Group 4: Pulmonary Hypertension due to Chronic Thrombotic or Embolic Disease Group 5: Miscellaneous Includes sarcoidosis, compression of pulmonary vessels, lymphangiomatosis, and histiocytosis X

Classification of congenital systemic-to-pulmonary shunts

• Simple (ASD, VSD, PDA, total or partial unobstructed

• Combined

• Complex (truncus arteriosus, atrioventricular defects, single

• Associated extra-cardiac abnormalities

• Correction status

• Dimensions

Small (ASD ≤2 cm and VSD ≤1 cm)

Large (ASD >2 cm and VSD >1 cm)

Modified from Simonneau G, Galie N, Rubin LJ, et al: Clinical classification of pulmonary hypertension. J Am Coll Cardiol 43:5S-12S, 2004. ASD, atrial septal defect; HIV, human immunodeficiency virus; PDA, patent ductus arteriosus; VSD, ventricular septal defect; COPD, chronic obstructive pulmonary disease.

Pathophysiology

In clinical practice, pulmonary arterial pressure is commonly assumed to be reflective of pulmonary vascular resistance, and in most circumstances this is the case. However, based on Equation 1-6, it is clear that pulmonary arterial pressure is also dependent on cardiac output and left atrial pressure. An increase in cardiac output can lead to an increase in pulmonary arterial pressure despite a fall in pulmonary vascular resistance. Conversely, an acute rise in pulmonary vascular resistance resulting in acute right ventricular failure and thus a fall in cardiac output may cause a fall in pulmonary arterial pressure.

Under normal circumstances, as cardiac output increases in response to increased metabolic demands, pulmonary vascular resistance falls due to distension and recruitment of pulmonary capillaries; thus, pulmonary arterial pressure is relatively unchanged. With elevated pulmonary vascular resistance, this normal response of the pulmonary vascular bed is lost, and pulmonary arterial pressure rises as cardiac output increases. Over time, as pulmonary vascular disease progresses, the ability of the right heart to increase its output is reduced and cardiac output becomes relatively fixed. Eventually, right ventricular failure develops and cardiac output is reduced even under resting conditions.

The extent to which the right ventricle can cope with increased pulmonary vascular resistance depends on the time period over which the increased resistance has occurred. An untrained, thin-walled right ventricle is sensitive to acute rises in afterload. Thus, an abrupt rise in pulmonary vascular resistance (e.g., due to a massive pulmonary embolism) that requires a mean pulmonary arterial pressure of more than 40 mmHg to perfuse the pulmonary bed will rapidly lead to right ventricular failure. In contrast, if pulmonary vascular resistance increases gradually, right ventricular hypertrophy develops, which allows resting cardiac output to be maintained in the face of very high pulmonary vascular resistance (e.g., >20 Wood units). In this situation, pulmonary arterial pressure may approach or even exceed systemic arterial pressure.

With raised left atrial pressure, increased pulmonary arterial pressure can occur without raised pulmonary vascular resistance (see Equation 1-6). This is termed passive pulmonary hypertension. In passive pulmonary hypertension, the increase in pulmonary arterial pressure is usually mild and the transpulmonary gradient (see Chapter 1) is normal. The common causes of passive pulmonary hypertension are mitral valve disease and left ventricular dysfunction. The term active pulmonary hypertension denotes pulmonary hypertension due to vasoconstriction or anatomic restriction within the pulmonary bed in association with normal left atrial pressure. Pulmonary vascular resistance and transpulmonary gradient are elevated. Causes of active pulmonary hypertension include chronic lung disease and chronically elevated flow through the pulmonary circulation, such as that which occurs with uncorrected systemic-to-pulmonary shunts. The term reactive pulmonary hypertension refers to active pulmonary hypertension due to long-standing passive pulmonary hypertension. Chronically elevated left atrial pressure eventually causes pathologic changes within the pulmonary arterioles. The most common cause of reactive pulmonary hypertension in cardiac surgery patients is chronic mitral valve disease, particularly mitral stenosis. Rarely, left ventricular failure leads to reactive pulmonary hypertension. Pulmonary hypertension may be severe.

