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Managing Right Ventricular Failure in PAH:
An Algorithmic Approach
 Teresa
De Marco, MD
Professor of Clinical Medicine
Director, Heart Failure and
Pulmonary Hypertension Program
Medical Director, Heart Transplantation
University of California,
San Francisco Medical Center
San Francisco, California |
 Dana
McGlothin, MD
Assistant Clinical
Professor of Medicine
Associate Director, Pulmonary
Hypertension Program
University of California, San Francisco Medical
Center
San Francisco, California
|
Pulmonary arterial hypertension (PAH) is a disorder
characterized by progressive elevation of pulmonary artery
pressure (PAP) and vascular resistance in the absence
of left-sided cardiac disease, pulmonary vein compression,
respiratory disorders, or thromboembolic disease. It is
defined by a mean PAP over 25 mmHg at rest or over 30
mmHg with exercise and a pulmonary artery occlusion pressure
(PAOP) of less than 15 mmHg. PAH is associated with a
poor prognosis. The estimated median survival from diagnosis
is 2.8 years and the 1-year and 5-year survival rates
are only 68% and 34%, respectively.1,2 More than 70% of
PAH patients will die as a result of right ventricular
failure and most of the remainder from dysrhythmia. Predictors
of a poor prognosis in PAH are related to the development
of right ventricular failure.1,3,4 The
objectives of this review are to examine the pathophysiologic
mechanisms leading to the development of right ventricular
failure due to PAH, the diagnostic features of right ventricular
failure, and the management of chronic right ventricular
failure with emphasis on acute decompensation in this
setting.
Pathophysiology
Clinical Manifestations and Hemodynamic Derangements The
normal right ventricle is a thin-walled (less than 0.6
cm), trabeculated, roughly triangular structure that weighs
less than 65 g in men and less than 50 g in women.5,6
It is designed to empty its volume into a low-impedance,
highcapacitance, pulmonary circulation by contracting
sequentially from inflow to outflow. The pulmonary circulation
can tolerate three- to fourfold increases in right-sided
cardiac output without significant increases in PAP. In
healthy individuals, pulmonary vascular resistance (PVR)
decreases as the cardiac output rises with exercise.7
In the setting of PAH, PVR does not sufficiently decrease
with exercise, resulting in dyspnea and poor exercise
capacity.
Progressive PAH presents a pressure overload
state to the right ventricle, increasing right ventricular
workload leading to concentric hypertrophy (Figure
1). The right ventricle compensates: the walls hypertrophy
while maintaining a normal or smaller chamber size, resulting
in normal or reduced right ventricular wall stress. During
this compensated phase of adaptive hypertrophy and normal
to reduced wall stress, the ventricle is able to eject
blood against the high PVR while maintaining an adequate
right-sided cardiac output and normal right atrial pressure.
During this phase patients exhibit few symptoms.
The right ventricle can compensate only
so long, initiating the symptomatic/declining phase (Figure
1). During this phase, with marked, maladaptive right
ventricular hypertrophy and variable degrees of interstitial
fibrosis, diastolic function may be impaired, altering
the right ventricular diastolic pressure-volume relationship
and leading to increases in right ventricular end-diastolic
and right atrial pressures. With persistent pressure overload,
the right ventricle undergoes a remodeling process eventually
leading to right ventricular failure. The right ventricular
chamber dilates and the concentric hypertrophy transitions
to eccentric hypertrophy, resulting in increased wall
stress and systolic dysfunction. Increased heart rate
and right ventricular wall stress lead to significant
increases in right ventricular myocardial oxygen consumption.
This, in combination with reduced right ventricular endomyocardial
coronary perfusion (due to reduced right coronary artery
pressure, rising right ventricular enddiastolic pressure,
and increased right ventricular mass), leads to right
ventricular ischemia and worsening right ventricular diastolic
and systolic function. The right ventricular ischemia
may be clinically manifest as chest pain. As the right
ventricle and the tricuspid valve annulus dilate, functional
tricuspid regurgitation progressively worsens. Tricuspid
regurgitation further compromises right ventricular forward
output, and ultimately, left ventricular filling. During
this phase of right ventricular remodeling, cardiac output
does not meet peripheral demands and right atrial pressure
rises further as reflected clinically by exercise intolerance,
progressive dyspnea, elevated jugular venous pressure,
and fluid retention with edema (the hallmarks of right
ventricular failure). These clinical signs reflect both
a low cardiac output and the detrimental activation of
neurohormones and other mediators.2,8,9
Natriuretic peptide levels become significantly elevated
in patients with right heart failure even in the absence
of left ventricular dysfunction. B-type natriuretic peptide
(BNP) levels increase in proportion to the extent of right
ventricular dysfunction in PAH and are predictive of mortality
in right ventricular failure.10,11
Progressive right ventricular dilation in the setting
of pericardial constraint and diastolic ventricular interdependence
compromise left ventricular filling via several mechanisms.
