Management of Crashing

P a t i e n t s wi t h Pu l m o n a r y
Hypertension
a, b
John C. Greenwood, MD *, Ryan M. Spangler, MD

KEYWORDS

Pulmonary hypertension
Right ventricular failure
Cardiogenic shock

KEY POINTS

Management goals for patients with pulmonary hypertension (PH) are to optimize preload
and volume status, maintain right ventricular function, prevent right coronary artery mal-
perfusion, reduce right ventricular afterload, and reverse the underlying cause whenever
possible.

Right ventricular failure is a hallmark finding in patients with decompensated PH.

The bedside echocardiogram is the most useful tool when evaluating patients with PH and
suspected right heart failure.

Atrial fibrillation, atrial flutter, and atrioventricular nodal reentrant tachycardia are the most
common dysrhythmias in patients with PH. Rhythm control is preferred over rate control in
patients with severe PH.

Unmonitored continuous fluid administration should be avoided in patients with PH
because it often worsens pressure overload of the right heart.

INTRODUCTION

Critically ill patients with pulmonary hypertension (PH) often seem well, but they can
decompensate dramatically in a short time. PH has several causes, classes, and com-
plications; but the natural progression eventually leads to right ventricular (RV) failure,
which can be extraordinarily difficult to manage. The purpose of this review is to
discuss the causes, signs, and symptoms of PH as well as its management strategies
and emergent complications. Treatment options are often limited, so it is imperative

Funding sources: nothing to disclose.

Conflict of interest: nothing to disclose.
a
Department of Emergency Medicine, Ground floor, Ravdin Hospital of the University of Penn-
sylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA; b Department of Emergency Medi-
cine, University of Maryland School of Medicine, 110 South Paca Street, 6th Floor, Baltimore,
MD 21201, USA
* Corresponding author.
E-mail address: [email protected]

Emerg Med Clin N Am 33 (2015) 623–643

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624 Greenwood & Spangler

that the emergency department (ED) physician can recognize and manage these pa-
tients in a timely fashion.

CLASSIFICATION

PH is defined by an elevated mean pulmonary artery pressure (PAP) (25 mm Hg) dur-
ing right heart catheterization (normal, 14–20 mm Hg).1,2 The first classification of PH
was published by the World Health Organization (WHO) in 1973. The classification has
been revised several times since then. The current structure, with 5 groups (Table 1), is
based on cause, physiology, pathology, and treatment (Fig. 1).
Group 1 PH is defined by a pulmonary wedge pressure of 15 mm Hg or less, indi-
cating isolated pulmonary arterial hypertension (PAH) and normal left ventricular (LV)
function.2 This group has a much lower prevalence than the others.3 In 1970, the his-
tologic differences between this group and the others were delineated.4 The differ-
ence is thought to be the result of a variety of homeostatic imbalances related to
vasoactive chemicals, growth factors, and prothrombotic and antithrombotic

Table 1
Current classification of PH

Group 1 PAH
1.1 Idiopathic PAH
1.2 Heritable PAH
1.3 Drug and toxin induced
1.4 Associated with connective tissue disorders, HIV infection, portal
hypertension, congenital heart disease, schistosomiasis
Group 10 Pulmonary venoocclusive disease and/or pulmonary capillary
hemangiomatosis
Group 2 PH caused by left heart disease
2.1 Left ventricular systolic dysfunction
2.2 Left ventricular diastolic dysfunction
2.3 Valvular disease
2.4 Congenital/acquired left heart inflow/outflow tract obstruction and
congenital cardiomyopathies
Group 3 PH caused by lung diseases and/or hypoxia
3.1 Chronic obstructive pulmonary disease
3.2 Interstitial lung disease
3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern
3.4 Sleep-disordered breathing
3.5 Alveolar hypoventilation disorders
3.6 Chronic exposure to high altitude
3.7 Developmental lung diseases
Group 4 Chronic thromboembolic PH
Group 5 PH with unclear multifactorial mechanisms
5.1 Hematologic disorders: chronic hemolytic anemia, myeloproliferative
disorders, splenectomy
5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis,
lymphangioleiomyomatosis
5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid
disorders
5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal
failure, segmental PH

Abbreviations: HIV, human immunodeficiency virus; PAH, pulmonary arterial hypertension.