Pulmonary hypertension may be fixed or responsive. Changes in the pulmonary vascular bed that accompany active or reactive pulmonary hypertension include vasoconstriction, endothelial and smooth muscle proliferation, thrombosis, and fibrosis. Pulmonary hypertension that is associated with extensive thrombosis, fibrosis, or tissue destruction tends to be fixed, whereas pulmonary hypertension that is associated with abnormal vasoconstriction may be responsive to pulmonary vasodilating agents. Impaired production of vasodilator substances, such as nitric oxide, prostacyclin, and vasoactive intestinal peptide, and increased production of vasoconstrictor substances, such as endothelin-1 and thromboxane-A2, have been identified for a range of conditions associated with pulmonary hypertension.¹ Alveolar hypoxemia is a potent stimulus for pulmonary vasoconstriction, and it contributes to pulmonary hypertension in patients with chronic lung disease.

DIAGNOSIS

The symptoms of secondary pulmonary hypertension are determined primarily by the underlying cardiac or respiratory pathology. Symptoms attributable to pulmonary hypertension per se relate to the relatively fixed cardiac output. These symptoms include dyspnea on exertion, dizziness, syncope, palpitations, and fatigue. Physical findings of pulmonary hypertension are those of right ventricular pressure overload, and are not usually apparent unless systolic pulmonary arterial pressure exceeds 50 mmHg. Physical findings include a right ventricular heave, a loud pulmonary component of the second heart sound (P₂), a large A wave on the jugular venous trace, a pulmonary ejection click, and a pulmonary flow murmur. Symptoms and signs of right ventricular failure may be present (see subsequent material).

With severe pulmonary hypertension, the electrocardiogram (ECG) typically demonstrates right ventricular hypertrophy and right axis deviation (Fig. 24-1). On the chest radiograph, characteristic features of pulmonary hypertension include enlargement of the main and central hilar pulmonary arteries (Fig. 24-2) and reduced vascular markings in the peripheries (pruning of the vessels). Signs of left ventricular dysfunction or lung disease may be evident.

Figure 24.1 An electrocardiogram in a patient with severe pulmonary hypertension. Right axis deviation (predominant S wave in lead I) and right atrial enlargement (peaked P wave in lead II; height, ≥2.5 mm) are present. A dominant R wave is seen in lead V1, and there is poor R wave progression. T wave inversion is present in leads V1 through V5, consistent with right ventricular strain.

Figure 24.2 Chest radiograph in a patient with severe pulmonary hypertension secondary to an atrial septal defect. There is enlargement of the main and central hilar pulmonary arteries (PA) and reduced vascular markings in the lung field peripheries. The central strut of an atrial septal defect closure device is seen (arrow).

Pulmonary Artery Catheterization

Pulmonary artery catheterization may be used as part of a diagnostic workup (see Chapter 5) or in the ICU as a guide to management (see Chapter 8). Diagnostic right heart catheterization involves measurement of pulmonary arterial pressure, measurement of cardiac output, calculation of pulmonary vascular resistance, assessment of reversibility with pulmonary vasodilators (100% oxygen, nitroprusside, nitric oxide) and, in patients with intracardiac shunting, measurements of various oxygen saturations so as to allow estimation of the ratio of pulmonary to systemic flow (described in Chapter 5).

With chronically increased pulmonary vascular resistance, pulmonary arterial pressure may be very high but if right ventricular failure has not developed, cardiac output and central venous pressure (CVP) will be within normal limits. In this situation, there will be a large step-up in pressure between the CVP and the mean pulmonary arterial pressure. With an acute increase in pulmonary vascular resistance (e.g., due to massive pulmonary embolism), pulmonary arterial pressure will not be dramatically elevated but there may be signs of right ventricular decompensation (see subsequent material).

Echocardiography

With chronic pulmonary hypertension, the right ventricle is typically hypertrophied (wall thickness >0.5 cm and occasionally >1 cm) and dilated but, in the absence of ventricular failure, systolic function is preserved. Chronic right ventricular pressure overload leads to characteristic abnormalities in the shape and motion of the interventricular septum, which are described in Chapter 7. In the absence of right heart failure, tricuspid regurgitation is typically mild. If pulmonary valve function is normal, the velocity of the tricuspid regurgitant jet can be used to estimate systolic pulmonary arterial pressure (from Equation 7-5). A velocity greater than 2 m/sec is consistent with pulmonary hypertension; greater than 4 m/sec, it is consistent with severe pulmonary hypertension. If right atrial pressure exceeds left atrial pressure, the interatrial septum bulges abnormally toward the left. If a patent foramen ovale (PFO) is present there may be right-to-left shunting across the atrial septum.

