of plateau pressure during
mechanical ventilation. An interaction between plateau
pressure and right heart failure was observed whereas
odds ratio of dying for an increase in plateau pressure
(from 1826 to 2735 cm H
2
O) in patients without right
heart failure was 1.05 (P = 0.635), in contrast to odds
ratio of 3.32 (P < 0.034) in patients with right heart fail-
ure [18]. The implementation of low tidal volume ven-
tilation in patients with ARDS has signicantly lowered
not only mortality (down to 32%), but also incidence of
acute right heart failure in this patient population [15].
In addition to being the major risk factor for ARDS devel-
opment, sepsis itself can sometimes lead to severe acute
arterial pulmonary hypertension [19].
In massive acute pulmonary embolism (APE), the in-
crease of PVR depends on the thrombosis load and poten-
tially on the pulmonary bed contraction caused by neu-
rohormonal reaction. Plasma endothelin concentrations
assessed on admission are not elevated in patients with
APE and it does not play as important role in acute phase
of increase of pressure in pulmonary arteries as in chronic
pulmonary hypertension [20].
Development of ALI in the critically ill is associated
with an array of abnormal interactions between the heart
and lungs. Of these abnormalities, increased PVR is com-
mon and seems to indicate a worse prognosis than when
PVR is normal. Increased pulmonary artery pressure,
which follows ALI in humans, has been attributed to
many factors. Early in ALI, PAH is secondary to an imbal-
ance between the release of vasoactive mediators derived
from arachidonic acid, endothelium-derived relaxing fac-
tor, and other metabolites. As ALI progresses, the com-
bination of mechanical obstruction and severe regional
hypoxic pulmonary artery vasoconstriction probably be-
comes the main factor responsible for PAH. In addition
to these elements, in situ and peripherally derived throm-
boembolism can be seen in ALI, owing to diverse distur-
bances in the coagulation and brinolytic processes. The
result is increased workload of the right ventricle, which
is caused by increased afterload and may induce hemo-
dynamic disturbances that culminate in overt RV failure.
However, epidemiologic studies have demonstrated that
death following ALI is more often the result of respira-
tory failure or sepsis. The absence of effective therapy
for PAH in ALI might be explained by the pathophysi-
ological and clinical course of the disease. A reasonable
conclusion from the contributing elements cited above
is that PAH complicating sepsis and trauma is simply a
marker of the gravity of the systemic insult that leads
to the development of ALI and probably not a separate
process [21].
Acute pulmonary hypertension (PH) is a character-
istic feature of the ARDS. The magnitude of PH has
been shown to correlate with the severity of lung in-
jury in patients with ARDS independently of the severity
of associated hypoxemia and has an adverse prognostic
signicance. Early in the histopathological evolution of
ARDS, pulmonary vasoconstriction, thromboembolism,
and interstitial edema contribute to the development of
PH, although pulmonary vascular remodeling probably
occurs eventually [22]. Many patients with severe ALI
do not respond to NO inhalational therapy with allevi-
ation of PAH and hypoxemia, so this treatment remains
controversial [23].
During Gram-negative sepsis, endotoxin lipopolysac-
charide (LPS) may activate host-inammatory responses,
resulting in the systemic inammatory response syn-
drome and the adult respiratory distress syndrome. In
cell culture systems, LPS activation of cellular responses
may be potentiated by plasma proteins. In the isolated
perfused rabbit lung, LPS administration markedly in-
creases the pulmonary hypertensive response to subse-
quent administration of platelet-activating factor (PAF).
Components of plasmapossibly LPS binding protein,
and soluble CD14potentiate the priming effect of en-
dotoxin, resulting in an augmented pulmonary hyper-
tensive response to PAF. Thus, plasma proteins decrease
the threshold at which endotoxin primes the lung and
may have a critical role in the pathogenesis of endotoxin-
induced ALI [24]. ALI is a common complication of gram-
negative sepsis. Pulmonary hypertension and increased
lung vascular permeability are central features of lung in-
jury following experimental bacteremia. PAF is a promi-
nent proinammatory mediator during bacterial sepsis.
E. coli bacteremia rapidly induces pulmonary hyperten-
sion stimulated by PAF and mediated at least in part by
endothelin-1 and neutrophil activation and sequestration
in the lung. Microvascular injury with leak is also medi-
ated by PAF during E. coli bacteremia, but the time course
of resultant hypoxemia and hemoconcentration is slower
than that of pulmonary hypertension. The contribution
of hypoxic vasoconstriction in exacerbating pulmonary
hypertension in gram-negative sepsis is probably a late
phenomenon [25].
In sepsis-caused acute PAH, studies demonstrated that
the early acute rise in PAP is caused by thromboxane.
The late sustained pulmonary hypertension of endotox-
emia, on the other hand, appears to be mediated by
endothelin. BMS182874, an endothelin receptor antag-
onist, blocks the effects of exogenously administered en-
dothelins in chronically instrumented awake sheep. Pre-
treatment with BMS182874 signicantly attenuated the
early endotoxin-induced acute increase in PAP and com-
pletely blocked the late sustained pulmonary hyperten-
sion, while having no affect on the increases in throm-
boxane levels. BMS182874 shifts the dose response curve
for U46619, a prostaglandin H2 analogue, to the right.
BMS182874, in addition to functioning as an endothe-
liumreceptor antagonist, appears to counteract the action
of thromboxane at the receptor level [26].
Surgery or Intervention-Related PAH
Some surgical interventions, in particular vascular, car-
diac, and thoracic surgery may cause acute elevation of
PAP either during the surgery or shortly after the inter-
vention has been completed. This is particularly danger-
ous in patients with preexisting PAH, since even short
periods of RV pressure overload can lead to profound
decompensation with all negative hemodynamic conse-
quences. Preexisting PAH is one of the major risk fac-
tors for morbidity and mortality in cardiothoracic surgery
patients [27]. PAH is a major determinant of perioper-
ative morbidity and mortality in special situations such
as heart and lung transplantation, pneumonectomy, and
ventricular assist device placement [28]. It is believed
that an elevated PAP during and after surgery develops
secondary-to-acute left heart failure/dysfunction or can
be a consequence of pulmonary parenchymal and en-
dothelial injury with activation of the systemic and pul-
monary inammatory response to cardiopulmonary by-
pass (CPB) circulation and/or ischemia reperfusion [29].
Protamine-mediated acute PAH and RV failure in the pe-
rioperative period are common (1.78%) complications of
CPB circulation during open heart operations [30]. PAH
can also develop later as a result of ARDS [31] or other
complications (Sepsis, PE, etc.) not directly related to ei-
ther surgery or anesthesia. Intraoperative management
should include prevention of exacerbating factors such as
hypoxemia, hypercarbia, acidosis, hypothermia, hyperv-
olemia, and increased intrathoracic pressure; monitoring
and optimizing RV function; and treatment with selective
pulmonary vasodilators.
Patients with increased (PVR) may experience acute
pulmonary hypertension after heart transplantation. PAP
or a transpulmonary gradient (TPG) >12 mmHg, is an es-
tablished risk factor for mortality in heart transplantation.
An increased PVR or an increased TPG is a risk factor for
increased 3-day and 3-month mortality after heart trans-
plantation (HTx). The reversibility of increased PVR or
TPGunder pharmacologic testing is supposed to indicate a
decreased probability of RV failure/death after transplan-
tation. PAPs greater than 50 mmHg, PVR greater than
6 Woods units, and TPG greater than 15 mmHg that are
unresponsive to optimal vasodilators are contraindica-
tions to orthotopic heart transplantation. Therapies used
to reduce PVR in the cardiac catheterization laboratory
include high-ow oxygen; sublingual nitroglycerin; and
intravenous inotropic agents, vasodilators, and selective
pulmonary vasodilators. Systemic hypotension may be
an undesirable side effect of vasodilators. Inhaled agents
such as NO and prostacyclin are specic to the pulmonary
vasculature and reduce PVR without causing systemic hy-
potension. All pharmacological therapies used to optimize
pulmonary hemodynamics before transplantation can be
used during transplantation in patients who are at high
risk for acute RV failure and death after orthotopic heart
transplantation because of elevated pulmonary hemody-
namic values. Use of larger donor hearts for patients with
elevated PVR and referral for heartlung transplantation
are potential treatment options [32].
