42: Pulmonary Hypertension

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CHAPTER 42 Pulmonary Hypertension

James Duke, MD, MBA

1 Define pulmonary hypertension

Although there is no widely accepted range for normal pulmonary blood pressures, pulmonary hypertension (PH) exists when the pulmonary systolic pressure exceeds 25 mm Hg in the presence of normal cardiac output (CO) and pulmonary capillary wedge pressure. During exercise PH is considered a pulmonary artery pressure (PAP) greater than 30 mm Hg.

2 List conditions that produce pulmonary hypertension

PH is said to be idiopathic if it is found in the absence of secondary causes such as pulmonary disease (congenital or parenchymal), cardiac disease (e.g., shunts, mitral stenosis, left ventricular failure), thromboembolic or obliterative pulmonary vascular disease, connective tissue disease (especially the scleroderma family), exogenous vasoconstrictive substances (e.g., the appetite suppressant flufenamine), or portal hypertension. Although rare in the general population, at-risk populations include those with connective tissue disease and human immunodeficiency virus. Idiopathic PH was formally called primary PH, is a diagnosis of exclusion, affects one to two per million populations, sometimes has a familial link, and is found more in women than in men. PAPs tend to be higher in idiopathic PH when compared to secondary causes of PH.

3 Discuss the pathophysiology and natural history of pulmonary hypertension

Endothelial cell injury leads to imbalances between vasodilator and vasopressor molecules. Reductions in the endogenous vasodilators nitric oxide (NO) and prostacyclin (PGI2) are noted, whereas the vasoconstrictors thromboxane and endothelin are increased. But vasoconstriction appears to be only part of the answer because thrombosis, inflammation, free radical generation, and smooth muscle hyperplasia are also common features noted in PH. Indeed, vascular remodeling is a prominent feature of PH.

The pulmonary circulation has high flow and low resistance. Changes in CO, airway pressure, and gravity affect the pulmonary circulation more than the systemic circulation. The right ventricle is thin walled and accommodates changes in volume better than changes in pressure. To accommodate increases in flow such as during exercise, unopened vessels are recruited, patent vessels distended, and pulmonary vascular resistance (PVR) may decrease. Such normal adaptive mechanisms can accommodate threefold to fivefold increases in flow without significant increases in PAPs.

Early in the evolution of PH, the pressure overload results in hypertrophy of the right ventricle without significant changes in CO or RV filling pressures either at rest or during exercise. As the disease progresses, the vessel walls thicken and smooth muscle cells hypertrophy and increase in number. Vessels become less distensible, and the actual cross-sectional area of the pulmonary circulation decreases. Initially with exercise CO eventually declines despite modest increases in right ventricular (RV) end-diastolic pressures (RVEDP). Mechanisms for enhancing contractility are few for the right ventricle. In time, RV failure (RV ejection fraction below 45%) ensues, and the patient is symptomatic even at rest. RV myocardial blood flow becomes compromised, and tricuspid regurgitation develops secondary to right ventricle distention, further increasing RVEDP and worsening failure. In addition, left ventricular (LV) diastolic function may deteriorate, and LV filling may be compromised by excessive septal incursion into the left ventricle, with a resultant decrease in CO.

Without treatment PH is universally fatal, with a mean survival of 2.8 years. One-, 3, and 5-year survival rates are 68%, 48%, and 34%, respectively. The mortality rate during pregnancy is 30% to 50%, and most experts recommend early termination of pregnancy in these women should pregnancy occur.

4 What is the blood supply to the right ventricle?

It depends on whether the right or left coronary artery is dominant. Usually the right and left anterior descending coronary arteries supply the septum and portions of the RV free wall. Normally the RV free wall is perfused during systole and diastole. RV performance is directly related to systemic pressure during PH.

5 How is pulmonary vascular resistance calculated and what are normal values?

image

where LAP is left atrial pressure. CO is often substituted for pulmonary blood flow, although intracardiac and other shunts make these unequal. Normal PVR is 1.1 to 1.4 Woods units or about 90 to 120 dynes/sec/cm−5. (A Woods units is 240 dynes/sec/cm−5.) A PVR greater than 300 dynes/sec/cm−5 is indicative of PH.

