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Article

Pulmonary Hypertension in the


Intensive Care Unit

Journal of Intensive Care Medicine


1-17
The Author(s) 2015
Reprints and permission:
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DOI: 10.1177/0885066615583652
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Jacob C. Jentzer, MD1,2 and Michael A. Mathier, MD1

Abstract
Pulmonary hypertension occurs as the result of disease processes increasing pressure within the pulmonary circulation, eventually
leading to right ventricular failure. Patients may become critically ill from complications of pulmonary hypertension and right
ventricular failure or may develop pulmonary hypertension as the result of critical illness. Diagnostic testing should evaluate for
common causes such as left heart failure, hypoxemic lung disease and pulmonary embolism. Relatively few patients with pulmonary hypertension encountered in clinical practice require specific pharmacologic treatment of pulmonary hypertension
targeting the pulmonary vasculature. Management of right ventricular failure involves optimization of preload, maintenance of
systemic blood pressure and augmentation of inotropy to restore systemic perfusion. Selected patients may require pharmacologic therapy to reduce right ventricular afterload by directly targeting the pulmonary vasculature, but only after excluding
elevated left heart filling pressures and confirming increased pulmonary vascular resistance. Critically-ill patients with pulmonary
hypertension remain at high risk of adverse outcomes, requiring a diligent and thoughtful approach to diagnosis and treatment.
Keywords
pulmonary hypertension, pulmonary arterial hypertension, right ventricular failure, right heart failure, pulmonary vasodilators

Introduction
Pulmonary hypertension (PH) develops through a final
common pathway of myriad cardiac and noncardiac disease
processes that increase pulmonary artery (PA) pressures.1 Pulmonary hypertension contributes to critical illness primarily
via right ventricular failure (RVF), ultimately leading to hemodynamic compromise and death.2-6 Disease processes directly
impairing right ventricular (RV) contractility can produce RVF
in the absence of PH.7-10 Most cases of PH encountered in clinical practice are produced by another disease process, being
secondary to critical illness rather than causative of it.1 Identifying causes of PH requiring specific therapy can be challenging in critically ill patients, and direct treatment of PH is
often less important than correcting the underlying disease process. Several reviews have discussed various aspects of PH
and/or RVF in critical care settings.2-9 In this review, we will
focus on the diagnosis and treatment of various etiologies of
PH encountered in intensive care unit (ICU) patients, with an
emphasis on management of critically ill patients with pulmonary arterial hypertension (PAH).

(TTE) in 28% of 449 unselected medical ICU patients at our


institution. Forty-two percent of the 299 patients in whom
PA pressures and left ventricular function could be evaluated
had PH.11 Pulmonary hypertension was predicted by left ventricular ejection fraction (LVEF) below 50%, pulmonary
embolism (PE), and lower serum bicarbonate.11 Potential etiologies of PH in these patients included reduced LVEF in 23%,
PE in 12%, and respiratory failure in 23%.11 Right ventricular
failure without PH can be produced by etiologies such as cardiomyopathy, RV ischemia/infarction, sepsis, and postoperative RVF.7-9 Common etiologies of PH encountered in the
ICU are listed in Table 1. Most PH is caused by left heart
disease (PH-LHD) or parenchymal/hypoxic lung disease (PHPLD), and true PAH is relatively infrequent.2,4,12,13 Acute PE
is the most common cause of new-onset PH causing RV strain

University of Pittsburgh Medical Center Heart and Vascular Institute,


Pittsburgh, PA, USA
2
Department of Critical Care Medicine, University of Pittsburgh Medical
Center, Pittsburgh, PA, USA

Received March 25, 2014, and in revised form March 13, 2015. Accepted
for publication March 16, 2015.

Incidence and Prognosis


The epidemiology of PH in the ICU is not well characterized,
but PH appears to be common in critically ill patients. An elevated tricuspid regurgitation (TR) velocity consistent with PH
was identified on Doppler transthoracic echocardiography

Corresponding Author:
Michael A. Mathier, University of Pittsburgh Medical Center Heart and
Vascular Institute HVI at UPMC Presbyterian 200 Lothrop Street Pittsburgh,
PA 15213, USA.
Email: mathierm@upmc.edu

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Journal of Intensive Care Medicine

Table 1. Causes of Pulmonary Hypertension in the ICU.a


Left heart disease
Left heart failure from systolic or diastolic dysfunction
Restrictive cardiomyopathy
Constrictive pericarditis
Mitral valve regurgitation/stenosis
Aortic valve regurgitation/stenosis
Hypoxemic/parenchymal lung disease
Acute respiratory distress syndrome
Interstitial lung disease
Chronic obstructive pulmonary disease
Obstructive sleep apnea
Obesityhypoventilation syndrome
Pneumonia
Pneumothorax
Sarcoidosis
Thromboembolism
Acute pulmonary embolism
Chronic thromboembolic pulmonary hypertension
Postoperative
After cardiopulmonary bypass
Cardiothoracic surgery complications
Pulmonary arterial hypertension
Idiopathic/familial/anorexigen associated
Connective tissue disease (especially scleroderma)
Eisenmenger syndrome/congenital heart disease
HIV associated
Portopulmonary hypertension
Hemoglobinopathy associated
Pulmonary veno-occlusive disease
Abbreviations: HIV, human immunodeficiency virus; ICU, intensive care unit.
a
Adapted from Zamanian et al.2

Venous oxygenaon
Hypoxic vasoconstricon

LV cardiac output
Systemic perfusion
Systemic BP
Heart rate

RV aerload
Coronary perfusion
RV ischemia

RV systolic funcon
RV cardiac output

LV lling

RV lling pressures
RV dilaon
Tricuspid regurgitaon

Figure 1. Pathophysiology of decompensated right ventricular


failure. BP indicates blood pressure; RV, right ventricle; LV, left
ventricle.2,3,5-7,9,10

and a frequent contributor to PH in acutely ill patients.4,7,14-18


Development of PH significantly increases mortality in heart
failure, lung disease, or PE.13-15,19-23 Echocardiographic PH
independently predicted mortality in our medical ICU patients

after controlling for other clinical factors (odds ratio 1.59,


P .036).11 Echocardiographic RV dysfunction and RVF are
major predictors of mortality in patients with PAH and predict
increased mortality in other medical conditions.7,8,12-14,22-25

Pathophysiology
Acute RVF represents the inability of the RV to maintain normal
cardiac output at a normal right atrial pressure (RAP), and the
pathophysiology of PH-induced RVF is reviewed in detail elsewhere (Figure 1).2,3,5-7,9,10,15,26 Pulmonary hypertension is defined
by elevated PA pressures, typically resulting from increased pulmonary vascular resistance (PVR) and/or increased pulmonary
venous pressures, with elevated cardiac output contributing to
some etiologies.12 Elevated PVR results from excessive pulmonary
arteriolar vasoconstriction and/or pulmonary vascular obstruction.12 Patients with PH-induced RVF are prone to rapid deterioration through a vicious cycle of progressive shock, and even
transient hypotension or hypoxemia can trigger an inexorably fatal
downward spiral unless corrected promptly (Figure 1).2,4,5,10 Worsening hypotension in patients with RV dysfunction can result from
inadequate RV preload, excessive RV afterload, deteriorating RV
contractility, or inappropriate systemic vasodilation.8
The RV is very sensitive to changes in afterload and cannot
maintain its stroke volume if PVR rises abruptly.2,7,8 Right
ventricular dilation is characteristic of RVF, as the RV attempts
to utilize preload reserve to compensate for acutely increased
afterload from rising PVR.5,9,10,15 Right ventricular dilation
increases RV wall tension and worsens TR, further reducing
forward RV stroke volume. A distended RV can impinge on
left ventricular (LV) diastolic filling and stroke volume through
ventricular interdependence.2,5,8,10 Decreased RV output
reduces LV filling and forward LV stroke volume, leading to
systemic hypotension and RV myocardial hypoperfusion that
can induce RV ischemia and further impair RV contractility.3,5-7,10 Tachycardia is often an adaptive mechanism to
maintain cardiac output in the face of reduced stroke volume
but can worsen RV ischemia and impair RV diastolic filling.
Low cardiac output results in venous blood oxygen desaturation, which worsens arterial hypoxemia when pulmonary
reserve is compromised. Hypoxia-induced pulmonary vasoconstriction constricts pulmonary arterioles in hypoxic lung segments to improve physiologic ventilationperfusion (V/Q)
matching and systemic oxygenation at the expense of increased
PVR.23 Inflammatory cytokine release (ie, from sepsis or cardiopulmonary bypass) worsens RVF by producing pulmonary
vasoconstriction, microvascular obstruction, myocardial
depression, and systemic vasodilation.8,10,15