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 Crashing Patients with Pulmonary Hypertension 625

Fig. 1. Anatomic and pathophysiological considerations for patients with PH.

chemicals in the pulmonary vasculature.5 Group 1 is broken into subgroups based on

cause.
Several drugs have been implicated as causing PAH and can be important in
assessing patients’ overall risk of disease (Table 2).6 In the 1960s, an epidemic of
PAH was linked to appetite-suppressing drugs. Toxic rapeseed oil and selective sero-
tonin reuptake inhibitors have been implicated as risk factors for the development of
PAH.7–9 Chin and colleagues10 found that nearly 30% of the patients with PAH in their
study had a history of stimulant use (methamphetamine, amphetamine, cocaine);
however, direct causation has not been proven.
Heritable PAH is associated with several acquired and congenital conditions as well
as connective tissue disorders, infection with the human immunodeficiency virus (HIV),
portal hypertension, and congenital heart defects.11 Patients with a history of sclero-
derma or with congenital heart disease are at a particularly high risk of mortality when
diagnosed with PAH.12,13 Schistosomiasis is the most prevalent cause of PAH world-
wide, with mortality approaching 15% at 3 years.14,15
Pulmonary venoocclusive disease (PVOD) and pulmonary capillary hemangiomato-
sis (PCH) share the unique category of group 1’. This distinction was made because,

Table 2
Drugs that can cause PH

Definite Association Likely Association Possible Association

Aminorex Amphetamines Cocaine
Fenfluramine L-tryptophan Phenylpropanolamine
Dexfenfluramine Methamphetamines St. John’s wort
Toxic rapeseed oil Dasatinib Chemotherapeutic agents
Benfluorex — Interferon a and b
Selective serotonin reuptake — Amphetaminelike drugs
inhibitor

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626 Greenwood & Spangler

although PVOD and PCH often cause pathologic changes similar to those seen in
group 1 PAH and have similar risk factors, they can cause physical examination find-
ings distinct from those associated with idiopathic PAH.16 Clinical outcomes in these
patients also tend to be worse than for those with group 1 PAH.17
Most patients with PH will be classified as group 2 PH, which is often a result of sig-
nificant left heart disease or left-sided valvular abnormalities.18 Untreated LV systolic
or diastolic dysfunction as well as mitral regurgitation, mitral stenosis, and aortic ste-
nosis can all cause chronically elevated pulmonary vascular pressures, leading to the
development of PH. The inciting factor is the backward transmission of pressures
resulting from valvular or LV dysfunction, causing what is initially a transient increase
in pulmonary vascular pressure. However, over time, this increased pressure results in
vascular remodeling and a new fixed PH.19
Group 3 encompasses several primary pulmonary disorders (eg, emphysema/
chronic obstructive pulmonary disease and interstitial lung disease) plus causes of
chronic hypoxemia (eg, living at high altitude and cystic fibrosis). Hypoxemia itself
constricts the pulmonary vasculature through a variety of neurohormonal and cellular
mechanisms, which, over time, leads to vascular hypertrophy and sustained PH.20
Most group 3 patients have mild pulmonary pressure elevation but rarely go on to
develop severe PH (mean PAP >40 mm Hg).21,22
Group 4 PH, referred to as chronic thromboembolic PH (CTEPH), occurs in approx-
imately 4% of patients after acute pulmonary embolism (PE).23 It is thought that PH
develops in patients with chronic PE as a result of persistent macrovascular obstruc-
tion that causes small vessel arteriopathy, leading to persistent small vessel pulmo-
nary vasoconstriction and thrombosis in situ.24,25
Group 5 comprises multiple forms of PH with unknown cause. These forms include
hematologic, systemic, metabolic, and mechanical disorders. The 2 diseases in this
category that are most commonly implicated are sarcoidosis and thyroid disease.26,27

RIGHT VENTRICULAR DYSFUNCTION

In healthy patients, the RV is a thin-walled, crescent-shaped structure that shares the

intraventricular septum with the LV. Together, the free wall and the septum contribute
equally to RV function. The free wall of the RV is highly elastic and responds readily to
changes in volume, whereas the LV is less compliant and more suited to overcome
changes in pressure. Normally, the RV is required to generate only 25% of the stroke
work because of the low resistance of the pulmonary vasculature.28 The principle of
ventricular interdependence is important, as superficial myocardial fibers encircle
both ventricles and the RV and LV work collectively in series to maintain cardiac
output. Because the ventricles share an intraventricular septum, and both are con-
tained within the same pericardial cavity (except in patients who have undergone car-
diac surgery), any disruption in the size or shape of these cavities can have deleterious
effects on cardiac output.29,30
Unlike the LV, the thin, compliant RV is unable to overcome large changes in after-
load. In the presence of chronic PH, the RV is subjected to pressure overload because
of excessive pulmonary vascular resistance (PVR). Chronic elevations in PVR cause
the RV to undergo both adaptive (preserved systolic and diastolic function) and mal-
adaptive remodeling (causing RV dysfunction).
Sustained elevations in PVR cause a pressure-induced growth of RV cardiomyo-
cytes and proliferation of a collagen-based extracellular matrix.31–33 RV enlargement
encroaches on LV filling, decreasing cardiac output. Reduced RV function is often
characterized by uncoupling of the RV and pulmonary vasculature, leading to

