Annals of Thoracic Medicine
: 2014  |  Volume : 9  |  Issue : 5  |  Page : 121--126

Saudi Guidelines on the Diagnosis and Treatment of Pulmonary Hypertension: Intensive care management of pulmonary hypertension

M. Ali Al-Azem1, Manal S. Al-Hazmi2,  
1 Department of Critical Care Medicine, King Fahd Specialist Hospital, Dammam, Saudi Arabia
2 Department of Pulmonary and Critical Care Medicine, King Fahd Medical City, Riyadh, Saudi Arabia

Correspondence Address:
M. Ali Al-Azem
MD, Chairman, Department of Critical Care, Consultant, Pulmonary, Critical Care and Sleep Medicine, Assistant Professor of Medicine (KSU), King Fahad Specialist Hospital, P. O. Box: 15215, Dammam
Saudi Arabia


Pulmonary hypertension (PH) in the Intensive Care Unit (ICU) may be due to preexisting pulmonary vascular lung disease, liver disease, or cardiac diseases. PH also may be caused by critical illnesses, such as acute respiratory distress syndrome (ARDS), acute left ventricular dysfunction and pulmonary embolism, or may occur after cardiac or thoracic surgery. Regardless of the underlying cause of PH, the final common pathway for hemodynamic deterioration and death is RV failure, which is the most challenging aspect of patient management. Therapy is thus aimed at acutely relieving RV overload by decreasing PVR and reversing RV failure with pulmonary vasodilators and inotropes.

How to cite this article:
Al-Azem MA, Al-Hazmi MS. Saudi Guidelines on the Diagnosis and Treatment of Pulmonary Hypertension: Intensive care management of pulmonary hypertension.Ann Thorac Med 2014;9:121-126

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Al-Azem MA, Al-Hazmi MS. Saudi Guidelines on the Diagnosis and Treatment of Pulmonary Hypertension: Intensive care management of pulmonary hypertension. Ann Thorac Med [serial online] 2014 [cited 2020 Jun 4 ];9:121-126
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Full Text

Pulmonary hypertension (PH) in the intensive care unit (ICU) may be due to preexisting pulmonary vascular lung disease, liver disease, or cardiac diseases. PH also may be caused by critical illnesses, such as acute respiratory distress syndrome (ARDS), acute left ventricular dysfunction and pulmonary embolism, or may occur after cardiac or thoracic surgery.

Idiopathic pulmonary arterial hypertension (IPAH) is the result of increased vasoconstriction, pulmonary vascular remodeling, and in situ thrombosis triggered by endothelial dysfunction, smooth muscle proliferation, and neointimal formation in the precapillary arteries and arterioles. [1],[2],[3] In acute lung injury, both hypoxemia and the accumulation of intravascular fibrin and cellular debris contribute to subsequent vascular obliteration and PH. The consequence of these aberrant cellular and molecular pathways is an increase in pulmonary vascular resistance (PVR) and impedance of flow, causing right ventricular (RV) strain that impairs filling and leading to RV volume and pressure overload. The RV then dilates and eventually hypertrophy develops, encroaching on the left ventricle and decreasing preload, cardiac output, and coronary perfusion. Increased RV wall stress results in RV ischemia, which lead to RV dysfunction and portends a poor prognosis. [4]

 Right Ventricular Dysfunction in Pulmonary Hypertension

Compared with the left ventricle, the RV demonstrates a heightened sensitivity to changes in afterload. RV stroke volume decreases proportionately to acute increases in afterload. [5] RV systolic dysfunction, severe tricuspid regurgitation, arrhythmias, and left ventricular dysfunction caused by ventricular interdependence may contribute to low cardiac output and hypotension in patients with PH. Ventricular interdependence refers to the concept that the size, shape, and compliance of one ventricle may affect the size, shape, and pressure-volume relationship of the other ventricle. In the presence of RV 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 PH and acute RV failure.

In fact, the challenge is to find the optimal preload to avoid the detrimental effects of ventricular interdependence. [6] Another consequence of RV failure in the setting of PH 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. Atrial and B-type natriuretic peptide levels recently have been described to be elevated in patients with RV failure and PH. [7] These markers appear to be important in the pathogenesis of the disease. Atrial and B-type natriuretic peptides are cardiac peptides that not only promote diuresis, but also inhibit pulmonary vasoconstriction.

