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Continuing Medical Education Article

Management strategies for patients with pulmonary hypertension

in the intensive care unit*Roham T. Zamanian, MD; Francois Haddad, MD; Ramona L. Doyle, MD; Ann B. Weinacker, MD

Pulmonary hypertension is

commonly encountered in theintensive care unit (ICU). Al-though new therapies for pul-

monary hypertension have emerged inrecent years, the management of criti-

cally ill patients with hemodynamically

significant pulmonary hypertension re-mains challenging. Patients with moder-ate to severe pulmonary hypertension candeteriorate rapidly and are unlikely tosurvive efforts at cardiopulmonary resus-

citation (1). Appropriate therapy depends

on identifying the underlying cause andhemodynamic effects of pulmonary hy-pertension. To reflect differences inpathophysiology, a revised World HealthOrganization classification of pulmonary

*See also p. 2210. Assistant Professor of Medicine (RTZ), Clinical In-

structor (FH), Pulmonary Hypertension Clinical Service,Associate Professor, Co-Director, Vera Moulton WallCenter for Pulmonary Vascular Disease (RLD), Associ-ate Professor of Medicine (ABW), Division of Pulmonary

& Critical Care Medicine, Associate Chair for Clinical Affairs, Department of Medicine (ABW), Stanford Uni-versity Medical Center, Stanford, CA.

Supported, in part, by grants from Actelion (RZ,RLD) and United Therapeutics (RLD).

Address requests for reprints to: Ann B. Weinacker,

MD, 300 Pasteur Drive, S102, Stanford, CA 943055110.

E-mail: [email protected]

Copyright 2007 by the Society of Critical Care

Medicine and Lippincott Williams & Wilkins

DOI: 10.1097/01.CCM.0000280433.74246.9E

LEARNING OBJECTIVES

On completion of this article, the reader should be able to:

1. Explain the pathophysiology of pulmonary hypertension.

2. Describe treatment modalities for pulmonary hypertension.

3. Use this information in the clinical setting.

Dr. Zamanian has disclosed that he is/was the recipient of grant/research funds from Entelligence-Actelions YoungInvestigators Program, is/was on the speakers bureau for Actelion, and was on the speakers bureau for Co-Therix, andEncysive. Dr. Doyle has disclosed that she is/was a consultant for Actelion, Encysive, and Gilead. Dr. Haddad has disclosedthat he has no financial relationships with or interests in any commercial companies pertaining to this educational activity.Dr. Weinacker has disclosed that she was the recipient of grant/research funds from Lilly.

The authors have disclosed that sildenafil has not been approved by the U.S. Food and Drug Administration for use in the treatmentof pulmonary hypertension in critically ill patients. Please consult product labeling for the approved usage of this drug or device.

Lippincott CME Institute, Inc., has identified and resolved all faculty conflicts of interest regarding this educational activity.

Visit the Critical Care Medicine Web site (www.ccmjournal.org) for information on obtaining continuing medical education credit.

Objective: Pulmonary hypertension may be encountered in the intensive

care unit in patients with critical illnesses such as acute respiratory distress

syndrome, left ventricular dysfunction, and pulmonary embolism, as well as

after cardiothoracic surgery. Pulmonary hypertension also may be encoun-

tered in patients with preexisting pulmonary vascular, lung, liver, or cardiac

diseases. The intensive care unit management of patients can prove extremely

challenging, particularly when they become hemodynamically unstable. The

objective of this review is to discuss the pathogenesis and physiology of

pulmonary hypertension and the utility of various diagnostic tools, and toprovide recommendations regarding the use of vasopressors and pulmonary

vasodilators in intensive care.

Data Sources and Extraction: We undertook a comprehensive review of

the literature regarding the management of pulmonary hypertension in the

setting of critical illness. We performed a MEDLINE search of articles pub-

lished from January 1970 to March 2007. Medical subject headings and

keywords searched and cross-referenced with each other were: pulmonary

hypertension, vasopressor agents, therapeutics, critical illness, intensive care,

right ventricular failure, mitral stenosis, prostacyclin, nitric oxide, sildenafil,

dopamine, dobutamine, phenylephrine, isoproterenol, and vasopressin. Both

human and animal studies related to pulmonary hypertension were reviewed.

Conclusions:Pulmonary hypertension presents a particular challenge in

critically ill patients, because typical therapies such as volume resuscitation

and mechanical ventilation may worsen hemodynamics in patients with

pulmonary hypertension and right ventricular failure. Patients with decom-

pensated pulmonary hypertension, including those with pulmonary hyperten-

sion associated with cardiothoracic surgery, require therapy for right ventric-

ular failure. Very few human studies have addressed the use of vasopressors

and pulmonary vasodilators in these patients, but the use of dobutamine,

milrinone, inhaled nitric oxide, and intravenous prostacyclin have the greatest

support in the literature. Treatment of pulmonary hypertension resulting from

critical illness or chronic lung diseases should address the primary cause of

hemodynamic deterioration, and pulmonary vasodilators usually are not nec-

essary. (Crit Care Med 2007; 35:20372050)

KEY WORDS: pulmonary hypertension; intensive care unit; vasopressor

agents; nitric oxide; prostacyclin; right ventricular failure; dobutamine

2037Crit Care Med 2007 Vol. 35, No. 9


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hypertension (Table 1) has been adopted(2). The revised classification separatescauses of pulmonary hypertension intothose that primarily affect the pulmonaryarterial tree (pulmonary arterial hyper-tension; PAH) or the pulmonary venoussystem, and those that affect the pulmo-nary vasculature because of alterations inlung structure or function. This new clas-sification thus provides a framework to

guide appropriate diagnosis and treat-ment of pulmonary hypertension in crit-ically ill patients (2).

Pulmonary hypertension is defined asa systolic pulmonary artery pressure(PAP) of35 mm Hg, or, alternatively, asa mean PAP of 25 mm Hg at rest or30 mm Hg with exertion (24). Pulmo-nary hypertension in the ICU may be dueto preexisting pulmonary vascular dis-ease, lung disease, liver disease, or car-diac disease. Pulmonary hypertensionalso may be caused by critical illnessessuch as acute respiratory distress syn-drome (ARDS), acute left ventricular dys-function, and pulmonary embolism, ormay occur after cardiac or thoracic sur-gery. In this paper we review the diagno-sis and treatment of critically ill patients

with pulmonary hypertension of varyingetiologies, and discuss strategies to treathemodynamic instability.

PATHOGENESIS AND

PHYSIOLOGY

Pulmonary hypertension encompassesa spectrum of pathologies best character-ized by their anatomical location: precap-illary arteries and arterioles, alveoli andcapillary beds, and postcapillary pulmo-nary veins and venules. Idiopathic pul-monary arterial hypertension is the resultof increased vasoconstriction, pulmonary

vascular remodeling, and in situ throm-bosis provoked by endothelial dysfunc-tion, smooth muscle proliferation, andneointimal formation (3, 5, 6) in the pre-capillary arteries and arterioles. The

more common causes of PAH (group 1 inTable 1) have similar histopathologicchanges. Hypoxemic lung diseases suchas interstitial lung disease and chronicobstructive pulmonary disease may causepulmonary hypertension as the result of

vascular destruction as well as alveolarhypoxemia. In acute lung injury, bothhypoxemia and the accumulation of in-travascular fibrin and cellular debris con-tribute to subsequent vascular oblitera-tion and pulmonary hypertension (7).