7,12,13 A shift of
the ventricular septum during diastole toward the left
ventricle reduces left ventricular compliance and diastolic
filling. As the right ventricle dilates in association
with increases in right ventricular and right atrial diastolic
pressure, a marked rise in intrapericardial pressure ensues.
The transmural left ventricular end-diastolic pressure
(end-diastolic pressure minus intrapericardial pressure),
the true preload of the left ventricle, is reduced and
by the Frank-Starling relationship results in low systemic
cardiac output. Furthermore, with marked elevation in
right atrial pressure the coronary sinus pressure also
rises, resulting in left ventricular myocardial congestion
and wall dimensions that limit left ventricular compliance.
This mechanism appears to act independently of diastolic
ventricular interaction due to pericardial constraint.14
As a consequence of decreased left ventricular preload,
systemic cardiac output is further compromised, first
with exercise only but eventually even at rest. It should
be noted that with extreme right ventricular failure and
dilation, left ventricular compliance can be so severely
impaired that at a certain point the left ventricular
end-diastolic pressure (LVEDP) and PAOP may rise due to
a shift of the left ventricular diastolic pressure volume
relationship upward and to the left such that even with
low left ventricular volume the left ventricular pressure
is increased.
The decompensated phase of right ventricular systolic
failure is manifest as symptoms with minimal activity
or at rest. It is marked by elevation in right atrial
pressure and systemic venous hypertension leading to hepatic
congestion, which combined with tricuspid regurgitation,
leads to an enlarged, pulsatile liver and ascites. A right
ventricular S3 gallop may be audible and renal and splanchnic
congestion can cause diuretic resistance. Renal venous
congestion combined with decreased renal arterial perfusion
will be exhibited as diuretic resistance, reduced urine
output, and prerenal azotemia.15 Also
evident is a low cardiac output state resulting in fatigue
and syncope or pre-syncope. In acute decompensated right
ventricular failure (ADRVF) reduced cardiac output is
evident by a narrow pulse pressure and hypotension with
peripheral tissue and vital organ hypoperfusion. The latter
increases the arterio-venous oxygen difference. Hypoxemia
may also be the consequence of right to left shunting
in PAH patients with a patent foramen ovale and elevated
right atrial pressure. Further, the destruction of the
cross-sectional pulmonary vascular bed (a pathologic consequence
of protracted PAH) also contributes to hypoxemia and with
reduction in peripheral oxygen delivery, acidosis, which
can lead to life-threatening dysrhythmias, may ensue.
Diagnostic Findings in
Right Ventricular Failure in PAH
Chest radiographs typically show enlarged pulmonary arteries
and distal tapering of the peripheral vessels and on lateral
view an enlarged right ventricular can be visualized by
filling of the retrosternal space. The electrocardiogram
in advanced stages of pulmonary hypertension and right
ventricular failure may reveal right axis deviation, RBBB,
p wave amplitude of more than 2.5 mm, and/or S1Q3T3 pattern
reflective of pressure overload state on the right ventricle.
The R wave will be prominent in V1 with deep S waves in
the lateral precordial leads indicating right ventricular
hypertrophy. Increased p wave amplitude in lead II, qR
pattern in lead V1, and right ventricular hypertrophy
are associated with an increased risk of death.16
Transthoracic echocardiography is the most useful and
readily available noninvasive tool to evaluate right ventricular
failure due to PAH. Typically the right ventricle is hypertrophied
and dilated with poor systolic function and the right
atrium is enlarged while the left ventricle is small and
underfilled. In a cross-sectional view, the left ventricle
appears “D” or crescent shaped as the ventricular septum
displaces or “flattens” toward the left ventricle. Septal
flattening during systole suggests right ventricular pressure
overload, whereas septal flattening during diastole occurs
with volume overload (tricuspid regurgitation). Typically
in right ventricular failure, septal flattening occurs
throughout the cardiac cycle due to both right ventricular
pressure and volume overload. The left ventricle contracts
normally or is hyperdynamic. However, the diastolic transmitral
filling characteristics are abnormal due to reduced left
ventricular compliance. Patients with right ventricular
failure have Doppler evidence of significant tricuspid
regurgitation and moderately to severely elevated pulmonary
artery systolic pressure (PAPs). The PAPs is estimated
from the peak tricuspid regurgitant velocity and an estimate
of right atrial pressure based on inferior vena cava size
and respiratory dynamics. In right ventricular failure,
the inferior vena cava is plethoric and does not collapse
with inspiration, indicative of high right atrial pressure.