 Diagnostic Tools in the Intensive Care Unit

Laboratory evaluation is undertaken to identify reversible causes of PH. In the ICU, however, many laboratory derangements result from critical illness itself.

Electrocardiography (ECG) is an insensitive measure of RV hypertrophy, but the findings of right axis deviation, R/S wave >1 in V1 with R wave >0.5 mV, and P pulmonale are >90% specific. [8] ECG changes reflecting RV abnormalities are significant predictors of mortality in patients with IPAH. [9]

Although these ECG findings have not been used for prognosis in the ICU, they provide evidence of advanced disease that may be difficult to manage in critically ill patients.

Plain chest radiography is of limited utility in diagnosing PH in the ICU, but may help define an underlying cause. Typical findings of RV hypertrophy, right atrial enlargement, and obscuring of the aortopulmonary window by enlarged pulmonary arteries are less obvious on portable radiographs. Nonetheless, diffuse severe pulmonary parenchymal abnormalities may suggest an underlying cause of PH. Computerized tomographic angiography, ventilation-perfusion scanning, or pulmonary angiography may identify thromboembolic disease as the cause of PH. [10]

Echocardiography is useful for diagnosing and determining the degree and significance of PH. [10] Echocardiography can estimate right atrial and pulmonary arterial pressures (PAP), evaluate the degree of RV dysfunction, and reveal potential causes of PH such as left ventricular systolic or diastolic dysfunction, mitral stenosis or regurgitation, and certain intra-cardiac shunts. Although images may be suboptimal in critically ill patients because of limitations of patient positioning, interference by dressings, or positive pressure ventilation, a transthoracic echocardiogram should be obtained as a screening test. [10] Echocardiographic signs of significant PH include RV dilation and hypertrophy, septal bowing into the left ventricle during late systole to early diastole (D-shaped left ventricle), RV hypokinesis, tricuspid regurgitation, right atrial enlargement, and a dilated inferior vena cava. [11],[12],[13] Demonstration of septal dyskinesia and RV enlargement indicate RV systolic and diastolic overload, respectively. [12],[13]

Right heart or pulmonary artery (PA) catheterization is the gold standard for the diagnosis of PH. [11],[14] In patients with significant PAH, the most useful information is obtained in the cardiac catheterization laboratory. Precise analysis of mixed venous oxygen saturations during insertion and passage of the PA catheter through the cardiac chambers can allow diagnosis of intra-cardiac shunts. A pulmonary artery wedge pressure (PAWP) <15 mmHg helps in ruling out left ventricular and pulmonary venous diseases. [11] Observation of real-time mean PAP (mPAP), cardiac output, and PVR allows immediate evaluation of response to vasodilator therapy. Although the definition of a substantial response to therapy remains controversial, the most recent definition requires a reduction in mPAP of at least 10 mmHg to <40 mmHg with an increased or unchanged cardiac output. [15] Because increased pulmonary arterial blood flow can elevate mPAP, documentation of the response to therapy also should include the change in PVR. Regardless of the parameters used, the presence of vasoreactivity may suggest a better prognosis and ultimately can help determine medical therapy. [16]

Despite current controversies regarding the utility of PA catheters in the ICU, hemodynamic data are valuable in the care of critically ill patients with PH. In this setting, technical and interpretive limitations must be recognized. Severe tricuspid regurgitation and elevated PAP often make placing a PA catheter challenging, and may necessitate the use of fluoroscopy. Accurate determination of cardiac output by thermodilution may be limited in patients with tricuspid regurgitation or low cardiac output. [17] The Fick method may be more accurate, but requires determination of oxygen consumption, which is challenging in critically ill patients. Complications of PA catheterization are particularly dangerous in patients with PH and RV strain. Tachyarrhythmias have potentially life-threatening consequences of decreased stroke volume due to shortened filling time, or deterioration into fatal arrhythmias. Obtaining a PAWP also may be difficult in patients with markedly elevated pulmonary pressures.


Echocardiography should be used as the screening tool to detect PH in critically ill patients (class of recommendation I; level of evidence C).Echocardiography may provide additional information about the causes of PH and evaluate the RV function (class of recommendation I; level of evidence B).Right hear (PA) catheterization should be performed to confirm the diagnosis before commencing therapy (class of recommendation I; level of evidence C).

 Management of Pulmonary Hypertension in the Intensive Care Unit

When managing a critically ill patient with PH in the ICU, primary considerations include:

The diagnosis and treatment of specific causes of PHThe application of PAH-specific therapies only when appropriateThe determination of the degree of RV failure and its appropriate therapy.

