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

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-Actelion’s Young Investigators Program, is/was on the speakers’ bureau for Actelion, and was on the speakers’ bureau for Co-Therix, and Encysive. Dr. Doyle has disclosed that she is/was a consultant for Actelion, Encysive, and Gilead. Dr. Haddad has disclosed that 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 treatment of 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 dopamine, dobutamine, phenylephrine, isoproterenol, and vasopressin. Both care unit in patients with critical illnesses such as acute respiratory distress human and animal studies related to pulmonary hypertension were reviewed. syndrome, left ventricular dysfunction, and pulmonary embolism, as well as Conclusions: Pulmonary hypertension presents a particular challenge in after cardiothoracic surgery. Pulmonary hypertension also may be encoun- critically ill patients, because typical therapies such as volume resuscitation tered in patients with preexisting pulmonary vascular, lung, liver, or cardiac and mechanical ventilation may worsen hemodynamics in patients with diseases. The intensive care unit management of patients can prove extremely pulmonary hypertension and right ventricular failure. Patients with decom- challenging, particularly when they become hemodynamically unstable. The pensated pulmonary hypertension, including those with pulmonary hyperten- objective of this review is to discuss the pathogenesis and physiology of sion associated with cardiothoracic surgery, require therapy for right ventric- pulmonary hypertension and the utility of various diagnostic tools, and to ular failure. Very few human studies have addressed the use of vasopressors provide recommendations regarding the use of vasopressors and pulmonary and pulmonary vasodilators in these patients, but the use of dobutamine, vasodilators in intensive care. milrinone, inhaled nitric oxide, and intravenous prostacyclin have the greatest Data Sources and Extraction: We undertook a comprehensive review of support in the literature. Treatment of pulmonary hypertension resulting from the literature regarding the management of pulmonary hypertension in the critical illness or chronic lung diseases should address the primary cause of setting of critical illness. We performed a MEDLINE search of articles pub- hemodynamic deterioration, and pulmonary vasodilators usually are not nec- lished from January 1970 to March 2007. Medical subject headings and keywords searched and cross-referenced with each other were: pulmonary essary. (Crit Care Med 2007; 35:2037–2050) hypertension, vasopressor agents, therapeutics, critical illness, intensive care, KEY WORDS: pulmonary hypertension; intensive care unit; vasopressor right ventricular failure, mitral stenosis, prostacyclin, nitric oxide, sildenafil, agents; nitric oxide; prostacyclin; right ventricular failure; dobutamine

ulmonary hypertension is cally ill patients with hemodynamically citation (1). Appropriate therapy depends commonly encountered in the significant pulmonary hypertension re- on identifying the underlying cause and intensive care unit (ICU). Al- mains challenging. Patients with moder- hemodynamic effects of pulmonary hy- though new therapies for pul- ate to severe pulmonary hypertension can pertension. To reflect differences in Pmonary hypertension have emerged in deteriorate rapidly and are unlikely to pathophysiology, a revised World Health recent years, the management of criti- survive efforts at cardiopulmonary resus- Organization classification of pulmonary

*See also p. 2210. & Critical Care Medicine, Associate Chair for Clinical MD, 300 Pasteur Drive, S102, Stanford, CA 94305–5110. Assistant Professor of Medicine (RTZ), Clinical In- Affairs, Department of Medicine (ABW), Stanford Uni- E-mail: [email protected] structor (FH), Pulmonary Hypertension Clinical Service, versity Medical Center, Stanford, CA. Copyright © 2007 by the Society of Critical Care Associate Professor, Co-Director, Vera Moulton Wall Supported, in part, by grants from Actelion (RZ, Medicine and Lippincott Williams & Wilkins Center for Pulmonary Vascular Disease (RLD), Associ- RLD) and United Therapeutics (RLD). ate Professor of Medicine (ABW), Division of Pulmonary Address requests for reprints to: Ann B. Weinacker, DOI: 10.1097/01.CCM.0000280433.74246.9E

Crit Care Med 2007 Vol. 35, No. 9 2037 hypertension (Table 1) has been adopted Table 1. Revised clinical classification of pulmonary hypertension (Venice 2003) (2). The revised classification separates causes of pulmonary hypertension into 1. Pulmonary arterial hypertension (PAH) 1.1. Idiopathic (iPAH) those that primarily affect the pulmonary 1.2. Familial (FPAH) arterial tree (pulmonary arterial hyper- 1.3. Associated with (APAH) tension; PAH) or the pulmonary venous 1.3.1. Collagen vascular disease system, and those that affect the pulmo- 1.3.2. Congenital systemic-to-pulmonary shunts nary vasculature because of alterations in 1.3.3. Portal hypertension 1.3.4. HIV infection lung structure or function. This new clas- 1.3.5. Drugs and toxins sification thus provides a framework to 1.3.6. Other (thyroid disorders, glycogen storage disease, Gaucher disease, hereditary guide appropriate diagnosis and treat- hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders, ment of pulmonary hypertension in crit- splenectomy) ically ill patients (2). 1.4. Associated with significant venous or capillary involvement 1.4.1. Pulmonary veno-occlusive disease (PVOD) Pulmonary hypertension is defined as 1.4.2. Pulmonary capillary hemangiomatosis (PCH) a systolic pulmonary artery pressure 1.5. Persistent pulmonary hypertension of the newborn (PAP) of Ͼ35 mm Hg, or, alternatively, as 2. Pulmonary hypertension with left heart disease a mean PAP of Ͼ25 mm Hg at rest or 2.1. Left-sided atrial or ventricular heart disease Ͼ30 mm Hg with exertion (2–4). Pulmo- 2.2. Left-sided valvular heart disease 3. Pulmonary hypertension associated with lung diseases and/or hypoxemia nary hypertension in the ICU may be due 3.1. Chronic obstructive pulmonary disease to preexisting pulmonary vascular dis- 3.2. Interstitial lung disease ease, lung disease, liver disease, or car- 3.3. Sleep-disordered breathing diac disease. Pulmonary hypertension 3.4. Alveolar hypoventilation disorders 3.5. Chronic exposure to high altitude also may be caused by critical illnesses 3.6. Developmental abnormalities such as acute respiratory distress syn- 4. Pulmonary hypertension due to chronic thrombotic and/or embolic disease drome (ARDS), acute left ventricular dys- 4.1. Thromboembolic obstruction of proximal pulmonary arteries function, and pulmonary embolism, or 4.2. Thromboembolic obstruction of distal pulmonary arteries may occur after cardiac or thoracic sur- 4.3. Non-thrombotic pulmonary embolism (tumor, parasites, foreign material) 5. Miscellaneous gery. In this paper we review the diagno- Sarciodosis, histiocytosis X, lymphangiomatosis, compression of pulmonary vessels sis and treatment of critically ill patients (adenopathy, tumor, fibrosing mediastinitis) with pulmonary hypertension of varying etiologies, and discuss strategies to treat HIV, human immunodeficiency virus. hemodynamic instability. Reproduced with permission from Simmoneau G, Galiè N, Rubin LJ, et al: Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2004; 43:10S.