Pulse wave Doppler in the right ventricular outflow tract
typically reveals a reduced velocity-time integral suggestive
of low forward output. Agitated saline contrast not only
will aid in the diagnosis of some congenital systemic-to-pulmonary
shunts, but may also detect a patent foramen ovale in
one third of patients. Echocardiographic predictors of
a poor prognosis include an enlarged right atrium, the
presence of a pericardial effusion, and a higher Doppler
global right ventricular index.3,4,17
Pulmonary Artery Catheterization
In right ventricular failure associated with PAH pulmonary
artery catheterization will reveal high right atrial,
right ventricular, and pulmonary arterial pressures with
a PAOP of greater than 15 mmHg. The cardiac and stroke
volume indices are reduced and the mixed venous oxygen
saturation is generally markedly reduced. With end-stage
right ventricular failure, paradoxically the PAP may not
be severely elevated and may actually fall as right ventricular
ejection and the cardiac output are so compromised that
the right ventricle cannot generate a high pulmonary pressure
in the setting of high PVR.18 Ultimately
in the throes of severe right ventricular dilation and
failure, the PAOP may be elevated as left ventricular
compliance is severely compromised with perturbation of
the left ventricular diastolic-pressure volume relationship.
Pulmonary artery catheterization is useful not only for the
diagnosis of right ventricular failure due to PAH but also for
its management. In the case of systemic hypoperfusion and
hypotension, catheterization can often identify the hemodynamic
mechanism for the hypotension. Blood pressure is the
product of cardiac output and SVR and hypotension in
patients with PAH may be a result of either low cardiac output
from right ventricular failure or reduced SVR from overvasodilation
or infection. Precise identification of the operative
hemodynamic derangement will guide therapy in right
ventricular failure due to PAH.
Chronic and Acute RV Failure in PAH
Goals of Therapy
The goals of treating chronic right ventricular failure
due to PAH are to 1) relieve symptoms, improve exercise
capacity, and quality of life; 2) reduce morbidity and
mortality; and 3) improve cardiopulmonary hemodynamics
to prevent worsening of right heart failure (ie, delay
disease progression). The immediate goals of treating
acute decompensatedright ventricular failure (ADRVF),
especially with hemodynamic compromise, are to 1) restore
oxygenation; 2) treat volume overload; and 3) restore
vital organ perfusion. The intermediate and long-term
goals are to optimize the medical regimen to alleviate
symptoms, prevent further disease progression, reduce
morbidity and mortality, and successfully bridge the patient
to lung or heart-lung transplantation in appropriate individuals.7,8
Chronic RV Failure: Medical Therapies
Table 1. Management of Chronic
Right Ventricular Failure in
Pulmonary Arterial Hypertension.
Diet and lifestyle considerations
• Sodium restriction
• Smoking cessation
• Weight loss
• Avoidance of physical exertion in setting
of pre or frank syncope
• Avoidance of pregnancy
• Avoidance of high altitude
Interventions for treatment of pulmonary arterial
hypertension
• Pulmonary vasodilators (endothelial receptor
antagonists, prostanoids, PDE-5 inhibitors)
• Supplemental oxygen
• Anticoagulation (maintain INR 2-3)
Pharmacologic interventions for right ventricular
failure
• Reduction of wall stress by decreasing excessive
preload
–Diuretics: loop, thiazide, and aldosterone
antagonists
• Improve inotropy and reduce neurohormonal
activation
–Digitalis glycosides
Invasive interventions
• Lung transplantation
• Heart-lung transplantation for complex congenital
heart disease
• Percutaneous blade-balloon atrial septostomy
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The long-term goals of managing chronic right ventricular
failure in PAH can be reached by applying the approaches
delineated in Table 1 that have been
reviewed elsewhere.8,19-21
Strategies to prevent and treat chronic right ventricular
failure are aimed at reducing right ventricular wall stress,
thereby minimizing myocardial oxygen consumption and ischemia,
and to improve the inotropic state of the right ventricle.