Patients with decompensated PH often require an aggressive combination of therapies for RV failure, including pulmonary vasodilators and inotropes. In patients with pulmonary venous hypertension, optimization of left-sided heart failure and valvular disease management is the most important facet of therapy. In patients with PH secondary to various causes of parenchymal lung disease and/or hypoxemia, primary therapy consists of treating the underlying cause. Patients with PH resulting from critical illness or chronic lung disease are less likely to suffer from significant underlying pulmonary vascular disease, [18] and their treatment should address the primary cause of their hemodynamic deterioration, such as sepsis or left ventricular dysfunction. These patients usually do not require treatment with pulmonary vasodilators.

Aggressive fluid balance management is critical in patients with decompensated PH and RV failure. Hypovolemia and hypervolemia can lead to suboptimal preload and decreased cardiac output. In the hemodynamically unstable patient, initiation of inotropic therapy may be necessary. [19]

 Effects of Mechanical Ventilation

In patients with PH and respiratory failure, mechanical ventilation may have untoward hemodynamic effects. Increases in lung volume and decreases in functional residual capacity can increase PVR and RV afterload. [19] However, in patients with preexisting or impending RV failure, lung hyperinflation and either inadequate or excessive positive end-expiratory pressure can fatally reduce cardiac output. [19],[20],[21] Data suggest that the optimal ventilator management of patients with PH may be with low tidal volumes and relatively low positive end-expiratory pressure. This strategy of low tidal volume ventilation is similar to the strategy used to ventilate patients with ARDS, but care should be taken to avoid permissive hypercapnia, which may have untoward hemodynamic effects. [22]


Oxygen inhalation has been shown to reduce PA pressure and improve cardiac output in patients with PH, regardless of the underlying cause. [23] In addition, hypoxic pulmonary vasoconstriction may contribute to PH in critically ill patients. [24] Thus, supplemental oxygen should not be overlooked as a key component of PH therapy in the ICU.

 Pharmacologic Therapy of Pulmonary Hypertension

Hemodynamic goals in patients with RV failure due to PH are to reduce PVR, augment cardiac output, and resolve systemic hypotension, while avoiding tachyarrhythmias. Most traditional vasopressors and inotropes are suboptimal in reducing PVR. Only a few small human studies address hemodynamic support in patients with PAH, RV failure, and hypotension, and most of the common vasopressors and inotropes have not been studied.

Vasopressors and inotropes

The use of vasopressors and inotropes in patients with PH must therefore be guided by knowledge of their effects on PVR and cardiac output, and must be individualized based on patient response. In many cases, combination therapy is required.


Dobutamine is an inotrope that acts primarily through β1-adrenergic receptors to augment myocardial contractility and reduce left ventricular afterload. [25] When combined with inhaled nitric oxide in both animal and human studies of acute and chronic PH, dobutamine improved cardiac index, decreased PVR indices, and significantly increased PaO 2 /FIO 2 . [26] These studies suggest that dobutamine doses in both acute and chronic PH should be maintained at <5 mcg/kg/min, and should be combined with pulmonary vasodilators such as inhaled nitric oxide when possible. However, dobutamine may cause systemic hypotension in some patients because of its β peripheral-adrenergic effects and may necessitate the use of norepinephrine or a peripheral vasoconstrictor. Therefore, dobutamine should be titrated in individual patients.


Norepinephrine stimulates α1 and β1-adrenergic receptors. When used in animal and human studies of both acute and chronic PH, it has been shown to increase mPAP and PVR. [27],[28] Unlike dobutamine, norepinephrine has vasoconstrictive effects that are much more pronounced than the chronotropic and inotropic effects. [28] Although norepinephrine may be useful in hypotensive patients and cause less tachycardia, dobutamine remains a superior choice in the setting of PH and RV failure.


Dopamine is an adrenergic and dopaminergic agonist that increases blood pressure and cardiac output. The augmented cardiac output comes at the price of significant tachycardia that may decrease left ventricular preload and worsen demand ischemia. [29]


Isoproterenol is primarily a β1 and β2-adrenergic agonist that has historically been used to treat PH during surgery. Because it is a stronger chronotropic agent than dobutamine, the use of isoproterenol is associated with significant tachyarrhythmias. Although it improves cardiac output and PVR, [28] the utility of isoproterenol in animal models of acute PH has been limited by the induction of arrhythmias and the lack of effect on PAP. [30]


Although commonly used to improve cardiac output and increase systemic vascular resistance in hypotensive patients in the ICU, epinephrine, a potent α- and β-adrenergic agent, has not been studied in the setting of PH.