PATHOGENESIS AND PHYSIOLOGY Pulmonary venous hypertension is typi- for PAH is thus based on re-establishing cally a result of left ventricular diastolic the balance in key molecular pathways Pulmonary hypertension encompasses dysfunction, valvular heart disease, or by increasing available nitric oxide and a spectrum of pathologies best character- pulmonary venous disorders. prostacyclin, or reducing the effects of ized by their anatomical location: precap- Multiple molecular pathways have endothelin-1 (Fig. 1). illary arteries and arterioles, alveoli and been implicated in the pathogenesis of The neurotransmitter serotonin and capillary beds, and postcapillary pulmo- PAH. Nitric oxide and prostacyclin are the serotonin receptor transporter also nary veins and venules. Idiopathic pul- endogenous vasodilators produced in have been implicated in the development monary arterial hypertension is the result the pulmonary vascular endothelium, of PAH. Some studies have linked high of increased vasoconstriction, pulmonary and in many types of pulmonary hyper- serotonin levels to PAH (11, 12). Further- vascular remodeling, and in situ throm- tension their production is impaired (7, more, appetite suppressants such as bosis provoked by endothelial dysfunc- 8). Endothelin-1 is an endogenous va- dexfenfluramine and aminorex that ele- tion, smooth muscle proliferation, and soconstrictor peptide secreted by the vate serotonin levels are associated with a neointimal formation (3, 5, 6) in the pre- vascular endothelium (7), and is impli- significantly increased incidence of PAH capillary arteries and arterioles. The cated in pulmonary vasoconstriction (13). Recent debate has focused on the more common causes of PAH (group 1 in and vascular smooth muscle prolifera- potential role of serotonin receptor trans- Table 1) have similar histopathologic tion (7). Endothelin-1 is excessively porter polymorphism as a genetic risk changes. Hypoxemic lung diseases such abundant in patients with idiopathic factor for developing PAH (14). as interstitial lung disease and chronic PAH, PAH associated with congenital The consequence of these aberrant obstructive pulmonary disease may cause heart disease, and pulmonary hyperten- cellular and molecular pathways is an in- pulmonary hypertension as the result of sion associated with thromboembolic crease in pulmonary vascular resistance vascular destruction as well as alveolar disease (8–10). Dysfunction in the ni- (PVR) and impedance of flow, causing hypoxemia. In acute lung injury, both tric oxide, prostacyclin, endothelin-1, right ventricular strain that impairs fill- hypoxemia and the accumulation of in- and other pathways produces an imbal- ing and causes right ventricular volume travascular fibrin and cellular debris con- ance between vasodilation and vasocon- and pressure overload (Fig. 2). The right tribute to subsequent vascular oblitera- striction, and between apoptosis and ventricle then dilates and eventually hy- tion and pulmonary hypertension (7). proliferation. The rationale for therapy pertrophy develops, encroaching on the

2038 Crit Care Med 2007 Vol. 35, No. 9 hypertension, the final common pathway for hemodynamic deterioration and death is right ventricular failure, which is the most challenging aspect of patient man- agement. Therapy is thus aimed at acutely relieving right ventricular over- load by decreasing PVR and reversing right ventricular failure with pulmonary vasodilators and inotropes.

RIGHT VENTRICULAR DYSFUNCTION IN PULMONARY HYPERTENSION Compared with the left ventricle, the right 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 acutely increase the mean PAP to more than 40 mm Hg (16). Right ventricular systolic dysfunction, severe tricuspid regurgita- Figure 1. Schematic representation of pathways implicated in pulmonary arterial hypertension, and sites tion, arrhythmias, and left ventricular of action of current therapies. The overabundance of endothelin-1 and the relative lack of prostaglandin I 2 dysfunction caused by ventricular in- and nitric oxide lead to the vasoconstriction and hyperproliferation associated with pulmonary terdependence may contribute to low 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 cardiac output and hypotension in pa- tients with pulmonary hypertension in vasodilation (red arrows). ETA, endothelin A; ETB, endothelin B; cAMP, cyclic adenosine (Fig. 2). Ventricular interdependence monophosphate; cGMP, cyclic guanosine monophosphate; NO, nitric oxide; PGI2, prostaglandin I2. refers to the concept that the size, shape, and compliance of one ventricle may affect the size, shape, and pres- sure–volume 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 filling and output. This has direct implications for the management of patients with pul- monary hypertension and acute right ventricular failure. In fact, the challenge is to find the optimal preload to avoid the detrimental effects of ventricular interde- pendence (17). Another consequence of right ventricular failure in the setting of pulmonary hypertension is the opening of the foramen ovale and development of right to left shunting that can cause or aggravate hypoxemia. Neurohormonal activation is important in acute and chronic right-sided failure. Figure 2. Implications of pulmonary hypertension on right ventricular (RV) function and hemody- Atrial and B-type natriuretic peptide levels 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- recently have been described to be elevated function also can result in the setting of right ventricular failure. The physiologic consequence of in patients with right ventricular failure ventricular dysfunction in conjunction with development of arrhythmias, tricuspid regurgitation (TR), and pulmonary hypertension (18), and are and worsening hypoxemia ultimately lead to hypotension and circulatory collapse. not only markers for pulmonary hyperten- sion but appear to be important in the left ventricle and decreasing preload, car- Tricuspid regurgitation develops as a re- pathogenesis of the disease. Atrial and B- diac output, and coronary perfusion. In- sult of right ventricular dysfunction and type natriuretic peptides are cardiac pep- creased right ventricular wall stress re- portends a poor prognosis (15). Regard- tides that not only promote diuresis but sults in right ventricular ischemia. less of the underlying cause of pulmonary also inhibit pulmonary vasoconstriction