Clinical Presentation
Acute RVF produces symptoms through systemic congestion
and/or low cardiac output. Typical symptoms of isolated RVF
include dyspnea and gastrointestinal symptoms, usually without orthopnea or paroxysmal nocturnal dyspnea.2,13 Signs and
symptoms of low output include exertional light-headedness or

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Jentzer and Mathier

Clinical ndings suggesve


of PH and/or RV failure
TTE with Doppler
Esmated PA pressure
RV structure/funcon
LV structure/funcon
Exclude shunt

PH not likely
TR jet velocity <3m/s
Normal RV structure
and funcon

Evaluate alternave
causes of symptoms
Consider RHC if
no other cause

PH likely
TR jet velocity >=3m/s
Abnormal RV structure
Abnormal RV funcon

Evident underlying cause


Le heart disease
Hypoxic lung disease
Thromboembolism

Addional causes?
Elevated PAWP
Hypoxemia
Concomitant PE

Right heart catheterizaon


Assess PAP, PAWP, PVR

High PAWP, normal PVR


Le heart disease

Normal PAWP, high PVR


Chest CT + CTA
Nocturnal oximetry

High PAWP, high PVR


Le heart disease with
reacve PH

Pulmonary congeson
PVOD

Evaluate causes of PAH


Serologic workup

Idiopathic PAH
Associated PAH

Figure 2. Diagnostic approach to newly recognized pulmonary hypertension in acutely ill patients. TTE indicates transthoracic echocardiogram;
TR, tricuspid regurgitation; RV, right ventricle; LV, left ventricle; RHC, right heart catheterization; PAWP, pulmonary artery wedge pressure; PE,
pulmonary embolism; PAP, pulmonary artery pressure; PVR, pulmonary vascular resistance; CT, computed tomography; CTA, CT angiography;
PVOD, pulmonary veno-occlusive disease.12,41

syncope, altered mental status, hypotension with narrow pulse


pressure, cool extremities, and renal insufficiency. Systemic
congestion produces elevated jugular venous pressure, hepatomegaly, and volume overload with edema and ascites. Patients
with PH-induced acute RVF of any etiology may present in
extremis with hypotension/shock, tachycardia, hypoxemia, and
tachypnea, mimicking massive acute PE. Inappropriate systemic vasodilation may occur as part of a systemic inflammatory response in end-stage RVF, even without infection.
Most patients with PH-induced RVF have adequate cardiac
output and elevated filling pressures.27 Patients with adequate
perfusion and normal filling pressures often have compensated
chronic RV dysfunction with a superimposed noncardiac illness. Patients with RVF admitted to the ICU often have hypotension and low cardiac output, despite elevated filling
pressures including overt cardiogenic shock. Patients with low
output and low filling pressures (cold and dry) from hypovolemia due to bleeding or excessive diuretic therapy are least
common but have worse outcomes.27 In our experience, most
patients with RVF having low output have elevated RV filling
pressures, even without overt volume overload.

Cardiorenal Syndrome in RV Failure


Acute renal dysfunction (cardiorenal syndrome) is a common
and morbid problem in acute RVF.28 Impaired renal function

is common in patients with RVF, with approximately 40%


to 50% having a glomerular filtration rate (GFR) below
60 mL/min and more than 20% having a GFR below
45 mL/min.29-31 Nearly 25% of patients with PAH admitted
to the hospital develop acute kidney injury (AKI), and up to
20% to 40% of patients with PAH admitted to the ICU may
require dialysis.31-33 Elevated creatinine, reduced eGFR, and
AKI predict increased mortality in hospitalized patients with
PAH having RVF, and in-hospital mortality reaches 70% in
patients requiring dialysis.29-32,34 Chronic kidney disease,
higher central venous pressure (CVP), and tachycardia predict
AKI in patients with PAH having RVF.31 Adversely prognostic laboratory features characterizing cardiorenal syndrome in
patients with PAH include anemia, hypoalbuminemia, and
hyponatremia.28-30,34,35
The pathophysiologic mechanisms of renal dysfunction
complicating PH-induced RVF likely overlap with those in
cardiorenal syndrome complicating acute LV failure.28,35
Impaired renal blood flow may develop due to hypovolemia
(overdiuresis or bleeding) or more often low cardiac output
with marked neurohormonal activation complicated by
ineffective circulating blood volume from anemia and
hypoalbuminemia.28,35 Venous congestion (elevated renal
venous pressure) plays a central role in acute cardiorenal syndrome, often to a greater extent than reduced cardiac output.10,28,31,36-39 Baseline GFR in patients with PH with or

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Journal of Intensive Care Medicine

Table 2. Causes of Acute Decompensation in Patients With Pulmonary Arterial Hypertension.2,3,5,27,29,34


Acute deterioration of chronic PAH
 Worsening of underlying disease
 Deterioration in right ventricular function
 Fluid overload or diuretic noncompliance
 Acute kidney injury + metabolic acidosis
 Hypovolemia (esp gastrointestinal bleeding)
 Arrhythmia (esp atrial arrhythmias > heart block)
 Medication noncompliance/withdrawal
 Infection/sepsis (esp pneumonia or line infection)
 Increased demand, ex pregnancy, anemia, surgery
 Right ventricular ischemia/injury
Worsening hypoxemia in PH
 Right ventricular failure with low mixed venous saturation
 Pump/catheter malfunction with IV prostanoids
 Pulmonary embolism or in situ pulmonary thrombosis
 Pneumonia/atelectasis (V/Q mismatch)
 Pneumothorax or large pleural effusion
 Sepsis (increased cardiac output / demand)
 Right-to-left shunt, ex via patent foramen ovale
 Pulmonary edema, esp PVOD
Worsening hypotension or cardiac output in PH
 Worsening right ventricular systolic function
 Increase in pulmonary vascular resistance
 Worsening tricuspid regurgitation
 Hypovolemia, esp bleeding
 Medication side effects
 Sepsis or vasodilatory state
 Arrhythmia
 Pericardial effusion with tamponade
 Initiation of mechanical ventilation
Abbreviations: IV, intravenous; V/Q, ventilation-perfusion; PAH, pulmonary
arterial hypertension; PH, pulmonary hypertension; esp, especially; PVOD,
pulmonary veno-occlusive disease.

without RVF is predicted by higher RAP, reduced renal blood


flow, and reduced cardiac output.36,39 Right ventricular dysfunction and TR can exacerbate venous congestion and are
associated with lower eGFR and/or lower cardiac output in
patients with chronic LV failure.38,40 Diuresis may transiently
worsen renal function in patients with acute cardiorenal syndrome, but relief of venous congestion is central to clinical
improvement.10,28