Acute PAH occurring after CPB can be a cause of
postoperative morbidity and mortality. Endogenous en-
dothelin is a mediator of acute pulmonary hyperten-
sion occurring after cardiopulmonary bypass. Bosentan,
a mixed endothelin antagonist completely prevented pul-
monary hypertension after CPB and may, therefore, have
therapeutic applications in the management of patients
following cardiac surgery [33]. Procedures using car-
diopulmonary bypass and aortic cross-clamping are as-
sociated with a variable degree of ischemia/reperfusion
of the lungs, leading to acute pulmonary hyperten-
sion (PHT). Pulmonary selectivity was demonstrated with
sildenal analog, because there were no similar changes
in systemic vascular resistance (SVR) and no signi-
cant changes in systemic hemodynamics. Sildenal ana-
log (UK343664), a PDE5 inhibitor, shows a promising
role for managing the PVR increases that occur following
CPB [34].
Absolute ethyl alcohol is used with increased frequency
in the treatment of conditions such as percutaneous ab-
lation of unresectable hepatic tumor, sclerotherapy of
esophageal varices, ventricular septal ablation, and intra-
venous embolization of arteriovenous malformation. The
postulated mechanism is severe pulmonary vasoconstric-
tion due to the sudden passage of absolute ethyl alco-
hol into pulmonary circulation, causing acute pulmonary
hypertention and RV strain. In patients at risk of sud-
den intravascular absorption of absolute ethyl alcohol,
an increased level of awareness for acute PAH, together
with prompt treatment of PAH with Sildenal analogue
or with a low dose of an NO-donor drug, will minimize
the resk of cardiovascular decompensation and may be
the treatment of such catastrophe [35].
Diagnosis and Monitoring of Patients
with Acute PAH
Effective management requires timely recognition and
accurate diagnosis of the disorder and appropriate selec-
tion among therapeutic alternatives. Since acute PAH are
a life-threatening disorder, elevated pressure and resis-
tance in the pulmonary vessels lead to progressive right
heart failure which results in functional limitations and
ultimately the death of most patients. Thus, the monitor-
ing of RV function is of great importance. The assessment
of PVR plays an important role in the diagnosis and man-
agement of PAH.
The broad availability of Doppler echocardiography has
helped with (earlier) detection of PAH. Doppler echocar-
diography has become a popular screening tool for the
diagnosis of PAH and in some clinical trials has been the
only measure of the severity of the PAH in response to
treatment [36]. Echocardiography is the initial investiga-
tion of choice for noninvasive detection of PAH but mea-
surement of PAP and cardiac output (CO) during right
heart catheterization is mandatory to conrm the diag-
nosis. So PAH is usually recognized when the patient de-
velops obvious signs of progressive RV failure, and during
hemodynamic monitoring by echocardiogram or a pul-
monary artery catheterization. In many cases, PAH re-
mains undiagnosed and its treatment begins only after
serious complications have developed. Timely assessment
of PAP, CO, and PVR with the help of pulmonary artery
catheterization and/or echocardiography is crucial for op-
timal management of patients with pulmonary hyperten-
sion.
One major disadvantage of the use of echocardio-
graphy as the diagnostic tool for evaluation of pul-
monary hemodynamics is the lack of adequate assess-
ment of transpulmonary blood ow and pulmonary
venous pressures. Therefore, right-sided heart catheter-
ization remains the current gold standard for diagno-
sis and vasoreactivity testing [37]. As the gold standard
for the diagnosis of pulmonary hypertension [38], pul-
monary artery (PA) catheterization could provide direct
measurement of the PAP. Besides direct measurement
of the pulmonary hemodynamic parameters, it also pro-
vides useful information regarding response to vasodila-
tor therapy. Analysis of mixed venous oxygen saturations
during passage of the PA catheter on its way through
the cardiac chambers can allow diagnosis of intracardiac
shunts. A PCWP measurement reects left ventricular
end-diastolic (lling) pressure. PCWP <15 mmHg rule
out left ventricular, valvular, and pulmonary venous dis-
eases as possible causes of the pulmonary hypertension
[25]. In critical care settings, PA catheterization and mon-
itoring is highly desirable in patients with severe PAH and
in patients with progressive heart failure [39]. It is impor-
tant to emphasize that the thresholds required for diag-
nosis of severe chronic PAH are incompatible with life in
patients with acute PAH and usually reect worsening of
preexisting chronic PAH.
Echocardiography is an important tool for diagnosing
and determining the degree and clinical signicance of
PAH in critically ill patients [4,14].
It can noninvasively visualize cardiac anatomy and
certain intracardiac shunts and valvular abnormalities,
estimate right atrial and PAP, determine the severity of
right and left ventricular dysfunction, wall motion abnor-
malities, and reveal other potential causes of PAH. In the
absence of pulmonary outow obstruction, pulmonary
artery systolic pressure is equivalent to RV systolic pres-
sure (RVSP), which can be calculated from measured
systolic regurgitant tricuspid ow velocity and estimated
right atrial pressure. Echocardiographic signs of signi-
cant PAH include RV dilation (D-shaped right ventricle)
and its hypertrophy (in sustained cases), septal dyskine-
sia, and bowing into the left ventricle during late sys-
tole to early diastole, RV hypokinesis, tricuspid regur-
gitation, right atrial enlargement, and a dilated inferior
vena cava [18,28,40]. Increased RV size combined with
increased outow resistance and reduced ejection frac-
tion have been also described in acute right heart fail-
ure [18]. A specic pattern of RV dysfunction in APE
has been characterized by a severe hypokinesia of the RV
mid-free wall, with normal contractions of the apical seg-
ment [41]. TTE results were poorly predictive of the risk
of death in patients who developed acute right heart fail-
ure [9]. However, denition of the acute right heart fail-
ure as RV end-diastolic area/left ventricular end-diastolic
area (RVEDA/LVEDA) ratio in the long axis greater than
0.6 associated with septal dyskinesia in the short axis
could be used to stratify the severity of the condition
[16,42]. TEE is more accurate and sensitive in critically
ill patients than TTE, especially in acute diseases such as
PE when acute pulmonary hypertension is highly sus-
pected [43,44]. Determination of pulmonary artery sys-
tolic pressure by Doppler echocardiography (based on the
pressure gradient between the right ventricle and right
atrium) or by right heart catheterization is useful in eval-
uating the severity and prognosis of cardiac disease [45].
PVR is an important hemodynamic variable in the man-
agement of patients with acute PAH. Doppler echocar-
diography could provide Doppler variables of time-
velocity integral of RV outow pulmonary artery ow
and peak tricuspid regurgitant pressure gradient (TRPG).
The TRPG/TVI ratio provides a reliable estimation of PVR
over a wide range in patients with PAH with various un-
derlying causes. [46] The noninvasive index of systolic
pulmonary arterial pressure (SPAP) to heart rate (HR)
times the RV outow tract time-velocity integral (TVI
[RVOT]) (SPAP/[HR TVI [RVOT]) provides clinically
useful estimations of PVR in PAH. The index of SPAP/
(HR TVI [RVOT]) provides useful estimations of PVRI
in patients with PAH [47].