Crit Care Med 2007 Vol. 35, No. 9 2039 (including hypoxic pulmonary vasocon- connective tissue disease (scleroderma nary arteries are less obvious on portable striction) by raising cyclic guanosine and lupus), hepatitis, or human immu- radiographs. Nonetheless, diffuse severe monophosphate levels, and patients with nodeficiency virus. pulmonary parenchymal abnormalities pulmonary hypertension have been demon- Cardiac enzymes may be elevated in may suggest an underlying cause of pul- strated to have decreased responsiveness to patients with right ventricular overdis- monary hypertension. Computerized to- these peptides (18, 19). tension and ischemia. Troponin I leak mographic angiography, ventilation- due to acute right ventricular strain from perfusion scanning, or pulmonary DIAGNOSTIC TOOLS IN THE pulmonary embolism has been described angiography may identify thromboem- ICU (21), and may predict mortality (22). B- bolic disease as the cause of pulmonary type natriuretic peptide (BNP) is a prog- hypertension (4). Pulmonary hypertension may first be nostic indicator in patients with severe Echocardiography is useful for diag- recognized when an echocardiogram is pulmonary hypertension (23). The utility nosing and determining the degree and obtained or a pulmonary artery catheter of measuring BNP in critically ill patients significance of pulmonary hypertension is placed for hemodynamic monitoring. with pulmonary hypertension is unclear, (4). Echocardiography can noninvasively Determining the cause and significance however. BNP levels may be elevated in estimate right atrial and pulmonary arte- of the elevated PAP then dictates appro- critically ill surgical patients (24), pa- rial pressures, determine the degree of priate therapy. A comprehensive work-up tients with shock (25), or critically ill right ventricular dysfunction, and reveal is then necessary to determine the cause patients with cardiac dysfunction of any potential causes of pulmonary hyperten- and hemodynamic consequence of pul- cause (26, 27). Although the diagnostic sion such as left ventricular systolic or monary hypertension. Physical, labora- utility of BNP in renal insufficiency has diastolic dysfunction, mitral stenosis or tory, and radiologic examinations can been thought to be limited, recent liter- regurgitation, and certain intracardiac help distinguish among three main ature (28) suggests that a plasma BNP of shunts. Although images may be subop- causes of pulmonary hypertension in the Ն150 pg/mL is a reliable marker of left timal in critically ill patients because of ICU (preexisting pulmonary vascular dis- ventricular overload and heart failure in limitations of patient positioning, inter- ease, acute or chronic cardiovascular dis- patients with chronic renal failure. In ference by dressings, or positive pressure ease, and acute or chronic pulmonary patients with renal failure, a relative ventilation, a transthoracic echocardio- disease), or other causes such as human reduction in BNP after hemodialysis gram should be obtained as a screening immunodeficiency virus or liver disease. can be a valid indicator of improved left test (4). Echocardiographic signs of sig- Physical examination of patients with ventricular wall tension (29), but the nificant pulmonary hypertension include right ventricular failure classically re- utility of its measurement in patients right ventricular dilation and hypertro- veals an elevated jugular venous pulse with concomitant right ventricular dys- phy, septal bowing into the left ventricle with a large v wave. An early finding is a function and critical illness remains during late systole to early diastole (D- prominent pulmonic component of the questionable (30). shaped left ventricle), right ventricular second heart sound. Other findings may Electrocardiography is an insensi- hypokinesis, tricuspid regurgitation, include a palpable right ventricular tive measure of right ventricular hyper- right atrial enlargement, and a dilated heave, and the holosystolic blowing mur- trophy, but the findings of right axis inferior vena cava (3, 34, 35). Increased Ͼ mur of tricuspid regurgitation murmur deviation, R/S wave 1inV1 with R right ventricular size and outflow imped- along the left lower sternal border (20). If wave Ͼ0.5 mV, and P pulmonale are ance combined with reduced ejection perceptible, accentuation of this murmur more than 90% specific (31). Electro- fraction have been described in acute during inspiration (Carvallo’s sign) dis- cardiography changes reflecting right cor pulmonale. Demonstration of septal tinguishes it from the murmurs of mitral ventricular abnormalities are signifi- dyskinesia and right ventricular en- regurgitation and aortic stenosis. There cant predictors of mortality in patients largement indicate right ventricular may be tender, even pulsatile hepatomeg- with idiopathic PAH (32). Although systolic and diastolic overload, respec- aly, and ascites or peripheral edema. The these electrocardiography findings have tively (34, 35). lung exam may suggest underlying lung not been used for prognosis in the ICU, In acute pulmonary embolism, Mc- disease. Patients with isolated right ven- they provide evidence of advanced dis- Connell and colleagues (36) also described tricular failure, however, do not exhibit ease that may be difficult to manage in a specific pattern of right ventricular dys- pulmonary edema. The finding of pulmo- critically ill patients. Electrocardiogra- function characterized by a severe hypoki- nary edema suggests left ventricular dys- phy scoring systems that correlate with nesia of the right ventricular mid-free wall, function, pulmonary venous hyperten- the extent of perfusion defects in acute with normal contractions of the apical sion, or a noncardiac cause such as pulmonary embolism also have been segment. Echocardiographic predictors ARDS. developed (33), and may prove useful in of poor outcomes in PAH include right Laboratory evaluation is undertaken the future to diagnose and stratify pa- atrial enlargement, septal bowing, and to identify reversible causes of pulmonary tients with pulmonary hypertension the development of a pericardial effu- hypertension. In the ICU however, many and right ventricular failure. sion (37). laboratory derangements result from Plain chest radiography is of limited Transesophageal echocardiography critical illness itself. Nonetheless, clues utility in diagnosing pulmonary hyper- may be more sensitive than transthoracic may be provided as to the underlying tension in the ICU, but may help define echocardiography, especially in acute dis- cause of pulmonary hypertension by an underlying cause. Typical findings of ease such as pulmonary embolism (38), polycythemia (suggesting chronic hy- right ventricular hypertrophy, right atrial and may provide clearer and more accu- poxemia), thyroid or liver function ab- enlargement, and obscuring of the aorto- rate information in critically ill patients normalities, or serologic markers of pulmonary window by enlarged pulmo- (39).