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 Crashing Patients with Pulmonary Hypertension 627

disruption of the normal relationship between the RV and the pulmonary arterial tree.34
Changes in the anatomic structure of the RV eventually result in systolic and diastolic
dysfunction of both ventricles as well as increase the risk of dysrhythmias related to
abnormal conduction.35,36
Perfusion of the right coronary artery (RCA) is severely impaired in patients with
advanced PH.37 The blood supply of the RV’s free wall varies according to the
anatomic dominance of the coronary system. In approximately 80% of the general
population, the RCA provides perfusion to the RV.38,39 The left anterior descending
coronary artery supplies the anterior two-thirds of the septum, and the posterior
descending artery supplies the inferoposterior third.28
Under normal circumstances, the RCA is perfused during both systole and dias-
tole.40 As RV remodeling progresses in patients with chronic PH, elevation in RV
wall tension and transmural pressure impairs RCA systolic perfusion to the point
that blood flow occurs almost exclusively during diastole.37,41–43 Malperfusion of the
RCA leads to RV ischemia and an increased risk of arrhythmias and can rapidly pre-
cipitate RV failure.

EMERGENCY DEPARTMENT PRESENTATION

PH in patients presenting to the ED can be very difficult to recognize and diagnose. In

general, the symptoms are highly nonspecific and slow to progress. Therefore, pa-
tients often go undiagnosed and are managed improperly for a long time, even if
they are symptomatic. Despite increasing clinical education and awareness, 20% of
cases of symptomatic PAH are undiagnosed for more than 2 years.3,44
Of even greater concern is that most patients with PAH do not receive a diagnosis
until they are severely debilitated (WHO functional classes III and IV) and have a much
higher risk of death.3,45,46 It is critical to assess for PH risk factors (Table 3) is an
important tool.
Many of the presenting complaints associated with PH are nonspecific. The most
common is dyspnea, either on exertion or at rest, occurring in 60% to 99% of
cases.3,44,47 Other presenting symptoms include peripheral edema, chest pain, syn-
cope, lightheadedness, palpitations, and fatigue.48,49 Syncope or presyncope sug-
gests more severe disease. It is seen in up to one-third of patients with PH and has
a variety of mechanisms, including fixed cardiac output, arrhythmias, and cardiac
ischemia.
In addition to the patients’ history, several clues suggesting PH can be picked up on
the physical examination. A midsystolic murmur, early systolic click, left parasternal
lift, and prominent jugular pulsation are all associated with increased PAP.47,50 An
accentuated P2 heart sound is found in almost 90% of patients.51 Central cyanosis
from Eisenmenger syndrome, clubbing caused by chronic lung disease,

Table 3
Risk factors for PH

Definite Likely Possible

Drugs and toxinsa Portal hypertension Pregnancy
Female sex Connective tissue disorder Systemic hypertension
HIV infection Congenital systemic-pulmonary cardiac shunts Thyroid disorder
a
See Table 2.
Adapted from Galiè N, Torbicki A, Barst R, et al. Guidelines on diagnosis and treatment of pul-
monary arterial hypertension. Eur Heart J 2004;25:2243–78.

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628 Greenwood & Spangler

hepatomegaly, spider angiomas, or signs of scleroderma and other connective tissue

disorders might also be seen. Hypotension, decreased pulse pressure, and cool ex-
tremities could indicate impending cardiovascular collapse.

DIAGNOSTIC STUDIES

When evaluating ED patients with suspected PH, several laboratory and diagnostic
studies can be useful (Table 4). Electrocardiography, chest radiography, and
computed tomography (CT) are commonly performed and should be considered.

