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Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 8e

Chapter 58: Pulmonary Hypertension Michael E. Winters

INTRODUCTION AND EPIDEMIOLOGY

Normally, the pulmonary vascular system is a high-flow, low-resistance circuit, with a mean pulmonary

arterial pressure that constitutes approximately 15% to 20% of the systemic circulation.1 Normal pulmonaryarterial systolic pressures range from 15 to 30 mm Hg, whereas diastolic pulmonary arterial pressures range

from 4 to 12 mm Hg.1 Pulmonary hypertension is defined as a mean pulmonary arterial pressure >25 mm Hg

at rest or >30 mm Hg during exertion.1,2

Pulmonary hypertension is classified based on measurements of pulmonary capillary wedge pressure(PCWP) and pulmonary vascular resistance. Patients with pulmonary arterial hypertension have a mean

pulmonary arterial pressure >25 mm Hg, a pulmonary vascular resistance >240 dynes/s/cm5, and a PCWP <15

mm Hg.2 In contrast, patients with pulmonary hypertension caused by le� heart disease, the most common

cause of pulmonary hypertension, have a PCWP >15 mm Hg.2 Although echocardiography can estimatepulmonary arterial pressure in a patient with suspected pulmonary hypertension, definitive diagnosisrequires right heart catheterization.

The World Health Organization classifies pulmonary hypertension into five categories based on cause and

response to treatment (Table 58-1).1,3 Some patients have features of multiple categories, but the majority

have one predominant type of pulmonary hypertension.4 Accurate classification of pulmonary hypertensionis key to directing treatments, which vary among the categories. Pulmonary venous hypertension is the most

common cause of pulmonary hypertension, a�ecting almost 4 million patients in the United States.4 Incontrast, pulmonary arterial hypertension is the least common cause of pulmonary hypertension, with an

estimated prevalence of 15 patients per million.4,5 Pulmonary hypertension develops in up to 4% of patients

with chronic thromboembolic disease.4,6,7 Regardless of the cause, patients with pulmonary hypertension

have high morbidity and mortality rates,4,8 with a 5-year mortality rate for patients with idiopathic

pulmonary arterial hypertension exceeding 30%.5

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TABLE 58-1

World Health Organization Classification of PulmonaryHypertension

Group 1: Pulmonary Arterial Hypertension

Idiopathic

Genetic/heritable abnormalities

Drug or toxin induced

Associated with known risk factors for pulmonary arterial hypertension (human immunodeficiency virus, liver

disease, collagen vascular disorders)

Group 2: Pulmonary Venous Hypertension (le� heart disease)

Systolic or diastolic dysfunction

Mitral or aortic valve disease

Group 3: Chronic Hypoxemic Lung Disease

Obstructive lung disorders (chronic obstructive pulmonary disease)

Interstitial lung disease

Idiopathic pulmonary fibrosis

Collagen vascular disorders

Sleep-disordered breathing (obstructive sleep apnea)

Chronic exposure to high altitude

Group 4: Embolic Disease

Group 5: Miscellaneous

Lymphatic obstruction

Hematologic disorders: myeloproliferative disorders

Systemic disorders: sarcoidosis, neurofibromatosis

Metabolic disorders: glycogen storage disease, thyroid disorders

PATHOPHYSIOLOGY

The exact pathophysiology of all forms of pulmonary hypertension remains unknown. In pulmonary arterialhypertension, the initial abnormality is endothelial dysfunction, which results in an imbalance betweenendogenous vasodilators (e.g., prostacyclin) and vasoconstrictors (e.g., endothelin-1). The net e�ect isvasoconstriction and the formation of in situ thrombi. Additional pathologic processes include alterations inmicrovascular permeability, abnormal hypoxic vasoconstriction, microvascular thrombosis, and theformation of plexiform lesions, leading to vascular remodeling. Ultimately, these abnormalities result insustained elevations of pulmonary vascular resistance and impairment of pulmonary blood flow.

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With persistent elevations in pulmonary vascular resistance, the right ventricle (RV) dilates to maintain anadequate stroke volume. RV dilation increases the ventricular wall tension, increases oxygen consumption,and eventually decreases contractility. With progressive RV dilation, the intraventricular septum is displacedtoward the le� ventricle. This displacement inhibits le� ventricular filling and ultimately impairs cardiacoutput and systemic perfusion.