2040 Crit Care Med 2007 Vol. 35, No. 9 Right heart or pulmonary artery (PA) the change in PVR. Regardless of the pa- Complications of PA catheterization catheterization is the gold standard for rameters used, the presence of vasoreac- are particularly dangerous in patients the diagnosis of pulmonary hypertension tivity may suggest a better prognosis and with pulmonary hypertension and right (3). In patients with significant PAH, the ultimately can help determine medical ventricular strain. Tachyarrhythmias most useful information is obtained in therapy (41). have potentially life-threatening conse- the cardiac catheterization laboratory. Despite current controversies regard- quences of decreased stroke volume due Precise analysis of mixed venous oxygen ing the utility of PA catheters in the ICU, to shortened filling time, or deterioration saturations during insertion and passage hemodynamic data are valuable in the into fatal arrhythmias. Obtaining a pul- of the PA catheter through the cardiac care of critically ill patients with pulmo- monary capillary wedge pressure also chambers can allow diagnosis of intracar- nary hypertension. In this setting, tech- may be difficult in patients with markedly diac shunts. A pulmonary capillary wedge nical and interpretive limitations must be elevated pulmonary pressures. pressure less than 15 mm Hg helps rule recognized. Severe tricuspid regurgita- out left ventricular and pulmonary ve- tion and elevated PAP often make placing MANAGEMENT OF PULMONARY nous diseases (3). Observation of real- a PA catheter challenging, and may ne- HYPERTENSION IN THE ICU time mean PA pressure (mPAP), cardiac cessitate the use of fluoroscopy. Accurate output, and PVR allows immediate eval- Overview uation of response to vasodilator therapy. determination of cardiac output by ther- Although the definition of a substantial modilution may be limited in patients When managing a critically ill patient response to therapy remains controver- with tricuspid regurgitation or low car- with pulmonary hypertension in the ICU, sial, the most recent definition requires a diac output (42). The Fick method may primary considerations include the diag- reduction in mPAP of at least 10 mm Hg be more accurate, but requires determi- nosis and treatment of specific causes of to Յ40 mm Hg with an increased or nation of oxygen consumption, which is pulmonary hypertension, the application unchanged cardiac output (40). Because challenging in critically ill patients. The of PAH-specific therapies only when ap- increased pulmonary arterial blood flow superiority of thermodilution vs. the Fick propriate, and determination of the de- can elevate mPAP, documentation of the method in critically ill patients remains gree of right ventricular failure and its response to therapy also should include controversial (43). appropriate 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.

Crit Care Med 2007 Vol. 35, No. 9 2041 The revised classification of pulmo- tion (45), thrombolysis, or thrombec- fect that was ameliorated with the nary hypertension (Table 1) provides a tomy (see section on pulmonary embo- application of low levels of positive end- framework for treatment of pulmonary lism). expiratory pressure between 3 cm H2O hypertension patients in the ICU. Pa- Aggressive fluid balance management and8cmH2O (50). These data suggest tients with PAH (World Health Organiza- is critical in patients with decompensated that the optimal ventilator management tion group 1) can benefit from prostacy- pulmonary hypertension and right ven- of patients with pulmonary hypertension clin, sildenafil, or from long-term tricular failure. Hypovolemia and hyper- may be with low tidal volumes and rela- bosentan therapy, depending on the se- volemia both can lead to suboptimal pre- tively low positive end-expiratory pres- verity of their illness and functional clas- load and decreased cardiac output. sure. This strategy of low tidal volume sification. Patients with decompensated Maintenance of sinus rhythm and atrio- ventilation is similar to the strategy used PAH often require an aggressive combi- ventricular synchrony is especially im- to ventilate patients with ARDS, but nation of therapies for right ventricular portant in the presence of right ventric- care should be taken to avoid permis- failure, including pulmonary vasodilators ular dysfunction. For example, atrial sive hypercapnia, which may have un- and inotropes. In patients with pulmo- fibrillation or complete atrioventricular toward hemodynamic effects (51). A nary venous hypertension (World Health block are poorly tolerated in patients with study of 18 patients after coronary ar- Organization group 2), optimization of acute pulmonary emboli or in chronic tery bypass graft surgery demonstrated left-sided heart failure and valvular dis- right ventricular failure (46). In the he- that hypercapnia increased PVR by 54% ease management is the most important modynamically unstable patient, initia- and mPAP by approximately 30% (52). facet of therapy. In patients with pulmo- tion of inotropic therapy may be neces- Whether these effects are mediated by nary hypertension secondary to various sary. Dobutamine is the inotrope that has hypercapnia itself or by acidosis re- causes of parenchymal lung disease been the most extensively studied in the mains unclear (53). and/or hypoxemia, primary therapy con- context of acute right-sided failure (see sists of treating the underlying cause. Pa- below), but other agents may be benefi- tients with pulmonary hypertension re- cial. In refractory right ventricular fail- Pharmacologic Therapy of sulting from critical illness (Table 2) or ure, early consideration of atrial septos- Pulmonary Hypertension chronic lung disease (44) are less likely to tomy (see below), heart or heart-lung suffer from significant underlying pulmo- transplantation, or right ventricular as- Vasopressors and Inotropes. Hemody- nary vascular disease, and their treat- sist-device placement may be life-saving namic goals in patients with right ven- ment should address the primary cause of (47). tricular failure due to pulmonary hyper- their hemodynamic deterioration, such tension are to reduce PVR, augment as sepsis or left ventricular dysfunction. Effects of Mechanical cardiac output, and resolve systemic hy- These patients usually do not require Ventilation potension while avoiding tachyarrhyth- treatment with pulmonary vasodilators. mias. Most traditional vasopressors and In patients with acute thromboembolic In patients with pulmonary hyperten- inotropes are suboptimal in reducing pul- disease, therapy consists of anticoagula- sion and respiratory failure, mechanical monary vascular resistance. Only a few ventilation may have untoward hemody- small human studies address hemody- namic effects. Increases in lung volume namic support in patients with PAH, Table 2. Common causes of pulmonary hyper- and decreases in functional residual ca- right ventricular failure, and hypoten- tension in the intensive care unit pacity can increase PVR and right ven- sion, and most of the common vasopres- tricular afterload (48). In patients with sors and inotropes have not been studied. Hypoxemia/parenchymal lung disease normal right ventricular function, tran- Animal studies predominately employ Acute respiratory distress syndrome Pulmonary embolism sient increases in PVR are inconsequen- models of acute pulmonary hypertension Interstitial lung disease tial. However, in patients with pre- and right ventricular failure, and may not Obstructive sleep apnea existing or impending right ventricular be applicable to patients with long- Chronic obstructive pulmonary disease failure, lung hyperinflation and either in- standing PAH and altered right ventricu- Left heart disease adequate or excessive positive end- lar mechanics. The use of vasopressors Acute myocardial infarction Valvular disease (mitral regurgitation/mitral expiratory pressure can fatally reduce and inotropes in patients with PAH must stenosis) cardiac output (48). therefore be guided by knowledge of their Severe diastolic dysfunction In a study of seven mechanically ven- effects on PVR and cardiac output, and Cardiomyopathy tilated patients with acute lung injury must be individualized based on patient Postoperative states and ARDS, six developed significant tri- response. In many cases, combination Coronary artery bypass grafting Cardiac transplantation cuspid regurgitation, elevated PAP, and therapy is required. The following discus- Lung/heart-lung transplantation increased pulmonary capillary wedge sion attempts to list agents in order of Pneumonectomy pressure during incremental increases in usefulness in treating pulmonary hyper- Thomboembolic lung disease positive end-expiratory pressure from 5 tension and associated right ventricular Pulmonary embolism Deterioration of chronic pulmonary arterial mm Hg to 20 mm Hg (49). The elevated failure. hypertension PAP correlated directly with increased Dobutamine. Dobutamine is an ino- ␤ Fluid overloaded state right atrial pressure and PVR. Other in- trope that acts primarily through 1- Arrhythmias vestigators demonstrated increased right adrenergic receptors to augment myocar- Pulmonary embolism ventricular outflow impedance in me- dial contractility and reduce left Acute on chronic pulmonary hypertension Medication withdrawal chanically ventilated patients as tidal vol- ventricular afterload (54). In animal ume was progressively increased, an ef- models of acute pulmonary hypertension,