Laboratory Testing
Laboratory assessment of symptomatic patients with PH is often critical and should be
directed toward excluding cardiac ischemia and new end-organ dysfunction and
assessing global perfusion. Specific tests to be considered include measurement of
troponin I to look for signs of myocardial strain and ischemia as well as a lactic acid
to evaluate for systemic hypoperfusion. Laboratory testing for electrolyte imbalances,
anemia, liver function, and coagulopathy can provide prognostic information as well as
give clues to an underlying correctable disturbance.46,52
Measurement of B-type natriuretic peptide (BNP) can be helpful in the acute setting
if the current level can be compared with previous values. This comparison can indi-
cate RV dysfunction in acutely decompensated patients.53,54 An increase in the BNP
or troponin value or worsening renal function is associated with a higher mortality
rate.46,55

Electrocardiogram
The electrocardiogram (ECG) is a cheap, rapid, and valuable diagnostic tool for pa-
tients with known or suspected PH. Common ECG findings in patients with PH are
listed in Box 1. They are often the result of significant right heart dysfunction.
Right axis deviation is found in 70% of patients with PH, along with signs of RV hy-
pertrophy, such as an incomplete right bundle branch block or a tall R wave in V1.56 A
tall P wave in the inferior leads can indicate right atrial enlargement.57 Signs of RV
strain include ST depressions and T-wave inversions in the inferior and right precordial
lead.57 The mortality rate may be increased among patients with PH and evidence of
right ventricular hypertrophy (defined by the WHO criteria) and dysfunction.57
The most common arrhythmias in patients with PH are supraventricular tachycar-
dias, including AV nodal reentrant tachycardia, atrial fibrillation, and atrial flutter.48 It
is imperative to recognize any dysrhythmia and treat it quickly. Atrial fibrillation is

Table 4
Testing for suspected PH

Emergency Testing Beyond the ED

ECG VQ scan
Chest film MRI
Echocardiography Pulmonary function tests
CT scan 6-min walk test
Troponin Right heart catheterization
BNP Genetic testing

Abbreviations: BNP, B-type natriuretic peptide; CT, computed tomography; ECG,

electrocardiogram.

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 Crashing Patients with Pulmonary Hypertension 629

Box 1
Common ECG findings associated with PH

Normal sinus rhythm

Right-axis deviation
Right bundle branch block
rSR0 in V1
qR V1
Large inferior P waves
ST depression or T-wave inversion inferiorly and in the V1
RV hypertrophy

particularly malignant in patients with PH and is associated with a mortality rate

exceeding 80%.48 Tachydysrhythmias are particularly problematic, as the loss of an
atrial kick can impair ventricular filling, leading to a reduction of cardiac output and
rapid cardiovascular collapse (Fig. 2).
Chest Radiography
A chest radiograph should be obtained in any symptomatic patient with suspected
PH. Common findings on the anterior-posterior view include enlarged hilar pulmonary
arterial shadow, pulmonary venous congestion, increased peripheral vascular mark-
ings (pruning), prominent right heart border, and right atrial enlargement. A common
radiologic phenomenon is vascular pruning, characterized as enlarged proximal pul-
monary arterial shadows that have an early, dramatic taper toward the periphery
(Fig. 3).47 In the lateral view, obliteration of the retrosternal space could indicate RV
enlargement caused by dilation or hypertrophy. However, the absence of these find-
ings does not exclude PH as a possible diagnosis, as they are not universally
present.47,58
Computed Tomography
CT of the chest can be helpful when evaluating patients with suspected PH because it
can show structural abnormalities of the heart and lung as well as vascular abnormal-
ities if performed with intravenous contrast or angiography. RV enlargement, hypertro-
phy, and dysfunction can be well visualized on a CT scan. Other findings suggestive of
PH include a main pulmonary artery diameter greater than 30 mm.59 In fact, there is a
96% positive predictive value for PH if the maximum transverse diameter of the main
pulmonary artery is greater than the diameter of the proximal ascending thoracic aorta
(Fig. 4).60
For any patient with new cardiopulmonary symptoms and known PH, early chest CT
should be considered strongly to evaluate for a new PE. Patients with chronic PH are
at higher risk for acute PE caused by preexisting RV dysfunction and reduced pulmo-
nary vascular flow. Even small acute PE can cause hemodynamic deterioration in
these patients. Current CT scans are valuable, as they can often differentiate old
from new thrombotic material.
Echocardiography
Echocardiography is one of the most useful diagnostic tools for the emergency physi-
cian when evaluating patients with suspected PH. A rapid, bedside transthoracic

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630 Greenwood & Spangler
Fig. 2. ECG of a patient with PAH, presenting with atrial fibrillation and signs of RV hypertrophy.
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 Crashing Patients with Pulmonary Hypertension 631

Fig. 3. (A) Evidence of right atrial enlargement and vascular pruning on posteroanterior
chest radiograph of patient with PAH. (B) Obliteration of the retrosternal space on lateral
chest radiography indicating RV hypertrophy or enlargement.