To reduce wall stress, one must lower right ventricular
afterload. This is accomplished with chronic pulmonary arterial
vasodilators: O2 therapy, endothelin receptor antagonists,
prostanoids, and phosphodiesterase V inhibitors as described
in recent reviews.19,20 Calcium channel
blockers should be avoided in patients with marginal blood
pressure and significant right heart failure as manifest
by right atrial pressures greater than 15 mmHg and low cardiac
index (less than 2.0 L/min/m2). Chronic anticoagulation
is recommended to prevent pulmonary arterial thrombosis
in situ, which contributes to narrowing and remodeling of
the pulmonary arterial bed, consequently increasing right
ventricular outflow impedance.22
Reduction in right ventricular preload and tricuspid
regurgitation to reduce right ventricular wall stress
can be accomplished with diuretics. Chronic therapy with
loop diuretics (furosemide, bumetanide, torsemide) alone
or in combination with intermittent potent thiazide diuretics
(ie, metolazone) and/or aldosterone antagonists (spironolactone,
eplerenone) are effective at controlling volume overload.
Right ventricular failure and hepatic congestion are associated
with aldosterone activation. Use of aldosterone antagonists
in appropriate doses and with close monitoring of electrolytes
can potentiate diuresis in patients treated with loop
diuretics. As aldosterone activation is associated with
sodium/fluid retention, potassium/ magnesium wasting,
increases in ventricular mass and fibrosis, and endothelial
dysfunction, even nondiuretic neurohormonal blocking doses
of the aldosterone antagonists (spironolactone or eplerenone
at 12.5 to 50 mg daily) often exert beneficial effects
in patients with right ventricular failure due to PAH.23
When attempts to decrease right ventricular wall stress
by pharmacologically manipulating right ventricular preload
and afterload are inadequate, an alternative strategy
is to improve right ventricular inotropy. In chronic right
ventricular failure, low dose digoxin (0.125 mg daily)
may be useful. Digoxin can produce a modest increase in
cardiac output and it has been shown to decrease circulating
catecholamine levels.24 Attenuation
of neurohormonal activation may ultimately slow progression
of right ventricular failure in patients with PAH. There
is a paucity of outcome data utilizing digoxin in right
ventricular failure due to PAH.
Chronic RV Failure: Surgical and Interventional Therapies
Atrial septostomy. It is well known that patients with
PAH and a patent foramen ovale have a better prognosis
compared to those without a patent foramen ovale.25
The interatrial communication allows right to left shunting,
thus reducing right atrial pressure and improving left
ventricular filling and cardiac output, delaying progression
of right ventricular failure. Percutaneous blade-balloon
atrial septostomy is a catheterbased technique that allows
the creation of a perforation in the atrial septum allowing
shunting of blood from right to left. It has been utilized
in select patients with right ventricular failure and
syncope.21,26 Atrial
septostomy has been shown to improve clinical status and
produce beneficial long-lasting hemodynamic effects.26
The procedure is limited by systemic arterial oxygen desaturation,
spontaneous closure of the atrial septal aperture, the
potential for paradoxical embolic events, and a high procedure-related
mortality. This investigational procedure should be performed
only by experienced operators. It should not be performed
in moribund patients or in those who have severe right
ventricular failure and are on maximal cardiorespiratory
support. A right atrial pressure greater than 20 mmHg,
a PVR index greater than 55 u/m2 and a predicted 1-year
survival less than 40% are significant predictors of procedure–
related death. Furthermore, patients should have an acceptable
baseline systemic oxygen saturation (greater than 90%
on room air). The procedure is indicated for recurrent
syncope or right ventricular failure, despite maximal
medical therapy, when no other options exist and/or as
a bridge to lung transplantation.27
Extracorporeal membrane oxygenator systems in conjunction
with atrial septostomy in a low cardiac output patient
with hypoxemia have not been studied, but could theoretically
be of value.