Pulmonary venous hypertension is typi-cally a result of left ventricular diastolic

dysfunction, valvular heart disease, orpulmonary venous disorders.

Multiple molecular pathways havebeen implicated in the pathogenesis ofPAH. Nitric oxide and prostacyclin areendogenous vasodilators produced inthe pulmonary vascular endothelium,and in many types of pulmonary hyper-tension their production is impaired (7,8). Endothelin-1 is an endogenous va-soconstrictor peptide secreted by the

vascular endothelium (7), and is impli-cated in pulmonary vasoconstriction

and vascular smooth muscle prolifera-tion (7). Endothelin-1 is excessivelyabundant in patients with idiopathicPAH, PAH associated with congenitalheart disease, and pulmonary hyperten-sion associated with thromboembolicdisease (810). Dysfunction in the ni-tric oxide, prostacyclin, endothelin-1,and other pathways produces an imbal-ance between vasodilation and vasocon-striction, and between apoptosis andproliferation. The rationale for therapy

for PAH is thus based on re-establishingthe balance in key molecular pathways

by increasing available nitric oxide andprostacyclin, or reducing the effects ofendothelin-1 (Fig. 1).

The neurotransmitter serotonin andthe serotonin receptor transporter alsohave been implicated in the developmentof PAH. Some studies have linked highserotonin levels to PAH (11, 12). Further-more, appetite suppressants such asdexfenfluramine and aminorex that ele-

vate serotonin levels are associated with asignificantly increased incidence of PAH(13). Recent debate has focused on the

potential role of serotonin receptor trans-porter polymorphism as a genetic riskfactor for developing PAH (14).

The consequence of these aberrantcellular and molecular pathways is an in-crease in pulmonary vascular resistance(PVR) and impedance of flow, causingright ventricular strain that impairs fill-ing and causes right ventricular volumeand pressure overload (Fig. 2). The right

ventricle then dilates and eventually hy-pertrophy develops, encroaching on the

Table 1. Revised clinical classification of pulmonary hypertension (Venice 2003)

1. Pulmonary arterial hypertension (PAH)1.1. Idiopathic (iPAH)1.2. Familial (FPAH)1.3. Associated with (APAH)

1.3.1. Collagen vascular disease1.3.2. Congenital systemic-to-pulmonary shunts1.3.3. Portal hypertension1.3.4. HIV infection1.3.5. Drugs and toxins1.3.6. Other (thyroid disorders, glycogen storage disease, Gaucher disease, hereditary

hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders,splenectomy)1.4. Associated with significant venous or capillary involvement

1.4.1. Pulmonary veno-occlusive disease (PVOD)1.4.2. Pulmonary capillary hemangiomatosis (PCH)

1.5. Persistent pulmonary hypertension of the newborn2. Pulmonary hypertension with left heart disease

2.1. Left-sided atrial or ventricular heart disease2.2. Left-sided valvular heart disease

3. Pulmonary hypertension associated with lung diseases and/or hypoxemia3.1. Chronic obstructive pulmonary disease3.2. Interstitial lung disease3.3. Sleep-disordered breathing3.4. Alveolar hypoventilation disorders3.5. Chronic exposure to high altitude3.6. Developmental abnormalities

4. Pulmonary hypertension due to chronic thrombotic and/or embolic disease4.1. Thromboembolic obstruction of proximal pulmonary arteries4.2. Thromboembolic obstruction of distal pulmonary arteries4.3. Non-thrombotic pulmonary embolism (tumor, parasites, foreign material)

5. MiscellaneousSarciodosis, histiocytosis X, lymphangiomatosis, compression of pulmonary vessels

(adenopathy, tumor, fibrosing mediastinitis)

HIV, human immunodeficiency virus.

Reproduced with permission from Simmoneau G, Gali N, Rubin LJ, et al: Clinical classification of

pulmonary hypertension. J Am Coll Cardiol 2004; 43:10S.

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left ventricle and decreasing preload, car-diac output, and coronary perfusion. In-creased right ventricular wall stress re-sults in right ventricular ischemia.

Tricuspid regurgitation develops as a re-sult of right ventricular dysfunction andportends a poor prognosis (15). Regard-less of the underlying cause of pulmonary

hypertension, the final common pathwayfor hemodynamic deterioration and deathis right ventricular failure, which is themost challenging aspect of patient man-agement. Therapy is thus aimed atacutely relieving right ventricular over-load by decreasing PVR and reversingright ventricular failure with pulmonary

vasodilators and inotropes.

RIGHT VENTRICULARDYSFUNCTION IN PULMONARY

HYPERTENSION

Compared with the left ventricle, theright ventricle demonstrates a height-ened sensitivity to changes in afterload.Right ventricular stroke volume de-creases proportionately to acute in-creases in afterload. In addition, a nor-mal right ventricle cannot acutelyincrease the mean PAP to more than 40mm Hg (16). Right ventricular systolicdysfunction, severe tricuspid regurgita-tion, arrhythmias, and left ventriculardysfunction caused by ventricular in-terdependence may contribute to lowcardiac output and hypotension in pa-tients with pulmonary hypertension(Fig. 2). Ventricular interdependencerefers to the concept that the size,shape, and compliance of one ventriclemay affect the size, shape, and pres-surevolume relationship of the other

ventricle. In the presence of right ven-tricular volume or pressure overload,the interventricular septum shifts toward

the left and limits left ventricular fillingand output. This has direct implicationsfor the management of patients with pul-monary hypertension and acute right

ventricular failure. In fact, the challengeis to find the optimal preload to avoid thedetrimental effects of ventricular interde-pendence (17). Another consequence ofright ventricular failure in the setting ofpulmonary hypertension is the openingof the foramen ovale and development ofright to left shunting that can cause oraggravate hypoxemia.

Neurohormonal activation is importantin acute and chronic right-sided failure.

Atrial and B-type natriuretic peptide levelsrecently have been described to be elevatedin patients with right ventricular failureand pulmonary hypertension (18), and arenot only markers for pulmonary hyperten-sion but appear to be important in thepathogenesis of the disease. Atrial and B-type natriuretic peptides are cardiac pep-tides that not only promote diuresis butalso inhibit pulmonary vasoconstriction

Figure 1. Schematic representation of pathways implicated in pulmonary arterial hypertension, and sitesof action of current therapies. The overabundance of endothelin-1 and the relative lack of prostaglandin I2and nitric oxide lead to the vasoconstriction and hyperproliferation associated with pulmonary

arterial hypertension (blue arrows). Therapies (red text) aimed at specific molecular pathways

attempt to regain control of proliferation and hypertrophy of vascular smooth muscle and result

in vasodilation ( red arrows). ETA, endothelin A; ETB, endothelin B; cAMP, cyclic adenosine

monophosphate; cGMP, cyclic guanosi ne monophosphate; NO, nitric oxide; PGI2, prostaglandin I2.