2042 Crit Care Med 2007 Vol. 35, No. 9 dobutamine in doses up to 5 ␮g/kg per blood pressure and cardiac output (62). useful in the management of pulmonary min significantly decreased PVR while One animal study suggests that the use of hypertension in the ICU requires further slightly increasing cardiac output (55, dopamine in acute embolic pulmonary investigation. 56). However, at doses of 5–10 ␮g/kg per hypertension augments cardiac output min, dobutamine caused significant and reduces PVR (63). A human study, Pulmonary Vasodilators tachycardia without improving pulmo- however, failed to demonstrate a consis- nary vascular resistance. In a canine tent reduction in PVR (64). In addition, Pulmonary vasodilators can be classi- model of acute right ventricular failure, the augmented cardiac output comes at fied into two main categories: those that dobutamine was superior to norepineph- the price of significant tachycardia that increase production of cyclic guanosine rine in promoting right ventricular- may decrease left ventricular preload and monophosphate and cyclic adenosine pulmonary artery coupling, a process worsen demand ischemia. monophosphate, such as nitric oxide and that reflects improved right ventricular Phenylephrine. Phenylephrine is an prostanoids, respectively; and those that de- ␣ function by optimizing pulmonary vaso- 1-adrenergic agent and a powerful arte- crease the breakdown of cyclic guanosine dilation (55), probably because of supe- riolar vasoconstrictor that can improve monophosphate, such as sildenafil and za- rior inotropic properties (57). When com- right ventricular coronary perfusion (59). prinast (5, 6), and of cyclic adenosine bined with inhaled nitric oxide in both However, phenylephrine increases mPAP monophosphate, such as milrinone. animal and human studies of acute and and PVR and decreases cardiac output, Nitric Oxide. Nitric oxide is a potent chronic pulmonary hypertension, dobut- thus worsening right ventricular pres- vasodilator that, when inhaled, dilates amine improved cardiac index, decreased sure overload in patients with chronic pulmonary vasculature in ventilated lung PVR indices (56, 58), and significantly pulmonary hypertension (59, 65). Phen- units, thereby improving oxygenation, re- increased PaO2/FIO2 (58). ylephrine also may cause reflex bradycar- versing hypoxic pulmonary vasoconstric- These studies suggest that dobut- dia (66), which may be detrimental to tion, and reducing PAP. Nitric oxide is amine doses in both acute and chronic right ventricular hemodynamics. In pa- quickly inactivated by reaction with he- pulmonary hypertension should be main- tients with significant pulmonary hyper- moglobin in the pulmonary capillaries, tained at less than 5 ␮g/kg per min, and tension, phenylephrine usually should be and has no systemic vasodilatory effects. should be combined with pulmonary va- avoided. Inhaled nitric oxide has been studied in sodilators such as inhaled nitric oxide Isoproterenol. Isoproterenol is pri- pulmonary hypertension of various etiol- ␤ ␤ when possible. However, dobutamine marily a 1- and 2-adrenergic agonist ogies (73–76). Several studies have fo- may cause systemic hypotension in some that has historically been used to treat cused on inhaled nitric oxide therapy in patients because of its peripheral ␤-ad- pulmonary hypertension during surgery. adults with pulmonary hypertension and renergic effects and may necessitate the Because it is a stronger chronotropic ARDS (73, 77, 78). Although ARDS pa- use of norepinephrine or a peripheral va- agent than dobutamine, the use of iso- tients without sepsis initially improve ox- soconstrictor. proterenol is associated with significant ygenation with inhaled nitric oxide, there Norepinephrine. Norepinephrine tachyarrhythmias. Although it improves is no evidence that outcomes are im- ␣ ␤ stimulates 1- and 1-adrenergic recep- cardiac output and PVR (60), the utility of proved (79). In chronic PAH, inhaled ni- tors. When used in animal and human isoproterenol in animal models of acute tric oxide significantly decreases mPAP studies of both acute and chronic pulmo- pulmonary hypertension has been limited and PVR without affecting systemic vas- nary hypertension, it has been shown to by the induction of arrhythmias and the cular resistance or cardiac output (58, increase mPAP and PVR (59, 60). How- lack of effect on PAP (67). 80). Of 26 patients diagnosed in an ICU ever, unlike phenylephrine, norepineph- Epinephrine. Although commonly with acute right heart syndrome, 14 had rine maintained or improved cardiac used to improve cardiac output and in- significant hemodynamic improvement output in patients with pulmonary hyper- crease systemic vascular resistance in hy- when treated with a mean concentration tension. Selective infusion of norepi- potensive patients in the ICU, epineph- of 35 ppm of inhaled nitric oxide. In these nephrine into the left atrium, combined rine, a potent ␣- and ␤-adrenergic agent, patients there was a 38% reduction in with prostaglandin E1 administration has not been studied in the setting of PVR, 36% increase in CO, and a 28% into the right atrium, has been useful in pulmonary hypertension. increase in PaO2/FIO2 (81). weaning patients with acute pulmonary Vasopressin. Vasopressin is a weak The use of nitric oxide is not without hypertension from cardiopulmonary by- nonadrenergic vasopressor that is be- potential problems, however. Although pass (61). There are no data that such lieved to be a systemic vasoconstrictor uncommon, the development of methe- selective infusion is beneficial in other and a selective pulmonary vasodilator moglobinemia may limit its use, espe- patient populations. Unlike dobutamine, (68–70). However, in an animal model of cially with prolonged administration at norepinephrine has vasoconstrictive ef- acute pulmonary hypertension, vasopres- higher concentrations (82). Also, the in- fects that are much more pronounced sin at an average dose of 1.16 units/kg per teraction of nitric oxide and high concen- than the chronotropic and inotropic ef- hr increased mPAP and PVR and de- trations of oxygen produces NO2, a sig- fects (55). Although norepinephrine may creased cardiac output (71). This sug- nificant oxidant (83). Abrupt withdrawal be useful in hypotensive patients and gests that vasopressin in high doses of nitric oxide has been associated with cause less tachycardia, dobutamine re- should be avoided in patients with pul- rebound pulmonary hypertension and he- mains a superior choice in the setting of monary hypertension. On the other hand, modynamic collapse in up to 48% of pa- pulmonary hypertension and right ven- recent data suggest that the optimal dose tients evaluated (81, 84). In spite of its tricular failure. of vasopressin in shock is much lower limitations, inhaled nitric oxide is a use- Dopamine. Dopamine is an adrenergic than used in the aforementioned study ful agent to treat pulmonary hyperten- and dopaminergic agonist that increases (72). Whether low-dose vasopressin is sion, particularly in combination with