Transplantation. Bilateral lung transplantation or heart-lung
transplantation for patients with complex congenital heart
disease may be indicated for suitable candidates with
chronic right ventricular failure who continue to deteriorate
with poor quality of life despite aggressive pharmacologic
therapy. With bilateral lung transplantation, survival
is 70%, 45%, and 20%; with heart-lung transplantation,
it is 65%, 40%, and 25% at 1 year, 5 years, and 10 years,
respectively.21 Long-term survival is
predominantly limited by the development of post-transplant
bronchiolitis obliterans.
ADRVF: Identification and Correction of Precipitating
Factors Factors that may precipitate ADRVF in patients
with chronic right ventricular failure must be sought
and corrected (Figure 2). These include
dietary indiscretion, intercurrent infection, anemia/erythrocytosis,
thyroid disorders, concomitant pulmonary embolus, and
dysrhythmias. Infection must be considered in patients
presenting with decompensated right ventricular failure
and hemodynamic compromise, especially in patients with
an indwelling central venous catheter for epoprostenol
infusion. Infection is poorly tolerated in patients with
right ventricular failure and limited right ventricular
contractile reserve. The increase in right ventricular
work associated with reduction in SVR will result in systemic
hypotension. In this scenario, beta- and alpha- agonists
such as dopamine or norepinephrine are indicated as initial
therapy to stabilize hemodynamics. Anemia also increases
right ventricular work and it has been shown to be associated
with worse quality of life and increased mortality in
patients with PAH.2,29
Erythrocytosis is associated with higher viscosity and
more cardiovascular events in patients with Eisenmenger
syndrome and cor pulmonale from respiratory disorders.8
Specifically, higher hemoglobin levels are associated
with worse cardiopulmonary hemodynamics.28 Pulmonary embolism
as a precipitating factor for ADRVF should be excluded
in the appropriate clinical setting in patients who are
not receiving anticoagulation or are receiving subtherapeutic
doses.
Atrial tachyarrhythmias should be slowed with digoxin,
amiodarone, or diltiazem. The use of beta-blockers or the calcium
blocker verapamil should be avoided as their negative
inotropic effects may exacerbate the low cardiac output state
while vasodilatory effects may reduce the SVR and cause
hypotension. Amiodarone is relatively safe in this setting and is
useful for the management of atrial fibrillation with rapid ventricular
response to slow the rate as well as to facilitate electrical
or chemical cardioversion to sinus rhythm. With symptomatic
bradydysrhythmias, temporary and/or permanent pacemaker
insertion should be considered in the appropriate situation.
Ventricular dysrhythmias usually occur in end-stage right
ventricular failure.
ADRVF: Restoration of Oxygenation and
Prevention of Acidemia
Oxygen is a pulmonary vasodilator and maintenance of adequate
oxygenation in right ventricular failure due to PAH is
of paramount importance. High-flow oxygen has been shown
to reduce PVR and increase cardiac index even in normoxic
patients with pulmonary hypertension30
and should be applied liberally in patients with right
ventricular failure or hypoxemia. Vapotherm is a high-flow
oxygen delivery device that heats and humidifies oxygen
for use with a nasal cannula, face mask, or tracheostomy
mask at flow rates of 6 to 14 L/min that may provide adequate
oxygen delivery without having to use positive pressure.31
Mechanical ventilation may be required for cardiorespiratory
collapse due to ADRVF in order to maintain adequate oxygenation.
However, by increasing transpulmonary pressures, especially
with positive end expiratory pressure (PEEP), mechanical
ventilation may increase right ventricular afterload and
decrease right ventricular stroke volume, aggravating
right ventricular failure and potentially exacerbating
hepatic, splanchnic, and renal congestion.7
The ventilator should be set to the lowest possible PEEP
and acidemia, a potent pulmonary vasoconstrictor, should
be avoided. Small degrees of alkalemia may be beneficial.32
ADRVF: Restoration of Vital Organ Perfusion
In the setting of ADRVF with hypotension once emergent
measures have been applied to stabilize the patient, pulmonary
arterial catheterization should be considered to identify
the hemodynamic mechanism for the hypotension and to guide
therapy. Pharmacologic therapy to reduce right ventricular
afterload and/or increase inotropy should be promptly
and aggressively administered to avoid vital organ damage.