Figure 2. Implications of pulmonary hypertension on right ventricular (RV) function and hemody-

namics. Development and progression of pulmonary hypertension leads to right ventricular pressure

overload, which impacts right ventricular systolic and diastolic function. Left ventricular (LV) dys-

function also can result in the setting of right ventricular failure. The physiologic consequence of

ventricular dysfunction in conjunction with development of arrhythmias, tricuspid regurgitation (TR),

and worsening hypoxemia ultimately lead to hypotension and circulatory collapse.



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(including hypoxic pulmonary vasocon-striction) by raising cyclic guanosinemonophosphate levels, and patients withpulmonary hypertension have been demon-strated to have decreased responsiveness tothese peptides (18, 19).

DIAGNOSTIC TOOLS IN THE

ICU

Pulmonary hypertension may first berecognized when an echocardiogram isobtained or a pulmonary artery catheteris placed for hemodynamic monitoring.Determining the cause and significanceof the elevated PAP then dictates appro-priate therapy. A comprehensive work-upis then necessary to determine the causeand hemodynamic consequence of pul-monary hypertension. Physical, labora-tory, and radiologic examinations canhelp distinguish among three maincauses of pulmonary hypertension in theICU (preexisting pulmonary vascular dis-ease, acute or chronic cardiovascular dis-ease, and acute or chronic pulmonarydisease), or other causes such as humanimmunodeficiency virus or liver disease.

Physical examination of patients withright ventricular failure classically re-

veals an elevated jugular venous pulsewith a large v wave. An early finding is aprominent pulmonic component of thesecond heart sound. Other findings mayinclude a palpable right ventricularheave, and the holosystolic blowing mur-mur of tricuspid regurgitation murmur

along the left lower sternal border (20). Ifperceptible, accentuation of this murmurduring inspiration (Carvallos sign) dis-tinguishes it from the murmurs of mitralregurgitation and aortic stenosis. Theremay be tender, even pulsatile hepatomeg-aly, and ascites or peripheral edema. Thelung exam may suggest underlying lungdisease. Patients with isolated right ven-tricular failure, however, do not exhibitpulmonary edema. The finding of pulmo-nary edema suggests left ventricular dys-function, pulmonary venous hyperten-

sion, or a noncardiac cause such asARDS.

Laboratory evaluation is undertakento identify reversible causes of pulmonaryhypertension. In the ICU however, manylaboratory derangements result fromcritical illness itself. Nonetheless, cluesmay be provided as to the underlyingcause of pulmonary hypertension bypolycythemia (suggesting chronic hy-poxemia), thyroid or liver function ab-normalities, or serologic markers of

connective tissue disease (sclerodermaand lupus), hepatitis, or human immu-nodeficiency virus.

Cardiac enzymes may be elevated inpatients with right ventricular overdis-tension and ischemia. Troponin I leakdue to acute right ventricular strain frompulmonary embolism has been described(21), and may predict mortality (22). B-type natriuretic peptide (BNP) is a prog-

nostic indicator in patients with severepulmonary hypertension (23). The utilityof measuring BNP in critically ill patients

with pulmonary hypertension is unclear,however. BNP levels may be elevated incritically ill surgical patients (24), pa-tients with shock (25), or critically illpatients with cardiac dysfunction of anycause (26, 27). Although the diagnosticutility of BNP in renal insufficiency hasbeen thought to be limited, recent liter-ature (28) suggests that a plasma BNP of150 pg/mL is a reliable marker of left

ventricular overload and heart failure inpatients with chronic renal failure. Inpatients with renal failure, a relativereduction in BNP after hemodialysiscan be a valid indicator of improved left

ventricular wall tension (29), but theutility of its measurement in patients

with concomitant right ventricular dys-function and critical illness remainsquestionable (30).

Electrocardiography is an insensi-tive measure of right ventricular hyper-trophy, but the findings of right axisdeviation, R/S wave 1 i n V 1 with R

wave 0.5 mV, and P pulmonale aremore than 90% specific (31). Electro-cardiography changes reflecting right

ventricular abnormalities are signifi-cant predictors of mortality in patients

with idiopathic PAH (32). Althoughthese electrocardiography findings havenot been used for prognosis in the ICU,they provide evidence of advanced dis-ease that may be difficult to manage incritically ill patients. Electrocardiogra-phy scoring systems that correlate withthe extent of perfusion defects in acute

pulmonary embolism also have beendeveloped (33), and may prove useful inthe future to diagnose and stratify pa-tients with pulmonary hypertensionand right ventricular failure.

Plain chest radiography is of limitedutility in diagnosing pulmonary hyper-tension in the ICU, but may help definean underlying cause. Typical findings ofright ventricular hypertrophy, right atrialenlargement, and obscuring of the aorto-pulmonary window by enlarged pulmo-

nary arteries are less obvious on portableradiographs. Nonetheless, diffuse severepulmonary parenchymal abnormalitiesmay suggest an underlying cause of pul-monary hypertension. Computerized to-mographic angiography, ventilation-perfusion scanning, or pulmonaryangiography may identify thromboem-bolic disease as the cause of pulmonaryhypertension (4).

Echocardiography is useful for diag-nosing and determining the degree andsignificance of pulmonary hypertension(4). Echocardiography can noninvasivelyestimate right atrial and pulmonary arte-rial pressures, determine the degree ofright ventricular dysfunction, and revealpotential causes of pulmonary hyperten-sion such as left ventricular systolic ordiastolic dysfunction, mitral stenosis orregurgitation, and certain intracardiacshunts. Although images may be subop-timal in critically ill patients because oflimitations of patient positioning, inter-ference by dressings, or positive pressure

ventilation, a transthoracic echocardio-gram should be obtained as a screeningtest (4). Echocardiographic signs of sig-nificant pulmonary hypertension includeright ventricular dilation and hypertro-phy, septal bowing into the left ventricleduring late systole to early diastole (D-shaped left ventricle), right ventricularhypokinesis, tricuspid regurgitation,right atrial enlargement, and a dilatedinferior vena cava (3, 34, 35). Increasedright ventricular size and outflow imped-

ance combined with reduced ejectionfraction have been described in acutecor pulmonale. Demonstration of septaldyskinesia and right ventricular en-largement indicate right ventricularsystolic and diastolic overload, respec-tively (34, 35).

In acute pulmonary embolism, Mc-Connell and colleagues (36) also describeda specific pattern of right ventricular dys-function characterized by a severe hypoki-nesia of the right ventricular mid-free wall,

with normal contractions of the apical

segment. Echocardiographic predictorsof poor outcomes in PAH include rightatrial enlargement, septal bowing, andthe development of a pericardial effu-sion (37).

Transesophageal echocardiographymay be more sensitive than transthoracicechocardiography, especially in acute dis-ease such as pulmonary embolism (38),and may provide clearer and more accu-rate information in critically ill patients(39).