The causes of pulmonary hypertension encountered in the cardiothoracic ICU are listed in Table 24-2. Clinically important pulmonary hypertension that occurs during the perioperative period is usually caused by the combination of chronically elevated pulmonary vascular resistance and an acute increase due to the effects of cardiopulmonary bypass (CPB), cardiac or thoracic surgery, mechanical ventilation, or impaired gas exchange.

Table 24-2 Causes of Pulmonary Hypertension in the Cardiothoracic Intensive Care Unit

Cardiac Surgery

Mitral surgery

Heart transplantation

Thoracic Surgery

Lung transplantation

Pneumonectomy

Chronic left ventricular dysfunction

Chronic Lung Disease

COPD

Interstitial lung disease

Obesity hypoventilation syndrome

Uncorrected chronic pulmonary-to-systemic shunts (including Eisenmenger syndrome)

Acute lung injury

Acute respiratory distress syndrome

Pulmonary edema

Pulmonary Embolus

Massive pulmonary embolus

Chronic pulmonary thromboembolism

COPD, chronic obstructive pulmonary disease.

ETIOLOGY

Increased Pulmonary Vascular Resistance During the Perioperative Period

CPB is associated with the systemic inflammatory response syndrome which, among other effects, causes an acute increase in pulmonary vascular resistance (see Chapter 2). Pulmonary vascular resistance may also be increased by raised intrathoracic pressure due to mechanical ventilation (see Chapter 29) and impaired gas exchange (acidemia and low alveolar oxygen tension; see Chapter 1). Elevated pulmonary vascular resistance is also a feature of acute lung injury and acute respiratory distress syndrome (ARDS). Acute, severe increases in pulmonary vascular resistance may occur due to ventilator dysynchrony, in which intrathoracic pressure increases dramatically concurrent with a sudden deterioration in gas exchange. Pulmonary hypertension is exacerbated by elevated left atrial pressure due to heart dysfunction. These perioperative effects add to any underlying chronic pulmonary hypertension and can precipitate acute right ventricular decompensation.

Mitral Valve Disease

Chronically elevated left atrial pressure due to mitral valve disease is associated with initially passive, but eventually reactive, pulmonary hypertension. Reactive pulmonary hypertension is common in severe mitral stenosis but may also occur with severe mitral regurgitation when left ventricular function is impaired. Reactive pulmonary hypertension is initially responsive to vasodilators but eventually becomes fixed.

As mitral valve replacement or repair corrects the cause of pulmonary hypertension, if the postoperative course is uncomplicated and the elevated pulmonary vascular resistance is at least partly reversible, pulmonary arterial pressure may significantly fall immediately following surgery. However, minimal improvement or even worsening of pulmonary hypertension may occur during the early postoperative period when pulmonary vascular resistance is fixed.

Congenital Heart Disease

A range of congenital cardiac abnormalities (see Table 24-1) that are associated with systemic-to-pulmonary (i.e., left-to-right) shunting are associated with pulmonary hypertension due to chronically high pulmonary blood flow. As with mitral valve disease, increased pulmonary vascular resistance is initially responsive to pulmonary vasodilators, but over time it becomes fixed. If pulmonary vascular resistance exceeds systemic vascular resistance, shunt reversal occurs, leading to systemic hypoxemia and the risk of paradoxic embolism. This condition is termed Eisenmenger syndrome (see Chapter 15). Once Eisenmenger syndrome has developed, shunt closure is contraindicated because closure will precipitate right ventricular failure. Even without Eisenmenger syndrome, shunt closure in the presence of raised pulmonary vascular resistance may still precipitate right ventricular failure because of the higher pulmonary resistance and impaired right ventricular function that accompany surgery.

Heart Transplantation

Patients presenting for heart transplantation typically have at least moderate pulmonary hypertension as the result of chronically elevated left atrial pressure. Pulmonary vascular resistance may increase further in the early postoperative period for the reasons outlined earlier. Increased pulmonary vascular resistance in the recipient, combined with myocardial stunning in the graft (due to the effects of explantation), can lead to postoperative right ventricular dysfunction.