Diagnostic Evaluation
In the ICU, patients may present with RVF from de novo
acute PH (newly diagnosed PH) or acute-on-chronic PH
(deterioration of prior chronic PH), along with patients having
incidentally discovered PH without overt RVF. The diagnostic assessment in de novo PH seeks to identify treatable
secondary causes and recognize patients who are likely to
benefit or be harmed by PAH-specific therapy (Figure 2),
while the diagnostic assessment in patients with established
PH aims to identify factors triggering decompensation
(Table 2). Distinguishing patients who are critically ill because
of PH (and will require PH treatment) from patients whose PH is

secondary to critical illness (who are more common in our experience) remains challenging. In critically ill patients, multiple
underlying disease processes often contribute to worsening PH
and/or RVF rather than a single correctible factor.
Transthoracic echocardiography remains the first-line test
for patients with suspected PH and/or RVF to estimate PA
systolic pressure (PASP) and assess RV structure and function.41-43 Echocardiographic assessment of PASP depends on
the peak TR jet Doppler velocity plus an estimate of the RAP,
although this method lacks both sensitivity and specificity for
PH.12,42,43 Patients with an estimated PASP >40 mm Hg or
peak TR jet velocity 3 m/s on echocardiogram are likely to
have PH at right heart catheterization (RHC), with higher
specificity at higher PASP values.41-43 In our medical ICU
patients, a TR jet velocity 3 m/s on TTE had up to 90% positive predictive value for PH in patients undergoing RHC,
despite a poor negative predictive value.11 Because of the limited ability of the RV to tolerate acute increases in afterload,
severe elevations in PA pressures generally represent a more
chronic disease process, allowing time for the RV to adapt
(especially in the presence of RV hypertrophy). Echocardiographic RV dysfunction is characterized by a dilated, hypocontractile RV with flattening or paradoxical motion of the
interventricular septum, and these findings are characteristic
of decompensated RVF.4,5,25 Echocardiographic evidence of
PH-LHD includes LV systolic or diastolic dysfunction, mitral
valve disease, left atrial enlargement, and/or Doppler evidence
of elevated LV filling pressures.13,43,44 Mild LV diastolic dysfunction (abnormal relaxation) can be induced by ventricular
interdependence from RV dilation, but higher degrees of LV
diastolic dysfunction suggest PH-LHD.13,44 Echocardiography
often identifies pericardial effusions in patients with PH, which
rarely cause tamponade but are associated with adverse prognosis and a high mortality rate after drainage.25,45
In critically ill patients with PH and/or RVF, we favor early
RHC to establish the diagnosis, determine the etiology, and
assess the filling pressures (Figure 2). This includes patients
in whom clinical suspicion for PH remains high, despite normal TR jet velocity (ie, an abnormal RV on echocardiogram).
Pulmonary hypertension is defined hemodynamically by an
elevated mean PA pressure (mPAP) 25 mm Hg by RHC, and
RHC helps to differentiate common types of PH.41 We typically use a PA catheter (PAC) to guide therapy in unstable
patients with PH and/or RVF, especially if PAH-specific therapy is considered.5,8 Early use of a PAC to guide therapy was
associated with reduced mortality in 1 study of patients with
PH having RVF, despite failure of PAC-guided therapy to
reduce mortality in general critically ill patients.32,46 Caution
is required during RHC in patients with PH due to the risk of
potentially fatal PA rupture.47 The RHC allows measurement
of PA wedge pressure (PAWP) and calculation of PVR, which
corrects for elevated PAWP and cardiac output to identify
pulmonary vascular disease.12 Pulmonary hypertension
caused by left heart disease (postcapillary PH) is defined by
an elevated PAWP >15 mm Hg with normal or reduced cardiac output. Most patients have normal PVR, although

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Jentzer and Mathier

First-line therapies

Treatment goals

Second-line therapies

Normalize oxygenaon

Supplemental oxygen
Noninvasive venlaon

Mechanical venlaon
Low airway pressures

Opmize preload (CVP)

Low CVP uids


High CVP diurecs

Transfusion if anemic
Ultraltraon

Maintain cardiac output

Stable BP inodilator
Low BP dopamine

Epinephrine

Restore systemic BP
SVR > PVR

Norepinephrine
Vasopressin

Epinephrine/dopamine
Phenylephrine

PAH +/- CTEPH


Intravenous epoprostenol

Inhaled prostanoids/NO
Add-on sildenal?

Reduce RV aerload
Selected paents

PH-LHD
Nitroglycerin
Nitroprusside

Milrinone > dobutamine


Chronic LVAD unloading

Advanced therapies

PH-PLD
Inhaled NO/prostanoids

ECMO if refractory

Figure 3. Clinical management of pulmonary hypertension-induced right ventricular failure. CVP indicates central venous pressure; BP, blood
pressure; SVR, systemic vascular resistance; PVR, pulmonary vascular resistance; CTEPH, chronic thromboembolic pulmonary hypertension;
PH-LHD, pulmonary hypertension due to left heart disease; PH-PLD, pulmonary hypertension due to parenchymal lung disease; ECMO,
extracorporeal membrane oxygenator support; NO, inhaled nitric oxide; LVAD, left ventricular assist device.2-10,12,13,22,48
Table 3. Simplified Approach to Right Ventricular Failure Etiology and Treatment.8,20
Blood pressure

Cardiac output

CVP

DPVR

Cause

Primary Treatment

#
#
#
#
$
$

#
#
#
$"
$"
$

#
"
"
$"
"
#

$"
"
$
$"
$"
$

Hypovolemia
Worsening PH
RV dysfunction
Vasodilation
Volume overload
Compensated

Volume
PAH-specific therapy
Inotropes
Vasopressors
Diuretics
None

Abbreviations: CVP, central venous pressure; DPVR, change in pulmonary vascular resistance; PAH, pulmonary arterial hypertension; PH, pulmonary hypertension; RV, right ventricular.
Note. Arrows reflect direction and magnitude of effect (# = reduction, $ = no change, $" = no change or increase, " = increase, ## = strong decrease, "" = strong
increase).

patients with elevated PVR and out-of-proportion PH have


a worse prognosis.12,13,44,48
Patients with mPAP 25 mm Hg, PAWP 15 mm Hg, and
PVR >3 Wood units (WU) have precapillary PH including
PAH, acute PE, hypoxic/parenchymal lung disease, chronic
thromboembolic PH (CTEPH), and other miscellaneous causes
(see Table 1).41 Exclusion of PE is warranted, given the frequent occurrence of occult PE in patients with other apparent
causes of PH such as lung disease or LV failure.16-18 Computed
tomography (CT) or invasive pulmonary angiography may be
appropriate for acutely ill patients, while radionuclide V/Q
scanning is more sensitive for excluding CTEPH in stable
patients.12,14,16,17,41 Chest radiography and chest CT can identify
parenchymal lung disease or features suggestive of pulmonary

veno-occlusive disease (PVOD) such as pulmonary congestion,


interstitial edema, pleural effusions, ground-glass opacities, and
thickened septal lines.2,49,50 Patients with precapillary PH and
negative imaging are likely to have PAH but require further
workup to identify specific diseases associated with PAH.41

Treatment of RVF
The treatment of acute RVF involves correcting reversible
causes of decompensation (Table 2), optimizing RV preload,
supporting RV contractility, and reducing PVR while maintaining systemic vascular resistance (SVR) and mean arterial
pressure (MAP; Figure 3).2-10,14,20,24,25,51 A simplified
approach to RVF (Table 3) emphasizes the diagnosis and

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Journal of Intensive Care Medicine

initial treatment of the dominant pathophysiologic process,


although combination therapy is often required to stabilize
patients with RVF.8,20