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Right heart or pulmonary artery (PA)catheterization is the gold standard forthe diagnosis of pulmonary hypertension(3). In patients with significant PAH, themost useful information is obtained inthe cardiac catheterization laboratory.Precise analysis of mixed venous oxygensaturations during insertion and passageof the PA catheter through the cardiacchambers can allow diagnosis of intracar-

diac shunts. A pulmonary capillary wedgepressure less than 15 mm Hg helps ruleout left ventricular and pulmonary ve-nous diseases (3). Observation of real-time mean PA pressure (mPAP), cardiacoutput, and PVR allows immediate eval-uation of response to vasodilator therapy.

Although the definition of a substantialresponse to therapy remains controver-sial, the most recent definition requires areduction in mPAP of at least 10 mm Hgto 40 mm Hg with an increased orunchanged cardiac output (40). Becauseincreased pulmonary arterial blood flowcan elevate mPAP, documentation of theresponse to therapy also should include

the change in PVR. Regardless of the pa-

rameters used, the presence of vasoreac-

tivity may suggest a better prognosis and

ultimately can help determine medical

therapy (41).

Despite current controversies regard-

ing the utility of PA catheters in the ICU,

hemodynamic data are valuable in the

care of critically ill patients with pulmo-

nary hypertension. In this setting, tech-

nical and interpretive limitations must berecognized. Severe tricuspid regurgita-

tion and elevated PAP often make placing

a PA catheter challenging, and may ne-

cessitate the use of fluoroscopy. Accurate

determination of cardiac output by ther-

modilution may be limited in patients

with tricuspid regurgitation or low car-

diac output (42). The Fick method may

be more accurate, but requires determi-

nation of oxygen consumption, which is

challenging in critically ill patients. The

superiority of thermodilution vs. the Fick

method in critically ill patients remains

controversial (43).

Complications of PA catheterizationare particularly dangerous in patients

with pulmonary hypertension and right ventricular strain. Tachyarrhythmiashave potentially life-threatening conse-quences of decreased stroke volume dueto shortened filling time, or deteriorationinto fatal arrhythmias. Obtaining a pul-monary capillary wedge pressure alsomay be difficult in patients with markedly

elevated pulmonary pressures.

MANAGEMENT OF PULMONARY

HYPERTENSION IN THE ICU

Overview

When managing a critically ill patientwith pulmonary hypertension in the ICU,primary considerations include the diag-nosis and treatment of specific causes ofpulmonary hypertension, the applicationof PAH-specific therapies only when ap-propriate, and determination of the de-gree of right ventricular failure and itsappropriate therapy (Fig. 3).

Figure 3. Suggested evaluation and treatment algorithm for pulmonary hypertension in the intensive care unit (ICU). WHO, World Health Organization;

PH, pulmonary hypertension; RV, right ventricle; LV, left ventricle; PAH, pulmonary arterial hypertension; BNP, B-type natriuretic peptide; iNO, inhaled

nitric oxide; CVP, central venous pressure; SVO2, mixed venous oxygen saturation; CO, cardiac output; PEEP, positive end-expiratory pressure; SVR,

systemic vascular resistance. *Bosentan initiation requires normal liver transaminases and may be associated with fluid retention and necessitate further

diuresis.**Sildenafil is contraindicated in concomitant use with nitroglycerin because of its hypotensive potential.



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The revised classification of pulmo-nary hypertension (Table 1) provides aframework for treatment of pulmonaryhypertension patients in the ICU. Pa-tients with PAH (World Health Organiza-tion group 1) can benefit from prostacy-clin, sildenafil, or from long-termbosentan therapy, depending on the se-

verity of their illness and functional clas-sification. Patients with decompensated

PAH often require an aggressive combi-nation of therapies for right ventricularfailure, including pulmonary vasodilatorsand inotropes. In patients with pulmo-nary venous hypertension (World HealthOrganization group 2), optimization ofleft-sided heart failure and valvular dis-ease management is the most importantfacet of therapy. In patients with pulmo-nary hypertension secondary to variouscauses of parenchymal lung diseaseand/or hypoxemia, primary therapy con-sists of treating the underlying cause. Pa-tients with pulmonary hypertension re-sulting from critical illness (Table 2) orchronic lung disease (44) are less likely tosuffer from significant underlying pulmo-nary vascular disease, and their treat-ment should address the primary cause oftheir hemodynamic deterioration, suchas sepsis or left ventricular dysfunction.These patients usually do not requiretreatment with pulmonary vasodilators.In patients with acute thromboembolicdisease, therapy consists of anticoagula-

tion (45), thrombolysis, or thrombec-tomy (see section on pulmonary embo-lism).

Aggressive fluid balance managementis critical in patients with decompensatedpulmonary hypertension and right ven-tricular failure. Hypovolemia and hyper-

volemia both can lead to suboptimal pre-load and decreased cardiac output.Maintenance of sinus rhythm and atrio-

ventricular synchrony is especially im-portant in the presence of right ventric-ular dysfunction. For example, atrialfibrillation or complete atrioventricularblock are poorly tolerated in patients withacute pulmonary emboli or in chronicright ventricular failure (46). In the he-modynamically unstable patient, initia-tion of inotropic therapy may be neces-sary. Dobutamine is the inotrope that hasbeen the most extensively studied in thecontext of acute right-sided failure (seebelow), but other agents may be benefi-cial. In refractory right ventricular fail-ure, early consideration of atrial septos-tomy (see below), heart or heart-lungtransplantation, or right ventricular as-sist-device placement may be life-saving(47).

Effects of Mechanical

Ventilation

In patients with pulmonary hyperten-sion and respiratory failure, mechanical

ventilation may have untoward hemody-namic effects. Increases in lung volume

and decreases in functional residual ca-pacity can increase PVR and right ven-tricular afterload (48). In patients withnormal right ventricular function, tran-sient increases in PVR are inconsequen-tial. However, in patients with pre-existing or impending right ventricularfailure, lung hyperinflation and either in-adequate or excessive positive end-expiratory pressure can fatally reducecardiac output (48).

In a study of seven mechanically ven-tilated patients with acute lung injury

and ARDS, six developed significant tri-cuspid regurgitation, elevated PAP, andincreased pulmonary capillary wedgepressure during incremental increases inpositive end-expiratory pressure from 5mm Hg to 20 mm Hg (49). The elevatedPAP correlated directly with increasedright atrial pressure and PVR. Other in-

vestigators demonstrated increased right ventricular outflow impedance in me-chanically ventilated patients as tidal vol-ume was progressively increased, an ef-

fect that was ameliorated with theapplication of low levels of positive end-expiratory pressure between 3 cm H2Oand 8 cm H2O (50). These data suggestthat the optimal ventilator managementof patients with pulmonary hypertensionmay be with low tidal volumes and rela-tively low positive end-expiratory pres-sure. This strategy of low tidal volume

ventilation is similar to the strategy used

to ventilate patients with ARDS, butcare should be taken to avoid permis-sive hypercapnia, which may have un-toward hemodynamic effects (51). Astudy of 18 patients after coronary ar-tery bypass graft surgery demonstratedthat hypercapnia increased PVR by 54%and mPAP by approximately 30% (52).