6 What are some electrocardiographic and radiologic features of the disease?

The electrocardiogram commonly shows right axis deviation, RV hypertrophy (tall R waves in V1-V3), RV strain (T-wave inversion in V1-V3), S wave in V6, and enlarged P waves in II, III, and aVF. Although atrial fibrillation is rare, its presence should be viewed with concern because the contribution of atrial kick to ventricular filling is unavailable.

Radiologic abnormalities have been observed in over 90% of cases. Abnormalities on chest radiographs suggestive of PH include prominence of the right ventricle and the hilar pulmonary artery trunk, rapid tapering of vascular markings, a hyperlucent lung periphery, and decrease in the retrosternal air space.

7 What signs and symptoms suggest pulmonary hypertension?

Symptoms

image Dyspnea, initially on exertion (almost all patients with PH eventually become dyspneic)
image Angina (50% of patients)
image Fatigue (20% of patients)
image Weakness
image Syncope

Early signs

image Increase in the pulmonic component of S2
image Narrowly split S2
image Ventricular fourth heart sound
image Early diastolic murmur of tricuspid regurgitation
image RV heave

Late signs

image Jugular venous distention (giant systolic V waves)
image Peripheral edema
image Cyanosis
image RV S3 gallop
image Ascites and hepatomegaly

8 Discuss the observed abnormalities on pulmonary function testing

Pulmonary function tests demonstrate mild restrictive defects secondary to the effects of the noncompliant pulmonary vasculature. Arterial blood gases reveal varying degrees of hypoxemia.

9 What additional diagnostic tests are available for evaluating pulmonary hypertension? What results may be expected?

An echocardiogram is an excellent noninvasive method for following progression of the disease. Echocardiographic features of PH include enlarged RV dimension, small LV dimension, thickened interventricular septum, systolic mitral valve prolapse, and abnormal septal motion. Determination of PAPs and PVR by pulsed Doppler echocardiography correlates well with values determined at cardiac catheterization.

Perfusion lung scans are particularly important in patients in whom thromboembolic disease is suspected. Thromboembolic disease is remediable with thromboendarterectomy and anticoagulation, whereas primary PH (PPH) is not. Lung scan demonstrates segmental defects in patients with thromboemboli but not in patients with PPH. Pulmonary angiography is indicated in patients demonstrating segmental perfusion scan defects, but it should be undertaken cautiously in patients with PH. Although they are not contraindications, the associated risks of this procedure, including hypotension, worsening oxygenation, and cardiac arrest, should be weighed carefully against the potential benefit. In particular, patients with RV failure and increased RVEDP tolerate this procedure poorly.

Finally, cardiac catheterization is mandatory for confirming the diagnosis of PH and ruling out intracardiac shunts as a cause. In PH catheterization may prove to be technically demanding and require guidewire assistance. Detection of an elevated wedge pressure is an indication for left-sided heart catheterization to rule out mitral stenosis, congenital heart disease, and left-sided heart failure as causes of PH.

The degree to which PAP and PVR can be decreased acutely by the administrator of a vasodilator reflects the extent to which smooth muscle constriction is contributing to the hypertensive state and suggests that vasodilator therapy may be of some benefit.

10 Discuss standard therapies for patients suffering from pulmonary hypertension

Supplemental oxygen therapy is common, the goal being to maintain saturations above at least 90%. Diuretics may be prescribed to patients with RV failure, hepatic congestion, and peripheral edema, although excessive diuresis may decrease RV preload and CO. Anticoagulation is often instituted (usually oral warfarin, dosed to achieve an international normalized ratio of 1.5 to 2.0), because patients are at great risk for thromboembolic events (which may prove to be terminal). Cardiac glycosides are used when there are signs of RV failure and in patients who have developed atrial arrhythmias (e.g., multifocal atrial tachycardia, atrial fibrillation, or atrial flutter), although serum electrolytes must be closely followed when digoxin is administered to a patient on diuretics. Vasodilator therapy is discussed subsequently. Finally lung or heart-lung transplantation must be considered a contemporary yet expensive option in selected patients with PH.

