Pulmonary Vascular Disease - PDF Free Download

Cardiol Clin 22 (2004) 353–365 Acute pulmonary embolism Victor F. Tapson, MD Division of Pulmonary and Critical Care Me...

Author: Ori Ben-Yehuda | Michael H. Crawford

48 downloads 1318 Views 6MB Size Report

This content was uploaded by our users and we assume good faith they have the permission to share this book. If you own the copyright to this book and it is wrongfully on our website, we offer a simple DMCA procedure to remove your content from our site. Start by pressing the button below!

Report copyright / DMCA form

DOWNLOAD PDF

Cardiol Clin 22 (2004) 353–365

Acute pulmonary embolism Victor F. Tapson, MD Division of Pulmonary and Critical Care Medicine, 353 Bell Building, Duke University Medical Center, Durham, NC 27710, USA

Background and incidence

Pathophysiology

Pulmonary embolism (PE) occurs when venous thrombosis, usually from the deep veins of the proximal legs, travels to the lungs causing a potential spectrum of consequences, including dyspnea, chest pain, hypoxemia, and sometimes death. Deep venous thrombosis (DVT) and PE represent a continuum of the disease entity known as venous thromboembolism (VTE). PE probably accounts for 100,000 to 200,000 deaths per year in the United States [1,2]. Although some patients dying from acute PE have an underlying terminal illness, this disease entity seems to be responsible for death in a considerable number of patients with an otherwise good prognosis. Autopsy studies have repeatedly documented the high frequency with which PE has gone unsuspected and thus undetected [3]. VTE occurs worldwide and is usually, but not always, associated with speciﬁc risk factors [1,4–6]. A crucial point is that DVT and, therefore, PE are often preventable. Although other substances such as malignant cells, fat droplets, air bubbles, and carbon dioxide can embolize to the lung, this article focuses on VTE. Because of the lack of speciﬁc symptoms and signs, DVT and PE are frequently clinically unsuspected, leading to substantial diagnostic and therapeutic delays and resulting in considerable morbidity and mortality [1,2]. Furthermore, prophylaxis continues to be dramatically underused [4,7]. The incidence of VTE is high in hospitalized patients, and both surgical as well as medical patients are at risk.

One or more components of Virchow’s triad (stasis, hypercoagulability, and intimal injury), described more than 150 years ago, are present in nearly all patients [8]. The risk increases with age. Idiopathic VTE is well described and probably involves an underlying prothrombotic state that is present but awaits characterization. Deep vein thrombi frequently originate in the calf veins and propagate proximally before embolizing. Although emboli may occasionally originate directly from calf vein thrombi, more than 95% of thrombi that embolize to the lungs detach from a proximal deep vein of the lower extremities (including and above the popliteal veins). Thrombosis developing in the axillary-subclavian veins caused by the presence of a central venous catheter, particularly in patients with malignant disease and also in those with eﬀort-induced upper extremity thrombosis, may result in PE as well. The impact of a particular embolic event depends on the extent of reduction of the crosssectional area of the pulmonary arterial bed and on the presence or absence of underlying cardiopulmonary disease [9,10]. Hypoxemia stimulates sympathetic tone with resulting systemic vasoconstriction, increased venous return, and a rise in stroke volume. With massive emboli, cardiac output is diminished but may be sustained as the mean right atrial pressure increases. The increase in pulmonary vascular resistance impedes right ventricular outﬂow and thus reduces left ventricular preload. In the absence of underlying cardiopulmonary disease, occlusion of 25% to 30% of the vascular bed by emboli is associated with a rise in pulmonary artery pressure [10]. With further vascular obstruction, hypoxemia worsens, stimulating

Division of Pulmonary and Critical Care Medicine, Box 31175, Duke University Medical Center, Durham, NC 27710. E-mail address: [email protected]

0733-8651/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ccl.2004.04.002

354

V.F. Tapson / Cardiol Clin 22 (2004) 353–365

vasoconstriction and a further rise in pulmonary artery pressure. More than 50% obstruction of the pulmonary arterial bed is usually present before there is substantial elevation of the mean pulmonary artery pressure. When the extent of obstruction of the pulmonary circulation approaches 75%, the right ventricle must generate a systolic pressure in excess of 50 mm Hg and a mean pulmonary artery pressure greater than 40 mm Hg to preserve pulmonary perfusion. A normal right ventricle is rarely able to meet this demand and, hence, fails. Patients with underlying cardiopulmonary disease often experience a more substantial deterioration in cardiac output than normal individuals in the setting of massive PE. Supportive measures may sustain a patient with massive PE, but additional increments in embolic burden may be fatal.