Whether these effects are mediated byhypercapnia itself or by acidosis re-mains unclear (53).

Pharmacologic Therapy of

Pulmonary Hypertension

Vasopressors and Inotropes. Hemody-namic goals in patients with right ven-tricular failure due to pulmonary hyper-tension are to reduce PVR, augmentcardiac output, and resolve systemic hy-potension while avoiding tachyarrhyth-mias. Most traditional vasopressors andinotropes are suboptimal in reducing pul-monary vascular resistance. Only a fewsmall human studies address hemody-namic support in patients with PAH,

right ventricular failure, and hypoten-sion, and most of the common vasopres-sors and inotropes have not been studied.

Animal studies predominately employmodels of acute pulmonary hypertensionand right ventricular failure, and may notbe applicable to patients with long-standing PAH and altered right ventricu-lar mechanics. The use of vasopressorsand inotropes in patients with PAH musttherefore be guided by knowledge of theireffects on PVR and cardiac output, andmust be individualized based on patient

response. In many cases, combinationtherapy is required. The following discus-sion attempts to list agents in order ofusefulness in treating pulmonary hyper-tension and associated right ventricularfailure.

Dobutamine. Dobutamine is an ino-trope that acts primarily through 1-adrenergic receptors to augment myocar-dial contractility and reduce left

ventricular afterload (54). In animalmodels of acute pulmonary hypertension,

Table 2. Common causes of pulmonary hyper-tension in the intensive care unit

Hypoxemia/parenchymal lung diseaseAcute respiratory distress syndromePulmonary embolismInterstitial lung diseaseObstructive sleep apneaChronic obstructive pulmonary disease

Left heart diseaseAcute myocardial infarctionValvular disease (mitral regurgitation/mitral

stenosis)Severe diastolic dysfunctionCardiomyopathy

Postoperative statesCoronary artery bypass graftingCardiac transplantationLung/heart-lung transplantationPneumonectomy

Thomboembolic lung diseasePulmonary embolism

Deterioration of chronic pulmonary arterial

hypertensionFluid overloaded state

ArrhythmiasPulmonary embolism

Acute on chronic pulmonary hypertensionMedication withdrawal



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dobutamine in doses up to 5 g/kg permin significantly decreased PVR whileslightly increasing cardiac output (55,56). However, at doses of 510 g/kg permin, dobutamine caused significanttachycardia without improving pulmo-nary vascular resistance. In a caninemodel of acute right ventricular failure,dobutamine was superior to norepineph-rine in promoting right ventricular-

pulmonary artery coupling, a processthat reflects improved right ventricularfunction by optimizing pulmonary vaso-dilation (55), probably because of supe-rior inotropic properties (57). When com-bined with inhaled nitric oxide in bothanimal and human studies of acute andchronic pulmonary hypertension, dobut-amine improved cardiac index, decreasedPVR indices (56, 58), and significantlyincreased PaO2/FIO2 (58).

These studies suggest that dobut-amine doses in both acute and chronicpulmonary hypertension should be main-tained at less than 5 g/kg per min, andshould be combined with pulmonary va-sodilators such as inhaled nitric oxide

when possible. However, dobutaminemay cause systemic hypotension in somepatients because of its peripheral -ad-renergic effects and may necessitate theuse of norepinephrine or a peripheral va-soconstrictor.

Norepinephrine. Norepinephrinestimulates 1- and 1-adrenergic recep-tors. When used in animal and humanstudies of both acute and chronic pulmo-

nary hypertension, it has been shown toincrease mPAP and PVR (59, 60). How-ever, unlike phenylephrine, norepineph-rine maintained or improved cardiacoutput in patients with pulmonary hyper-tension. Selective infusion of norepi-nephrine into the left atrium, combined

with prostaglandin E1 administrationinto the right atrium, has been useful in

weaning patients with acute pulmonaryhypertension from cardiopulmonary by-pass (61). There are no data that suchselective infusion is beneficial in other

patient populations. Unlike dobutamine,norepinephrine has vasoconstrictive ef-fects that are much more pronouncedthan the chronotropic and inotropic ef-fects (55). Although norepinephrine maybe useful in hypotensive patients andcause less tachycardia, dobutamine re-mains a superior choice in the setting ofpulmonary hypertension and right ven-tricular failure.

Dopamine. Dopamine is an adrenergicand dopaminergic agonist that increases

blood pressure and cardiac output (62).One animal study suggests that the use ofdopamine in acute embolic pulmonaryhypertension augments cardiac outputand reduces PVR (63). A human study,however, failed to demonstrate a consis-tent reduction in PVR (64). In addition,the augmented cardiac output comes atthe price of significant tachycardia thatmay decrease left ventricular preload and

worsen demand ischemia.Phenylephrine. Phenylephrine is an1-adrenergic agent and a powerful arte-riolar vasoconstrictor that can improveright ventricular coronary perfusion (59).However, phenylephrine increases mPAPand PVR and decreases cardiac output,thus worsening right ventricular pres-sure overload in patients with chronicpulmonary hypertension (59, 65). Phen-

ylephrine also may cause reflex bradycar-dia (66), which may be detrimental toright ventricular hemodynamics. In pa-tients with significant pulmonary hyper-tension, phenylephrine usually should beavoided.

Isoproterenol. Isoproterenol is pri-marily a 1- and 2-adrenergic agonistthat has historically been used to treatpulmonary hypertension during surgery.Because it is a stronger chronotropicagent than dobutamine, the use of iso-proterenol is associated with significanttachyarrhythmias. Although it improvescardiac output and PVR (60), the utility ofisoproterenol in animal models of acutepulmonary hypertension has been limited

by the induction of arrhythmias and thelack of effect on PAP (67).

Epinephrine. Although commonlyused to improve cardiac output and in-crease systemic vascular resistance in hy-potensive patients in the ICU, epineph-rine, a potent - and -adrenergic agent,has not been studied in the setting ofpulmonary hypertension.

Vasopressin. Vasopressin is a weaknonadrenergic vasopressor that is be-lieved to be a systemic vasoconstrictorand a selective pulmonary vasodilator

(6870). However, in an animal model ofacute pulmonary hypertension, vasopres-sin at an average dose of 1.16 units/kg perhr increased mPAP and PVR and de-creased cardiac output (71). This sug-gests that vasopressin in high dosesshould be avoided in patients with pul-monary hypertension. On the other hand,recent data suggest that the optimal doseof vasopressin in shock is much lowerthan used in the aforementioned study(72). Whether low-dose vasopressin is

useful in the management of pulmonaryhypertension in the ICU requires furtherinvestigation.

Pulmonary Vasodilators

Pulmonary vasodilators can be classi-fied into two main categories: those thatincrease production of cyclic guanosinemonophosphate and cyclic adenosine

monophosphate, such as nitric oxide andprostanoids, respectively; and those that de-crease the breakdown of cyclic guanosinemonophosphate, such as sildenafil and za-prinast (5, 6), and of cyclic adenosinemonophosphate, such as milrinone.