Lung Transplantation

End-stage lung disease is commonly associated with severe pulmonary hypertension. During surgery, right ventricular decompensation and hemodynamic instability are not uncommon. Following reperfusion of the grafts, pulmonary arterial pressure typically falls, but occasionally acutely elevated pulmonary vascular resistance develops in the grafts secondary to reperfusion injury. Severe reperfusion injury in the grafts, combined with right ventricular dysfunction due to the effects of surgery and CPB, can precipitate postoperative right ventricular failure.

Lung Resection

Lung resection is associated with loss of some of the pulmonary vascular bed. If the loss is extensive (e.g., following pneumonectomy) or the remaining lung tissue is diseased, pulmonary vascular resistance and pulmonary arterial pressures will rise postoperatively. Despite this, right ventricular failure is relatively uncommon following pneumonectomy.

RIGHT VENTRICULAR FAILURE

Right ventricular failure can occur because of (1) systolic dysfunction; (2) volume overload; or (3) pressure overload (see Table 20-7). In this chapter, only right ventricular decompensation due to acute and chronic pressure overload is considered.

Right ventricular perfusion pressure (RVPP) is the difference between mean arterial pressure (MAP) and right ventricular end-diastolic pressure (RVEDP):

(1)

Increased pulmonary vascular resistance leads to an increase in RVEDP, which reduces RVPP. Perfusion pressure may be further compromised by systemic hypotension (e.g., due to vasodilators) or further increases in RVEDP (e.g., due to excess fluid administration or acute elevations in pulmonary vascular resistance). This can induce a cycle of myocardial ischemia, right ventricular systolic dysfunction, and falling cardiac output, which may eventually culminate in cardiovascular collapse.

Clinically, patients with right ventricular failure are very unwell and show signs of cardiogenic shock: cool clammy peripheries, pallor, tachycardia, a third heart sound, and hypotension. In addition, there may be signs of systemic venous hypertension with distended neck veins and a pulsatile liver. There may be a murmur of tricuspid regurgitation. Patients may complain of severe right upper-quadrant abdominal pain caused by acute hepatic engorgement. There may be massive elevation of the hepatic transaminases (aspartate and alanine aminotransferase). If right ventricular failure develops over several days or weeks, patients typically develop ascites, pleural effusions, and systemic edema, but in the acute setting these features may be absent.

Important information is obtained from systemic arterial and CVP monitoring. The CVP is elevated and giant V waves, indicative of tricuspid regurgitation, may be seen. In a patient with known pulmonary hypertension, the combination of rising CVP and falling blood pressure is suggestive of acute right ventricular failure. If a pulmonary artery catheter is in situ, cardiac output is usually low. The absolute value of pulmonary arterial pressure is determined by whether right ventricular pressure overload is acute or acute-on-chronic, and in itself is nondiagnostic for right ventricular failure. However, irrespective of the absolute value, right ventricular decompensation is associated with falling pulmonary arterial pressure. Because right ventricular volume overload causes marked displacement of the interventricular septum into the left ventricle, PAWP may be elevated despite low left ventricular preload.

Echocardiography shows the right ventricle to be grossly dilated and hypokinetic. There is often severe tricuspid regurgitation. Ventricular septal motion is typically abnormal and has features of acute right ventricular volume overload (see Fig. 7-15). The interventricular septum is displaced to the left in late diastole, making the left ventricle appear hypovolemic. The interatrial septum bulges abnormally to the left.

Hypoxemia and a Patent Foramen Ovale

A particular feature of acute right ventricular failure is the potential for the development of hypoxemia due to right-to-left shunting across a PFO. A PFO is present in about 25% of adults; it is a flap-like atrial septal defect that allows flow only from right to left. Because right atrial pressure is normally less than left atrial pressure, under normal circumstances no flow occurs across a PFO. With right ventricular dysfunction, right atrial pressure typically exceeds left atrial pressure and right-to-left shunting occurs, leading to hypoxemia. This is important because in ventilated patients, a clinician’s first response to hypoxemia is likely to be to increase the level of positive end-expiratory pressure (PEEP), which may worsen right ventricular function and increase shunting. Thus, any patient with right ventricular dysfunction who develops unexplained hypoxemia despite normal lung compliance and an unremarkable chest radiograph should undergo an urgent, ideally transesophageal, echocardiogram to search for right-to-left shunting across a PFO.