Inhaled nitric oxide (via endotracheal tube or by face
mask) up to 40 ppm can be administered.33,34
Inhaled nitric oxide is a selective pulmonary vasodilator
that reduces the PVR via the cyclic guanosine monophosphate
system without affecting the SVR as it is quickly inactivated
by hemoglobin.33 With the reduction
in pulmonary afterload the cardiac output increases and
the blood pressure can stabilize.34
Alternatively, inhaled epoprostenol or iloprost may be
considered, but unlike inhaled nitric oxide, these agents
can exert systemic vascular effects.35-37
Once stabilized patients can be transitioned to intravenous
epoprostenol which has pulmonary vasodilator properties
and may exert inotropic effects on right ventricular function.38
Continuous intravenous infusion of epoprostenol should
be started at 1 ng/kg/min and titrated by 0.5 to1 ng/kg/min
every 30 minutes while maintaining a systolic blood pressure
of greater than 80 mmHg, until a maximum tolerated dose
is reached. This point is usually marked by the development
of hypotension or other dose-limiting side effects such
as headache, nausea/vomiting, diarrhea, myalgias, arthralgias,
and trismus. If the patient maintains an adequate systemic
blood pressure and cardiac output, inhaled nitric oxide
can be weaned slowly by 5 ppm increments until a dose
of 5 ppm is reached. Thereafter, nitric oxide should be
weaned by 1 ppm increments until off to prevent rebound
increases in pulmonary hypertension. While administering
nitric oxide, methemoglobin levels must be monitored every
6 hours and maintained at less than 5% of hemoglobin to
avoid methemoglobin toxicity.39
Nitric oxide and epoprostenol may be used together in
refractory cases, given that the combination may be additive
as they exert their effects via different cyclic nucleoside
pathways. It must be emphasized that if an acute effect
to epoprostenol is not apparent, the therapy should not
be abandoned (provided multiorgan failure has not occurred)
as its benefits may be delayed. The effects of epoprostenol
on the pulmonary circulation will take time (weeks) and
prove to be effective while the cardiac output and blood
pressure are supported with inotropic agents to avoid
vital organ hypoperfusion. In addition to its pulmonary
vasodilator effects epoprostenol may exert positive right
ventricular inotropic effects via activation of the cyclic
adenosine monophosphate pathway.38 It
should replace or be added to any chronic oral or inhalational
pulmonary vasodilator agent the patient may already be
receiving for PAH when ADRVF supervenes. Intravenous epoprostenol
can assist with the weaning process from inhaled nitric
oxide and beta-adrenergic inotropes in severe right ventricular
failure.
In ADRVF, low dose beta-adrenergic agents such as dobutamine
or dopamine at 1 to 2 mcg/kg/min may improve cardiac output
and restore vital organ perfusion.7 In
the initial treatment of hypotension/hypoperfusion, dopamine
or norepinephrine should be considered to restore right
ventricular function, systemic hemodynamics and coronary
perfusion. These agents may be more beneficial than phenylephrine
alone, which is a selective alpha-agonist.40
Phenylephrine with low-dose dobutamine is a combination
that may be desirable in tachycardic patients with vital
organ hypoperfusion. Manipulating these drugs separately
will allow the clinician to attain specific hemodynamic
effects. The institution of inotropic and vasopressor
agents is a double-edged sword as they can increase right
ventricular work and exert vasopressor effects on the
pulmonary circulation. However, in the appropriate clinical
situation they are essential to restore and maintain systemic
perfusion. The lowest possible dose of these drugs should
be utilized to minimize tachycardia, proarrhythmia, myocardial
oxygen consumption and ischemia, and pulmonary vasoconstriction.
In patients with ADRVF, central venous congestion, and
hypotension volume infusion should not be employed. The
failing right ventricle is operating on the flat to descending
portion of its Frank-Starling curve and further increase
in right ventricular preload will not improve cardiac
output and blood pressure. Volume loading will further
dilate the right ventricle, resulting in worsening tricuspid
regurgitation and right ventricular wall stress. In addition,
as a result of diastolic ventricular interdependence imposed
by pericardial constraint, volume loading will exacerbate
the low systemic cardiac output state due to compromised
left ventricular filling as previously discussed.41,42
The phosphodiesterase-3 inhibitor, milrinone, is an
intravenous inodilator that should be avoided in right
ventricular failure from PAH as its vasodilatory properties
may overwhelm its inotropic effect. Milrinone may reduce
the SVR without affecting the PVR in this patient population
and may exacerbate systemic hypotension. By the same token,
nitric oxide donors such as nitroprusside or nitrates
should not be used in ADRVF due to PAH as they can exacerbate
systemic hypotension.15
Although the recombinant B-type natriuretic peptide
nesiritide is effective in pulmonary hypertension due
to leftsided heart failure, it has not been shown to decrease
PVR when administered acutely in patients with PAH with
or without right ventricular failure.43
Data are lacking for this agent in PAH and concerns for
systemic hypotension do not support use of nesiritide
in this patient population at this time.