echocardiogram (TTE) often provides critical diagnostic information about the func-
tional status of the right and left sides of the heart. Evaluation of the RV is the single
most important component of the echocardiographic examination.
In the presence of elevated pulmonary pressures, patients often develop right atrial
and RV dilation. In contrast to PH secondary to acute PE, in which the RV is dilated and
thin, the RV in most patients with PH is thickened (Fig. 5) (seen in almost all standard
TTE views).
Other signs of RV dysfunction include an RV:LV ratio greater than 1 in the apical 4-
chamber view or an RV end-diastolic diameter greater than 20 mm with or without
inspiratory collapse of the inferior vena cava.61 Signs of RV pressure overload can
be found by focusing on the shape of the intraventricular septum in the parasternal
short-axis view. The classic D sign can be seen as the septum shifts paradoxically to-
ward the LV during early diastole. Complete bowing of the septum into the LV is a poor
prognostic sign and can indicate severe RV overload or end-stage disease, impairing
LV filling (Fig. 6).49,59

Fig. 4. Chest CT scan showing signs of PH, including vascular pruning and a main pulmonary
artery diameter greater than the proximal ascending aorta.

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632 Greenwood & Spangler

Fig. 5. (A) Evidence of chronic PH caused by dilated and hypertrophied RV with a dilated RA.
(B) Evidence of acute PH with dilated and thin RV and atrium. LA, left atrium; RA, right
atrium.

INITIAL MANAGEMENT

In general, the primary management goals should focus on identifying the underlying
cause and improving RV function. Patients with symptomatic PH can progress rapidly
to obstructive shock, cardiogenic shock, or cardiac arrest. RV systolic dysfunction,
secondary LV dysfunction, severe tricuspid regurgitation, and arrhythmias can
contribute to low cardiac output and hypotension. Specific attention should be
directed toward optimizing intravascular volume (preload), RV systolic function,
RCA perfusion, and RV afterload. It is important to note that guidelines for the manage-
ment of patients with PH have not been published, so most current recommendations
are based on expert opinion.

Preload and Volume Status

Intravascular volume assessment in patients with PH can be extraordinarily difficult.
Traditional methods of assessing fluid responsiveness, such as central venous pres-
sure, pulse pressure variation, and stroke volume variation, are unreliable in patients
with RV dysfunction.62,63 Elevation in plasma atrial natriuretic peptide and BNP seems
to increase proportionately to the extent of RV dysfunction in patients with PH.54,64
The traditional gold standard for the diagnosis and management of PH and RV

Fig. 6. The D sign. Transthoracic echocardiographic evidence of RV dysfunction and pressure

overload.

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 Crashing Patients with Pulmonary Hypertension 633

dysfunction is pulmonary artery catheterization (PAC). Although PAC can aid in diag-
nosis, its routine use has not been shown to improve patient outcomes.65,66
The goal of fluid resuscitation in patients with PH is to ensure adequate, but not
excessive, RV preload. Most patients with PH have elevated right heart pressures at
baseline but can augment their cardiac output with intravenous fluid administration.67
As a result, most experts agree that aggressive volume loading should be avoided in
patients with evidence of increased RV filling pressures. Administering intravenous
fluids to patients with a measured right atrial pressure or central venous pressure of
greater than 10 to 15 mm Hg can worsen right heart performance by further distending
the RV, increasing the septal shift toward the LV, and consequently worsen cardiac
output by further distorting ventricular interdependence.68
For hemodynamically stable patients with volume overload, diuretic therapy can be
considered, with a goal of maintaining a negative fluid balance, as many patients have
an overstretched RV operating on the flat portion of the Frank-Starling curve. Diuretics
have been a conventional therapy for patients with PH related to pulmonary vascular
disease or LV failure.69 Common agents, such as furosemide or bumetanide, may be
used in patients with an adequate glomerular filtration rate and should be adjusted ac-
cording to the patients’ hemodynamic response.
For hypotensive patients with PH, or those who seem to be hypovolemic, a 500-mL
bolus of an isotonic crystalloid solution should be administered. Repeated boluses
may be administered but should be monitored to confirm a favorable hemodynamic
response. RV failure and hypotension are more often the result of increased RV after-
load and hypervolemia rather than volume depletion.70 Continuous, unmonitored fluid
administration is not recommended. Many unstable patients with PH who are hyper-
volemic require early initiation of vasopressor and inotropic medications rather than
repeated fluid boluses.