TREATMENT OF PULMONARY HYPERTENSION DURING THE PERIOPERATIVE PERIOD

Pulmonary hypertension per se does not require treatment. Treatment is directed to the underlying cause of the pulmonary hypertension—predominantly pulmonary or left heart pathology—and to any resulting right ventricular decompensation. For instance, in passive pulmonary hypertension, treatment should be directed to reducing left atrial pressure, for example, by improving left ventricular function or relieving mitral stenosis, rather than to reducing pulmonary vascular resistance, which in this situation may be relatively normal.

This section outlines treatment strategies to be used in the ICU environment for right ventricular dysfunction due to acute (or acute-on-chronic) pressure overload. The management of right ventricular dysfunction caused by volume overload and that caused by systolic dysfunction is similar and is described in Chapter 20.

General Supportive Measures

In most patients with pulmonary hypertension there is a dynamic component to the elevated pulmonary resistance. It is important to avoid further increases in pulmonary vascular resistance due to the effects of pain, anxiety, or patient-ventilator dysynchrony. Ventilated patients with right ventricular failure should be heavily sedated and given adequate analgesia and, if necessary, muscle relaxants. Hypoxemia and acidemia can cause an abrupt increase in pulmonary vascular resistance and, if possible, these parameters should be controlled. During the early postoperative period when pulmonary vascular resistance is particularly labile, fractional inspired oxygen concentration should be kept above 50%, irrespective of the arterial oxygen tension. In patients with acute lung injury or ARDS, the risks involved in using aggressive ventilation to control pulmonary hypertension are generally outweighed by the risk of iatrogenic lung injury.

Although mechanical ventilation may impair right ventricular function by increasing right ventricular afterload and reducing right ventricular preload (see Chapter 29), when gas exchange is impaired, the benefits of mechanical ventilation greatly outweigh the risks, and this intervention should not be withheld if indicated. However, high airway pressures and high levels of PEEP should be avoided.

Fluid Therapy

Judicious volume loading may have a role in treating patients with right ventricular failure due to systolic dysfunction (see Chapter 20). However, with right ventricular pressure overload it is likely to be harmful because it increases RVEDP and reduces perfusion pressure to the right ventricle. Fluid administration also increases the severity of tricuspid regurgitation and leads to further leftward displacement of the interventricular septum, worsening left ventricular filling.

Vasoactive Support

A critical component of treating right ventricular failure due to pressure overload is maintaining right ventricular perfusion pressure by supporting blood pressure.² Norepinephrine is the vasopressor of choice.²

If right ventricular systolic dysfunction is considered an important coexisting problem (as is often the case following heart transplantation), coadministration of an inodilating agent such as milrinone or dobutamine should be considered. Inodilating drugs have the added effect of reducing right ventricular afterload, but they should be used cautiously because they can cause systemic hypotension.

Systemically Administered Vasodilators

Systemically administered vasodilators reduce right ventricular afterload and can reverse right ventricular failure. However, they must be used cautiously for two reasons. First, these drugs are largely nonselective and cause reduction in both pulmonary and systemic vascular resistances. This risk is greatest when pulmonary vascular resistance is fixed because preferential vasodilation of the systemic circulation occurs. Second, systemically administered vasodilators inhibit hypoxic pulmonary vasoconstriction and thus have the potential to cause hypoxemia, which may adversely affect pulmonary vascular resistance.

Commonly used vasodilators (e.g., nitroglycerin, sodium nitroprusside, prostacyclin, and diltiazem) and inodilators (e.g., milrinone, dobutamine, and isoproterenol) all cause pulmonary arteriolar vasodilatation. If introduced at low doses and titrated to effect, these drugs may significantly improve right ventricular function—though it is important to remember that the goal is improvement in right ventricular function, not reduction in pulmonary arterial pressure. Sildenafil (see subsequent material) is used predominantly to treat chronic pulmonary hypertension, but in one report, 50 mg administered enterally was used successfully to treat pulmonary hypertension following cardiac surgery.³

Inhaled Therapy

Inhaled pulmonary vasodilators have the advantages of not causing systemic hypotension and, because they are distributed only to ventilated lung units, of enhancing ventilation-perfusion matching within the lung.