Preload Optimization
Volume loading. The dysfunctional RV may require an abnormally elevated RAP (up to 12-15 mm Hg) to maintain cardiac
output due to diastolic dysfunction, so patients with RVF having hypotension and/or hypoperfusion may require volume
loading to optimize cardiac output.3,7,8 This practice is primarily based on expert opinion, with few primary data to guide the
quantity, rate, or targets of fluid therapy in patients with PH.
Patients with acute PH (particularly acute PE) may be more
likely to respond favorably to volume administration compared
to patients with chronic PH who usually have elevated RV filling pressures even in the absence of gross volume overload.3,7,14,15,24,52 Despite favorable effects in animal models,
patients with acute RV dysfunction caused by RV infarction
may not consistently respond to volume loading and responded
more reliably to inotropic support in some studies.53-55 Volume
loading is considered more appropriate when CVP is low but
should be discontinued if CVP rises without improved systemic
hemodynamics. Cautious fluid administration can be continued
if the CVP remains low without pulmonary congestion.7,14,24,52
Based on expert opinion, a reasonable fluid challenge for a
patient with acute RV dysfunction or acute PH is up to 500
mL over 15 to 20 minutes, while the fluid challenge in a patient
with chronic PH should be smaller (up to 250 mL).5,9,7,14,24,52
A CVP >15 mm Hg is rarely needed to optimize RV stroke
volume, and markedly elevated CVP (especially >20 mmHg)
can impair RV function via increased RV wall stress and functional TR, leading to worsening systemic hemodynamics.3,4,7
Empiric fluid administration can worsen decompensated RVF
and is not recommended without assessment of CVP.5-9
Volume removal. Patients with systemic congestion in the
absence of hypotension or hypoperfusion typically improve
with volume removal alone and may not need vasoactive drugs.
Relief of RV volume overload can improve RV function by
reversing RV overdistention and septal shift, so volume
removal may be warranted even in patients with hypotension
having low output and high CVP.3,4 Most acutely ill patients
with PH-induced RVF warrant empiric diuresis, particularly
with worsening hypoxemia, gross fluid overload, or elevated
CVP.3 Intravenous loop diuretics are first line for volume
overload and titrated to the lowest filling pressures that relieve
congestion while maintaining adequate systemic hemodynamics.51 We prefer a continuous furosemide infusion to allow
gradual diuresis and avoid abrupt swings in filling pressures.
Furosemide infusion rates 30 mg/h have been reported in the
literature.33,56 Resistance to an adequate loop diuretic dose
(10-20 mg/h furosemide infusion) can often be overcome
by adding a thiazide-type diuretic.33,51,56 In our experience,
diuretic resistance in RVF is usually due to low cardiac output,
especially in the presence of hypotension, hyponatremia, and/or

worsening renal function. Extracorporeal fluid removal via ultrafiltration can be used for persistent volume overload, despite
combination diuretic therapy, although the need for dialysis
or ultrafiltration to manage refractory cardiorenal syndrome
portends a grim prognosis.4,32,51,57

Vasoactive Therapies
Support with vasoactive drugs including vasodilators, inotropes, and/or vasopressors may be required to reverse severe
RVF with low output and/or systemic hypotension when preload optimization is inadequate to restore hemodynamics. The
goals of vasoactive drug therapy are to reduce PVR, maintain
SVR, and increase cardiac output to improve MAP and organ
perfusion.2 Most patients with hypotension having RVF have
low cardiac output, but hypotension with preserved cardiac
output and low SVR suggests inappropriate vasodilation
requiring vasopressor therapy (Table 3).20 Hypotension with
reduced cardiac output and adequate/increased CVP suggests
worsening RVF from excessive RV afterload (increased PVR)
and/or reduced RV contractility (stable PVR; Table 3).20 Pulmonary arterial hypertensionspecific therapies can be effective monotherapy for worsening RVF when elevated PVR is
the dominant etiology. Inotropic support is often required for
low-output RVF, especially if RV contractility is impaired.
Certain vasoactive drugs including PAH-specific therapies
can simultaneously increase RV inotropy and reduce PVR
to reverse RVF.8,10,13,58-60 Vasopressors may be required to support MAP in patients with severe hypotension, especially with
inadequate vascular tone. In-hospital mortality approaches
50% in patients with severe PAH-induced RVF who require
support with vasopressors and/or inotropes, especially at
higher doses.27,29,30,32,34,61
Pulmonary arterial hypertensionspecific therapies. The underlying
etiology of PH determines the need for therapy targeting the
pulmonary vasculature and the most appropriate type of drug
(if indicated; Figure 3). Treatment with PAH-specific drugs has
only been associated with improved outcomes in outpatients
with chronic PAH, representing a minority of all patients with
PH.12 Relatively few critically ill patients with PH and/or RVF
will have an underlying etiology that warrants PAH-specific
therapy, so PH is not always a plausible target for therapy and
PAH-specific therapies are unlikely to improve outcomes in
unselected patients.2 Appropriate use of PAH-specific therapy
can be lifesaving in severe RVF due to PAH and may obviate
the need for inotropic therapy, but off-label use of systemic
PAH-specific drugs in patients with other forms of PH may
lead to life-threatening complications when used injudiciously.12 In his article, we discuss off-label uses of these drugs
in selected non-PAH patient subsets based on evidence from
clinical studies and personal experience supporting a limited
role in certain situations, but PAH-specific drugs should not
be used routinely in non-PAH patients. Importantly, there is
no evidence supporting any outcomes benefit for off-label use

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Jentzer and Mathier

Table 4. Vasoactive Drugs Used for Support in Right Ventricular


Failure.5,6,9,58-60,65,81-86,92
Inotropes

Effect on PVR Effect on SVR PVR/SVR Ratio

Dobutamine58-60,81-83
Milrinone59,60,84,85
Norepinephrine65,92
Dopamine
Epinephrine
Vasopressin85,86
Phenylephrine65,92

#$a
##
"
"
"
#
""

#$a
#
"
"
"
"
"

$
#
$
$
$
#
"

Abbreviations: PVR, pulmonary vascular resistance; SVR, systemic vascular


resistance.
a
The effects of dobutamine on PVR and SVR are variable based on pathophysiology and dosing.

of PAH-specific therapies, and such use is investigational and


potentially harmful when used inappropriately.
Patients with precapillary PH (elevated PVR and normal
PAWP) without parenchymal/hypoxemic lung disease or
acute PE (especially PAH or CTEPH) are more likely to have
low-output RVF with severely elevated PVR requiring
PAH-specific therapies for stabilization, including intravenous prostanoids.3 Correction of the underlying disease process causing PH is often more important than treating
elevated PA pressures, especially in patients with PH-LHD
or PH-PLD. Selected patients with persistent RVF after correction of underlying conditions may be candidates for offlabel PAH-specific therapy if PVR is significantly elevated.12
Inhaled pulmonary vasodilators may have broader applicability, including selected patients with PH-PLD, postoperative
PH, and RVF without PH.6-8,21-23,25
Pulmonary vascular resistance is a more relevant therapeutic target in RVF than PA pressures because deteriorating RV
function and declining cardiac output can reduce PA pressures.7,8,12 While the acute effects of PAH-specific drugs on
PVR may involve pulmonary arteriolar vasodilation, their
chronic disease-modifying effects involve favorable pulmonary vascular remodeling.12,62,63 Most systemic vasoactive
drugs produce parallel effects on the pulmonary and systemic
vessels, contrary to the goal of reducing PVR while increasing
SVR (Table 4).5,9,13,64,65 Pulmonary arterial hypertensionspecific drugs produce relatively greater pulmonary vasodilation than systemic vasodilation, but systemic vasodilation
often produces hypotension.5,8,9 Only inhaled pulmonary
vasodilators, such as nitric oxide (NO) or inhaled prostanoids,
can reduce PVR without significant effects on MAP.58,64,66-77
The use of PAH-specific therapies and inhaled pulmonary
vasodilators is discussed subsequently in the section on PAH.
Inotropes. Inotropic drugs may reverse low cardiac output
due to RVF at the expense of tachycardia, increased myocardial oxygen demand, arrhythmias, and potentially systemic vasodilation (Table 4).6 Dobutamine and dopamine
are the most commonly used inotropes for patients with