Optimize Right Ventricular Systolic Function

In addition to preload optimization, RV systolic function should be maximized.
Inotropic therapy is often required for patients with advanced PH and should be
considered if there is evidence of inadequate oxygen delivery or volume overload
that cannot be managed with diuretics alone.
The two most commonly used inotropic medications are dobutamine and milrinone.
Dobutamine is a selective b1-agonist that increases myocardial contractility, reduces
PVR and systemic vascular resistance (SVR), and improves PA/RV coupling. It is the
preferred inotropic medication for patients with PH.69,71,72 Dobutamine is superior to
vasopressors (eg, norepinephrine) alone in patients with pressure-induced right heart
failure.72 In normotensive patients with PH with RV dysfunction, a dobutamine infusion
should be initiated at 2 mcg/kg/min and titrated to a maximum of 10 mcg/kg/min. Infu-
sion rates greater than 10 mcg/kg/min should be avoided, as they have been shown to
increase RV afterload and produce reflexive tachycardia and are associated with an
increased mortality rate.72,73 It is important to anticipate complications, such as sys-
temic hypotension, secondary to dobutamine’s b2-mediated systemic vasodilatory
properties. If hypotension does occur, vasopressor therapy should be initiated rapidly.
Milrinone is a selective phosphodiesterase-3 inhibitor that increases contractility by
increasing cyclic AMP levels and the concentration of intracellular calcium. In patients
with pulmonary vascular dysfunction in the setting of multifactorial PH, LV failure,
postventricular assist, or cardiac transplantation, milrinone has been shown to reduce
pulmonary pressures and improve RV function.74–76 A milrinone infusion can be
started at 0.375 mcg/kg/min and titrated to a maximum of 0.75 mcg/kg/min. The

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634 Greenwood & Spangler

use of milrinone is also limited by systemic hypotension at higher doses and might
require the coadministration of vasopressor therapy.

Maintain Right Coronary Artery Perfusion

Preservation of RCA perfusion to prevent RV ischemia requires a mean arterial blood
pressure that is greater than the PAP. If PVR exceeds SVR, RCA perfusion will occur
only during diastole, which leads to increased RV ischemia.37 In hypotensive patients
with PH, vasopressor therapy should be instituted promptly to increase the SVR:PVR
ratio and preserve coronary blood flow.
Little has been published regarding the use of specific vasopressors in the setting of
PH. Norepinephrine is considered by many to be the vasopressor of choice, as it im-
proves RV function through increases in SVR and cardiac output. In a comparison with
dopamine, norepinephrine was found to have a lower 28-day mortality rate in patients
with cardiogenic shock and a reduced rate of tachydysrhythmias.77 The initial dosage
of norepinephrine is 0.05 mcg/kg/min. Although there is no true maximum dose of
norepinephrine, higher doses have been reported to cause pulmonary vasoconstric-
tion, a detrimental effect for patients with impaired RV function.
Vasopressin is an intriguing vasopressor option, given its minimal effect on PVR. At
lower doses, vasopressin may in fact cause pulmonary vasodilation through the pro-
duction of endothelium-mediated nitric oxide (NO), but its role in managing decom-
pensated patients with PH requires further investigation.69 Phenylephrine is a potent
a1-adrenergic agonist and a strong arteriolar vasoconstrictor that can worsen RV
pressure overload in patients with chronic PH.78,79 In general, phenylephrine should
be avoided in patients with PH because it increases mean PAP and PVR, thereby
worsening RV systolic function.

Reduce Right Ventricular Afterload

Increased RV afterload caused by excessive PAP is often the central cause of decom-
pensation in patients with PH. RV afterload can be reduced by ensuring adequate
oxygenation, avoiding prolonged hypercapnia, minimizing acidosis, and adminis-
tering pulmonary vasodilators. Prolonged hypoxemia and hypercapnia are common
precipitants of increased PVR.80–82 Supportive therapy should begin with supple-
mental oxygen to maintain the arterial oxygen saturation greater than 90%.70,83
Adequate oxygenation has been shown to selectively dilate pulmonary vasculature
and improve cardiac output, regardless of the primary cause of PH.84 Continuous
positive airway pressure or noninvasive, bilevel positive airway pressure ventilation
may be considered and can be particularly helpful when managing patients with
group 2 or group 3 PH but should be used with caution if there is a concern for inad-
equate preload.
Every attempt should be made to avoid endotracheal intubation and mechanical
ventilation. Initiation of positive-pressure ventilation in unstable patients with PH can
have negative hemodynamic effects by increasing PVR and reducing venous return.
If mechanical ventilation is required, etomidate is the preferred induction agent
because of its minimal effect on SVR, PVR, and cardiac contractility. The use of
lung-protective ventilator settings is recommended to avoid ventilator-associated
lung injury and increases in PVR. Permissive hypercapnia should be avoided, as it
can increase PVR by approximately 50% and mean PAP by approximately 30%.85
Plateau pressures should be monitored frequently, the goal plateau pressure being
less than 30 cm H2O. Excessive plateau pressures can cause direct compression of
the pulmonary vasculature, further increasing PVR.