Recent advances in magnetic resonance imaging (MRI)
technology have led to the development of techniques for
noninvasive assessment of cardiovascular structure and
function, including hemodynamic parameters in the pul-
monary circulation, which are superior in their identi-
cation of RV morphologic changes. These advantages
make cardiac MRI an attractive modality for following up
and providing prognoses in patients with PAH. Over the
coming decade, it can be anticipated that continued im-
provements in MRI image acquisition, spatial and tem-
poral resolution, and analytical techniques will result in
improved understanding of PAH pathophysiology, diag-
nosis, and prognostic variables, and will supplement, and
may even replace, some of the invasive procedures cur-
rently applied routinely to the evaluation of PAH [48].
Cardiac MRI has several advantages over other imaging
methods. The use of cine acquisition techniques allows
precise description of characteristic volumetric and func-
tional variables, such as RV volumes, muscle mass, stroke
volume, ejection fraction, or cardiac output. Impaired RV
contractility and function have also been assessed using
measures like ventricular septal bowing and pressure
volume loops. MRI investigations have been performed
to monitor medical treatment, and the improvement in
well-established prognostic factors, such as the 6-min
walk, were correlated with measures of RV function.
Flow-derived parameters of the pulmonary arteries (such
as peak velocity, acceleration time and volume, or pul-
monary owprole) are available using velocity-encoded
imaging, and may detect early signs of remodeling. Addi-
tionally, magnetic resonance angiography is a promising
new tool to visualize pulmonary perfusion and to diag-
nose CTEPH [49].
Biomarker May Serve as Tools for the Diagnosis
of Acute PAH
The most useful biochemical biomarker available to
date may be brain natriuretic peptide (BNP) (and/or
N-terminal prohormone brain natriuretic peptide), which
can inform on the pressure load on the right ventricle and
has prognostic value [50,51]. A reduction in circulating
BNP levels should accompany the response to an effective
treatment. There is increasing recognition of the impor-
tance of maintaining RV function in pulmonary hyper-
tension, but the primary goal is to retard and regress the
pulmonary vascularpathology. As such, BNP levels give
limited information about the response of patients with
pulmonary hypertension to treatment. Elevated BNP is
an important prognostic indicator and correlates strongly
with PVR, cardiac output, and functional status in pa-
tients with PAH [52]. A high level of plasma BNP, and
in particular, a further increase in plasma BNP during
follow-up, may have a strong, independent association
with increased mortality rates in patients with PAH [53].
However, the signicance of measuring BNP level in pa-
tients with PAH in the acute setting remains to be de-
ned. N-terminal pro-BNP (NT-proBNP) is a byproduct
of the BNP that was shown to be of prognostic value in
pulmonary hypertension (PH). The role of NT-proBNP in
PH has to be determined, especially under the inuence
of renal impairment that might lead to an accumulation
of the peptide, and may be a sign of increased mortality
per se. However, NT-proBNP could be superior to BNP as
a survival parameter in PH because it integrates hemody-
namic impairment and renal insufciency, which serves
as a sign of increased mortality per se [54].
Serum troponin may be elevated in patients with pul-
monary hypertension and has been associated with RV
overdistension and/or ischemia. Troponin I leak due to
acute RV strain from PE has been well studied, and may
predict mortality [55,56].
Management of Acute PAH
Recently published data addressing certain molecular
mechanisms for pathogenesis of PAH have led to the suc-
cessful therapeutic interventions. This review will focus
on the common and critical molecular pathways includ-
ing genetic basis of the development of PAH that on the
whole may be new targets for therapeutic interventions.
For the acute PAH, conventional therapy includes right
uid management, ventilation management and nonspe-
cic drugs (oxygen, warfarin, diuretics). The following
three classes of drugs targeting the correction of abnor-
malities in endothelial dysfunction have been approved
recently for the treatment of PAH: (1) prostanoids; (2) en-
dothelin receptor antagonists; and (3) phosphodiesterase-
5 inhibitors. The efcacy and safety of these compounds
have been conrmed in uncontrolled studies in patients
with PAH. Intravenous epoprostenol is the rst-line treat-
ment for the most severe patients. In the other situa-
tions, the rst-line therapy may include bosentan, silde-
nal, or a prostacyclin analogue. Recent advances in the
management of PAH have markedly improved progno-
sis. The endothelin-1 receptor antagonist bosentan, the
phosphodiesterase-5 inhibitor sildenal, and prostanoids
have been shown to improve symptoms, exercise capac-
ity, and hemodynamics. Intravenous prostacyclin (PGI
2
)
is the rst-line treatment for the most severely affected
patients [57]. The evolution of therapy from vasodilators
to antiproliferative agents reects the advancement in the
understanding of the mechanisms mediating PAH [58].
RV failure may result from a newly developed disease
(e.g., as a consequence of ARDS or of severe pulmonary
embolism) or of already present pulmonary hyperten-
sion (PHT). There is as yet no generally recognized def-
inition of acute or chronic RV failure. The particular clin-
ical picture and the associated hemodynamics determine
this condition. RV failure in the course of PHT represents
a great challenge in clinical and intensive care practice.
Once the vicious circle of right heart failure is reached an
optimal balance has to be found between preload and af-
terload. In addition to optimizing blood volume, positive
inotropic drugs (e.g., dobutamine) are available to main-
tain systemic blood pressure. Furthermore, an increase
in RV contractility by inodilators is aimed at. The cen-
tral goal in the treatment of right heart failure as part
of PHT is to lower PVR and thus decrease RV afterload.
However, it is very difcult to break the vicious circle in-
volved in the acute right heart syndrome; it must be the
primary aim of treatment to recognize as early as possi-
ble any worsening of PHT and prevent acute right heart
failure. Lung transplantation or surgical atrioseptostomy
may represent possible ultimate therapeutic options for
patients with PHT [59].
General Management Principles
Right uid management is the basis for recovery of acute
PAH. In patients with PAH, RV dysfunction/failure can
reduce LV lling and lead to cardiogenic shock. Patients
with cardiogenic shock secondary to RV dysfunction usu-
ally have a very high (>20 mmHg) RV lling pressure
[60]. In addition to decreased RV contractility and car-
diac output, RV dilatation can further limit LV lling via
ventricular interdependence, which causes shifting of the
interventricular septum toward the LV cavity. The chal-
lenge in uid management in those patients is to nd
the optimal RV preload necessary to avoid the detrimen-
tal effects of ventricular interdependence on LV function.
Hemodynamic monitoring of patients with RV failure due
to acute RV myocardial infarction showed that cardiac
and stroke indexes increased and the RV reached its max-
imum stroke work index when the lling pressure was
1014 mmHg. These values may be regarded as the opti-
mal level of RV lling pressure in patients with RV infarc-
tion [61]. There are no data on optimal RV lling pressure
in patients with RV dysfunction secondary to acute PAH.
Right ventilation management is another important
basis for recovery of acute PAH. It was found that con-
trolled ventilation altered RV function primarily by in-
creasing RV afterload during the lung ination period
[62]. Transpulmonary pressure (and related tidal vol-
ume), but not airway pressure itself, was the main de-
terminant factor of RV afterload during mechanical ven-
tilation [63]. This supports a low-volume strategy in
ARDS, recommended as a protective measure for lung
parenchyma, which might also represent a protective
measure for the RV and pulmonary circulation [55]. Fre-
quency of acute right heart failure in ARDS patients de-
clined from 61% to 25% over the last 1530 years, which
could be explained in part by fundamental alterations in
respiratory support and implementation low tidal volume
ventilation [15]. Lower incidence of acute right heart fail-
ure in ARDS patients was associated with lower (less than
2730 mmHg) plateau pressure [20].