11 What medications are available to treat increased pulmonary artery pressures?

Almost all classes of vasodilators have been investigated, including direct smooth muscle vasodilators, α-adrenergic antagonists, β-adrenergic agonists, calcium channel blockers, prostaglandins, phosphodiesterase inhibitors, and angiotensin-converting enzyme inhibitors. Intravenous medications available for intraoperative use and intensive care management include nitroglycerin, nitroprusside, prostaglandin E1 (alprostadil), PGI2, phentolamine, and isoproterenol. Calcium channel blockers are the current outpatient therapy of choice. High doses of nifedipine, diltiazem, or amlodipine have produced reductions in PA pressures and PVR and regression of RV hypertrophy. Verapamil is not used because of its negative inotropic effects. The phosphodiesterase III inhibitors milrinone and amrinone have successfully been used to treat postcardiac surgery PH. Adenosine may decrease PVR and has been used in conjunction with calcium channel blockers. However, because of its negative inotropic and chronotropic effects and its effects on sinus and atrioventricular nodal conduction, it should be used with caution in patients with ischemic heart disease. Finally, endothelin receptor antagonists are now available. They include bosentan, sitaxsentan, and ambrisentan.

12 A patient with a history of pulmonary hypertension presents for a surgical procedure. How should this patient be monitored intraoperatively?

In addition to the routine monitors, invasive monitoring is standard management for patients with PH. Intra-arterial pressure monitoring allows beat-to-beat assessment of blood pressure and frequent blood gas analysis. Central venous pressure (CVP) monitoring is inaccurate when there is tricuspid regurgitation or when RV compliance is decreased. A PA catheter allows direct monitoring of PAP and right atrial pressure and indirect assessment of LV volume and performance through measuring of pulmonary occlusion pressures. However, it should be recognized that patients with PH having PA catheterization are at increased risk for PA rupture.

Transesophageal echocardiography (TEE) is particularly useful in assessing volume status, LV and RV performance and valvular regurgitation, and early detection of segmental wall motion abnormalities secondary to myocardial ischemia. Because of the concerns for PA rupture, in skilled hands TEE may obviate the need for PA catheterization.

13 What intraoperative measures may decrease PH?

image As hypoxemia and hypercarbia increase PAPs, optimize the patient’s oxygenation and ventilation. In contrast to systemic vessels, pulmonary vessels constrict with hypoxia. Recruitment maneuvers may improve ventilation-perfusion matching, but avoid overinflation. High levels of positive end-expiratory pressure (PEEP) may narrow vessels to well-ventilated areas of the lung, decreasing PO2. Levels of PEEP greater than 15 cm H2O should be avoided.
image Assess myocardial performance; increasing PA pressures may be secondary to a failing left ventricle. If ischemia is associated with a decreasing CO, consider infusing nitroglycerin to improve coronary perfusion. Inotropic drugs such as dobutamine or dopamine may enhance contractility and improve CO.
image Assess volume status. Although the right ventricle is less preload responsive than the left ventricle, CVP values less than 10 mm Hg suggest the need for preload augmentation. Before surgery an endogenous volume loading test can be performed by raising the patient’s legs. Responders have an improvement in blood pressure with this maneuver and would be candidates for intraoperative fluid challenge. Nonresponders probably have RV failure, and fluid challenges may worsen this.
image Correct acidosis and ensure the patient is not becoming hypothermic. Both acid-base abnormalities and hypothermia may cause increased PA pressure. The effects of acidosis are worse in the presence of hypoxemia. Moderate hyperventilation (a PaCO2 of about 30 mm Hg) is suggested.
image Deepen the anesthetic. Catecholamine release will increase PA pressure.
image Consider the use of inotropes in the setting of RV failure. The phosphodiesterase III inhibitors milrinone and amrinone prevent the breakdown of cyclic guanosine monophosphate (cGMP) and increase LV contractility while dilating the pulmonary vasculature. Dobutamine is also an option.
image If systemic hypotension and coronary perfusion are problematic, vasoconstrictors may be superior to volume loading and inotropes. Because of the balance between α- and β-adrenergic effects, norepinephrine is the vasoconstrictor of choice. Norepinephrine should be administered carefully because it can increase PA pressure.
image Consider the use of direct-acting vasodilators. This will be discussed in further detail.