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 Crashing Patients with Pulmonary Hypertension 635

Nitric oxide
Inhaled NO (iNO) is a potent pulmonary vasodilator that can be administered by face
mask as a temporizing measure to prevent intubation or during mechanical ventilation.
Local effects of iNO include a reduction in PAP and PVR, improved oxygenation, and
reversal of hypoxic vasoconstriction without affecting SVR or cardiac output.71,86 iNO
therapy seems to have a short-term benefit in patients with acute right heart failure
secondary to PH but does not seem to provide an overall mortality benefit other
than for patients with acute postoperative PH.87,88 Abrupt discontinuation of iNO
therapy can result in rebound PH and, therefore, should be avoided. Prolonged iNO
therapy has also been associated with methemoglobinemia, so it is recommended
that serum concentrations should be determined before initiation of therapy and
monitored every 6 hours during treatment.59
Continuous infusions of pulmonary vasodilators are rarely administered to treat-
ment-naı̈ve or hemodynamically unstable patients with PH in the ED. Given their
frequent use in patients with stable PAH, it is important for the emergency physician
to be familiar with them. The pulmonary vasodilators that are commonly used in PH
are prostanoids, phosphodiesterase inhibitors, and endothelin receptor antagonists.
For any patient with PH presenting to the ED, it is critical to determine if any of these
medications have been discontinued abruptly. If so, the medication must be reinitiated
as soon as possible to prevent rebound PH and cardiovascular collapse.89,90 In all
cases, these medications can be restarted through a peripheral intravenous catheter
and do not require immediate central venous access.

Prostanoids
Most patients with previously diagnosed, advanced PAH are receiving continuous
prostanoid therapy. Epoprostenol, treprostinil, and iloprost cause pulmonary vasodi-
lation and have both antiplatelet and antiproliferative effects. Their effects are often
limited by hypotension as well as nausea, flushing, headache, and diarrhea.91 Prosta-
cyclin treatment should be avoided in patients with significant LV dysfunction, as
initiation can lead to the development of worsening pulmonary edema and further
reduce LV function.92
Epoprostenol was the first therapy approved for use in advanced PAH and classi-
cally is the initial treatment of choice. It is administered continuously through a periph-
erally inserted central catheter. This drug has an extremely short half-life of just 2 to
5 minutes.93,94 Treprostinil can be administered through a continuous intravenous
infusion or subcutaneously. In contrast to epoprostenol, the half-life of treprostinil is
approximately 4 to 5 hours, making it a more attractive alternative for outpatient man-
agement. The initial dosages and half-lives of prostanoids are listed in Table 5. If infu-
sion pump malfunction or catheter occlusion occurs, both epoprostenol and
treprostinil can be administered through a peripheral intravenous catheter. In patients

Table 5
Prostenoid infusions for use in PAH

Drug Starting Dosage Target Dosage Half-life Steady State

Epoprostenol (IV) 2.0 mg/kg/min 20–40 mg/kg/min 2–5 mina 15 min
Treprostinil (SC) 1.25 mg/kg/min 40 mg/kg/min 4.0–4.5 h 10 h
Treprostinil (IV) 1.25 mg/kg/min 40 mg/kg/min 4.0–4.5 h 10 h

Abbreviations: IV, intravenous; SC, subcutaneous.

a
At a temperature of 37 C and a pH of 7.4.

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636 Greenwood & Spangler

with PAH on chronic prostacyclin therapy, treatment can be reinitiated at the home
infusion rate if they are hemodynamically stable. If they are unstable, or presenting
with vasodilatory or mixed shock, lower infusion rates can be considered; but it is
important to weigh the risks of worsening systemic hypotension with the benefits of
treatment.