Crit Care Med 2007 Vol. 35, No. 9 2043 other agents such as dobutamine or mil- nation with inhaled nitric oxide, milri- 3–4 hrs, and the accompanying systemic rinone (see below). none produces selective and additive pul- hypotension suggest caution in critically Prostaglandins. Early studies of intra- monary vasodilatation in pediatric ill patients. Sildenafil is contraindicated venous prostaglandin E1 and prostacyclin patients after repair of congenital heart in patients receiving nitrates because of (or epoprostenol) in an animal model of defects (96), and after cardiac surgery in the potential for severe systemic hypoten- acute embolic pulmonary hypertension animal studies (94). However, compared sion. showed significant reductions in PVR and with zaprinast, a selective phosphodies- Nesiritide. Recombinant human BNP mPAP, as well as augmentation of cardiac teraseϪ5 inhibitor, milrinone has infe- (nesiritide) is a recently developed drug output (80). Prostaglandin E1 and pros- rior pulmonary vasodilatory effects and that increases cyclic guanosine mono- tacyclin were more effective than isopro- more pronounced lowering of systemic phosphate and dilates vascular smooth terenol and nifedipine, with nearly 40% arterial pressures (97). Thus, based on muscle. Its vasodilatory effect reduces reduction in PVR and approximately 35% animal data and limited human data, se- right and left ventricular preload and may improvement in cardiac output. More re- lective phosphodiesteraseϪ5 inhibition benefit patients with pulmonary hyper- cent studies have demonstrated the effi- may be more beneficial than milrinone. tension resulting from biventricular fail- cacy of both inhaled and intravenous Milrinone may have some utility in the ure (113). In a recent small study of pa- prostacyclin (85–88). In a retrospective treatment of hemodynamic instability in tients with PAH (19), BNP infusion alone study of 33 ICU patients with hypoxemia patients with pulmonary hypertension, did not significantly improve pulmonary and pulmonary hypertension from car- although systemic hypotension often lim- hemodynamics, but was safe and aug- diac and noncardiac causes, inhaled pros- its its use. Further studies are needed to mented the vasodilatory effects of silde- tacyclin improved mPAP and hypoxemia verify the effects of milrinone in patients nafil. However, others have shown that (89). Other studies and case reports have with pulmonary hypertension. the reduction of systemic vascular resis- demonstrated the utility of inhaled pros- Sildenafil. Sildenafil is a specific phos- tance by nesiritide may cause detrimental tacyclin and of the prostacyclin analog, phodiesteraseϪ5 inhibitor with acute and systemic hypotension in patients with iloprost, in reducing PAP and improving chronic hemodynamic effects in patients PAH and isolated right ventricular failure cardiac output (90–93), although pro- with pulmonary hypertension (98–100), (114). Currently, therefore, the use of ne- spective studies in critically ill patients and recently has been approved for the siritide should be limited to patients with with pulmonary hypertension are lack- treatment of PAH. However, there are biventricular failure who are not hypo- ing. Subcutaneous or intravenous trepro- only case reports or small case series de- tensive. stinil, another prostacyclin analog, is also scribing its use in critically ill patients. A an effective treatment for pulmonary hy- retrospective case review of eight adults Miscellaneous Therapy pertension (6), but its long half life (3–4 with pulmonary hypertension after mitral hrs) makes it less appropriate in hemo- valve repair or placement of a left ventric- Oxygen. Oxygen inhalation has been dynamically unstable patients in the ICU. ular assist device showed that sildenafil shown to reduce PA pressure and im- In patients with PAH and right ven- significantly reduced mPAP and reduced prove cardiac output in patients with pul- tricular failure, chronic therapy with in- PVR with only a minimal drop in mean monary hypertension, regardless of the travenous epoprostenol may be life- arterial pressure, thus facilitating wean- underlying cause (115). In addition, hy- saving. Epoprostenol has an elimination ing of inhaled and intravenous pulmo- poxic pulmonary vasoconstriction may half-life of 3–6 mins and is typically nary vasodilators (101). contribute to pulmonary hypertension in started at a dose of 1–2 ng/kg per min, In stable patients, sildenafil alone or in critically ill patients (116). Thus, supple- titrated upward at a rate of 0.5–1.0 ng/kg combination with inhaled nitric oxide or mental oxygen should not be overlooked per min at intervals of 15–30 mins or epoprostenol reduces mPAP and PVR and as a key component of pulmonary hyper- more. An increase in cardiac output with increases cardiac output (102, 103). In tension therapy in the ICU. a decrease in PAP and PVR is considered patients with idiopathic PAH, sildenafil Diuretics. Diuretics have long been a favorable response. also can significantly improve cardiac conventional therapy for pulmonary hy- The use of epoprostenol to reduce PA output (100). Furthermore, limited hu- pertension, whether caused by pulmo- pressures acutely is limited by dose- man and animal data suggest that silde- nary vascular disease or left ventricular dependent systemic side effects (88), partic- nafil and zaprinast may augment and failure. Although human studies of di- ularly systemic hypotension. In conscious maintain the effects of inhaled nitric ox- uretic use in pulmonary hypertension are patients, headache, nausea, vomiting, and ide (98, 104–108) and iloprost (109) and lacking, there is evidence in the setting of diarrhea also may limit rapid titration of minimize rebound pulmonary hyperten- exercise-induced pulmonary hyperten- epoprostenol. In patients treated chroni- sion after withdrawal of these agents sion in race horses (117). The goal of cally with epoprostenol, abrupt discontinu- (110, 111). Additionally, some authors diuretic use is to decrease volume load on ation of the infusion may cause severe re- speculate that sildenafil may improve the distended, failing right ventricle in bound pulmonary hypertension and death pulmonary hemodynamics and myocar- advanced pulmonary hypertension with- within minutes (40). dial perfusion after coronary artery by- out compromising preload. Optimization Milrinone. Milrinone is a selective pass graft surgery (112). of diuresis in this setting is complex and phosphodiesterase-3 inhibitor with ino- The hemodynamic effects of sildenafil should be adjusted according to hemody- tropic and vasodilatory effects. In animal start within 15 mins of administration namic response. models of both acute and chronic pulmo- and last up to several hours, although Digoxin. The use of digoxin in patients nary hypertension, milrinone signifi- peak hemodynamic effects are seen with pulmonary hypertension and right cantly reduced PVR and improved right within 30–60 mins. The relatively rapid ventricular dysfunction is controversial. ventricular function (94, 95). In combi- onset of action, its diminution during In a study of the short-term effects of