Perfusion of the right coronary artery (RCA) depends on the gradient between the aorta and RV. Normally,the RCA is perfused during both systole and diastole. In patients with advanced pulmonary hypertension,

RCA perfusion occurs almost exclusively during diastole.9,10 Decreased perfusion results in right ventricularischemia and further impairment of le� ventricular output. Eventually, this cycle results in right ventricularfailure and cardiovascular collapse.

CLINICAL FEATURES

The most common symptom of pulmonary hypertension is dyspnea, either at rest or with exertion, which is

present in over 50% of patients.1,11 Other symptoms include fatigue, chest pain, near syncope, syncope, and

exertional lightheadedness.3,11,12 Since these initial symptoms are nonspecific, it is not surprising thatdelays in diagnosis are common, with an average interval between symptom onset and diagnosis of

pulmonary hypertension of 2 years.13 As pulmonary arterial pressure increases, patients can develop earlysatiety, anorexia, orthopnea, paroxysmal nocturnal dyspnea, and peripheral edema.

The physical examination is o�en normal in the early stages of pulmonary hypertension.1 As pulmonaryhypertension worsens, findings of right ventricular failure emerge (e.g., a holosystolic tricuspid regurgitation

murmur, jugular venous distention, hepatomegaly, ascites, and lower extremity edema).1,4 Additionalfindings include an increased intensity of the pulmonary component of the second heart sound (P2), a

parasternal heave, and a subxiphoid thrust in patients with right ventricular hypertrophy.1,4

DIAGNOSTIC TESTING

ELECTROCARDIOGRAM

The most common ECG abnormality seen in pulmonary hypertension patients is right axis deviation.12

Additional findings associated with pulmonary hypertension include an R/S ratio >1 in lead V1, an R/S ratio

<1 in leads V5 and V6, a qR complex in lead V1, an S1Q3T3, right atrial enlargement in the inferior leads, and an

incomplete or complete right bundle branch block14 (Figure 58-1). These findings are neither sensitive norspecific for the identification of pulmonary hypertension.

FIGURE 58-1.

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ECG with findings predictive of pulmonary hypertension: S wave in V1 <2 mm, R/S ratio in V1 >1, R/S ratio in

V6 <1, and QRS axis >110 degrees.

The ECG may show signs of right ventricular ischemia or dysrhythmia. The most common dysrhythmias inpatients with pulmonary hypertension are atrial fibrillation, atrial flutter, and atrioventricular nodal

reentrant tachycardia.15,16 Of these, atrial fibrillation is associated with the highest mortality rate.15

LABORATORY TESTING

Routine laboratory testing (e.g., CBC, comprehensive metabolic panel) is o�en nonspecific in the initialevaluation of the pulmonary hypertension patient with dyspnea. B-type natriuretic peptide and N-terminalB-type natriuretic peptide are o�en elevated and correlate with outcomes in patients with pulmonary

hypertension but have limited impact in ED care.17,18,19 Elevations in troponin from myocardial ischemia or

a strain-induced leak can be seen and are associated with higher morbidity and mortality.20,21

IMAGING

Common chest radiographic abnormalities associated with pulmonary hypertension include enlargement of

the right atrium, RV, and hilar pulmonary arteries.12,22 Depending on the cause of the pulmonaryhypertension, additional radiographic findings might include pulmonary edema, hyperinflation, orinterstitial lung disease. In most patients presenting with dyspnea, a chest radiograph is obtained to identifyother causes of dyspnea, such as pneumonia or pneumothorax.

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Transthoracic echocardiography is the best initial diagnostic test to assess pulmonary hypertension in the

ED. It allows estimation of the pulmonary artery systolic pressure4 and detection of decreased RV function,right atrial hypertrophy, and right ventricular hypertrophy, each of which is indicative of more severe

disease.1 Additional echocardiographic findings in patients with severe pulmonary hypertension includele�ward deviation of the intraventricular septum and a right ventricle-to-le� ventricle end-diastolic diameter

>1 in the four-chamber view.1,23 Figures 58-2, 58-3, and 58-4 demonstrate typical echocardiographic findingsin patients with pulmonary hypertension.