Nitric Oxide

Inhaled nitric oxide has been used to treat pulmonary hypertension following cardiac surgery4,5 and pulmonary hypertension associated with ARDS.6 Doses of nitric oxide that range between 5 and 40 parts per million improve oxygenation, reduce pulmonary arterial pressure, and increase cardiac output. However, with pulmonary hypertension secondary to ARDS, about 30% of patients do not respond to treatment.7 Another difficulty with inhaled nitric oxide is the development of rebound pulmonary hypertension once the drug is discontinued, so the dose must be tapered slowly over many hours. A reasonable approach is to commence inhaled nitric oxide at 20 to 40 parts per million and then, if a beneficial effect is seen, to reduce the dose to the lowest effective level. In the United States, nitric oxide is approved by the Federal Drug Administration for use only in neonates. However, off-label use in adults is widespread.

Because nitric oxide combines with oxygen to form the toxic gas nitrogen dioxide, clinical use of nitric oxide requires an accurate gas-delivery system in which concentrations of nitric oxide and nitrogen dioxide are continuously monitored. The requirements of these sophisticated delivery and monitoring systems means that nitric oxide therapy is expensive. Systemically absorbed nitric oxide combines with hemoglobin to form methemoglobin. The concentration of methemoglobin is not usually significant at clinically used doses of nitric oxide (<2% of total hemoglobin), but regular checks of methemoglobin concentration should be made.

Prostacyclin

Prostacyclin (prostaglandin I₂, epoprostenol) is a short-acting prostaglandin with vasodilatory and antiplatelet effects. It may be given by intravenous infusion (see subsequent material) or by inhalation. Inhaled prostacyclin is well described for treating pulmonary hypertension following cardiac surgery and is similar to inhaled nitric oxide in its ability to reduce pulmonary vascular resistance, improve oxygenation, and augment cardiac output. Impaired platelet function has been observed but it has not been associated with increased postoperative bleeding.^8,⁹ Doses in the range of 5 to 50 ng/kg/min have been used.^8,⁹ Because of its short half-time, prostacyclin must be given by continuous nebulization via a low-flow jet nebulizer placed in the inspiratory limb of the ventilator circuit. The syringe and nebulizer should be foil-wrapped to protect the drug from light. One method of drug delivery involves formulating a solution such that a dose of 50 ng/kg/min is delivered at a volume of 8 ml/hour via a syringe driver into the jet nebulizer.^9,¹⁰ (Thus, for a 70 kg patient, 1.58 mg of prostacyclin is diluted into a 60 ml syringe.) The infusion is started at 8 ml/hr, and the rate is adjusted downward as tolerated.

Iloprost

Iloprost is an analog of prostacyclin that has been used successfully to treat pulmonary hypertension following cardiac surgery.¹¹ Like prostacyclin, it has vasodilatory and antiplatelet effects, but it has a longer half-life (20 to 30 minutes) and improved solubility in saline than prostacyclin, making it suitable for administration by intermittent nebulization. When given by the inhaled route, iloprost is well tolerated and has minimal systemic hemodynamic effects. To treat acute pulmonary hypertension, iloprost may be given at a dose of 12 to 20 μg every 4 to 6 hours by intermittent nebulization. The contents of one iloprost ampoule (50 μg/0.5 ml) can be diluted with saline in a 10-ml syringe, and 3 ml (15 μg) can be given per dose. If refrigerated, the solution is stable for 24 hours.

Unlike inhaled nitric oxide, neither iloprost nor prostacyclin cause rebound pulmonary hypertension. One disadvantage of iloprost is that for ventilated patients with acute lung injury, the patient’s circuit must be interrupted every few hours to allow intermittent nebulization, with a resultant loss of PEEP.