Nitric Oxide. Nitric oxide is a potent vasodilator that, when inhaled, dilatespulmonary vasculature in ventilated lungunits, thereby improving oxygenation, re-

versing hypoxic pulmonary vasoconstric-tion, and reducing PAP. Nitric oxide isquickly inactivated by reaction with he-moglobin in the pulmonary capillaries,and has no systemic vasodilatory effects.Inhaled nitric oxide has been studied inpulmonary hypertension of various etiol-ogies (7376). Several studies have fo-cused on inhaled nitric oxide therapy inadults with pulmonary hypertension and

ARDS (73, 77, 78). Although ARDS pa-tients without sepsis initially improve ox-

ygenation with inhaled nitric oxide, thereis no evidence that outcomes are im-proved (79). In chronic PAH, inhaled ni-tric oxide significantly decreases mPAPand PVR without affecting systemic vas-

cular resistance or cardiac output (58,80). Of 26 patients diagnosed in an ICU

with acute right heart syndrome, 14 hadsignificant hemodynamic improvement

when treated with a mean concentrationof 35 ppm of inhaled nitric oxide. In thesepatients there was a 38% reduction inPVR, 36% increase in CO, and a 28%increase in PaO2/FIO2 (81).

The use of nitric oxide is not withoutpotential problems, however. Althoughuncommon, the development of methe-moglobinemia may limit its use, espe-

cially with prolonged administration athigher concentrations (82). Also, the in-teraction of nitric oxide and high concen-trations of oxygen produces NO2, a sig-nificant oxidant (83). Abrupt withdrawalof nitric oxide has been associated withrebound pulmonary hypertension and he-modynamic collapse in up to 48% of pa-tients evaluated (81, 84). In spite of itslimitations, inhaled nitric oxide is a use-ful agent to treat pulmonary hyperten-sion, particularly in combination with



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other agents such as dobutamine or mil-rinone (see below).

Prostaglandins. Early studies of intra-venous prostaglandin E1 and prostacyclin(or epoprostenol) in an animal model ofacute embolic pulmonary hypertensionshowed significant reductions in PVR andmPAP, as well as augmentation of cardiacoutput (80). Prostaglandin E1 and pros-tacyclin were more effective than isopro-

terenol and nifedipine, with nearly 40%reduction in PVR and approximately 35%improvement in cardiac output. More re-cent studies have demonstrated the effi-cacy of both inhaled and intravenousprostacyclin (85 88). In a retrospectivestudy of 33 ICU patients with hypoxemiaand pulmonary hypertension from car-diac and noncardiac causes, inhaled pros-tacyclin improved mPAP and hypoxemia(89). Other studies and case reports havedemonstrated the utility of inhaled pros-tacyclin and of the prostacyclin analog,iloprost, in reducing PAP and improvingcardiac output (9093), although pro-spective studies in critically ill patients

with pulmonary hypertension are lack-ing. Subcutaneous or intravenous trepro-stinil, another prostacyclin analog, is alsoan effective treatment for pulmonary hy-pertension (6), but its long half life (34hrs) makes it less appropriate in hemo-dynamically unstable patients in the ICU.

In patients with PAH and right ven-tricular failure, chronic therapy with in-travenous epoprostenol may be life-saving. Epoprostenol has an elimination

half-life of 36 mins and is typicallystarted at a dose of 12 ng/kg per min,titrated upward at a rate of 0.51.0 ng/kgper min at intervals of 1530 mins ormore. An increase in cardiac output witha decrease in PAP and PVR is considereda favorable response.

The use of epoprostenol to reduce PApressures acutely is limited by dose-dependent systemic side effects (88), partic-ularly systemic hypotension. In consciouspatients, headache, nausea, vomiting, anddiarrhea also may limit rapid titration of

epoprostenol. In patients treated chroni-cally with epoprostenol, abrupt discontinu-ation of the infusion may cause severe re-bound pulmonary hypertension and death

within minutes (40).Milrinone. Milrinone is a selective

phosphodiesterase-3 inhibitor with ino-tropic and vasodilatory effects. In animalmodels of both acute and chronic pulmo-nary hypertension, milrinone signifi-cantly reduced PVR and improved right

ventricular function (94, 95). In combi-

nation with inhaled nitric oxide, milri-none produces selective and additive pul-monary vasodilatation in pediatricpatients after repair of congenital heartdefects (96), and after cardiac surgery inanimal studies (94). However, compared

with zaprinast, a selective phosphodies-terase5 inhibitor, milrinone has infe-rior pulmonary vasodilatory effects andmore pronounced lowering of systemic

arterial pressures (97). Thus, based onanimal data and limited human data, se-lective phosphodiesterase5 inhibitionmay be more beneficial than milrinone.Milrinone may have some utility in thetreatment of hemodynamic instability inpatients with pulmonary hypertension,although systemic hypotension often lim-its its use. Further studies are needed to

verify the effects of milrinone in patientswith pulmonary hypertension.

Sildenafil. Sildenafil is a specific phos-phodiesterase5 inhibitor with acute andchronic hemodynamic effects in patients

with pulmonary hypertension (98100),and recently has been approved for thetreatment of PAH. However, there areonly case reports or small case series de-scribing its use in critically ill patients. Aretrospective case review of eight adults

with pulmonary hypertension after mitralvalve repair or placement of a left ventric-ular assist device showed that sildenafilsignificantly reduced mPAP and reducedPVR with only a minimal drop in meanarterial pressure, thus facilitating wean-ing of inhaled and intravenous pulmo-

nary vasodilators (101).In stable patients, sildenafil alone or in

combination with inhaled nitric oxide orepoprostenol reduces mPAP and PVR andincreases cardiac output (102, 103). Inpatients with idiopathic PAH, sildenafilalso can significantly improve cardiacoutput (100). Furthermore, limited hu-man and animal data suggest that silde-nafil and zaprinast may augment andmaintain the effects of inhaled nitric ox-ide (98, 104108) and iloprost (109) andminimize rebound pulmonary hyperten-

sion after withdrawal of these agents(110, 111). Additionally, some authorsspeculate that sildenafil may improvepulmonary hemodynamics and myocar-dial perfusion after coronary artery by-pass graft surgery (112).

The hemodynamic effects of sildenafilstart within 15 mins of administrationand last up to several hours, althoughpeak hemodynamic effects are seen

within 3060 mins. The relatively rapidonset of action, its diminution during

34 hrs, and the accompanying systemichypotension suggest caution in criticallyill patients. Sildenafil is contraindicatedin patients receiving nitrates because ofthe potential for severe systemic hypoten-sion.

Nesiritide. Recombinant human BNP(nesiritide) is a recently developed drugthat increases cyclic guanosine mono-phosphate and dilates vascular smooth

muscle. Its vasodilatory effect reducesright and left ventricular preload and maybenefit patients with pulmonary hyper-tension resulting from biventricular fail-ure (113). In a recent small study of pa-tients with PAH (19), BNP infusion alonedid not significantly improve pulmonaryhemodynamics, but was safe and aug-mented the vasodilatory effects of silde-nafil. However, others have shown thatthe reduction of systemic vascular resis-tance by nesiritide may cause detrimentalsystemic hypotension in patients withPAH and isolated right ventricular failure(114). Currently, therefore, the use of ne-siritide should be limited to patients withbiventricular failure who are not hypo-tensive.