ADRVF: Treatment of Volume Overload
In severe right heart failure when diuretic resistance
is operative, aggressive intravenous and combination diuretic
therapy should be instituted. Diuretic resistance may
result from 1) poor intestinal absorption of oral diuretic
secondary to bowel wall edema; 2) pre-existing renal disease;
3) low cardiac output with renal arterial hypoperfusion
and inadequate delivery of solute to the distal renal
tubule; 4) renal arterial hypoperfusion combined with
renal venous congestion resulting in reduced glomerular
filtration; 5) tubular cell hypertrophy due to chronic
diuretic use; 6) intense neurohormonal activation; and/or
7) concomitant administration of nonsteroidal anti-inflammatory
agents or COX-2 inhibitors.44,45 Intravenous
bolus loop diuretic therapy or a continuous infusion of
loop diuretic (furosemide 5 to 20 mg/h, bumetanide 0.5
to 1 mg/h, and torsemide 5 to 10 mg/h) after a priming
bolus dose often overcomes the diuretic resistance.45
The constant infusion strategy will maintain a continuous
renal threshold of drug without the peak and valleys of
the higher dose intermittent bolus administration and
effect a constant diuresis with less ototoxicity. If loop
diuretic drip alone is ineffective, then intermittent
intravenous chlorothiazide (not to exceed 2 gm over a
24 hour period) can be instituted. Intermittent metolazone
can also be administered provided that absorption of the
oral drug is felt to be adequate. The use of an aldosterone
antagonist in conjunction with loop or thiazide diuretics
will often be effective. Aldosterone antagonists should
be avoided in patients with hyperkalemia and significantly
compromised renal function. Electrolytes should be monitored
closely with these agents.
In the patient who is markedly volume overloaded and not
responding adequately to aggressive diuresis, or in whom the
blood urea nitrogen and creatinine are rising, low dose dobutamine
and dopamine should improve renal perfusion and potentiate
diuresis. If diuretic manipulation with inotrope assistance
fails to adequately deal with the volume overload, mechanical
fluid removal usually with continuous venous-venous hemodialysis
or other methods of ultrafiltration should be promptly
employed to decompress the right ventricle, improve right ventricular
performance and left ventricular preload, and reduce
vital organ congestion.
Once hemodynamic stabilization has been achieved with
the maneuvers delineated above, optimization of chronic therapy
should be instituted. For patients who are suitable candidates
for lung or heart-lung transplantation, strategies should
be put in place to successfully bridge them to surgery. For those
who are unstable and/or have refractory right ventricular failure
and are not candidates for transplantation, the emphasis of
care should shift to palliation of symptoms and hospice care
when appropriate.
Conclusions
In patients with PAH, right ventricular failure is associated
with a poor prognosis. Established therapies for PAH should
be instituted early and optimized to prevent right ventricular
failure. Diuretics are the mainstay of therapy for right ventricular
failure and should be optimized. For patients who
present with ADRF an aggressive approach should be undertaken.
Pharmacologic therapy including oxygen, inhalational
nitric oxide, epoprostenol, and inotropic support must be
instituted rapidly to prevent vital organ hypoperfusion.
Volume overload must be treated promptly to decompress
the right ventricle and promote left ventricular filling.
Sequential nephron blockade with intravenous loop and thiazide
diuretics as well as aldosterone antagonists should be
instituted. Mechanical fluid removal should be applied if
diuretic therapy fails. In suitable patients who continue to
deteriorate despite optimal medical therapy, prompt evaluation
and listing for lung or lung-transplantation is indicated.
At specialized centers, atrial septostomy should be considered
for severe right ventricular failure, recurrent syncope, or
as a bridge to lung transplantation. Intravenous epoprostenol
and beta-adrenergic inotropic agents may be utilized in
combination as a bridge to transplantation. For end-stage
right ventricular failure, when all treatment options are
exhausted or are inappropriate, the focus of management
should transition to palliative care.
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