2044 Crit Care Med 2007 Vol. 35, No. 9 digoxin in 17 patients with severe pri- pressures of Ͼ20 mm Hg, significant hy- embolism (134) and is being used in- mary pulmonary hypertension (118), car- poxemia, and a PVR index Ͼ4400 dynes creasingly in many centers. diac index improved mildly and catechol- sec/cm5 per m2 (47, 127). amine levels decreased, but PVR did not Mitral Stenosis change and mPAP increased. Nonethe- MISCELLANEOUS CAUSES OF less, because there are more effective Mitral stenosis increases left atrial and PULMONARY HYPERTENSION drugs to treat right ventricular failure pulmonary venous pressures, and may and supraventricular tachyarrhythmias, eventually lead to pulmonary hyperten- Some causes of pulmonary hyperten- digoxin is not commonly used in the ICU sion. Diuretics are the mainstay of med- sion and hemodynamic instability en- for this purpose. ical management and can improve car- countered in the ICU require urgent Calcium Channel Blockers. There are diac output. Rate control also is crucial, therapy of the underlying disorder. no studies of calcium channel blockers in and may be achieved with diltiazem. Con- Even in these cases, the aforemen- critically ill patients with PAH, and be- comitant atrial fibrillation and right ven- tioned drugs are sometimes useful in the cause of their negative inotropic effects tricular failure may be treated with short term. they may precipitate fatal worsening of ␤-blockers. Although inhaled nitric oxide right ventricular failure. In chronic PAH, can be useful for short-term management calcium channel blocker use should be Pulmonary Embolism (135), valvuloplasty or valve replacement limited to stable patients with a demon- are the definitive therapies. strated response to acute vasodilator Acute, massive pulmonary embolism challenge (40). Cautious use of calcium may cause acute pulmonary hypertension Chronic Liver Disease channel blockers may help control the and right ventricular failure (81) requir- heart rate in patients with pulmonary hy- ing inotropic support. In a large multi- Portopulmonary hypertension is an pertension and heart failure secondary to center study of pulmonary embolism, uncommon cause of pulmonary hyper- mitral stenosis and certain tachyarrhyth- hospital mortality in patients presenting tension in the ICU, and is a manifestation mias, although agents with the greatest with hemodynamic instability was 31% of chronic liver disease. Acute liver fail- negative inotropic effects (such as vera- (128). Therapy for acute massive pulmo- ure rarely leads to portopulmonary hy- pamil) should be avoided. nary embolism with associated hemody- pertension, but congestive hepatopathy is Anticoagulants. Anticoagulation is namic instability or shock thus aims to frequently noted as a consequence of considered the standard of care in pa- urgently relieve mechanical obstruction right heart failure. Patients with porto- tients with idiopathic PAH. However, of the pulmonary vasculature caused by pulmonary hypertension may have aside from recent guidelines established thrombus and intense vasoconstriction. higher cardiac output and lower systemic for the treatment of acute and chronic When pulmonary embolism is associated vascular resistance indices than patients thromboembolic diseases (119), data for with hemodynamic instability, urgent with idiopathic PAH (136). Although anticoagulation of patients with pulmo- pharmacologic thrombolysis is recom- treating patients with portopulmonary nary hypertension in the ICU are lacking. mended unless contraindicated, and is as- hypertension may be particularly chal- Although anticoagulants may play a role sociated with more rapid resolution of lenging because of preexisting systemic in critical illnesses such as sepsis and thrombus than anticoagulation alone, al- hypotension, limited data suggest that acute lung injury (120, 121), their use in though the mortality benefit is unclear the therapy is essentially the same as in critically ill patients with pulmonary hy- (119). If thrombolysis fails or is contrain- patients with decompensated pulmonary pertension has not been examined. dicated, surgical embolectomy is indi- hypertension of other etiologies (137). cated in centers where an experienced Portopulmonary hypertension is often Surgical Therapy cardiac surgical team is available (119). asymptomatic and is discovered inciden- Percutaneous mechanical clot disruption tally when patients with end-stage liver Atrial Septostomy. The observations also has been reported, but data compar- disease undergo evaluation for liver of improved survival patients with pul- ing outcomes to pharmacologic throm- transplantation. Case reports and case se- monary hypertension and a patent fora- bolysis or surgical thrombectomy are ries most commonly describe treating men ovale (122), and patients with con- limited (129, 130). In submassive pulmo- portopulmonary hypertension with intra- genital heart diseases and Eisenmenger’s nary embolism associated with echocar- venous epoprostenol (138, 139) or silde- physiology (123, 124), suggested that cre- diographic evidence of right ventricular nafil (140, 141), often as a bridge to liver ation of an atrial septal shunt would im- strain but without hemodynamic insta- transplantation. There are no studies of prove survival in patients with pulmonary bility, thrombolysis is recommended by therapy for critically ill patients with por- hypertension. Since the first palliative some, although this remains controver- topulmonary hypertension either before atrial septostomy in 1983, several studies sial (131). or after liver transplantation. have evaluated atrial septostomy for pul- Data supporting specific pharmaco- Portopulmonary hypertension is most monary hypertension (125, 126), or as a logic therapy of acute pulmonary embo- problematic in the perioperative period bridge to transplantation (127). Still con- lism with right ventricular failure are surrounding liver transplantation. Some troversial in the nonurgent setting, atrial sparse. Animal studies suggest that nor- degree of pulmonary hypertension exists septostomy has a very high associated epinephrine may be useful to treat hypo- in up to 31% of liver transplant recipients morbidity and mortality in critically ill tension in acute pulmonary embolism (142), but severe pulmonary hyperten- patients with severe right ventricular fail- (132, 133), but data in humans are lack- sion (mPAP Ͼ45 mm Hg) is considered ure (125–127). It should not be per- ing. Inhaled nitric oxide also may im- by most to be a contraindication to liver formed in patients with mean right atrial prove hemodynamics in acute pulmonary transplantation. The mortality rate after