Clinical manifestations Unfortunately, history and physical examination are notoriously insensitive and nonspeciﬁc for both DVT and PE [11–13]. Patients with lower-extremity venous thrombosis often do not exhibit erythema, warmth, pain, swelling, or tenderness. When these signs are present, they are nonspeciﬁc but may still merit further evaluation. Pain with dorsiﬂexion of the foot (Homans’ sign) may be present in the setting of DVT, but this ﬁnding is neither sensitive nor speciﬁc. The most common symptom of acute PE is dyspnea that is often sudden in onset. Pleuritic chest pain and hemoptysis occur more commonly with pulmonary infarction caused by smaller, peripheral emboli. Palpitations, cough, anxiety, and lightheadedness are among the nonspeciﬁc symptoms of acute PE but may result from a number of other entities, contributing to the diﬃculty in making the diagnosis. Syncope or sudden death may occur with massive PE. Pulmonary embolism should always be considered whenever unexplained dyspnea, syncope, hypotension, or hypoxemia is present [11–13]. Tachypnea and tachycardia are the most common signs of pulmonary embolism but are also nonspeciﬁc. Other physical ﬁndings include fever, wheezing, rales, a pleural rub, a loud pulmonic component of the second heart sound, a right-sided fourth heart sound, and a right ventricular lift. Dyspnea, tachypnea, and hypoxemia in patients with concomitant cardiopulmonary disease (such as congestive heart failure, pneumonia, or chronic obstructive pulmonary disease) may be caused

by the underlying disease or by superimposed acute PE. Symptoms and signs consistent with PE (Tables 1 and 2) should be particularly heeded in patients with risk factors for VTE such as concomitant malignancy, immobility, or the postoperative state. Diagnosis The diﬀerential diagnosis for acute DVT and for PE depends on the clinical presentation and the presence of concomitant disease. For example, when patients present with calf pain or swelling in the setting of risk factors for VTE, a diagnostic study should be pursued unless there is a clear, alternative explanation. For dyspnea or chest pain, the diﬀerential diagnosis includes a ﬂare of asthma or chronic obstructive lung disease, pneumothorax, pneumonia, anxiety with hyperventilation, heart failure, angina or myocardial infarction, musculoskeletal pain, rib fracture, pericarditis, pleuritis from collagen vascular disease, herpes zoster, intrathoracic cancer, and, occasionally, intra-abdominal processes such as acute cholecystitis. The presence of obvious risk factors for VTE, such as prolonged immobility [14], trauma [15–17], recent surgery [18], medical illness with reduced mobility [19], cancer [20,21], pregnancy [22], myocardial infarction [23], recent prolonged travel [24– 26], or previous thromboembolism in the setting of compatible symptoms and signs should prompt consideration of this entity. Acute PE can be superimposed upon another underlying cardiopulmonary disease, on which new or worsening symptoms are sometimes blamed. Table 1 Symptoms of acute pulmonary embolism

Symptom Dyspnea Pleuritic chest pain Cough Leg pain Hemoptysis Palpitations Wheezing Angina like pain

All Patients (n = 383)

Patients without Previous Cardiopulmonary Disease (n = 117)

78%

73%

59% 43% 27% 16% 13% 14%

66% 37% 26% 13% 10% 9%

6%

4%

Data from Refs. [12,13] and Stein PD, editor. Pulmonary embolism. Baltimore (MD): Williams and Wilkins; 1996.

V.F. Tapson / Cardiol Clin 22 (2004) 353–365 Table 2 Signs of acute pulmonary embolism

Tachypnea (20/min) Crackles Tachycardia (>100/min) Leg swelling Loud P2 DVT Wheezes Diaphoresis Temperature ($38.5() Pleural rub Fourth heart sound Third heart sound Cyanosis Homans’ sign Right ventricular lift

All Patients (n = 383)

Patients without Previous Cardiopulmonary Disease (n = 117)

73%

70%

55% 30%

51% 30%

31% 23% 15% 11% 10% 7%

28% 23% 11% 5% 11% 7%

4% –

3% 24%

5%

3%

3% 3% –

1% 4% 4%

DVT, deep venous thrombosis; P2, pulmonic component of second heart sound. Data from Refs. [12,13] and Stein PD, editor. Pulmonary embolism. Baltimore (MD): Williams and Wilkins; 1996.