RV systolic function was generally negatively affected
by end-expiratory pressure (PEEP) in ARDS patients un-
dergoing mechanical ventilation. In those patients PEEP
titration signicantly affected RV outow impedance, the
lowest values of which was associated with the achieved
better total quasi-static lung compliance (calculated by
dividing tidal volume by the difference between plateau
and end-expiratory airway pressures) [64]. This suggests
that lung hyperination along with either inadequate or
excessive PEEP can signicantly reduce RV systolic func-
tion and cardiac output. On the other hand, in an ex-
perimental study on healthy animals, the open lung con-
cept ventilation resulted in signicantly improved lung
aeration with no negative effect on RV afterload or LV
afterload. This is possibly explained by a loss of hypoxic
pulmonary vasoconstriction due to alveolar recruitment.
The reductions in the CO and in the mean PAP were the
consequences of a reduced preload [65]. A clinical study
in patients after cardiac surgery found no evidence that
ventilation according to the open lung concept affects RV
afterload [66].
Hypercapnia has been shown to induce pulmonary hy-
pertension in animal models. Study on healthy volun-
teers revealed that human pulmonary vascular responses
to hypercapnia and hypocapnia consist, respectively, of
constriction and dilatation that take 1.52 h to reach a
steady level. The time courses for recovery in eucapnia
are similar. Hypercapnia generated a rise in cardiac out-
put by changing heart rate; hypocapnia produced a fall in
cardiac output by changing stroke volume. The nding of
marked vasodilatation in response to hypocapnia demon-
strates that there is normally a substantial vascular tone
in the human pulmonary circulation [67].
Treatment with 100% oxygen is a selective pulmonary
vasodilator in patients with sustained pulmonary hyper-
tension, regardless of primary diagnosis, baseline oxy-
genation, or RV function [68]. In patients with ALI vas-
cular response to oxygen was different and administra-
tion of 100% O2 worsened intrapulmonary shunt possi-
bly secondary to collapse of unstable alveolar units with
very low ventilation-perfusion (V A/Q) ratios. This is in
contrast to administration of 100% O2 to patients with
COPD, in whom only the dispersion of the blood ow
distribution was changed, suggesting release of hypoxic
pulmonary vasoconstriction [69]. Optimal supplemental
oxygen management is an integral component of pul-
monary hypertension therapy [70].
Patients with chronic pulmonary hypertension usually
have multiple predisposing factors, which make them
more vulnerable to acute conditions and explain de-
creased ability to survive acute illness [14]. Tighter moni-
toring combined with early diagnosis and appropriate in-
tervention increases the chance of survival. Treatment
strategies for such patients should be generally directed
at rapid reversal of the precipitating condition as well
as at relieving RV pressure overload and maintaining
systemic pressure for coronary and end-organ perfu-
sion. Unlike patients with acute pulmonary hyperten-
sion [13], patients who develop acute pulmonary hy-
pertension on top of preexisting pulmonary hyperten-
sion can generate higher PAP and also require higher
RV preload (because of RV hypertrophy). Therapy for
acute massive PE with associated hemodynamic instabil-
ity or cardiogenic/obstructive shock aims at urgently re-
lieving mechanical obstruction of the pulmonary circu-
lation by either pharmacologic thrombolytic or by surgi-
cal or catheter thrombectomy (or mechanical clot disrup-
tion) [46,71,72]. Patients with massive PE but without
hemodynamic instability are less likely to benet from
thrombolytic therapy. The time the resolution of RV di-
latation, which usually takes between 10 and 20 days,
is hastened by thrombolytic therapy [16]. The therapy of
acute pulmonary hypertension in patients with sepsis and
ARDS is generally aimed at optimizing gas exchange and
minimizing ventilator-induced lung injury. Inhaled pul-
monary vasodilators are sometimes used in order to pre-
vent or relieve acute right heart failure.
Pulmonary Vasodilators
A number of vascular mediators have been implicated
in the pathophysiology of PAH, including prostacyclin,
thromboxane A2, endothelin-1, and NO [73]. Various
treatments approved by the United States Food and Drug
Administration for the management of PAH target three
of the many pathways implicated in the development of
PAH: prostacyclin-, endothelin-1 (ET-1), and nitric oxide-
mediated pathways.
Over the last decade, treatment of PPH has gained
major progress through medication such as analogue
of prostacyclin (Epoprostenol [74]) and dual antagonist
of endothelin receptor (Bosentan [75]), or inhibitors of
phosphodiesterase (Milrinone and Sildenaphil). All of
these medicines have proven highly clinically effective.
Pulmonary emb basis H of non-cardiac etiologyervention such
as Inhaled Nitric oxide (iNO) is a potent vasodilator that
dilates pulmonary vasculature in ventilated lung areas,
thereby improving ventilation/perfusion (V/Q)match and
oxygenation, and reducing PAP [76] and RV oxygen
demand [77]. This improves cardiac performance with-
out altering RV contractility [78] and cardiac output in
hemodynamically stable patients with a variety of causes
of pulmonary hypertension [79,80]. Multiple studies on
utilization of the iNO in ARDS patients showed improved
oxygenation for 2448 h, variable improvement in MPAP
[81] and no signicant impact on the duration of ven-
tilatory support or mortality in this patient population
[82,83]. A combination of iNO and other interventions,
such as positive end-expiratory pressure and prone posi-
tioning, yielded benecial and additive effects on arterial
oxygenation [63]. iNO has been successfully used and as-
sociated with improved outcomes in critically ill postop-
erative patients, who developed severe PAH or RV failure
[84].
Because iNO is a selective pulmonary vasodilator with-
out signicant effects on systemic blood pressure, reduc-
tions in PAP is the result of the pulmonary vasodila-
tory response. A combination treatment of iNO with
other pulmonary vasodilators (milrinone, sildenal, etc.)
has been used in management of acute pulmonary hy-
pertension in different conditions. [85,86] iNO treat-
ment is associated with multiple side effects including
methemoglobinemia [56,87] and NO
2
formation [68].
Abrupt withdrawal of nitric oxide has been associated
with rebound pulmonary hypertension, signicant drop
in PaO
2,
and life-threatening hemodynamic deterioration
[68,88]. Close monitoring and gradual discontinuation
are important to prevent and detect rebound pulmonary
hypertension.
Prostaglandin E
1
and prostacyclin both produce signif-
icant pulmonary vasodilatation and can lower PVR. Both
possess antithrombotic, antiproliferative, and antiinam-
matory properties. In patients with chronic severe PAH,
intravenous prostacyclin is highly effective and associ-
ated with a signicant survival benet [89,90]. Prosta-
cyclin, subcutaneous or intravenous treprostinil, intra-
venous PGE1, and other prostanoids have relatively long
half-lives and can signicantly affect systemic hemody-
namics. This feature limits their use in critically ill or
hemodynamically unstable patients. PGI
2
in combination
with norepinephrine and dopamine was effective in the
treatment of protamine-mediated acute PAH and RV fail-
ure in the setting of open heart surgery [25]. Prosta-
cyclin and its analogs (iloprost and treprostinil) in in-
haled forms are as effective as intravenous forms in pa-
tients with chronic PAH [91]. Inhaled prosaglandins have
been used to treat severe sustained pulmonary hyperten-
sion and intractable hypoxia, but were associated with
systemic hypotension [92]. Inhaled iloprost effectively
decreased PAP and improved RV performance immedi-
ately after separation from CPB [93]. Inhaled iloprost
was effective in the treatment of acute RV dysfunction
in the setting of preexisting PAH in heart transplant re-
cipients during weaning from CPB circulation and was
not associated with signicant systemic side-effects. De-
spite the observation that RV ejection fraction increased
on inhaled NO, but not with PGI
2
, both inhaled NO
and PGI2 aerosol showed benecial effects on RV perfor-
mance and may prove helpful in the treatment of acute
PAH [47]. Inhaled prostacyclin showed different effect on
oxygenation and pulmonary hemodynamics in patients
presenting with primary pulmonary ARDS (reduction
in PaO2/FIO2) compared with extrapulmonary cause of
ARDS (increase in PaO2/FIO2 along with a decrease in
mean pulmonary artery pressure) [94]. In a compara-
tive trial in patients with PAH, both inhaled and infused
prostacyclin had profound effects on pulmonary hemody-
namics, almost equipotently reducing PVR, whereas only
inhaled prostacyclin signicantly reduced PAP [95]. In-
halation of iloprost in patients with severe PH associated
with lung brosis resulted in the same degree of reduc-
tion of PVR as intravenous prostacyclin, only inhaled ilo-
prost preserved gas exchange [96].