PH-induced RVF, with no direct comparisons supporting


either drug.27,29,30,32,34 Dopamine and dobutamine produce
relatively similar hemodynamic effects at usual doses of 2
to 10 mg/kg/min, with higher doses producing worsening
tachycardia without improving cardiac output, and dobutamine produces greater augmentation of cardiac output,
while dopamine increases MAP and SVR to a greater
extent.2,5-7,9,58,78-80 In our clinical experience, dopamine
tends to cause excessive tachycardia limiting dose titration,
while the modest systemic vasodilating effects of dobutamine can produce hypotension. We prefer dobutamine over
dopamine for acute inotropic support in unstable patients,
although dopamine is a reasonable choice in patients who
are hypotensive and not excessively tachycardic.2,3,6-9,30,34
The effects of dobutamine on PVR in humans with PH
remain uncertain, with conflicting effects reported by various studies in heterogeneous patient populations. The primary effect of dobutamine in PH appears to be an
increase in cardiac output that reduces the measured PVR
with minimal if any direct effects on the pulmonary vasculature.2,5-7,9,58,81-83
Milrinone produces a greater reduction in PVR and SVR
and less tachycardia than dobutamine for a given increase in
cardiac output and/or RV systolic function, leading to greater
reductions in MAP, PA pressures, and PAWP, despite a lesser
inotropic effect.6,8,10,13,59,60 Dobutamine and milrinone primarily lower PVR by increasing cardiac output, with lesser direct
effects on pulmonary vascular tone that are more significant
with milrinone.58,81,84 Milrinone is our preferred inotrope for
RVF, especially in normotensive patients and those with PHLHD, postoperative PH, or undifferentiated PH.3,5,6,8-10,25
Vasopressors may be required to counteract the prominent
systemic vasodilating effects of milrinone, and combining
milrinone and vasopressin may support cardiac output and
reduce PVR while maintaining MAP, especially after cardiac
surgery.6,9,21,25,68,85-87 At low doses, epinephrine effectively
augments RV contractility and may be synergistic with milrinone when used for postoperative RVF.2,6,9,88-91 In PAHinduced RVF, reduction in RV afterload using PAH-specific
therapies is more important than RV inotropic support, but
epoprostenol and sildenafil can have positive inotropic effects
on the RV.8,10,13
Vasopressors. Patients with severe hypotension having PH and
RVF require vasopressors to support organ perfusion pressure
and prevent death from progressive hemodynamic deterioration, particularly in the setting of inappropriate systemic vasodilation (Table 4). Vasopressor therapy should generally
maintain the MAP higher than mPAP (ie, SVR greater than
PVR) to reduce septal bowing and ensure an adequate pressure gradient for RV perfusion.5,6 Alpha 1 agonist vasopressors (including high doses of dopamine and epinephrine)
constrict both pulmonary and systemic vessels, potentially
worsening RV afterload while supporting MAP.5,6,9,65,92
Norepinephrine appears to have more favorable effects on
cardiac output and calculated PVR than phenylephrine due

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Journal of Intensive Care Medicine

to modest inotropic effects.2,6,9,65,92 Vasopressin may produce endothelium-dependent pulmonary vasodilation to


slightly reduce PVR while increasing SVR, making this drug
useful when SVR is low in patients with RVF.2,6,9,85-87,93,94
Norepinephrine is our first-line vasopressor for patients with
severe hypotension, and we often add vasopressin based on its
slight PVR lowering and lack of tachycardic effects.2,3,5,6,8,9,34,94
Dopamine can be useful for vasopressor support due to its
positive inotropic effects, despite an increased risk of tachyarrhythmias and less effective MAP augmentation than norepinephrine.6,27,29,32,78 Epinephrine can effectively raise MAP
and support RV inotropy but often produces tachycardia,
arrhythmias, and lactic acidosis.88,89

Supportive Care
Oxygenation. Oxygen is the most important physiologic pulmonary vasodilator, and increased fraction of inspired oxygen
(FIo2) can counter hypoxic pulmonary vasoconstriction and
reduce PVR, making supplemental oxygen the first-line therapy for patients with hypoxemia having PH.95 Worsening
hypoxemia is common in decompensated PAH (see Table
2), and patients should receive supplemental oxygen to raise
SaO2 >92%.3,5,8 For selected patients with PAH having low
systemic oxygen delivery, using higher FIo2 to increase SaO2
may maximize reduction in PVR.95 For some patients with
PH-PLD, restoration of normoxia may be sufficient to reverse
PH.22 Hypoxemia in patients with PH usually responds to supplemental oxygen, although intracardiac shunting through a
patent foramen ovale can produce hypoxemia that may
resolve with lowering RAP and increasing SVR.2,7 Maintenance of normocapnia (PaCO2 35-40 mm Hg) is recommended
because hypercarbia and acidosis can further increase PVR by
augmenting hypoxic pulmonary vasoconstriction, while
hyperventilation can improve PVR transiently.2,6-8,20 Ventilator management of patients with PH is discussed subsequently
in the section on PH due to lung disease.
Arrhythmia management. Atrial fibrillation and atrial flutter are
the most frequent sustained arrhythmias in patients with
PAH-induced RVF and may be associated with increased
mortality.29,30,61 The dysfunctional RV is highly dependent
on atrial contraction to maintain adequate filling, particularly
at rapid heart rates.3,5 Cardiac arrhythmias that impair atrioventricular (AV) synchrony, such as atrial fibrillation/flutter
or complete heart block, often produce hemodynamic compromise in patients with RVF.2,7,9 Electrical therapy is the
first line for unstable patients, including cardioversion for
tachyarrhythmias, and bradyarrhythmias (i.e. after cardioversion) are poorly tolerated and respond best to AV sequential
pacing.3,7,9 Amiodarone is the first line for most tachyarrhythmias due to its lower risk of hypotension and lesser negative inotropic effects.3 Digoxin can provide rate control of
atrial arrhythmias in selected patients with preserved renal
function, but its positive inotropic effects are not clinically
relevant in severe RVF.3,96

Table 5. Mortality Predictors of Hospitalized Patients With Pulmonary Artery Hypertension.27,29,30,32,34,61,97


Baseline patient characteristics
Connective tissue diseaseassociated PAH27,29
PH due to hypoxemic lung disease32
WHO functional class29
Chronic use of prostanoids32
Comorbidity index29
Clinical presentation
Colddry hemodynamic profile27
Higher respiratory rate30
Lower systolic/mean blood pressure29,34
Sepsis/infection during hospitalization32,34,61
Respiratory failure32
Atrial fibrillation61
Higher mean airway pressure61
Testing abnormalities
Lower sodium29,30,34
Higher creatinine/lower GFR29,30,34
Higher BNP/NT-proBNP30,32,34
Higher CRP34
Greater degree of tricuspid regurgitation30
Lower albumin30
Severity of illness scores
APACHE-II32
SAPS-II34
Treatments provided
Inotropes/vasopressors, esp. higher dose27,34,61
Dialysis32
Mechanical ventilation32
Cardiopulmonary resuscitation32,97
Lack of early PA catheter-guided therapy32
Abbreviations: WHO, World Health Organization; GFR, glomerular filtration
rate; BNP, B-type natriuretic peptide; NT-proBNP, N-terminal pro-BNP; CRP,
C-reactive protein; APACHE, Acute Physiology and Chronic Health Evaluation
Score; SAPS, Severe Acute Physiology Score; PA, pulmonary artery; PAH,
pulmonary arterial hypertension; PH, pulmonary hypertension.