TREATMENT OF CHRONIC PULMONARY HYPERTENSION IS UNRELATED TO CARDIAC OR PULMONARY DISEASE

Patients with severe chronic pulmonary arterial hypertension that is unrelated to cardiac or pulmonary disease ¹² (predominantly groups 1 and 5 in Table 24-1) are admitted to the ICU only rarely, usually following a noncardiac surgical procedure. Occasionally, such patients are offered lung transplantation or, with chronic pulmonary embolic disease, pulmonary thromboendarterectomy (see Chapter 23). Occasionally, patients with end-stage pulmonary hypertension present for the first time in an acutely unwell state, in which case mechanical ventilation and vasoactive support may be instituted until the diagnosis is established. However, aggressive treatment of patients with end-stage disease is not appropriate in the ICU unless there is a clearly identified reversible problem, which is rare.

Most patients with chronic severe pulmonary arterial hypertension present with dyspnea on exertion or presyncope and undergo investigation with a 6-minute walk test, an echocardiogram, a right heart catheter study, and a computed tomogram pulmonary angiogram. Diagnostic testing for various collagen-vascular diseases is also undertaken. Patients who are symptomatic (New York Heart Association functional class III or IV) typically have a pulmonary vascular resistance above 10 Wood units (normal <3.2 Wood units), which is demonstrated by right heart catheterization.

Pharmacotherapy that should be considered in all symptomatic patients consists of anticoagulation with warfarin, diuretics for right ventricular failure, and oxygen for hypoxemia. In a minority of patients with severe pulmonary hypertension, marked reversibility is documented during right heart catheterization. These patients may be treated by administering a calcium channel blocker. However, most patients with severe pulmonary hypertension have limited reversibility or significant right ventricular dysfunction. These patients should be considered for treatment by one or more of the following: bosentan,^13,¹⁴ sildenafil,¹⁵ or prostacyclin¹⁶; all of these drugs have been shown to improve functional capacity in patients with severe symptomatic disease.

Bosentan is an orally administered, nonselective endothelin receptor antagonist. A dose of 125 mg twice daily has been shown to be effective and is well tolerated. The main side effect is elevated hepatic transaminases.

Sildenafil, a subtype-5 phosphodiesterase inhibitor, may be administered in a dose of 20 to 80 mg three times daily. Side effects are minor but include flushing, dyspepsia, and diarrhea.

Intravenous prostacyclin (prostaglandin I₂, epoprostenol) is also effective in improving functional capacity, but its use is limited by its very short duration of effect and side effects. It must be administered by continuous intravenous infusion, usually via a tunneled central venous catheter. Doses in the range of 15 to 40 ng/kg/min have been used. Side effects include jaw pain, headache, diarrhea, flushing, leg pain, and nausea. Serious complications are caused primarily by catheter-related sepsis. Alternatives to epoprostenol include the prostacyclin analogues treprostinil, beraprost, and iloprost. Treprostinil has a longer duration of action than epoprostenol and may be administered by continuous subcutaneous infusion. Use of the drug is limited by local pain at the infusion site. Beraprost is an orally active form of prostacyclin. It has been shown to provide improved functional capacity at 6 months, but this benefit was not sustained at 12 months.¹⁷ Inhaled iloprost avoids the needs for intravenous or subcutaneous injection and improves functional capacity in patients with severe pulmonary hypertension.¹⁸ However, it must be given 6 to 12 times per day, which limits its tolerability.

REFERENCES

1 Farber HW, Loscalzo J. Pulmonary arterial hypertension. N Engl J Med. 2004;351:1655-1665.

2 Mebazaa A, Karpati P, Renaud E, et al. Acute right ventricular failure—from pathophysiology to new treatments. Intens Care Med. 2004;30:185-196.

3 Madden BP, Sheth A, Ho TB, et al. Potential role for sildenafil in the management of perioperative pulmonary hypertension and right ventricular dysfunction after cardiac surgery. Br J Anaesth. 2004;93:155-156.

4 Maxey TS, Smith CD, Kern JA, et al. Beneficial effects of inhaled nitric oxide in adult cardiac surgical patients. Ann Thorac Surg. 2002;73:529-532.

5 Kieler-Jensen N, Lundin S, Ricksten SE. Vasodilator therapy after heart transplantation: effects of inhaled nitric oxide and hintravenous prostacyclin, prostaglandin E1, and sodium hnitroprusside. J Heart Lung Transplant. 1995;14:436-443.

6 Taylor RW, Zimmerman JL, Dellinger RP, et al. Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial. JAMA. 2004;291:1603-1609.