PGI
2
is a recommended rst-line therapy for unsta-
ble patients in NYHA functional class IV [97,98,99]. How
prostacyclin improves cardiac output in right-heart fail-
ure in conjunction with pulmonary hypertension has
been evaluated in a dog model of acute afterload-induced
RV failure [67]. In this model, prostacyclin improved
right ventriculoarterial coupling and increased cardiac
output by decreasing pulmonary arterial resistance, be-
cause of vasodilating effects, without a detectable effect
on contractility. It is likely that clinical RV failure in hu-
man PAH might be due to aggravated right ventriculoar-
terial decoupling, and eventually a decrease in right ven-
tricle contractility. These observations provide a rationale
for inotropic interventions added to prostacyclin therapy
in patients with PAH who present with RV decompensa-
tion [100].
Continuous intravenous epoprostenol improves exer-
cise capacity, hemodynamics, and survival in IPAH and
is the preferred treatment option for the most critically
ill patients. Treprostinil, a prostanoid, may be delivered
via either continuous intravenous or subcutaneous in-
fusion. Iloprost is a prostanoid delivered by an adaptive
aerosolized device 6 times daily.
Phosphodiesterase inhibitor Sildenal is a selective in-
hibitor of phosphodiesterase type 5 with sustained pul-
monary vasodilatatory effect. Sildenal lowers PVR and
PAP and increases CO in patients with different forms
of chronic PAH [101,102] including patients with PAH
secondary to congestive heart failure [103]. This effect
is mainly achieved by balancing pulmonary and sys-
temic vasodilation. In patients, after coronary artery by-
pass graft surgery, sildenal may improve myocardial
perfusion, reduce platelet activation, and potentially re-
duce early graft occlusion [104]. In the chronic setting, it
is highly effective both alone and in combination with
other pulmonary vasodilators: epoprostenol [105], ilo-
prost [106,107], BNP [108] and iNO [89]. Although
mostly used in patients with chronic PAH and in hemo-
dynamically stable patients sildenal possesses multiple
features that could be effective in treatment of critically ill
patients with severe RV dysfunction related to secondary
PAH [109]. Its ability to augment and prolong the hemo-
dynamic effects of other pulmonary vasodilators has been
successfully used to minimize rebound pulmonary hyper-
tension after iNO discontinuation [110,111,112], wean-
ing from intravenous vasodilators in patients after car-
diac surgery [105] as well as in chronic PAH therapy
[113]. Experimental evaluation of the inhaled and in-
travenous sildenal administration showed similar ef-
fects on pulmonary endothelium-dependent relaxation,
overall hemodynamic prole, and oxygenation after car-
diopulmonary bypass. Both administration routes pre-
vented a signicant increase in mPAP without severe sys-
temic hypotension [114]. Its chronic administration has
been shown to improve exercise capacity, World Health
Organization functional class, and hemodynamics in pa-
tients with symptomatic PAH. Sudden cessation of silde-
nal monotherapy, in patients with PAH, carries with it
a signicant and unpredictable risk of rapid clinical de-
terioration. It is recommended that if sildenal needs to
be ceased, it would be more prudent to consider concur-
rent vasodilator therapy before the gradual cessation of
sildenal [115]. Pilot study suggested benecial effects in
favor of sildenal in several secondary endpoints at both
3 months and 12 months [116].
CCBs were introduced for the treatment of hyperten-
sion in the 1980s [117]. CCBs have been used in hemo-
dynamically stable patients with PAH who demonstrated
pulmonary vascular response to acute vasodilator chal-
lenge [118]. There are no studies of CCBs in critically ill
patients with acute PAH. Acute administration of nifedip-
ine did not cause pulmonary vasodilation, and in contrast
led to increased RVEDP and decreased RV contractility
[46]. Prolonged half-life and negative inotropic effects,
which may precipitate fatal worsening of RV failure, limit
the use of CCBs in treatment of acute pulmonary hyper-
tension. Treatment with high doses of CCBs has been
shown to have a sustained benecial effect in a very
small subset of patients with severe idiopathic PAH who
demonstrated an acute fall in PAP in response to a pul-
monary vasodilator [119]. The empirical use of CCBs is
discouraged because of the risks of systemic hypotension
and impaired right-sided heart function [120]. Conse-
quently, the current recommendations for the treatment
of PAH propose that the acute response of the pulmonary
circulation to a pulmonary vasodilator should be used as
the basis for selecting patients for high-dose CCB treat-
ment [121]. A retrospective analysis of 557 patients with
IPAH showed that only 13% of patients displayed vasore-
activity, as dened by a decrease of more than 20% in
both mPAP and PVR. Of the patients displaying vasore-
activity, only about half beneted from treatment with
long-term CCBs. Patients who beneted from these med-
ications tended to have had a more profound short-acting
vasodilator response during invasive testing [122].
ETRAs basic research in vascular biology has impli-
cated endothelin-1 (ET-1) and its receptors (ETA and
ETB) in diverse preclinical models of PAH, and ET-1
has been shown to contribute signicantly to PAH in
human patients [123]. The introduction of ETRAs to
clinical medicine has substantially expanded therapeu-
tic approach toward severe PAH [124]. Bench-to-bedside
scientic research has shown that endothelin-1 (ET-1)
is overexpressed in several forms of pulmonary vascular
disease and may play an important pathogenetic role in
the development and progression of PAH. Endothelin re-
ceptor antagonism has emerged as an important thera-
peutic approach in PAH.
Oral ETRAs improved exercise capacity, functional sta-
tus, pulmonary hemodynamics, and delayed the time
to clinical worsening in several randomized placebo-
controlled trials. Two ETRAs are currently approved by
the US Food and Drug Administration: bosentan, a dual
ETRAs for patients with class III and IV PAH, and am-
brisentan, selective ETRAs for patients with class II and III
PAH. Sitaxsentan, another selective ETRAs, has been ap-
proved in Europe, Canada, and Australia [125]. ET recep-
tors (ET[A] and ET[B]) have different densities and dis-
tributions throughout the body and are dynamically reg-
ulated, such that blockade of ET(A) and ET(B) receptors
may have different results in normal versus pathological
conditions. Although differences in biological effects can
be found in studies of isolated cells, blood vessels and ani-
mal models, clinical treatment studies have not identied
clear differences in efcacy among the various ETRAs.
The main differences appear to be in safety proles, with
a greater frequency of serum liver function abnormali-
ties occurring with the available dual ET(A)/ET(B) antag-
onist, and possibly higher rates of peripheral edema noted
with selective ET(A) agents [126].