Miscellaneous Therapy

Oxygen. Oxygen inhalation has beenshown to reduce PA pressure and im-prove cardiac output in patients with pul-monary hypertension, regardless of theunderlying cause (115). In addition, hy-poxic pulmonary vasoconstriction may

contribute to pulmonary hypertension incritically ill patients (116). Thus, supple-mental oxygen should not be overlookedas a key component of pulmonary hyper-tension therapy in the ICU.

Diuretics. Diuretics have long beenconventional therapy for pulmonary hy-pertension, whether caused by pulmo-nary vascular disease or left ventricularfailure. Although human studies of di-uretic use in pulmonary hypertension arelacking, there is evidence in the setting ofexercise-induced pulmonary hyperten-

sion in race horses (117). The goal ofdiuretic use is to decrease volume load onthe distended, failing right ventricle inadvanced pulmonary hypertension with-out compromising preload. Optimizationof diuresis in this setting is complex andshould be adjusted according to hemody-namic response.

Digoxin. The use of digoxin in patientswith pulmonary hypertension and right ventricular dysfunction is controversial.In a study of the short-term effects of



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digoxin in 17 patients with severe pri-mary pulmonary hypertension (118), car-diac index improved mildly and catechol-amine levels decreased, but PVR did notchange and mPAP increased. Nonethe-less, because there are more effectivedrugs to treat right ventricular failureand supraventricular tachyarrhythmias,digoxin is not commonly used in the ICUfor this purpose.

Calcium Channel Blockers. There areno studies of calcium channel blockers incritically ill patients with PAH, and be-cause of their negative inotropic effectsthey may precipitate fatal worsening ofright ventricular failure. In chronic PAH,calcium channel blocker use should belimited to stable patients with a demon-strated response to acute vasodilatorchallenge (40). Cautious use of calciumchannel blockers may help control theheart rate in patients with pulmonary hy-pertension and heart failure secondary tomitral stenosis and certain tachyarrhyth-mias, although agents with the greatestnegative inotropic effects (such as vera-pamil) should be avoided.

Anticoagulants. Anticoagulation isconsidered the standard of care in pa-tients with idiopathic PAH. However,aside from recent guidelines establishedfor the treatment of acute and chronicthromboembolic diseases (119), data foranticoagulation of patients with pulmo-nary hypertension in the ICU are lacking.

Although anticoagulants may play a rolein critical illnesses such as sepsis and

acute lung injury (120, 121), their use incritically ill patients with pulmonary hy-pertension has not been examined.

Surgical Therapy

Atrial Septostomy. The observationsof improved survival patients with pul-monary hypertension and a patent fora-men ovale (122), and patients with con-genital heart diseases and Eisenmengersphysiology (123, 124), suggested that cre-ation of an atrial septal shunt would im-

prove survival in patients with pulmonaryhypertension. Since the first palliativeatrial septostomy in 1983, several studieshave evaluated atrial septostomy for pul-monary hypertension (125, 126), or as abridge to transplantation (127). Still con-troversial in the nonurgent setting, atrialseptostomy has a very high associatedmorbidity and mortality in critically illpatients with severe right ventricular fail-ure (125127). It should not be per-formed in patients with mean right atrial

pressures of20 mm Hg, significant hy-poxemia, and a PVR index 4400 dynessec/cm5 per m2 (47, 127).

MISCELLANEOUS CAUSES OF

PULMONARY HYPERTENSION

Some causes of pulmonary hyperten-sion and hemodynamic instability en-countered in the ICU require urgent

therapy of the underlying disorder.Even in these cases, the aforemen-tioned drugs are sometimes useful in theshort term.

Pulmonary Embolism

Acute, massive pulmonary embolismmay cause acute pulmonary hypertensionand right ventricular failure (81) requir-ing inotropic support. In a large multi-center study of pulmonary embolism,hospital mortality in patients presenting

with hemodynamic instability was 31%(128). Therapy for acute massive pulmo-nary embolism with associated hemody-namic instability or shock thus aims tourgently relieve mechanical obstructionof the pulmonary vasculature caused bythrombus and intense vasoconstriction.

When pulmonary embolism is associated with hemodynamic instability, urgentpharmacologic thrombolysis is recom-mended unless contraindicated, and is as-sociated with more rapid resolution ofthrombus than anticoagulation alone, al-

though the mortality benefit is unclear(119). If thrombolysis fails or is contrain-dicated, surgical embolectomy is indi-cated in centers where an experiencedcardiac surgical team is available (119).Percutaneous mechanical clot disruptionalso has been reported, but data compar-ing outcomes to pharmacologic throm-bolysis or surgical thrombectomy arelimited (129, 130). In submassive pulmo-nary embolism associated with echocar-diographic evidence of right ventricularstrain but without hemodynamic insta-

bility, thrombolysis is recommended bysome, although this remains controver-sial (131).

Data supporting specific pharmaco-logic therapy of acute pulmonary embo-lism with right ventricular failure aresparse. Animal studies suggest that nor-epinephrine may be useful to treat hypo-tension in acute pulmonary embolism(132, 133), but data in humans are lack-ing. Inhaled nitric oxide also may im-prove hemodynamics in acute pulmonary

embolism (134) and is being used in-creasingly in many centers.

Mitral Stenosis

Mitral stenosis increases left atrial andpulmonary venous pressures, and mayeventually lead to pulmonary hyperten-sion. Diuretics are the mainstay of med-ical management and can improve car-

diac output. Rate control also is crucial,and may be achieved with diltiazem. Con-comitant atrial fibrillation and right ven-tricular failure may be treated with-blockers. Although inhaled nitric oxidecan be useful for short-term management(135), valvuloplasty or valve replacementare the definitive therapies.

Chronic Liver Disease

Portopulmonary hypertension is anuncommon cause of pulmonary hyper-tension in the ICU, and is a manifestationof chronic liver disease. Acute liver fail-ure rarely leads to portopulmonary hy-pertension, but congestive hepatopathy isfrequently noted as a consequence ofright heart failure. Patients with porto-pulmonary hypertension may havehigher cardiac output and lower systemic

vascular resistance indices than patients with idiopathic PAH (136). Althoughtreating patients with portopulmonaryhypertension may be particularly chal-lenging because of preexisting systemichypotension, limited data suggest that

the therapy is essentially the same as inpatients with decompensated pulmonaryhypertension of other etiologies (137).

Portopulmonary hypertension is oftenasymptomatic and is discovered inciden-tally when patients with end-stage liverdisease undergo evaluation for livertransplantation. Case reports and case se-ries most commonly describe treatingportopulmonary hypertension with intra-

venous epoprostenol (138, 139) or silde-nafil (140, 141), often as a bridge to livertransplantation. There are no studies of

therapy for critically ill patients with por-topulmonary hypertension either beforeor after liver transplantation.