Crit Care Med 2007 Vol. 35, No. 9 2045 transplantation in patients with porto- compared 317 postoperative patients with glass opacities and thickened septal lines pulmonary hypertension is 36% (102), 59 medical patients and found the high- (162). In spite of its rarity, pulmonary and in patients with severe pulmonary est survival rates in patients who had veno-occlusive disease deserves men- hypertension is 50% to 100%, predomi- received heart or lung transplants, and tion, because pulmonary vasodilator nately due to right heart failure (142). the lowest survival rates in medical pa- therapy typically used for PAH may Because of these poor outcomes, the tients (152). The vast majority of the cause life-threatening pulmonary number of patients with moderate to se- postoperative patients in this study re- edema. Nonetheless, options for treat- vere portopulmonary hypertension who ceived nitric oxide for severe pulmonary ment are limited, and a cautious trial of have been transplanted is small. As a re- hypertension or right ventricular failure short-acting pulmonary vasodilators is sult, there are only rare case reports of after cardiac transplantation, lung trans- reasonable (163). the use of epoprostenol or inhaled nitric plantation, cardiac surgery, or ventricu- oxide after liver transplantation (103, lar assist device placement. After cardiac Pulmonary Hypertension 143), and no prospective studies. transplantation, the use of inhaled nitric and Pregnancy oxide is associated with improved PVR Postoperative Pulmonary and right ventricular function and a The mortality rate in women with pul- Hypertension trend toward improved survival when monary hypertension who become preg- compared with historic controls (153). nant ranges from 30% to 56%, depending Cardiac and thoracic surgery may be Treatment of postcardiac surgery pulmo- on the underlying cause (162). Pregnancy complicated by postoperative pulmonary nary hypertension with inhaled nitric ox- causes an increase in circulating blood hypertension. Pulmonary hypertension is ide, compared with milrinone, also has volume by nearly 50%, with a concomi- recognized as a major risk factor for mor- been shown to cause less heart rate ele- tant increase in cardiac output and de- bidity and mortality in cardiothoracic vation, improved right ventricular ejec- creased systemic vascular resistance, as surgery (144). Although the etiology of tion fraction, and a decreased need for well as an increase in oxygen consump- postoperative pulmonary hypertension is vasopressor therapy (154). tion. After delivery, circulating blood vol- unclear, pulmonary parenchymal and en- In a group of patients who were diffi- ume increases further and venous return dothelial injury due to cardiopulmonary cult to wean from cardiopulmonary by- increases as the uterus involutes, wors- bypass (145–147) and ischemia-reperfu- pass because of isolated right ventricular ening right ventricular strain. Hospital- sion injury (148) have been implicated failure, inhaled iloprost was successfully ization is recommended at approximately after cardiac surgery, cardiac or lung used to reduce pulmonary vascular resis- 20 wks and treatment to avoid volume transplantation, and pneumonectomy. A tance (155). Inhaled iloprost also was overload is an important part of manage- variety of approaches to the therapy of shown to be effective in treating pulmo- ment. Epoprostenol is often necessary, pulmonary hypertension and right ven- nary hypertension and acute right ven- and inhaled nitric oxide has been used in tricular failure have been used in patients tricular dysfunction in another small the immediate peripartum period. In an- who have undergone cardiac or thoracic perioperative study of eight cardiac trans- imals studies, inhaled iloprost has been surgery or transplantation, and combined plant patients (156). linked to teratogenicity and fetal wastage therapy is commonly used. Sildenafil also has been cited in case (162) and bosentan can be teratogenic In small series, both inhaled prostacy- reports in combination with inhaled ni- (163). clin and nitric oxide have been shown to tric oxide (157) or as an aid to weaning be valuable in treating pulmonary hyper- inhaled nitric oxide after left ventricular CONCLUSIONS tension after mitral valve replacement assist-device placement (158) or cardiac (149, 150) and other types of cardiac sur- transplantation complicated by severe Pulmonary hypertension and concom- gery requiring cardiopulmonary bypass pulmonary hypertension (159). It also itant right ventricular failure present a (148). Pulmonary hypertension in the was useful in a series of eight patients to particular therapeutic challenge in he- early postoperative period after cardiac facilitate weaning from intravenous vaso- modynamically unstable patients in the transplantation may be particularly diffi- dilators after mitral valve surgery or left ICU. Typical therapies such as volume cult to manage, and approaches such as ventricular assist-device placement (101), resuscitation and mechanical ventilation the use of inhaled nitric oxide, prostacy- but no prospective studies of its use in may worsen hemodynamics and further clin, and prostaglandin E1 have been used the ICU have been published. complicate management. To determine in small case series (151). In patients appropriate therapy, the approach to pa- with pulmonary hypertension related to Pulmonary Veno-Occlusive tients with pulmonary hypertension in low cardiac output following cardiac sur- Disease the ICU must begin with identification of gery, dobutamine and milrinone may be the underlying cause. Patients with de- useful (146), but may cause hypotension Pulmonary veno-occlusive disease is a compensated PAH, including patients requiring the concomitant use of vaso- rare cause of pulmonary hypertension, with preexisting PAH or with pulmonary pressor therapy. accounting for only about 10% of idio- hypertension associated with cardiac or In spite of a paucity of prospective pathic cases (160). Pulmonary veno- thoracic transplant surgery, require ther- data, inhaled nitric oxide is being increas- occlusive disease is characterized patho- apy for right ventricular failure. Hemo- ingly used in critically ill patients and is logically by fibrotic changes in small dynamic collapse caused by acute massive associated with improved outcomes in pulmonary veins and by dilation of pul- pulmonary embolism requires urgent re- postoperative patients when compared monary and pleural lymphatics. Chest ra- lief of vascular obstruction. Patients with with critically ill medical patients. A ret- diographs may show Kerley B lines (161); pulmonary hypertension resulting from rospective study of inhaled nitric oxide computed tomography reveals ground critical illness or chronic lung disease are

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