Bosentan, a dual endothelin receptor antagonist, is in-
dicated for the treatment of patients with PAH. Following
oral administration, Bosentan attains peak plasma con-
centrations after approximately 3 h. The terminal half-
life after oral administration is 5.4 h and is unchanged
at steady state. Steady-state concentrations are achieved
within 35 days after multiple-dose administration, when
plasma concentrations are decreased by about 50% be-
cause of a 2-fold increase in clearance, probably due to in-
duction of metabolizing enzymes. The pharmacokinetics
of bosentan is dose proportional up to 600 mg (single
dose) and 500 mg/day (multiple doses). The pharmacoki-
netics of bosentan in pediatric PAH patients are compa-
rable to those in healthy subjects, whereas adult PAH
patients show a 2-fold increased exposure. Severe re-
nal impairment (creatinine clearance 1530 mL/min) and
mild hepatic impairment (ChildPugh class A) do not
have a clinically relevant inuence on the pharmacoki-
netics of bosentan. Bosentan should generally be avoided
in patients with moderate or severe hepatic impairment
and/or elevated liver aminotransferases. In healthy sub-
jects, bosentan doses >300 mg increase plasma levels
of endothelin-1. In a pharmacokinetic-pharmacodynamic
study in PAH patients, the hemodynamic effects lagged
the plasma concentrations of bosentan [127]. An open-
label study suggests a benecial effect of bosentan ther-
apy not only on pulmonary hemodynamics, but also on
quality of life and exercise capacity for patients with se-
vere CTEPH [128].
Sitaxsentan is the rst oral ETRA with high selectivity
for the endothelin-A (ET [A]) receptor to be approved for
clinical use by regulatory agencies in Europe for the treat-
ment of PAH. Sitaxsentan therapy appears safe and efca-
cious for patients with PAH; reductions in mortality and
the risk for clinical worsening events provide support for
durability of efcacy at 1 year [129]. Clinical trials have
shown it to be well tolerated and to improve exercise tol-
erance, functional class, and pulmonary hemodynamics
in PAH, results which appear to be at least as good as
those for the mixed ETRA bosentan. Importantly, com-
pared to bosentan, Sitaxsentan has a lower incidence of
liver toxicity and no interaction with sildenal [130].
Ambrisentan is the second selective endothelin-A re-
ceptor antagonist to be licensed in Europe, and the rst
in the United States, for the management of PAH. It has
been shown to be clinically effective in improving ex-
ercise tolerance and functional class. Furthermore, am-
brisentan is well tolerated and associated with low rates
of liver toxicity and minimal interactions with other
medicines commonly used to treat PAH. Overall, current
data support a role for ambrisentan in the management
of PAH. However, the results of longer-term follow-up
studies are still required to fully assess efcacy and safety
[131]. Ambrisentan has been shown to be an effective
ETRAs in patients with PAH, at the same time, a signi-
cant advantage of ambrisentan is the lack of any clinically
important drug interactions with warfarin and sildenal,
which are frequently used by patients being treated for
PAH [132].
Platelet-derived growth factor (PDGF) has the abil-
ity to induce the proliferation and migration of smooth
muscle cells and broblasts, and PDGF and its recep-
tors are overexpressed in human and experimental PAH
[133]. Novel therapeutic agents, such as imatinib me-
sylate, inhibit several tyrosine kinases, including PDGF
receptors and . Imatinib has been demonstrated to
reverse pulmonary vascular remodeling in animal mod-
els of pulmonary hypertension. Four cases of clinical and
hemodynamic improvements have also been reported in
human PAH[134,135,136]. Concerns have arisen about
the cardiac safety of tyrosine kinase inhibitors, especially
in patients with preexisting cardiac conditions [137,138].
Safety and efcacy of tyrosine kinase inhibitors are cur-
rently being evaluated in multicenter randomized trials.
Imatinib, as a selective antagonist of the platelet-derived
growth factor receptor, was effective in the case of a sin-
gle patient with severe treatment-refractory familial PAH
[139], suggesting that such antiproliferative drugs may
reverse pulmonary vascular remodeling, thus alleviating
PAH.
A signicant venodilator effect of nitroglycerine de-
creases RV preload leading to adverse consequences in
patients with right heart failure. Inhaled nitroglycerin
may be a safer therapeutic option leading to a signicant
reduction in both mean PAP and PVR in patients after
mitral valve operations without reducing systemic mean
arterial pressure [140]. Intravenous adenosine is a pul-
monary vasodilator with a very short half-life (610 sec-
onds) and can be effective for short term lowering PVR
[76]. In the setting of acute PAH, adenosine infusion may
help lower PAP without lowering systemic arterial pres-
sure and reverse the clinical state of shock by achieving
pulmonary vasodilatation [141]. However, higher doses
(70 mg/kg per min to 100 mg/kg per min) cause systemic
vasodilatation [142]. Adenosine is used to treat persis-
tent pulmonary hypertension of the newborn [143,144].
Treatment with the use of vasoactive intestinal peptide
also may elicit benecial effects in PAH and warrants fur-
ther investigation [145].
Inotropic Agents
Critically ill patients with associated acute pulmonary
hypertension frequently develop profound and refrac-
tory systemic arterial hypotension. In cases with severe
acute arterial pulmonary hypertension (e.g., massive PE),
relieving the acute obstruction (either mechanically or
with pulmonary vasodilators) of the pulmonary circula-
tion can successfully resolve systemic arterial hypoten-
sion. In acute pulmonary hypertension associated with
decreased cardiac contractility and/or SVR, the use of
vasopressors with or without pulmonary vasodilators is
necessary to maintain coronary and end-organ perfu-
sion. Progression of RV failure should be always con-
sidered in the management plan. Cases of severe acute
PAH combined with heart failure and systemic arterial
hypotension require tight hemodynamic monitoring and
aggressive treatment with combinations of pulmonary
vasodilators, inotropic agents, and systemic arterial vaso-
constrictors. The choice of vasopressor and inotropes in
patients with acute pulmonary hypertension should take
into consideration their effects on PVR and cardiac output
when used alone or in combinations with other agents,
and must be individualized based on individual patient
response.
Dobutamine is predominantly a
1
-adrenergic agonist,
with weak 2 activity, and
1
selective activity, although
it is used clinically in cases of cardiogenic shock for its
1
inotropic effect in increasing heart contractility and car-
diac output. At doses of 15 g/kg per min dobutamine
decreased PVR, lowered MAP and slightly increased car-
diac output [146]; at doses of 510 g/kg per min,
dobutamine caused signicant tachycardia and systemic
hypotension without improving PVR [142,147]. Admin-
istration of dobutamine augments myocardial contractil-
ity and reduces left ventricular afterload. It can cause
systemic hypotension in some patients because of pe-
ripheral vasodilatory effects, which may require use of
norepinephrine or other peripheral vasoconstrictors to
maintain appropriate systemic perfusion pressures. In
combination with inhaled NO dobutamine administra-
tion had additive effects on pulmonary circulation [137],
increased cardiac performance, and improved oxygena-
tion [148] with no effect on systemic hemodynamics.
In an animal model of acute RV failure secondary to
acute PAH, dobutamine was superior to norepinephrine
in improving RV function by optimizing pulmonary va-
sodilation, decreasing PA resistance and elastance, and
increasing RV contractility [143]. An arterial catheter
should be placed as soon as possible in patients with sep-
tic shock. Vasopressors are indicated to maintain mean
arterial pressure of <65 mmHg, both during and fol-
lowing adequate uid resuscitation. Norepinephrine or
dopamine is the vasopressor of choice in the treatment
of septic shock. Norepinephrine may be combined with
dobutamine when cardiac output is being measured.
Epinephrine, phenylephrine, and vasopressin are not rec-
ommended as rst-line agents in the treatment of sep-
tic shock. Vasopressin may be considered for salvage
therapy. Low-dose dopamine is not recommended for
the purpose of renal protection. Dobutamine is recom-
mended as the agent of choice to increase cardiac output
but should not be used for the purpose of increasing car-
diac output above physiologic levels [149].