Blood tests Hypoxemia is common in acute PE. Some individuals, particularly young patients without underlying lung disease, may have a normal arterial oxygen tension (PaO2) and even, rarely, a normal alveolar-arterial diﬀerence [11,13]. A sudden decrease in the PaO2 or in the oxygen saturation in a patient unable to communicate an accurate history (eg, a demented or mechanically ventilated patient) suggests the possibility of acute PE. The diagnostic utility of plasma measurements of circulating D-dimer (a speciﬁc derivative of cross-linked ﬁbrin) in patients with acute PE has been extensively evaluated [27–30]. A normal ELISA seems to be sensitive in excluding PE, particularly when the clinical suspicion is relatively low. A number of D-dimer assays are available, and their sensitivity and speciﬁcity vary [30]. A positive D-dimer test means that DVT or PE is possible, but it is by no means proof. Similarly, although a negative D-dimer may strongly suggest that VTE is absent, a high clinical suspicion should not be ignored.

355

Clinical probability scores based on simple clinical parameters have been used together with a negative D-dimer to help exclude PE. In a recent prospective clinical trial, the SimpliRed D-dimer (AGEN Biomedical Limited, Brisbane, Australia) test, a rapid red blood cell agglutination D-dimer assay, was used together with simple scoring parameters readily available in the emergency department [28]. Of the 437 patients with a negative D-dimer result and low clinical probability in this study, only one developed PE during followup (Table 3). Whether or not such scoring systems are used, D-dimer assays may prove increasingly useful in excluding acute DVT and PE, particularly when low clinical suspicion supports its absence. Both cardiac troponin T and troponin I levels have been found to be elevated in acute PE [32,33]. This enzyme is speciﬁc for cardiac myocyte damage. The right ventricle seems to be the source of the enzyme elevation in acute PE and, in particular, in more massive embolism in which myocyte injury caused by right ventricular strain might be expected. Troponin levels cannot, however, be used like D-dimer testing; that is, when clinical suspicion is relatively low, they are not sensitive enough to rule out PE without additional diagnostic testing. Electrocardiography Electrocardiographic ﬁndings, which are present in most patients with acute PE, are nonspeciﬁc, but these abnormalities, including ST-segment abnormalities, T-wave changes, and left or right axis deviation, are common. Only one third of patients with massive or submassive emboli have manifestations of acute cor pulmonale such as the S1 Q3 T3 pattern, right bundle branch block, P-wave pulmonale, or right axis deviation. The usefulness of electrocardiography in suspected acute PE lies in its ability to establish or exclude alternative diagnoses such as acute myocardial infarction [13]. Chest radiography The chest radiograph is often abnormal in patients with acute PE, but, as with electrocardiography, it is nearly always nonspeciﬁc. Common radiographic ﬁndings include atelectasis, pleural eﬀusion, pulmonary inﬁltrates, and mild elevation of a hemidiaphragm [13]. Classic ﬁndings of pulmonary infarction such as Hampton’s hump or decreased vascularity (Westermark’s sign) are

356

V.F. Tapson / Cardiol Clin 22 (2004) 353–365

Table 3 Determining pretest probability of acute pulmonary embolism using point system and D-dimer result Variable DVT symptoms/signs PE as or more likelya HR >100 beats/min Immobilization/surgeryb Previous DVT or PE Hemoptysis Malignancy Total score <2.0 2.0 to 6.0 >6.0

Points 3.0 3.0 1.5 1.5 1.5 1.0 1.0 Pretest Probabilityc Low Moderate High

DVT, deep venous thrombosis; HR, heart rate; PE, pulmonary embolism. a PE is as likely or more likely than an alternative diagnosis. Physicians were told to use clinical information along with chest radiography, electrocardiography, and laboratory tests. b If within previous 4 weeks. c Of the 437 patients with a negative D-dimer result and low clinical probability, only one developed PE during follow-up; thus, the negative predictive value for the combined strategy of using the clinical model with D-dimer testing in these patients was 99.5%. Data from Ref [28].