Disease-Specific PH Therapy
Pulmonary Arterial Hypertension
Hospital admission in patients with PAH is a morbid occurrence, with in-hospital mortality of 9% overall that increases
to 14% to 17% for patients with RVF.29,30 Critically ill
patients with PAH admitted to the ICU have in-hospital mortality rates exceeding 30% to 40% plus an additional 10% to
20% mortality during the next 3 to 6 months for hospital survivors.27,29,30,32,34,61 Mortality predictors of hospitalized
patients with PAH are shown in Table 5.27,29,30,32,34,61,97
Death in hospitalized patients with PAH is most often due
to hemodynamic compromise from progressive RVF ultimately resulting in cardiac arrest, often with a bradycardic
arrest rhythm.29,30,97 Patients with PAH having cardiac arrest
have dismal outcomesonly 21% of resuscitative attempts
are initially successful, with 90-day survival of 6%.32,97 The
most common reason for hospital admission in patients with
PAH is RVF, followed by infection/sepsis (especially line
sepsis and pneumonia), medication noncompliance, respiratory failure, bleeding (especially gastrointestinal), syncope,

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Jentzer and Mathier

arrhythmias (especially atrial fibrillation/flutter), and


PE.27,29,34 Infection and sepsis are important causes of death
in patients with PAH, and severe septic shock in patients with
PAH may be associated with a 1-year survival of below
30%.27,29,30,32,34,61 Potential triggers for decompensation of
chronic PAH are listed in Table 2, although a cause for
decompensation can only be identified in about half of the
patients.2,3,5,7,27,29,34 Interruption of chronic prostanoid infusion can lead to rapid deterioration including rebound PH and
death.12,62,98 For patients with PAH admitted with decompensated RVF, initiation or intensification of PAH-specific therapies is generally required for stabilization.
Intravenous prostanoid therapy. Intravenous prostanoids (prostacyclin derivatives) are the most potent PAH-specific drugs and
are indicated for severely ill patients with PAH.2,3,12,62,63,98 Critically ill patients with PAH warrant parenteral prostanoid therapy
rather than oral therapy, and inhaled pulmonary vasodilators can
be useful for acute stabilization.2,3,12,69 Intravenous epoprostenol
(Flolan (GlaxoSmithKline, London, UK) and Veletri (Actelion
Pharmaceuticals, Basel, Switzerland)) is preferred for unstable
patients due to its short half-life (less than 6 minutes), allowing
rapid titration (Figure 3).8,9,62,98 The longer acting analogue treprostinil (Remodulin) has a half-life of up to 4 hours, making it
more suitable for chronic therapy.62,98 Early initiation of intravenous epoprostenol is recommended for critically ill patients with
RVF due to PAH, who are not on systemic prostanoid therapy,
titrated to the maximum-tolerated dose while avoiding systemic
hypotension.3 The de novo starting epoprostenol dose is 1 to 2
ng/kg/min that can be increased by 0.5 to 1 ng/kg/min (up to 2
ng/kg/min) as often as every 15 to 30 minutes in the ICU up to
an initial target dose of 6 to 10 ng/kg/min, then increased more
gradually to the usual chronic dose of 25 to 40 ng/kg/min or
more.2,8,12,62,98 Epoprostenol dose titration is limited by systemic
hypotension or side effects such as headache, flushing, nausea/
vomiting/diarrhea, jaw or musculoskeletal pain; and mild to moderate thrombocytopenia often occurs and may promote gastrointestinal bleeding.62,98 When side effects warrant dose reduction of
epoprostenol, the dose is decreased by 1 to 2 ng/kg/min every 15
minutes to the highest tolerated dose.62 Patients who develop worsening RVF despite chronic systemic prostanoids may require an
increased dose, and we often switch subcutaneous to intravenous
prostanoid therapy to ensure reliable drug delivery.
Complications of parenteral prostanoids. Clinical deterioration
after initiation of systemic PAH therapy in a patient with PH
should prompt drug discontinuation and confirmation of the
underlying PH etiology. Worsening hypoxemia after initiation
of intravenous prostanoid therapy occurs due to V/Q mismatch
or development of pulmonary edema, suggesting an etiology
other than pure PAH. Systemic PAH-specific therapy can produce V/Q mismatch in the presence of parenchymal lung disease
or PE by antagonizing hypoxic pulmonary vasoconstriction and
increasing perfusion of poorly ventilated lung units.4,5,8,23 Worsening hypoxemia unresponsive to supplemental oxygen after
starting a systemic PAH-specific drug may warrant switching

to an inhaled pulmonary vasodilator.4,22 New-onset pulmonary


edema after initiation of intravenous prostanoid therapy suggests either elevated PAWP (PH-LHD) or PVOD, requiring
empiric diuresis and often discontinuation of prostanoid therapy.13,49 Catheter infection and malfunction are common complications of chronic intravenous prostanoid use, requiring
peripheral intravenous prostanoid infusion to prevent lifethreatening drug interruption when the catheter is
removed.12,62,98 Chronic prostanoid overdosing can produce
high-output HF requiring dose reduction.98
Inhaled therapies. Inhaled pulmonary vasodilators locally dilate
pulmonary arterioles in ventilated lung units, improving oxygenation via V/Q matching and reducing PVR.6,22,23,58,64,66-77,99
Inhaled pulmonary vasodilators can be useful to stabilize
patients with PAH, while intravenous prostanoids are titrated
and may be first line for postoperative RVF with or without
PH.5,8,21,25,69,70 When initiating any PAH-specific drug, PAWP
should be controlled prior to starting inhaled pulmonary vasodilator therapy to prevent pulmonary edema.69 The best studied
inhaled pulmonary vasodilator is NO, but recent reports
describe the use of inhaled epoprostenol, inhaled iloprost, and
inhaled milrinone.58,64,66-77,99,100 Inhaled NO has several limitations including high cost, flat dose response, and risk of dangerous rebound PH after withdrawal.69 At usual starting doses
of 10 parts per million (ppm), inhaled NO can improve V/Q
matching and hypoxemia, while doses of 20 ppm may reduce
PVR more effectively and doses of 40 to 80 ppm appear to add
little in clinical efficacy.13,69 Addition of sildenafil can
increase the response to inhaled NO and may reduce the risk
of rebound PH after inhaled NO withdrawal.6,101-105
Inhaled epoprostenol is administered at a usual dose of
*50 ng/kg/min (range 10-85 ng/kg/min) or a fixed concentration of 10 to 20 mg/mL nebulized at 0.2 to 0.3 mL/min. The
drug is often started at maximum dose then downtitrated based
on the response.6,70 Nebulization of epoprostenol at up to 50 to
85 ng/kg/min provides similar hemodynamic effects as inhaled
NO at 20 ppm but costs significantly less.70,72-76 Inhaled
iloprost (Ventavis, Actelion Pharmaceuticals, Basel, Switzerland) has a moderate half-life (20-30 minutes) that allows intermittent administration in patients who are not mechanically
ventilated, unlike inhaled NO or inhaled epoprostenol that must
be continuously administered through the ventilator.62,98 Usual
inhaled iloprost doses for chronic therapy are 2.5 to 5 mg every
3 to 4 hours (6-9 per day), but single doses up to 10 to 20 mg
have been reported during weaning from cardiopulmonary
bypass.21,62,71,98 Inhaled milrinone (1 mg/mL nebulized at 0.20.3 mL/min) reduces PVR and improves V/Q matching with less
hypotension compared to intravenous milrinone.6,66,68 To date,
no studies have shown a mortality benefit of inhaled pulmonary
vasodilators in any patient population.
Oral agents. Oral PAH-specific therapies are used primarily for
chronic PAH in stable outpatients and are rarely started acutely
in the ICU except in selected treatment-naive patients with
PAH after stabilization with intravenous prostanoids.12,25 When