Norepinephrine acts as a drug that will increase blood
pressure by its prominent increasing effects on the vas-
cular tone from -adrenergic receptor activation. The re-
sulting increase in vascular resistance triggers a compen-
satory reex that overcomes its direct stimulatory effects
on the heart, called the baroreceptor reex, which results
in a drop in heart rate called reex bradycardia. Nore-
pinephrine has signicant inotropic effects and produces
vasoconstriction. It is widely used in critical care settings
to treat hemodynamically unstable patients. In addition
to positive effects on cardiac output and systemic arte-
rial pressure, norepinephrine increases PVR and wors-
ens PAH [150]. However, norepeinephrine is superior
to phenylephrine in restoring systemic arterial pressure,
decreasing PVR, augmenting RV myocardial blood ow
and improving cardiac output in animal model of acute
PE [151]. Alfa-adrenergic stimulation can cause a dis-
proportionate rise in PVR [152], which is implicated in
the development of acute PAH in critical illnesses. Be-
sides disproportional increase in PVR, phenylephrine also
causes bradycardia [153] with detrimental consequences
on pulmonary and systemic hemodynamic. The effects
of phenylephrine and norepinephrine in the treatment
of systemic hypotension were evaluated in patients with
chronic PAH who developed systemic hypotension fol-
lowing induction of anesthesia. In contrast to phenyle-
phrine, norepinephrine decreased the ratio of PAP to
systemic blood pressure without a change in cardiac in-
dex. Thus, norepinephrine has been considered to be
preferable to phenylephrine for the treatment of hy-
potension in patients with chronic PAH [145]. There
are growing data on successful combination of nore-
pinephrine and selective pulmonary vasodilators in the
treatment of patients with acute and chronic pulmonary
hypertension [154]. In a small animal study of sepsis-
induced pulmonary hypertension, epinephrine infusion
increased SVR and cardiac output and lowered PVR
[155].
Dopamine is a sympathomimetic catecholamine that
exhibits alpha adrenergic, beta adrenergic, and dopamin-
ergic agonism. Dopamine produces dose-dependent
dopaminergic, beta- and alpha- adrenergic effects on car-
diac output and vascular tone. Low dose: 25 g/kg
per min. Little effect was seen on heart rate or car-
diac output. Increased blood ow accompanied by in-
creased urine output. Intermediate doses: 515 g/kg per
min. An increase in cardiac contractility and cardiac out-
put results in increased normal blood ow and heart
rate. High dose: 15 g/kg per min. Alpha-adrenergic ef-
fects begin to dominate: increased systemic and PVR.
Decrease in normal perfusion. In patients with chronic
PAH dopamine, infusion led to increased heart rate,
mPAP, aortic mean pressure, and cardiac index with con-
comitant fall of SVR [156]. Administration of dopamine,
similar to epinephrine, is associated with high risk of
tachyarrhythmia, with potentially fatal consequences in
patients with severe pulmonary hypertension [146].
Isoproterenols effects on the cardiovascular system re-
late to its actions on cardiac 1 receptors and 2 recep-
tors on skeletal muscle arterioles. Isoproterenol has pos-
itive inotropic and chronotropic effects on the heart. In
skeletal muscle arterioles, it produces vasodilatation. Its
inotropic and chronotropic effects elevate systolic blood
pressure, while its vasodilatory effects tend to lower dias-
tolic blood pressure. Isoproterenol has positive inotropic
and chronotropic effect, which in therapeutic doses in-
creases cardiac output and produces pulmonary and pe-
ripheral vasodilation. As a pulmonary vasodilator, isopro-
terenol is one of the preferred inotropic agents in heart
transplantation patients with elevated PVR. The dosage of
isoproterenol should be reduced gradually because PVR
may return quickly to elevated baseline levels after dis-
continuation of this drug [148]. In animals with acute
PAH, administration of isoproterenol did not reduce PAP,
and instead produced signicant tachycardia and was as-
sociated with arrhythmias [157].
Vasopressin is derived from a preprohormone precur-
sor that is synthesized in the hypothalamus and stored
in vesicles at the posterior pituitary. Vasopressin is an en-
dogenous peptide hormone with weak nonadrenergic va-
sopressor effect on the systemic vasculature and an ability
to produce NO-mediated selective pulmonary vasodila-
tion [158]. In healthy animals, a linear relationship was
observed between vasopressin levels and systemic vascu-
lar resistance. However, vasopressin did not affect PVR
or any vascular compliance [159]. It was very effective
(at dose of 0.1 U/min) in treating refractory low SVR hy-
potension concomitant with pulmonary hypertension in
postoperative patients [160]. Experimental data on use of
vasopressin in acute pulmonary hypertension are contro-
versial: In one setting of acute pulmonary vasoconstric-
tion vasopressin infusion produced signicant pulmonary
vasodilation [161]. Use of high dose of vasopressin (1.16
units/kg per hour) in another animal model of acute pul-
monary hypertension led to increased PVR and decreased
cardiac output with a decrease in RV contractility, leading
the authors to cautioning against its use when RV func-
tion is compromised [162].
Surgical Intervention
Patients with advanced RV failure who have not bene-
ted from pharmacologic treatment and who have arte-
rial oxygen saturations within an acceptable range should
be considered for percutaneous balloon atrial septostomy
[163,164]. Atrial septostomy has been developed as an
alternative/bridge treatment and applied in patients with
lack of response to medical therapy in the absence of
other surgical treatment options. It has a substantial mor-
bidity and mortality in critically ill patients with severe
RV failure [165]. With growing experience, procedure-
related death rates have been reduced to 5.4%, and the
most suitable patient group has been identied among
patients with a mean right atrial pressure between 10 and
20 mmHg [166]. Acute right heart failure after orthotopic
heart transplantation was successfully managed by de-
compression of the RV through the patent foramen ovale
of the donor heart and inhalation of iloprost [167]. Both
pericardiectomy and creation of atrial septal defects have
been used in extreme cases of acute RV failure secondary
to acute MI [168]. Decompression of the RV through the
septostomy may potentially be an effective alternative in
the management of severe acute pulmonary hyperten-
sion. The defect could be subsequently closed using a
transcatheter septal occlusion device, after the patients
condition has been stabilized. It has been observed that
patients with PPH who have a patent foramen ovale have
a better survival rate than patients with an intact sep-
tum. In an effort to create the more favorable condition
of intraatrial communication, the technique of atrial sep-
tostomy for congenital cardiac defects such as transposi-
tion of the great arteries has been applied to patients with
severe pulmonary hypertension and right heart failure.
This also has been utilized as a bridge to lung transplan-
tation for patients with severe PPH [169].
Mechanical Support Devices
Cardiac surgical patients who do not respond to medical
therapy may be candidates for mechanical support with
a RV assist device. In cases of acute right heart failure af-
ter heart transplantation, mechanical circulatory support
systems, such as RV assist devices, extracorporeal mem-
brane oxygenation, femoral vein-to-femoral artery roller,
or centrifugal pumps, may facilitate hemodynamic stabil-
ity until the transplanted heart has recovered, or until
a new heart has been found for retransplantation [170].
They possibly could be successfully applied in other cases
of potentially reversible acute PAH and right heart fail-
ure. Intraaortic balloon counterpulsation (IABP) has long
been the mainstay of mechanical therapy for cardiogenic
shock. Not every patient has a hemodynamic response
to IABP [188]. However, in patients with acute PAH
and RV failure associated with systemic hypotension, it
could improve coronary and peripheral perfusion and
augment LV performance with an acute decrease in af-
terload [171]. Severe pulmonary hypertension refractory
to medical treatment is a contraindication to orthotopic
heart transplantation in most centers. A study supports
that LVAD support and continuous nonpulsatile mechan-
ical unloading of the left ventricle can reverse medically
unresponsive pulmonary hypertension and render pa-
tients eligible for orthotopic heart transplantation [172].
Mechanical support using an implantable LVAD is a very
efcient approach with an acceptable risk to treat se-
vere pulmonary hypertension in end-stage heart failure
patients before heart transplantation. Adequate reduc-
tion of PVR can be expected within 36 months. Sub-
sequent heart transplantation is associated with a good
outcome [173]. Severely elevated PVR is a relative con-
traindication to orthotopic heart transplantation. A po-
tential novel strategy to reverse elevated PVR may be
implantation of a chronic left ventricular assist device
(LVAD) with subsequent left ventricular unloading. Pa-
tient underwent placement of biventricular assist devices
and subsequently could experience a marked reduction
of PVR, ultimately enabling successful heart transplanta-
tion [174].