Pulmonary vasodilators

Pulmonary vasodilators can be classified into two main categories: Those that increase production of cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP), such as nitric oxide and prostanoids, respectively; and those that decrease the breakdown of cGMP, such as sildenafil, [31] and of cAMP such as milrinone.

Nitric oxide

Nitric oxide is a potent vasodilator that, when inhaled, dilates pulmonary vasculature in ventilated lung units, thereby improving oxygenation, reversing hypoxic pulmonary vasoconstriction, and reducing PAP. Nitric oxide is quickly inactivated by reaction with hemoglobin in the pulmonary capillaries, and has no systemic vasodilatory effects. Inhaled nitric oxide has been studied in PH of various etiologies. [32],[33] Although ARDS patients without sepsis initially improve oxygenation with inhaled nitric oxide, there is no evidence that outcomes are improved. [34],[35]

Abrupt withdrawal of nitric oxide has been associated with rebound PH and hemodynamic collapse in up to 48% of patients evaluated. [35],[36] In spite of its limitations, inhaled nitric oxide is a useful agent to treat PH in the ICU, particularly in combination with other agents, such as dobutamine or milrinone.


Recent studies have demonstrated the efficacy of both inhaled and intravenous prostacyclin in managing PH. [37],[38],[39] In a retrospective study of 33 adult ICU patients with hypoxemia and PH from cardiac and noncardiac causes, inhaled prostacyclin improved mPAP and hypoxemia. [40] Other studies and case reports have demonstrated the utility of inhaled prostacyclin and of the prostacyclin analog, iloprost, in reducing PAP and improving cardiac output, [41],[42],[43] although prospective studies in critically ill patients with PH are lacking.

In patients with PAH and RV failure, chronic therapy with intravenous epoprostenol may be lifesaving. Epoprostenol has an elimination half-life of 3-6 min and is typically started at a dose of 1-2 ng/kg/min, titrated upward at a rate of 0.5-1.0 ng/kg/min at intervals of 15-30 min or more. An increase in cardiac output with a decrease in PAP and PVR is considered a favorable response. The use of epoprostenol to reduce PA pressures acutely is limited by dose dependent systemic side-effects, [43] particularly systemic hypotension. In conscious patients, headache, nausea, vomiting, and diarrhea also may limit rapid titration of epoprostenol.


Milrinone is a selective phosphodiesterase-3 inhibitor with inotropic and vasodilatory effects. In animal models of both acute and chronic PH, milrinone significantly reduced PVR and improved RV function. [44],[45] In combination with inhaled nitric oxide, milrinone produces selective and additive pulmonary vasodilatation in pediatric patients after repair of congenital heart defects, [46] and after cardiac surgery in animal studies. [43]

Milrinone may have some utility in the treatment of hemodynamic instability in patients with PH, although systemic hypotension often limits its use. Further studies are needed to verify the effects of milrinone in patients with PH.


Sildenafil is a specific phosphodiesterase-5 inhibitor with acute and chronic hemodynamic effects in patients with PH. [47],[48],[49],[50]

However, there are only case reports or small case series describing its use in critically ill patients. A retrospective case review of eight adults with PH after mitral valve repair or placement of a left ventricular assist device showed that sildenafil significantly reduced mPAP and reduced PVR with only a minimal drop in mean arterial pressure, thus facilitating weaning of inhaled and intravenous pulmonary vasodilators. [50]

In stable patients, sildenafil alone or in combination with inhaled nitric oxide or epoprostenol reduces mPAP and PVR and increases cardiac output. [51],[52],[53] In patients with IPAH, sildenafil also can significantly improve cardiac output. [49] Furthermore, limited human and animal data suggest that sildenafil may augment and maintain the effects of inhaled nitric oxide [47],[54],[55] and iloprost [53] and minimize rebound PH after withdrawal of these agents. [56],[57]

The hemodynamic effects of sildenafil start within 15 min of administration and last up to several hours, although peak hemodynamic effects are seen within 30-60 min. The relatively rapid onset of action, its diminution during 3-4 h, and the accompanying systemic hypotension suggest caution in critically ill patients. Sildenafil is contraindicated in patients receiving nitrates because of the potential for severe systemic hypotension.