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Journal of Intensive Care Medicine

patients with PAH on chronic oral PAH-specific therapy decompensate and develop RVF, initiation of prostanoid therapy is
indicated, but preexisting oral PAH-specific drugs can be continued in the absence of adverse effects.12,98 Hypotension from
oral PAH-specific therapy is typically mild and may not warrant
drug discontinuation, but holding oral PAH-specific drugs when
the patient is hypotensive (ie, from sepsis) is reasonable and
rarely associated with rebound worsening of PH, especially if
the patient is receiving an alternative PAH-specific drug. The
phosphodiesterase (PDE)-5 inhibitor sildenafil is the only oral
PAH-specific drug we consider using in the acute setting due
to its rapid onset (15-30 minutes) and short duration of action
(up to 4-6 hours).2,8,62,98 Sildenafil at usual doses of 20 to 40
mg every 8 hours can improve hemodynamics in selected
patients with PAH, PH-LHD, or postoperative PH and can facilitate weaning of inhaled pulmonary vasodilators at a modest risk
of systemic hypotension.6,8,13,101-103,105,106 Both milrinone and
PDE-5 inhibitors may synergistically augment the effects of
prostanoids and inhaled NO, suggesting a role for combination
therapy.66,101-105 We avoid endothelin receptor antagonists
(ERAs) in acutely ill patients due to their prolonged duration
of action, delayed onset of effect, and risk of fluid retention and
hepatoxicity.8,12,13 The new guanlyate cyclase activator riociguat mimics the effect of a PDE-5 inhibitor by directly stimulating guanlyate cyclase.107,108 Studies of oral PAH-specific
drugs in critically ill patients are lacking, except for studies
examining off-label use in selected patient populations that
have not shown an outcome benefit.
Disease-specific considerations in PAH. Hemoptysis is an uncommon but potentially fatal complication of PAH, related to bronchial artery hypertrophy and/or hemodynamic progression
complicated by coagulopathy from chronic anticoagulation and
antiplatelet effects of prostanoid therapy.109,110 Bronchial artery
embolization may be effective for terminating acute episodes of
hemoptysis but recurrent hemoptysis is frequent.110,111 Pulmonary arterial hypertension associated with connective tissue disease (particularly systemic lupus erythematosus) may worsen
during disease flares, requiring augmented immunosuppression.3 Pulmonary veno-occlusive disease is a dangerous subtype
of PAH producing postcapillary pulmonary vascular obstruction
resulting in hydrostatic pulmonary edema in response to dilation
of pulmonary arterioles by PAH-specific therapy.2,12,49 With
aggressive diuretic therapy, some patients with PVOD may tolerate low-dose intravenous prostanoid therapy but prognosis
remains poor.3,12,49 The following 3 PAH scenarios require
especially careful management in conjunction with a PAH specialist and will not be discussed in detail here: portopulmonary
hypertension, PAH from congenital heart disease complicated
by right-to-left shunting (Eisenmenger syndrome), and management of patients with PAH in the peripartum period.

Pulmonary hypertension Associated With LV Disease


Pulmonary hypertension caused by left heart disease is the
most common cause of PH overall but rarely warrants therapy

targeting the pulmonary vasculature.4,12,13 For most patients


with PH-LHD, elevated PA pressures reflect elevated LV
filling pressures from diastolic dysfunction.13,44 Volume
removal is central to treatment of PH-LHD, and PA pressures
often normalize after diuresis and reduction in PAWP.13 Nonselective vasodilators are the preferred vasoactive drugs for
treatment of PH-LHD, with inotropes reserved for patients
with inadequate systemic hemodynamics (Figure 3).5,13 Nonselective vasodilators such as nitroglycerin and nitroprusside
reduce SVR and decrease PA pressures by lowering PAWP
with lesser effects on PVR and are first line when MAP is normal or elevated.13,51,64,112 Nesiritide was associated with
renal dysfunction in patients with PH and RVF and may not
lower PVR.113-115 Both milrinone and dobutamine provide
inotropic support when vasodilators are inadequate in RVF
due to PH-LHD. We prefer milrinone due to its more effective
lowering of PAWP and PVR, but inotropes should not be used
for lowering PVR in patients without impaired systemic
perfusion.59,60,84
The off-label use of PAH-specific therapies in PH-LHD has
not been shown to improve clinical outcomes and remains
investigational. For selected patients with PH-LHD, persistently elevated PVR despite normalized LV filling pressures,
chronic off-label oral PDE-5 inhibitor therapy may improve
hemodynamics and/or symptoms without improving outcomes,
and other PAH-specific therapies such as prostanoids have
been associated with increased mortality during chronic use
in PH-LHD.13 Any drug selectively lowering PVR can raise
LV filling pressures, precipitate acute pulmonary edema, and/
or induce chronic fluid overload in PH-LHD patients, so PAWP
should be normalized before initiating any PAH-specific
therapy.12,13 Heart transplantation (HT) is the gold standard
treatment of end-stage heart failure, but markedly elevated
PVR is a contraindication.13,112 Chronic treatment with milrinone and/or off-label PDE-5 inhibitors may improve PVR in
HT candidates, but chronic LV unloading with an left ventricular assist device (LVAD) is generally more effective.13,116-118

Pulmonary Hypertension Due to Lung Disease


Lung disease is the second most common cause of PH overall
and an important cause of PH in the ICU, but PAH-specific
therapy has not improved outcomes in PH-PLD.2,3,10,12,22,23
The PH-PLD is most common in lung transplant candidates
and/or during acute lung disease exacerbations, but PH is usually mild to moderate and rarely produces severe low-output
RVF.2,3,12,22 Significant PH and clinical RVF are more common in mechanically ventilated patients with severe ARDS
and high airway pressures but rarely require PAH-specific
therapy.2,23 Management of PH-PLD involves treatment of the
underlying lung disease, correction of hypoxemia and hypercarbia, and minimization of potentially harmful mechanical
ventilator settings.2,22,23 A suggested RV-sparing approach to
ventilator management in patients with ARDS involves maintaining a plateau pressure <28 cm H2O via low tidal volumes
(<6 mL/kg) and limitation of positive end-expiratory pressure

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Jentzer and Mathier

11

(PEEP, ideally <12 cm H2O), maintaining PaCO2 <55 to 60 mm


Hg by increasing respiratory rate.5,23 In patients with ARDS,
inhaled pulmonary vasodilators (NO and prostanoids) may
improve oxygenation, PA pressures, and RV function but do
not improve clinical outcomes and are reserved for refractory
hypoxemia.63,69,70,76,99,106 When drug therapy is indicated to
lower PVR in PH-LHD complicated by severe RVF, inhaled
pulmonary vasodilators are preferred to avoid worsening
oxygenation due to V/Q mismatch (Figure 3).22,23 Sarcoidosis
can produce PH via hypoxemic/parenchymal lung disease and
pulmonary vascular disease. Off-label PAH-specific therapy
can lower PA pressures but risks worsening hypoxemia in
proportion to parenchymal lung disease.12,22
Mechanical ventilation in PAH. Up to one-third of hospitalized
patients with PAH admitted to the ICU develop respiratory
failure requiring mechanical ventilation, increasing hospital
mortality up to 10-fold.29,30,32 The PH-PLD producing
respiratory failure and RVF should be distinguished from preexisting PAH complicated by respiratory failure.11,22,23
Patients with PH-induced RVF are at risk of adverse hemodynamic effects from positive pressure ventilation, and higher
inspiratory pressures predicted mortality in mechanically ventilated patients with PH.29,30,32,61,119 Positive pressure ventilation increases intrathoracic pressures, decreasing venous
return and increasing RV afterload to impair RV stroke volume, especially with high airway pressures and/or
PEEP.2,5,8,20,22,23,119 Intubation can trigger profound hypotension in patients with severe PH and RVF, so we avoid intubation whenever possible and initiate inotropes and/or
vasopressors preemptively before intubation.5,8,34 Right ventricular protective mechanical ventilation should be used for
intubated patients with PAH as described earlier for ARDS,
targeting normal PaO2 and PaCO2 to minimize hypoxic pulmonary vasoconstriction.5,8,9,20,23,119

Thromboembolic PH
Acute PE is a common cause of new-onset PH and RVF, and
patients with PE complicated by RVF are at increased risk of
death.14 Antithrombotic therapy is the cornerstone of acute
PE therapy, including thrombolytic therapy or embolectomy
for massive PE causing hemodynamic instability or refractory
hypoxemia.14,120 With appropriate antithrombotic therapy, RV
dysfunction from acute PE typically improves or resolves,
although a minority of patients will go on to develop
CTEPH.12,14 Fluid resuscitation with or without inotrope and/
or vasopressor therapy is typically adequate for hemodynamic
stabilization in acute PE.52 Systemic PAH-specific therapy
may worsen V/Q mismatch, so inhaled pulmonary vasodilator
therapy is preferable when necessary. Patients with CTEPH
may present with severe PH and low-output RVF, warranting
PAH-specific therapies including off-label parenteral prostanoids and riociguat (Figure 3).3,12,108 Pulmonary thromboendarterectomy can significantly improve symptoms and
outcomes in selected patients with CTEPH.12,14 Patients with