Fixed pulmonary hypertension in cardiac transplant
candidates can be lowered using LVADs. The posttrans-
plant survival of these patients is uncertain as pulmonary
hypertension may reappear, possibly affecting posttrans-
plant survival. LVAD therapy lowers xed pulmonary
hypertension in cardiac transplant candidates with xed
pulmonary hypertension. Thereafter, long-term post-
transplant survival is comparable to cardiac transplant re-
cipients without pulmonary hypertension [175]. Elevated
PVR in heart transplant candidates can be reduced using
a LVAD, and LVAD is proposed to be the treatment of
choice for candidates with PH. Pretransplant LVAD ther-
apy reduces an elevated PVR in heart transplant recipi-
ents, but there was no statistically signicant difference
in posttransplant survival in patients with PH with, or
without LVAD therapy [176]. Acute RV failure after car-
diac surgery occurring in the rst postoperative hours is
associated with a bad prognosis. We have used a centrifu-
gal pump either for left, right, or biventricular assistance.
However, the use of this device for pure RV assistance is
rare. We report a 30-year-old female undergoing a mi-
tral valve replacement and a 42-year-old male undergo-
ing a cardiac transplantation, who had a successful RV
assistance using a centrifugal pump, due to a failing right
ventricle, as the result of insufcient myocardial protec-
tion and severe pulmonary hypertension. These two cases
illustrate the value of the mechanical ventricular assist
device for the treatment of right heart failure [177].
The Management of Renal Impairment
Due to PAH
Renal blood ow is the main factor determining GFR
glomerular ltration rate in patients with cardiac dys-
function. Venous congestion, characterized by an in-
creased Right Atrial Pressure, adjusted for RBF is also re-
lated to GFR. Treatment to preserve GFR should not only
focus on improvement of renal perfusion, but also on de-
creasing venous congestion [178].
Combined Therapy Approach
Combination therapy using drugs with different mecha-
nisms of action to maximize clinical benet is an emerg-
ing therapeutic option in PAH [179,180,181,182]. The
choice of drug depends on a variety of factors including
accessibility, approval status, and patients preferences
[183]. The use of combinations of targeted oral thera-
pies for the treatment of PAH is becoming increasingly
commonplace, and benets of early diagnosis and treat-
ment of PAH recently have become apparent [184,185].
The situations and corresponding treatment combina-
tions could be but not limit to as follows:
(1) Protamine-mediated acute PAH and RV failure in the
setting of open heart surgery. PGI
2
in combination with
norepinephrine and dopamine was effective [26].
(2) Acute and chronic pulmonary hypertension and sys-
temic hypotension. Combination of norepinephrine and
selective pulmonary vasodilators should be adopted.
(3) Severe pulmonary hypertension leading to impaired
RV function presented in ARDS. The combination of iNO
and intravenously administered prostacyclin (i.v. PGI2)
might be more useful than either drug alone [186].
(4) Severe pulmonary hypertension. iNO therapy alone
or in combination with a PDE5 inhibtor could be a thera-
peutic alternative [187].
(5) Long-term treatment of PAH and CTEPH patients.
The combination of sildenal and inhaled treprostinil was
well tolerated and induced additive, pulmonary selective
vasodilatation in pulmonary hypertension patients [188].
(6) In combination with iNO, milrinone produced addi-
tive pulmonary vasodilatation in animal model of acute
pulmonary hypertension. A combination of milrinone
and sildenal led to more effective pulmonary vasodi-
lation and increased RV contractility, without additional
systemic vasodilatation in an animal model. Cardiac out-
put and RV performance were signicantly improved
after milrinone or both drugs combined, but not with
sildenal alone.
(7) The combination of PDE3 inhibitor and PDE4 in-
hibitor: Milrinone and sildenal are effective pulmonary
vasodilators, with independent action and additive ef-
fect. Both drugs combined, achieved a better hemody-
namic prole, with greater pulmonary vasodilatation and
increased contractility but without additional systemic
vasodilatation. The systemic hemodynamic prole (sys-
temic vasodilation, cardiac output, RV dP/dT) is improved
with milrinone but not with sildenal [189].
(8) Bosentan has not been studied in acute care settings.
Currently, the only possible implication of Bosentan in
critically ill patients would be weaning or conversion
from inhaled or intravenous pulmonary vasodilators to
oral medication (Bosentan), but ET blockers are prob-
ably not a good option for acute PAH due to ARDS.
Some study investigating the combination of Bosen-
tan and prostacyclin analogue showed clinical improve-
ment. Additional Bosentan therapy may also reduce
the epoprostenol dose and therefore decrease its side
effects.
(9) PAH patients with NYHA IIIV symptoms. A non-
randomized, uncontrolled trial in reported the effective-
ness of bosentan monotherapy followed by the addition
of sildenal and/or inhaled iloprost [190].
(10) Acute PAH after heart transplantation: Superim-
posed acute RV dysfunction in the setting of preexisting
pulmonary hypertension is a nearly fatal complication af-
ter heart transplantation. The optimal treatment modal-
ity remains a matter of debate. Recently, sildenal citrate,
in combination with iNO, has gained popularity and was
proved safe and effective in the treatment of acute PAH
after heart transplant [191].
Suggestions of Interventions
for Acute PAH
No current treatment approach to PAH provides a cure.
Rather, treatment goals are to reduce PVR, PAP, and
symptoms and to increase patient activity and longevity.
With an increasing number of pharmacologic treatment
options available, the decision regarding when and how
to use such treatment have taken on added complexity
and importance. Although head-to-head comparative tri-
als of available medications are not available, most ex-
perienced investigators and clinicians agree that patients
with more advanced PAH should be treated initially with
parenteral prostacyclin analogues, especially in the set-
ting of RV failure. PDE5 inhibitors or ETRAs are rea-
sonable initial therapies for patients who have mild-to-
moderate PAH (i.e., WHO functional class II or III) or for
patients who are not candidates for more invasive ther-
apies. Conversely, intravenous therapies with a prosta-
cyclin analogue should be considered as rst-line ther-
apy for patients with severe symptoms (WHO functional
class IV) or for patients whose disease progresses on less
invasive therapy. Use of inhaled iloprost and subcuta-
neously administered treprostinil allows for the admin-
istration of an effective prostacyclin analogue without
some of the risks associated with continuous intravenous
infusion. However, when inhaled or delivered subcuta-
neously, these agents appear to be less efcacious than
when delivered via the parenteral route and may not be
well tolerated by the patient. Interventional procedures
such as atrial septostomy and lung transplantation are in-
dicated in patients with advanced NYHA class III and IV
symptoms and refractory to available medical treatment.
Patients who respond to an acute trial of a vasodila-
tor may be treated with oral CCB, whereas oral therapies
such as sildenal and bosentan have been effective in pa-
tients with mild-to-moderate symptoms. Infusions of the
prostacyclin analogues epoprostenol and treprostinil ap-
pear to be the treatment of choice for moderate-to-severe
PAH, and agents with alternate routes of delivery such as
inhaled iloprost may be advantageous in adjunctive roles.
Future trials that focus on the long-term effects of cur-
rently available agents, as well as on combination ther-
apy, are needed [192].
In patients at risk of sudden intravascular absorption of
absolute ethyl alcohol, an increased level of awareness for
acute PAH, together with prompt treatment of PAH with
Sildenal analogue or with a low dose of an NO-donor
drug, will minimize the risk of cardiovascular decompen-
sation and may be the treatment of such catastrophe.
Conict of Interest
The authors have no conict of interest.
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