Diuretics have long been conventional therapy for PH, whether caused by pulmonary vascular disease or left ventricular failure. The goal of diuretic use is to decrease volume load on the distended, failing right ventricle in advanced PH without compromising preload. Optimization of diuresis in this setting is complex and should be adjusted according to hemodynamic response.


Critically unstable patients with decompensated PH often require an aggressive combination of therapies (class of recommendation I; level of evidence C).The treatment should be directed towards the specific causes of PH (class of recommendation I; level of evidence C).The determination of the presence and the degree of RV failure should direct the line of therapy (class of recommendation I; level of evidence C).The use of vasopressors and inotropes in PH patients in the ICU must be guided by knowledge of the effect of each drug on PVR and cardiac output, and must be individualized based on patient response (class of recommendation I; level of evidence C).The application of PAH-specific therapies should be carefully applied only when appropriate (class of recommendation I; level of evidence C).


1Farber HW, Loscalzo J. Pulmonary arterial hypertension. N Engl J Med 2004;351:1655-65.
2Voelkel NF, Cool C. Pathology of pulmonary hypertension. Cardiol Clin 2004;22:343-51, v.
3Idrees M. Pulmonary hypertension: Another light in the dark tunnel. Learning the lesson from cancer. Ann Thorac Med 2013;8:69-70.
4Weitzenblum E, Chaouat A. Pulmonary hypertension due to chronic hypoxic lung disease. In: Peacock AJ, Rubin LJ, editors. Pulmonary Circulation: Diseases and their Treatment. 2 nd ed. New York, NY: Oxford University Press; 2004. p. 376.
5Chin KM, Kim NH, Rubin LJ. The right ventricle in pulmonary hypertension. Coron Artery Dis 2005;16:13-8.
6Via G, Braschi A. Pathophysiology of severe pulmonary hypertension in the critically ill patient. Minerva Anestesiol 2004;70:233-7.
7Charloux A, Chaouat A, Piquard F, Brandenberger G, Weitzenblum E, Geny B. Renal hyporesponsiveness to brain natriuretic peptide: Both generation and renal activity of cGMP are decreased in patients with pulmonary hypertension. Peptides 2006;27:2993-9.
8Murphy ML, Thenabadu PN, de Soyza N, Doherty JE, Meade J, Baker BJ, et al. Reevaluation of electrocardiographic criteria for left, right and combined cardiac ventricular hypertrophy. Am J Cardiol 1984;53:1140-7.
9Bossone E, Paciocco G, Iarussi D, Agretto A, Iacono A, Gillespie BW, et al. The prognostic role of the ECG in primary pulmonary hypertension. Chest 2002;121:513-8.
10Barst RJ, McGoon M, Torbicki A, Sitbon O, Krowka MJ, Olschewski H, et al. Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol 2004;43:40S-7.
11Chemla D, Castelain V, Hervé P, Lecarpentier Y, Brimioulle S. Haemodynamic evaluation of pulmonary hypertension. Eur Respir J 2002;20:1314-31.
12Bossone E, Bodini BD, Mazza A, Allegra L. Pulmonary arterial hypertension: The key role of echocardiography. Chest 2005;127:1836-43.
13Jardin F, Vieillard-Baron A. Monitoring of right-sided heart function. Curr Opin Crit Care 2005;11:271-9.
14Idrees MM, Al-Hajjaj M, Khan J, Al-Hazmi M, Alanezi M, Saleemi S, et al. Saudi guidelines on diagnosis and treatment of pulmonary arterial hypertension. Ann Thorac Med 2008;3(1):1-57[Supplement].
15Badesch DB, Abman SH, Ahearn GS, Barst RJ, McCrory DC, Simonneau G, et al. Medical therapy for pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 2004;126:35S-62.
16McLaughlin VV, Presberg KW, Doyle RL, Abman SH, McCrory DC, Fortin T, et al. Prognosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 2004;126:78S-92.
17Cigarroa RG, Lange RA, Williams RH, Bedotto JB, Hillis LD. Underestimation of cardiac output by thermodilution in patients with tricuspid regurgitation. Am J Med 1989;86:417-20.