RVF from acute PE or CTEPH are often considered for inferior


vena cava filter based on their limited physiological reserve in
the event of a recurrent PE.14,120-122

Postoperative PH
Postoperative PH after cardiothoracic surgery occurs due to
acutely raised PVR from lung injury and adverse effects of
cardiopulmonary bypass superimposed on preexisting pulmonary vascular disease and/or elevated LV filling pressures.2,21,25 Abnormalities in RV filling and contractility
may drive postoperative RVF without overt PH.25,123 Risk
of postoperative RVF is highest after LVAD implantation and
relatively common after pneumonectomy, mitral valve surgery, and HT.12,21,25 The management of postoperative RVF
involves volume management and inotropic support, with
inhaled pulmonary vasodilators sometimes added even when
PVR is not dramatically elevated.21,25,123 Aggressive fluid
removal may be required to ameliorate elevated filling pressures, and early ultrafiltration is suggested in patients with
CVP >20 mm Hg, despite diuretic therapy.25,112 The combination of milrinone and vasopressin can support MAP and
cardiac output with favorable effects on PVR.6,21,25,85-87
Inhaled pulmonary vasodilators reduce PVR and/or improve
hypoxemia with minimal effects on systemic BP in postoperative
PH and/or RVF.2,6,8,12,21,25,66,68-74,77,100,101 Inhaled NO was more
effective than intravenous milrinone for improving postoperative
RV function without increasing the need for vasopressors.100
Perioperative off-label oral sildenafil may increase the response
to inhaled NO and facilitate weaning of NO with a low risk of
hypotension.21,25,101,103-106

Undifferentiated PH
For critically ill patients with de novo PH and/or RVF, medical stabilization may be required prior to complete diagnostic
evaluation (Figure 2). We recommend RHC and echocardiography to guide vasoactive therapies, and patients without
RV dilation or flattening of the interventricular septum generally do not require therapy to reduce PVR.3,4 Pulmonary
hypertension caused by left heart disease, PH-PLD, and PE
account for the majority of cases and rarely warrant PAHspecific therapy.2-4,12 Oxygenation should be optimized,
using RV-protective mechanical ventilator settings and adequate FIO2.23,95 Empiric diuresis is appropriate with clinical
volume overload or elevated filling pressures.3 Milrinone may
be first line for lowering PVR based on its balanced vasodilator and inotropic properties, with vasopressin added if SVR is
low due to favorable effects on PVR.5,9,85-87 Systemic PAHspecific therapy (especially intravenous prostanoids) should
be discouraged in patients with PH of unknown etiology, and
inhaled pulmonary vasodilators may be more appropriate in
selected cases where PVR must be reduced. Empiric thrombolysis for possible PE can be considered in acutely unstable
patients after weighing the risks and benefits.14

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Perioperative PH Management
Perioperative risk of PH is proportional to the severity of PH
and the degree of RVF, and elective surgeries should generally be avoided in patients with PH-induced RVF and elevated
RAP.20 Fluid shifts, mechanical ventilation, and inflammatory mediator release can contribute to worsening PH and
RV function perioperatively.20 Patients with significant PH
have a mortality up to 7% to 10% within 1 month after major
noncardiac surgery, with frequent postoperative complications including respiratory failure and RVF.20 Patients with
decompensated RVF evidenced by elevated RAP and/or
reduced cardiac output should be stabilized prior to necessary
surgery. A recent review provides an in-depth discussion of
perioperative PH management.20

Advanced Therapies for PH-Induced RV


Failure
Selected patients with medically refractory PH and/or RVF
may be considered for advanced therapies such as double lung
transplantation (DLT), mechanical circulatory support and balloon atrial septostomy (BAS) at experienced centers.124-126
Patients with end-stage RVF who are not candidates for
advanced therapies have a poor prognosis and are unlikely to
survive cardiac arrest.3,5,97 Double lung transplantation is the
definitive treatment for end-stage PAH, PVOD, or PH-PLD.
Right ventricular function usually normalizes in the absence
of severe RVF, so heartlung transplantation is reserved for
selected patients with severe irreversible PH and concomitant
severe cardiac disease.10,12,63,124,125 Survival early after DLT
is lower in patients with PAH and/or RV dysfunction, but
long-term outcomes are comparable to other DLT recipients.127
Mechanical circulatory support can be considered for potential transplant candidates to prevent progressive end-organ dysfunction once medically refractory RVF develops. Mechanical
circulatory support can function as a bridge to recovery or stabilization for acute or new-onset PH, allowing medical therapy
to take effect. For appropriate candidates, venoarterial extracorporeal membrane oxygenation (ECMO) can support hemodynamics and oxygenation as a bridge to DLT in RVF
refractory to conventional therapy, allowing vasopressor and
inotrope withdrawal.3,8-10,63,124,125,128 Outcomes after DLT in
critically ill patients (particularly those bridged with ECMO)
may be inferior to stable DLT recipients, but survival remains
superior to the natural history of end-stage disease.127,129 The
use of RV assist devices in patients with PH-induced RVF and
significantly elevated PVR remains experimental, and
increased flow into the diseased PA can result in pulmonary
hemorrhage and/or edema.10,124,126
Balloon atrial septostomy can be used as a palliative
therapy or a bridge to DLT for patients with medically
refractory PAH prior to the development of respiratory failure or uncontrolled RVF.12,63,124 Percutaneous BAS creates
an atrial-level right-to-left shunt that bypasses the
obstructed pulmonary circulation to increase LV filling and

systemic blood flow, improving systemic oxygen delivery,


despite a modest reduction in SaO2.124 Periprocedural mortality in patients with medically refractory PAH who
undergo BAS is 5% to 7% or less in most published series,
although mortality at 1 month may be up to 15% to
20%.12,124,130,131 Predictors of mortality after BAS include
higher RAP, decompensation requiring ICU admission,
lower postprocedural SaO2, and BAS for an indication other
than syncope.124,130 Balloon atrial septostomy is contraindicated in critically ill patients with severe RVF requiring
hemodynamic support and in patients with RAP >20 mm
Hg, resting SpO2 <90% on room air, or LVEDP (left ventricular end-diastolic pressure) >18mm Hg.63,124 Well-selected
candidates receiving BAS prior to the development of endstage RVF may have a median survival of 60 months or
more when PAH-specific therapy is added.124,131

Conclusion
Pulmonary hypertension is common in critically ill patients and
may cause circulatory compromise from RVF. Numerous etiologies produce PH in critically ill patients, particularly LV failure and hypoxemic lung disease. Diagnostic evaluation in the
ICU should rapidly exclude common etiologies via RHC and
chest CT imaging. Pulmonary arterial hypertension itself is
relatively infrequent, but patients with PAH who become critically ill have poor outcomes and require aggressive treatment
including intravenous prostanoid therapy. Management of RVF
in PH involves optimization of preload, reduction in PVR, and
support of RV inotropy and systemic perfusion. Empiric PAHspecific therapy prior to diagnostic assessment can produce disastrous consequences. Many commonly used vasoactive drugs
affect the pulmonary vasculature with favorable or detrimental
effects on RV afterload. The PAH-specific therapies can be
used for carefully selected patients with severe RVF and PH
but risk systemic hypotension and worsening hypoxemia.
Inhaled pulmonary vasodilators may have greater applicability
based on their ability to improve V/Q matching and hypoxemia. Prostanoid therapy should be reserved for patients with
normal lung parenchyma and normal left ventricular filling
pressures. Highly selected patients with refractory symptoms
may be considered for advanced therapies including DLT,
ECMO, or BAS. Despite the availability of an increasing therapeutic armamentarium for chronic PAH, acutely ill patients
with PH and RVF remain challenging to manage with a high
risk of mortality.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.

Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.

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