Portopulmonary hypertension is mostproblematic in the perioperative periodsurrounding liver transplantation. Somedegree of pulmonary hypertension existsin up to 31% of liver transplant recipients(142), but severe pulmonary hyperten-sion (mPAP 45 mm Hg) is consideredby most to be a contraindication to livertransplantation. The mortality rate after



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transplantation in patients with porto-pulmonary hypertension is 36% (102),and in patients with severe pulmonaryhypertension is 50% to 100%, predomi-nately due to right heart failure (142).Because of these poor outcomes, thenumber of patients with moderate to se-

vere portopulmonary hypertension whohave been transplanted is small. As a re-sult, there are only rare case reports of

the use of epoprostenol or inhaled nitricoxide after liver transplantation (103,143), and no prospective studies.

Postoperative Pulmonary

Hypertension

Cardiac and thoracic surgery may becomplicated by postoperative pulmonaryhypertension. Pulmonary hypertension isrecognized as a major risk factor for mor-bidity and mortality in cardiothoracicsurgery (144). Although the etiology ofpostoperative pulmonary hypertension isunclear, pulmonary parenchymal and en-dothelial injury due to cardiopulmonarybypass (145147) and ischemia-reperfu-sion injury (148) have been implicatedafter cardiac surgery, cardiac or lungtransplantation, and pneumonectomy. A

variety of approaches to the therapy ofpulmonary hypertension and right ven-tricular failure have been used in patients

who have undergone cardiac or thoracicsurgery or transplantation, and combinedtherapy is commonly used.

In small series, both inhaled prostacy-

clin and nitric oxide have been shown tobe valuable in treating pulmonary hyper-tension after mitral valve replacement(149, 150) and other types of cardiac sur-gery requiring cardiopulmonary bypass(148). Pulmonary hypertension in theearly postoperative period after cardiactransplantation may be particularly diffi-cult to manage, and approaches such asthe use of inhaled nitric oxide, prostacy-clin, and prostaglandin E1 have been usedin small case series (151). In patients

with pulmonary hypertension related to

low cardiac output following cardiac sur-gery, dobutamine and milrinone may beuseful (146), but may cause hypotensionrequiring the concomitant use of vaso-pressor therapy.

In spite of a paucity of prospectivedata, inhaled nitric oxide is being increas-ingly used in critically ill patients and isassociated with improved outcomes inpostoperative patients when compared

with critically ill medical patients. A ret-rospective study of inhaled nitric oxide

compared 317 postoperative patients with59 medical patients and found the high-est survival rates in patients who hadreceived heart or lung transplants, andthe lowest survival rates in medical pa-tients (152). The vast majority of thepostoperative patients in this study re-ceived nitric oxide for severe pulmonaryhypertension or right ventricular failureafter cardiac transplantation, lung trans-

plantation, cardiac surgery, or ventricu-lar assist device placement. After cardiactransplantation, the use of inhaled nitricoxide is associated with improved PVRand right ventricular function and atrend toward improved survival whencompared with historic controls (153).Treatment of postcardiac surgery pulmo-nary hypertension with inhaled nitric ox-ide, compared with milrinone, also hasbeen shown to cause less heart rate ele-

vation, improved right ventricular ejec-tion fraction, and a decreased need for

vasopressor therapy (154).In a group of patients who were diffi-

cult to wean from cardiopulmonary by-pass because of isolated right ventricularfailure, inhaled iloprost was successfullyused to reduce pulmonary vascular resis-tance (155). Inhaled iloprost also wasshown to be effective in treating pulmo-nary hypertension and acute right ven-tricular dysfunction in another smallperioperative study of eight cardiac trans-plant patients (156).

Sildenafil also has been cited in casereports in combination with inhaled ni-

tric oxide (157) or as an aid to weaninginhaled nitric oxide after left ventricularassist-device placement (158) or cardiactransplantation complicated by severepulmonary hypertension (159). It also

was useful in a series of eight patients tofacilitate weaning from intravenous vaso-dilators after mitral valve surgery or left

ventricular assist-device placement (101),but no prospective studies of its use inthe ICU have been published.

Pulmonary Veno-Occlusive

Disease

Pulmonary veno-occlusive disease is arare cause of pulmonary hypertension,accounting for only about 10% of idio-pathic cases (160). Pulmonary veno-occlusive disease is characterized patho-logically by fibrotic changes in smallpulmonary veins and by dilation of pul-monary and pleural lymphatics. Chest ra-diographs may show Kerley B lines (161);computed tomography reveals ground

glass opacities and thickened septal lines(162). In spite of its rarity, pulmonary

veno-occlusive disease deserves men-tion, because pulmonary vasodilatortherapy typically used for PAH mayc a us e l i fe - thr e at e ning p ul mo na ryedema. Nonetheless, options for treat-ment are limited, and a cautious trial ofshort-acting pulmonary vasodilators isreasonable (163).

Pulmonary Hypertension

and Pregnancy

The mortality rate in women with pul-monary hypertension who become preg-nant ranges from 30% to 56%, dependingon the underlying cause (162). Pregnancycauses an increase in circulating blood

volume by nearly 50%, with a concomi-tant increase in cardiac output and de-creased systemic vascular resistance, as

well as an increase in oxygen consump-tion. After delivery, circulating blood vol-ume increases further and venous returnincreases as the uterus involutes, wors-ening right ventricular strain. Hospital-ization is recommended at approximately20 wks and treatment to avoid volumeoverload is an important part of manage-ment. Epoprostenol is often necessary,and inhaled nitric oxide has been used inthe immediate peripartum period. In an-imals studies, inhaled iloprost has beenlinked to teratogenicity and fetal wastage(162) and bosentan can be teratogenic(163).

CONCLUSIONS

Pulmonary hypertension and concom-itant right ventricular failure present aparticular therapeutic challenge in he-modynamically unstable patients in theICU. Typical therapies such as volumeresuscitation and mechanical ventilationmay worsen hemodynamics and furthercomplicate management. To determineappropriate therapy, the approach to pa-tients with pulmonary hypertension in

the ICU must begin with identification ofthe underlying cause. Patients with de-compensated PAH, including patients

with preexisting PAH or with pulmonaryhypertension associated with cardiac orthoracic transplant surgery, require ther-apy for right ventricular failure. Hemo-dynamic collapse caused by acute massivepulmonary embolism requires urgent re-lief of vascular obstruction. Patients withpulmonary hypertension resulting fromcritical illness or chronic lung disease are



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unlikely to suffer from underlying pul-monary vascular disease, and their treat-ment should address the primary cause oftheir hemodynamic deterioration. Al-though very few human studies have ad-dressed the use of vasopressors and pul-monary vasodilators in critically ill,hypotensive patients with chronic PAHand right ventricular failure, the use ofdobutamine, inhaled nitric oxide, and in-

travenous prostacyclin have the greatestsupport in the literature. The use of otheragents should be guided by an under-standing of their effects on the right ven-tricle and pulmonary circulation, and bythe comorbid conditions of the patientsbeing treated.

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