18Thabut G, Dauriat G, Stern JB, Logeart D, Lévy A, Marrash-Chahla R, et al. Pulmonary hemodynamics in advanced COPD candidates for lung volume reduction surgery or lung transplantation. Chest 2005;127:1531-6.
19Miro AM, Pinsky MR. Heart-lung interactions. In: Tobin MJ, editor. Principles and Practice of Mechanical Ventilation. New York, NY: McGraw-Hill; 1994. p. 647-72.
20Jardin F, Vieillard-Baron A. Right ventricular function and positive pressure ventilation in clinical practice: From hemodynamic subsets to respirator settings. Intensive Care Med 2003;29:1426-34.
21Carvalho CR, Barbas CS, Medeiros DM, Magaldi RB, Lorenzi Filho G, Kairalla RA, et al. Temporal hemodynamic effects of permissive hypercapnia associated with ideal PEEP in ARDS. Am J Respir Crit Care Med 1997;156:1458-66.
22Roberts DH, Lepore JJ, Maroo A, Semigran MJ, Ginns LC. Oxygen therapy improves cardiac index and pulmonary vascular resistance in patients with pulmonary hypertension. Chest 2001;120:1547-55.
23Moloney ED, Evans TW. Pathophysiology and pharmacological treatment of pulmonary hypertension in acute respiratory distress syndrome. Eur Respir J 2003;21:720-7.
24Leier CV, Webel J, Bush CA. The cardiovascular effects of the continuous infusion of dobutamine in patients with severe cardiac failure. Circulation 1977;56:468-72.
25Vizza CD, Rocca GD, Roma AD, Iacoboni C, Pierconti F, Venuta F, et al. Acute hemodynamic effects of inhaled nitric oxide, dobutamine and a combination of the two in patients with mild to moderate secondary pulmonary hypertension. Crit Care 2001;5:355-61.
26Kwak YL, Lee CS, Park YH, Hong YW. The effect of phenylephrine and norepinephrine in patients with chronic pulmonary hypertension. Anaesthesia 2002;57:9-14.
27Ducas J, Duval D, Dasilva H, Boiteau P, Prewitt RM. Treatment of canine pulmonary hypertension: Effects of norepinephrine and isoproterenol on pulmonary vascular pressure-flow characteristics. Circulation 1987;75:235-42.
28Holloway EL, Polumbo RA, Harrison DC. Acute circulatory effects of dopamine in patients with pulmonary hypertension. Br Heart J 1975;37:482-5.
29Prielipp RC, McLean R, Rosenthal MH, Pearl RG. Hemodynamic profiles of prostaglandin E1, isoproterenol, prostacyclin, and nifedipine in experimental porcine pulmonary hypertension. Crit Care Med 1991;19:60-7.
30Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med 2004;351:1425-36.
31Griffi ths MJ, Evans TW. Inhaled nitric oxide therapy in adults. N Engl J Med 2005;353:2683-95.
32Creagh-Brown BC, Griffi ths MJ, Evans TW. Bench-to-bedside review: Inhaled nitric oxide therapy in adults. Crit Care 2009;13:221.
33Cockrill BA, Kacmarek RM, Fifer MA, Bigatello LM, Ginns LC, Zapol WM, et al. Comparison of the effects of nitric oxide, nitroprusside, and nifedipine on hemodynamics and right ventricular contractility in patients with chronic pulmonary hypertension. Chest 2001;119:128-36.
34Taylor RW, Zimmerman JL, Dellinger RP, Straube RC, Criner GJ, Davis K Jr, et al. Low-dose inhaled nitric oxide in patients with acute lung injury: A randomized controlled trial. JAMA 2004;291:1603-9.
35Christenson J, Lavoie A, O′Connor M, Bhorade S, Pohlman A, Hall JB. The incidence and pathogenesis of cardiopulmonary deterioration after abrupt withdrawal of inhaled nitric oxide. Am J Respir Crit Care Med 2000;161:1443-9.
36Bhorade S, Christenson J, O′connor M, Lavoie A, Pohlman A, Hall JB. Response to inhaled nitric oxide in patients with acute right heart syndrome. Am J Respir Crit Care Med 1999;159:571-9.
37McLaughlin VV, Genthner DE, Panella MM, Rich S. Reduction in pulmonary vascular resistance with long-term epoprostenol (prostacyclin) therapy in primary pulmonary hypertension. N Engl J Med 1998;338:273-7.
38McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: The impact of epoprostenol therapy. Circulation 2002;106:1477-82.