suggestive of the diagnosis but are infrequent. A normal chest radiograph in the setting of severe dyspnea and hypoxemia without evidence of bronchospasm or anatomic cardiac shunt is strongly suggestive of PE. Pulmonary embolism frequently coexists with underlying heart or lung disease. Symptoms, signs, radiographic ﬁndings, electrocardiography, and the plasma D-dimer measurement cannot be considered diagnostic of PE. Similarly, symptoms, signs, and blood studies cannot prove the presence of DVT. When these entities are suspected, further evaluation with noninvasive or invasive testing is necessary. Deep venous thrombosis: the radiographic approach Venography has been the time-honored standard for the diagnosis of acute DVT. With the advent of ultrasound, a diagnostic test that is more than 90% sensitive in the setting of symptomatic DVT, venography is rarely used [34]. Similarly, another sensitive test, impedance plethysmography, is almost never used. MRI has proven extremely sensitive for both acute and chronic DVT [34–36], although it is generally not necessary. It is reasonable to consider MRI in the setting of suspected DVT when ultrasound cannot

be eﬀectively used. A major limitation of ultrasound is its reduced sensitivity in the setting of asymptomatic DVT. Thus, ultrasound is not generally used as a screening test. Pulmonary embolism: the radiographic approach Ventilation-perfusion scanning Historically, the ventilation-perfusion (VQ) scan was the most commonly used diagnostic test when PE was suspected. During the past decade, spiral (helical) CT scanning has essentially replaced it at most centers. A normal perfusion scan rules out the diagnosis with a high enough degree of certainty that further diagnostic evaluation is almost never necessary [37]. Matching areas of decreased ventilation and perfusion in the presence of a normal chest radiograph generally represent a process other than PE. Nondiagnostic scans of low or intermediate probability are commonly found with PE, however, and in such situations further evaluation with pulmonary arteriography is often appropriate. In the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED), when the clinical suspicion was considered very high PE was present in 96% of patients with high-probability scans, in 66% of patients with intermediate scans, and in 40% of patients with low-probability scans [12]. If the clinical setting suggests the diagnosis, the possibility of PE should be rigorously pursued even when the lung scan shows low or intermediate probability. Stable patients with suspected acute PE, nondiagnostic lung scans, and adequate cardiopulmonary reserve (absence of hypotension or severe hypoxemia) may undergo noninvasive lower extremity testing in an attempt to diagnose DVT [38]. A positive compression ultrasound may present the opportunity to treat without further testing. If the ultrasound is negative, pulmonary angiography is an appropriate option. Serial noninvasive lower extremity testing in the setting of suspected PE should be performed only in centers where followup is guaranteed and validated protocols are used. MRI of the lower extremities may also be useful after a nondiagnostic lung scan if the medical facility has experience with this technique. Pulmonary arteriography Pulmonary arteriography remains the accepted standard technique for the diagnosis of acute PE. It is an extremely sensitive, speciﬁc, and safe test [39]. Complications of pulmonary arteriography in 1111 patients suspected of having PE in the

V.F. Tapson / Cardiol Clin 22 (2004) 353–365

357

PIOPED included death in 0.5% and major nonfatal complications in 1% [12]. Pulmonary arteriography is used when PE must be diagnosed or excluded and preliminary testing has been nondiagnostic. In some centers, pulmonary arteriography can be performed at the bedside using a pulmonary artery catheter and ﬂuoroscopic guidance. It is being used less frequently because CT has increasingly been employed.