Phosphodiesterase inhibitors
Phosphodiesterase-5 (PDE-5) inhibitors (eg, sildenafil) increase cyclic GMP signaling
and can potentiate the effects of NO. PDE-5 inhibitors can reduce PVR acutely, in-
crease cardiac output, and reduce pulmonary capillary wedge pressure. Although
these agents can improve clinical end points in stable patients with chronic PAH, their
use has not been evaluated in setting of acute RV failure, so they should not be used in
the acute setting.70,89

ADDITIONAL CONSIDERATIONS
Dysrhythmias
Atrial dysrhythmias represent one of the most common precipitants of acute decom-
pensation in patients with PH. Supraventricular tachydysrhythmias, specifically atrial
fibrillation and atrial flutter, are the most prevalent, with an annual incidence of
2.8% in patients with PAH or inoperable CTEPH.48 More than 80% of patients with
PH presenting with atrial fibrillation or atrial flutter experience hemodynamic compro-
mise or acute RV failure. The incidence of tachydysrhythmias in patients with PH is an
independent predictor of death.48,95 In general, most patients with atrial fibrillation or
atrial flutter should be managed aggressively with electrical or chemical cardioversion
to restore sinus rhythm.48 Rate control with b-adrenergic receptor antagonists or cal-
cium channel blockers is not recommended, as these medications can impair cardiac
contractility, leading to cardiogenic shock.

Anemia
Underlying hemoglobinopathies and significant anemia can worsen RV ischemia in the
setting of PH. In decompensated patients with PH, the transfusion risks along with
consideration of the patients’ volume status must be weighed against the potential
benefit, as specific transfusion thresholds are not well established. General practice
would suggest to maintain a hemoglobin level greater than7 g/dL; however, the ideal
level in patients with RV failure secondary to PH has never been studied.96 Theoreti-
cally, reduced oxygen-carrying capacity secondary to worsening anemia or specific
hemoglobinopathies could exacerbate RV ischemia. Some investigators have sug-
gested that hemoglobin levels should be maintained at greater than 10 g/dL.70,97

Anticoagulation
Anticoagulation therapy is a mainstay of outpatient treatment of patients with idio-
pathic PAH and CTEPH. A goal international normalized ratio of 2.0 to 3.0 in patients
with CTEPH has been suggested and of 1.5 to 2.5 in those receiving long-term contin-
uous prostacyclin therapy.2,98 Oral anticoagulation therapy has been associated with
improved outcomes; however, specific therapeutic targets have not been well estab-
lished.83 Data for anticoagulation of patients with PH in the acute setting are also lack-
ing. If an acute venothromboembolic event is suspected to be the precipitant cause of
clinical decompensation, unfractionated heparin should be initiated, starting at 18
units/kg/h, with a goal activated partial thromboplastin time of 1.5 to 2.5 times the
control.

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 Crashing Patients with Pulmonary Hypertension 637

Mechanical Circulatory Support

The use of extracorporeal life support (ECLS) or extracorporeal membrane oxygena-
tion (ECMO) has been reported as salvage therapy for patients with PH in refractory
shock.95,99,100 The purpose of ECLS is to provide a bridge to definitive treatment,
such as transplantation or initiation of pulmonary vasodilator therapy.101 For severely
hypoxic patients with early signs of RV failure, percutaneous venovenous ECMO can
be initiated rapidly and improve hemodynamics significantly by reversing hypoxic pul-
monary vasoconstriction and the deleterious effects of severe acidemia. In the setting
of imminent cardiovascular collapse, percutaneous venoarterial ECMO can be per-
formed to provide both cardiovascular and pulmonary support. After ECMO is initi-
ated, many patients experience a rapid reversal of hemodynamics, decreased
vasopressor requirements, reduced inotropic dependence, improved gas exchange,
and increased end-organ perfusion.102 The use of ECLS in patients with PH is
extremely resource intensive and should be considered on a case-by-case basis.

SUMMARY

Patients with PH are some of the most critically ill patients in the ED. The diagnosis is
often delayed until patients are highly dysfunctional before receiving appropriate treat-
ment. Careful attention must be directed toward addressing volume status, optimizing
RV function, maintaining RCA perfusion, and reducing RV afterload. Continuous infu-
sion of a prostanoid, such as epoprostenol, is used only in patients with significant
end-stage disease and should only be initiated after a thorough work-up and evalua-
tion as in-patients. If the administration is stopped abruptly, it must be restarted
immediately to avoid rapid deterioration and cardiovascular collapse. ECMO support
can be considered, on a case-by-case basis, for patients in extreme shock related to
severe PH and RV failure.

ACKNOWLEDGMENTS

The authors would like to thank and acknowledge Linda J. Kesselring, MS, ELS for
copyediting the article and incorporating revisions into the final article.

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