39Badesch DB, Tapson VF, McGoon MD, Brundage BH, Rubin LJ, Wigley FM, et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial. Ann Intern Med 2000;132:425-34.
40Haché M, Denault AY, Bélisle S, Couture P, Babin D, Tétrault F, et al. Inhaled prostacyclin (PGI2) is an effective addition to the treatment of pulmonary hypertension and hypoxia in the operating room and intensive care unit. Can J Anaesth 2001;48:924-9.
41De Wet CJ, Affl eck DG, Jacobsohn E, Avidan MS, Tymkew H, Hill LL, et al. Inhaled prostacyclin is safe, effective, and affordable in patients with pulmonary hypertension, right heart dysfunction, and refractory hypoxemia after cardiothoracic surgery. J Thorac Cardiovasc Surg 2004;127:1058-67.
42Hoeper MM, Schwarze M, Ehlerding S, Adler-Schuermeyer A, Spiekerkoetter E, Niedermeyer J, et al. Long-term treatment of primary pulmonary hypertension with aerosolized iloprost, a prostacyclin analogue. N Engl J Med 2000;342:1866-70.
43Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 1996;334:296-301.
44Deb B, Bradford K, Pearl RG. Additive effects of inhaled nitric oxide and intravenous milrinone in experimental pulmonary hypertension. Crit Care Med 2000;28:795-9.
45Chen EP, Bittner HB, Davis RD Jr, Van Trigt P 3rd. Milrinone improves pulmonary hemodynamics and right ventricular function in chronic pulmonary hypertension. Ann Thorac Surg 1997;63:814-21.
46Khazin V, Kaufman Y, Zabeeda D, Medalion B, Sasson L, Schachner A, et al. Milrinone and nitric oxide: Combined effect on pulmonary artery pressures after cardiopulmonary bypass in children. J Cardiothorac Vasc Anesth 2004;18:156-9.
47Lepore JJ, Maroo A, Pereira NL, Ginns LC, Dec GW, Zapol WM, et al. Effect of sildenafi l on the acute pulmonary vasodilator response to inhaled nitric oxide in adults with primary pulmonary hypertension. Am J Cardiol 2002;90:677-80.
48Bhatia S, Frantz RP, Severson CJ, Durst LA, McGoon MD. Immediate and long-term hemodynamic and clinical effects of sildenafil in patients with pulmonary arterial hypertension receiving vasodilator therapy. Mayo Clin Proc 2003;78:1207-13.
49Michelakis E, Tymchak W, Lien D, Webster L, Hashimoto K, Archer S. Oral sildenafi l is an effective and specifi c pulmonary vasodilator in patients with pulmonary arterial hypertension: Comparison with inhaled nitric oxide. Circulation 2002;105:2398-403.
50Trachte AL, Lobato EB, Urdaneta F, Hess PJ, Klodell CT, Martin TD, et al. Oral sildenafi l reduces pulmonary hypertension after cardiac surgery. Ann Thorac Surg 2005;79:194-7.
51Ghofrani HA, Wiedemann R, Rose F, Olschewski H, Schermuly RT, Weissmann N, et al. Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension. Ann Intern Med 2002;136:515-22.
52Ghofrani HA, Rose F, Schermuly RT, Olschewski H, Wiedemann R, Kreckel A, et al. Oral sildenafi l as long-term adjunct therapy to inhaled iloprost in severe pulmonary arterial hypertension. J Am Coll Cardiol 2003;42:158-64.
53Lepore JJ, Maroo A, Bigatello LM, Dec GW, Zapol WM, Bloch KD, et al. Hemodynamic effects of sildenafi l in patients with congestive heart failure and pulmonary hypertension: Combined administration with inhaled nitric oxide. Chest 2005;127:1647-53.
54Preston IR, Klinger JR, Houtches J, Nelson D, Farber HW, Hill NS. Acute and chronic effects of sildenafi l in patients with pulmonary arterial hypertension. Respir Med 2005;99:1501-10.
55Nagamine J, Hill LL, Pearl RG. Combined therapy with zaprinast and inhaled nitric oxide abolishes hypoxic pulmonary hypertension. Crit Care Med 2000;28:2420-4.
56Ng J, Finney SJ, Shulman R, Bellingan GJ, Singer M, Glynne PA. Treatment of pulmonary hypertension in the general adult intensive care unit: A role for oral sildenafil? Br J Anaesth 2005;94:774-7.
57Atz AM, Wessel DL. Sildenafi l ameliorates effects of inhaled nitric oxide withdrawal. Anesthesiology 1999;91:307-10.