FIGURE 58-2.

US of elevated right atrial pressures. Inferior vena cava (IVC) and hepatic vein dilation. [Image used withpermission of Haney Mallemat, MD, in the Department of Emergency Medicine at the University of MarylandSchool of Medicine.]

FIGURE 58-3.

Cardiac US, parasternal short-axis view of right and le� ventricles. Notice the flattening of theinterventricular septum occurring in systole, suggesting elevated right ventricular systolic pressures. This isalso known as a D-shaped septum. IVC = inferior vena cava. [Image used with permission of Haney Mallemat,MD, in the Department of Emergency Medicine at the University of Maryland School of Medicine.]

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FIGURE 58-4.

Apical four-chamber view of right and le� ventricles. The right ventricle is dilated with hypertrophy of theright ventricular trabeculae, indicating chronic right ventricular overload. The interventricular septum is alsoshi�ed toward the le� ventricle in systole, suggesting right ventricular pressure overload. IVC = inferior venacava. [Image used with permission of Haney Mallemat, MD, in the Department of Emergency Medicine at theUniversity of Maryland School of Medicine.]

Echocardiography can also detect precipitating factors for right ventricular failure, including pericardial

e�usion, regional wall motion abnormalities of the RV or le� ventricle, and acute valvular abnormalities.24

TREATMENT

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Abbreviations: RCA = right coronary artery; RV = right ventricle.

No consensus guidelines exist for the management of critically ill patients with pulmonary hypertension inthe ED. The mainstays of ED therapy include supplemental oxygen, optimizing intravascular volume,augmenting right ventricular function, maintaining coronary artery perfusion, and decreasing right

ventricular a�erload (Table 58-2).25

TABLE 58-2

Drugs for Pulmonary Hypertension

Condition Drug Comments

RV failure Dobutamine 2–10

micrograms/kg/min OR

Milrinone 0.375

micrograms/kg/min

Avoid >10 micrograms/kg/min

Higher doses can cause hypotension

RCA

perfusion

Norepinephrine 0.05–0.75

micrograms/kg/min

Avoid high doses of norepinephrine; avoid dopamine

and phenylephrine

RV

a�erload

Prostanoids Rarely initiated in ED

OXYGEN AND MECHANICAL VENTILATION

While the optimal oxygen saturation is unknown, consensus opinion is to titrate supplemental oxygen to

maintain a level >90%.25 Although intubation and mechanical ventilation are common ED therapies for thepatient with acute respiratory failure, be wary of the complications. In patients with severe pulmonaryhypertension, intubation and ventilation can cause rapid cardiovascular collapse due to increasedintrathoracic pressure from positive-pressure ventilation and e�ects of sedative medications on rightventricular function and systemic vascular resistance.

When mechanical ventilation is needed, set the ventilator to maintain low airway pressure,25 using lung-protective settings (i.e., a tidal volume of 6 mL/kg of ideal body weight and the lowest positive end-expiratorypressure to maintain the oxygen saturation above 90%). Monitor serial plateau pressure measurements andtarget pressures to <30 cm H2O. Adjust the respiratory rate to avoid hypercapnia, which can increase

pulmonary vascular resistance, pulmonary artery pressure, and RV strain.26

INTRAVASCULAR VOLUME

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Volume overload can cause RV dilation, displacing the intraventricular septum, impairing le� ventricular

output, and ultimately compromising tissue perfusion.3 For patients who are hypovolemic, give serialboluses of an isotonic crystalloid solution in 250- to 500-mL aliquots with close monitoring. As a result ofbaseline elevations in right-sided pressures, common methods used to monitor volume responsiveness, suchas absolute values of central venous pressure and respiratory variation of the inferior vena cava with US, areless reliable in the patient with pulmonary hypertension.

RIGHT VENTRICULAR FUNCTION

For RV failure, start an inotropic medication to augment function and improve cardiac output. Dobutamine is

preferred,25,27,28 starting at 2 micrograms/kg/min and titrated to 10 micrograms/kg/min. Avoid doses >10micrograms/kg/min, because large doses can increase pulmonary vascular resistance and cause

tachydysrhythmias and hypotension.29,30 For patients unable to tolerate dobutamine, milrinone is analternative. Milrinone is a phosphodiesterase-3 inhibitor and can indirectly augment right ventricular

function through a reduction in pulmonary vascular resistance.25 Start milrinone at 0.375micrograms/kg/min and titrate to a maximum of 0.75 micrograms/kg/min. Higher doses of milrinone cancause hypotension.