14 Discuss the effect of volatile anesthetics and nitrous (not nitric) oxide on the pulmonary circulation

When used as part of a maintenance anesthetic, isoflurane at 1 to 1.2 minimum alveolar concentration (MAC) levels has been demonstrated to lower PAP and PVR and improve CO in this setting. Its presumed mechanism is direct action on pulmonary vascular smooth muscle. Of the volatile anesthetics, isoflurane probably has the greatest effect on vascular smooth muscle. The suggested MAC levels maintain PaO2 as well, suggesting that hypoxic pulmonary vasoconstriction (HPV) is not inhibited at this depth of anesthesia. However, isoflurane and any other volatile anesthetic should be titrated carefully since impaired RV function is a risk.

Nitrous oxide can increase PVR and attenuate HPV; its use in PH is best avoided.

15 What are the effects of intravenous anesthetics on pulmonary artery pressure and hypoxic pulmonary vasoconstriction?

Propofol infusions have been shown to decrease PAP and PVR. Simultaneous reductions in mean arterial pressure also occur. Intravenous anesthetics have minimal effect on hypoxic pulmonary vasoconstriction and oxygenation. Opioids do not have a direct vasodilator effect but may attenuate the vasoconstrictor effect of noxious pain stimuli. In children with intracardiac shunts ketamine may prevent reversal of left-to-right shunts because it increases systemic vascular resistance to a greater extent than PVR.

16 Are regional anesthetics an option?

Epidural anesthesia has been used safely in patients with PH. Acute changes in systemic vascular resistance (SVR) associated with spinal anesthesia suggest that epidural anesthesia is preferred. Invasive monitoring is still suggested. Loss of cardioaccelerator fibers found from T1-T4 may result in undesirable bradycardia. Before the procedure the patient should be cautiously preload augmented, and medications to treat acute decreases in SVR or heart rate should be at hand.

17 Discuss the advantages and disadvantages of the intravenous nitrovasodilators

Because of their ready availability, titratability, and common use, intravenous nitrovasodilators are popular in the acute management of increased PAPs. Commonly used nitrovasodilators include nitroglycerin and sodium nitroprusside, and their mechanism of effect is release of NO. Nitroglycerin has the advantage of providing coronary vasodilation. Principally a venodilator, nitroglycerin may excessively decrease preload. Nitroglycerin infusion is started at about 1 mcg/kg/min and ordinarily produces a smooth reduction in vascular pressures. Above 3 mcg/kg/min, venodilation may become excessive, decreasing preload and requiring intravenous fluid augmentation.

Sodium nitroprusside (SNP) is an extremely potent, principally arterial vasodilator. Infusions begin about 0.5 to 1 mcg/kg/min and are carefully adjusted upward to effect. SNP is extremely effective at afterload reduction. Despite its potency and potential for creating excessive hypotension, SNP is safe for short-term use. Long-term use is associated with tachyphylaxis and the potential for cyanide toxicity.

Despite their effects of pulmonary vascular resistance, they are nonselective and also decrease systemic blood pressure and threaten myocardial ischemia, especially in the setting of a hypertrophied ventricle. Further, they nonselectively dilate pulmonary blood vessels, increase perfusion of underventilated alveoli, and increase ventilation-perfusion mismatch, resulting in hypoxemia.

18 Discuss the properties of nitric oxide (NO)

NO is a small molecule produced by vascular endothelium. Formed from the action of NO synthetase on arginine, NO crosses into vascular smooth muscle and stimulates guanylate cyclase, resulting in formation of 3″,5″-cGMP. Subsequently cGMP produces smooth muscle relaxation and vasodilation.

NO is administered by inhalation and crosses the alveolar membrane to the vascular endothelium, producing smooth muscle relaxation. But when it crosses into the circulation, it is rapidly bound to hemoglobin (with an affinity 1500 times greater than carbon monoxide) and deactivated; thus it has no systemic vasodilator effect. In addition, since it is only delivered to perfused alveoli, it may increase blood flow to ventilated alveoli. Dosage ranges can be quite wide, but 20 to 40 parts per million is not an atypical dose.

Deactivation on entering the circulation also limits the effectiveness of NO to the period in which it is administered by inhalation. Because storage in oxygen produces toxic higher oxides of nitrogen, especially nitrogen dioxide (NO2), NO is stored in nitrogen and blended with ventilator gases immediately before administration. The potential for increased methemoglobin levels during NO administration should also be recognized. It has proinflammatory and antiinflammatory effects, and the significance of this is not fully understood. It also impairs platelet aggregation and adhesion.