RIGHT CORONARY ARTERY PERFUSION

Adequate perfusion of the RCA is necessary to maintain right ventricular function and cardiac output. Tomaintain RCA blood flow, arterial pressure at the aortic root must be higher than the pulmonary arterypressure. For the hypotensive pulmonary hypertension patient, use a vasopressor to increase aortic rootpressure and maintain RCA perfusion. Although there are limited data regarding a singular superior agent,

norepinephrine is recommended.25 Norepinephrine improves cardiac output and is initiated at a dose of 0.05micrograms/kg/min. Avoid high doses of norepinephrine because it can increase pulmonary vascularresistance and impair right ventricular output. Avoid dopamine and phenylephrine because these drugs cancause tachydysrhythmias and can elevate pulmonary artery pressure and pulmonary vascular resistance.

RIGHT VENTRICULAR AFTERLOAD

Reducing right ventricular a�erload with pulmonary vasodilators is a critical component in the managementof stable patients with pulmonary hypertension. The most commonly used pulmonary vasodilators areprostanoids, endothelin receptor antagonists, and phosphodiesterase-5 (PDE-5) inhibitors. Thesemedications are used primarily in the treatment of patients with pulmonary arterial hypertension; they arerarely, if ever, administered in the ED, but understanding the therapeutic agents is important. Prostanoids(epoprostenol, treprostinil, and iloprost) are potent vasodilators and are the initial treatment of choice inpatients with pulmonary arterial hypertension and right ventricular failure. These medications have

antiplatelet and antiproliferative properties.1 Epoprostenol is the only therapy proven to improve survival.25

It has a half-life of just 2 to 5 minutes and must be given by continuous IV infusion.31,32 In contrast,treprostinil has a half-life of 4 to 5 hours and is approved for both IV and SC administration.

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1. 

For the acutely ill pulmonary hypertension patient receiving ongoing IV prostanoid, the first step is to confirmcatheter and pump function. If occlusion or malfunction is detected, consult with the primary provider. Bothepoprostenol and treprostinil can be administered by peripheral IV. Iloprost is given as an aerosol and is

usually reserved for patients unable to tolerate a parenteral prostanoid.25 Side e�ects of prostanoids include

headache, nausea, vomiting, flushing, diarrhea, and jaw pain.1

Endothelin receptor antagonists are administered orally and increase exercise capacity, improvehemodynamics, and can delay the time to clinical worsening in pulmonary hypertension

patients.1,33,34,35,36,37 Currently, bosentan and ambrisentan are the only available endothelin receptorantagonists, but neither drug has been evaluated in the acutely decompensating pulmonary hypertension

patient with right ventricular failure.25 Side e�ects of these medications include an elevation in liver

transaminase levels and a decrease in hemoglobin concentration.1

The PDE-5 inhibitors sildenafil and tadalafil are approved for use in patients with pulmonary hypertension.They are administered orally, seeking to improve hemodynamics and exercise capacity in patients with

pulmonary arterial hypertension.1,38,39,40,41,42,43 Like the endothelin receptor antagonists, they are notcurrently used in acutely ill pulmonary hypertension patients. Side e�ects of the PDE-5 inhibitors include

headache, flushing, dyspepsia, and hypotension when used concomitantly with nitrates.1

DISPOSITION AND FOLLOW-UP

When patients with pulmonary hypertension present to an ED, they are o�en critically ill, with signs andsymptoms of acute right heart failure. As a result, nearly all require admission, o�en to an intensive care orcoronary care unit with expertise in pulmonary hypertension. On rare occasions, a mildly symptomaticpatient may be discharged home a�er consultation, care plan development, and close follow-up with theprimary provider.

PRACTICE GUIDELINES

No consensus guidelines exist for the evaluation and management of critically ill ED patients with pulmonaryhypertension. Current recommendations are based on expert opinion.

Acknowledgment: The author gratefully acknowledges the contributions of David M. Cline and Alberto J.Machado to this chapter in the previous edition.

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