19 Discuss the therapeutic usefulness and limitations of nitric oxide in pulmonary hypertension

During evaluation of a patient diagnosed with PH, inhaled NO (and intravenous epoprostenol or adenosine) is used to assess vasodilator response. A positive response is a decrease in mean PAP of 10 mm Hg to a value of less than 40 mm Hg and a maintained or increased CO. Patients with such a response are candidates for long-term oral calcium channel blocker therapy.

Cardiopulmonary bypass (CPB) induces pulmonary endothelial injury, probably caused by ischemia-reperfusion injury, although other factors are probably involved as well. Levels of the vasoconstrictors thromboxane and endothelin are increased, whereas levels of the vasodilators PGI2 and endogenous NO are decreased. PH coming off of CPB is a predictor of increased mortality and postoperative myocardial infarction. NO has been tested for the treatment of PH after valve replacement, correction of congenital cardiac defects, and cardiac transplantation; improvements in outcome have not been uniformly beneficial. It has also been used as a bridge to lung transplantation.

There are numerous investigations concerning the efficacy of NO in improving oxygenation and PH in adult respiratory distress syndrome (ARDS). Factors that produce PH in ARDS include parenchymal destruction, microthrombi, airway collapse, pulmonary vasoconstriction, and adverse effects of PEEP. Although oxygenation improves, taking all comers, there are no randomized, controlled studies that show improved outcomes when ARDS is treated with NO.

Numerous neonatal conditions are associated with PH, including congenital diaphragmatic hernias, congenital heart disease, and persistent PH of the neonate. At this time, NO is only approved for use in infants with respiratory distress syndrome.

Portal pulmonary hypertension (PPHTN) is a complication of cirrhosis and portal hypertension and has previously been considered a contraindication to liver transplantation. Epoprostenol has demonstrated some benefit in PPHTN; the benefit of NO has been less convincing.

KEY POINTS: Pulmonary Hypertensionimage

1. Give fluid infusions.
2. Optimize oxygenation and ventilation.
3. Correct acid-base status.
4. Establish normothermia.
5. Decrease the autonomic stress response by deepening the anesthetic.
6. Administer vasodilator therapy.

20 What are prostanoids and their therapeutic counterparts?

Prostanoids are found in vascular endothelium and act via specific prostaglandin receptors to stimulate adenylate cyclase and increase cyclic adenosine monophosphate. Prostaglandins relax smooth muscle relaxation and platelet inhibition. The production of the naturally occurring PGI2 is decreased in PH.

When administered by continuous intravenous infusion, epoprostenol (PGI2) has a half-life of 2 to 3 minutes. Like the nitrovasodilators, intravenous prostanoids lack pulmonary selectivity, and systemic hypotension and decreased RV coronary perfusion are a risk.

Prostanoid analogs are now available that may be delivered by the inhaled route, subcutaneously, or orally. The inhaled route has some limitations because aerosolization is rather inefficient for delivery of the active agent to distal airways.

21 What is the value of adenosine?

Adenosine relaxes smooth muscle cells in the pulmonary circulation. It has a half-life of only 9 seconds; thus, when administered intravenously, its actions are relatively confined to the pulmonary circulation. Although it is a potent vasodilator, ventilation-perfusion mismatch increases.

22 What are phosphodiesterase-5 inhibitors?

PDE5 is an enzyme that degrades cGMP. The PDE-5 inhibitors are orally administered vasodilators that prevent the degradation of cGMP, potentiating the effect of NO. Currently available PDE5 inhibitors include zaprinast and sildenafil. They are synergistic when used in conjunction with NO or prostanoids.

SUGGESTED READINGS

1 Alam S., Palevsky H.I. Standard therapies for pulmonary arterial hypertension. Clin Chest Med. 2007;28:91-115.

2 Blaise G., Langleben D., Hubert B. Pulmonary arterial hypertension. Anesthesiology. 2003;99:1415-1432.

3 Fischer L.G., Van Aken H., Bürkle H. Management of pulmonary hypertension: physiological and pharmacological considerations for the anesthesiologist. Anesth Analg. 2003;96:1603-1616.

4 Granton J., Moric J. Pulmonary vasodilators—treating the right ventricle. Anesthesiology Clin. 2008;26:337-353.

5 McLaughlin V.V., Mcgoon M.D. Pulmonary arterial hypertension. Circulation. 2006;114:1417-1431.

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