MRI

Spiral (helical) CT

Echocardiography in acute pulmonary embolism

Spiral CT scanning can be used for diagnosing both acute and chronic PE and is replacing VQ at many centers. Some clinical trials have suggested good sensitivity and speciﬁcity, but others reports have been less favorable. Retrospective reconstructions can be performed. A contrast bolus is required for imaging of the pulmonary vasculature. In at least one clinical trial, spiral CT was associated with greater than 95% sensitivity and speciﬁcity [40]. More recent and larger trials have suggested a lower sensitivity [41–48]. A large, prospective Swiss study revealed a sensitivity of 70%, suggesting that a negative CT scan may not absolutely rule out smaller emboli [49]. Data from the large, multicenter PIOPED II trial in the United States and Canada comparing CT (of the chest and legs) and VQ scanning is currently being analyzed. Spiral CT has the greatest sensitivity for emboli in the main, lobar, or segmental pulmonary arteries. The speciﬁcity for clot in these vessels is excellent. For subsegmental emboli, spiral CT seems to be less accurate, although the importance of emboli of this size has been questioned. The outcome of selected patients with a negative CT scan in the setting of suspected PE seems to be good in trials published thus far [50]. The use of thinner sections and techniques such as multiplanar three-dimensional reformation may enhance the usefulness of spiral CT for diagnosing PE. An advantage of spiral CT over VQ scanning and arteriography is the ability to deﬁne nonvascular structures such as lymphadenopathy, lung tumors, emphysema, and other parenchymal abnormalities as well as pleural and pericardial disease [51]. Another advantage of spiral CT over other diagnostic methods is the rapidity with which a study can be performed. Potential disadvantages of CT are that it is not portable at present and, because intravenous contrast is necessary, patients with signiﬁcant renal insuﬃciency cannot be scanned without risk of renal failure.

Echocardiography, which can often be obtained more rapidly than either lung scanning or pulmonary arteriography, may reveal ﬁndings that strongly support hemodynamically signiﬁcant pulmonary embolism [53]. Imaging or Doppler abnormalities of right ventricular size or function may suggest the diagnosis. Unfortunately, because these patients often have underlying cardiopulmonary disease such as chronic obstructive lung disease, neither right ventricular dilation nor hypokinesis can be used reliably even as indirect evidence of PE. In patients with documented acute PE, echocardiographic evidence of right ventricular dysfunction has been suggested as a means by which to determine the need for thrombolytic therapy [54]. Such cases need to be considered individually, and severe right ventricular dysfunction should lower the threshold for thrombolytic therapy once contraindications have been considered. Transesophageal echocardiography has also been evaluated in the setting of acute PE, and although it is less convenient, it may prove to have advantages over the transthoracic approach. (The role of echocardiography in acute and chronic pulmonary embolism is further discussed by Daniels et al in this issue). Intravascular ultrasound imaging has been shown in both experimental and clinical settings to image large emboli adequately and may be performed at the bedside [55]. Published guidelines suggest that clinicians be aﬀorded a certain degree of ﬂexibility in the diagnostic approach to suspected acute PE [56].

MRI has been used to evaluate clinically suspected PE, but at present the main advantage of MRI in this disease process is the excellent sensitivity and speciﬁcity for the diagnosis of DVT [41,52]. Disadvantages include the potential diﬃculty in transporting and performing the technique in critically ill patients. Additional prospective investigations will determine the role of this modality in the evaluation of VTE.

Treatment Options for treatment of acute DVT and PE include anticoagulation with low-molecular-weight heparin (LMWH) (Box 1) or standard heparin, thrombolytic therapy, and inferior vena cava ﬁlter placement. Massive PE is occasionally treated

358

V.F. Tapson / Cardiol Clin 22 (2004) 353–365

Box 1. Initiation of LMWH for therapy of acute DVT or PE Determine appropriateness of outpatient therapya Begin subcutaneous administration of LMWHb. Determine whether monitoring is needed (in patients with extremes of weight, renal insufficiency, or pregnancy). Administer warfarin from day 1 at an initial dose of 5 to 10 mg, adjusted according to INR. Check platelet count between days 3 and 5 for heparin-induced thrombocytopenia. Stop LMWH after 5 or more days of combined therapy and when INR is 2.0 or more for 2 consecutive days. Anticoagulate with warfarin for 3 months or longer (goal, INR 2.0–3.0)c. DVT, deep venous thrombosis; LMWH, low-molecular-weight heparin; INR, international normalized ratio; PE, pulmonary embolism. a Potential outpatients should be medically stable without severely symptomatic DVT. They should be compliant, capable of self-administration (or have a family member or visiting nurse for administration), and at low risk of bleeding; reimbursement should be addressed. b Enoxaparin (Lovenox) and tinzaparin (Innohep) are the two LMWHs that are approved by the Food And Drug Administration (FDA) for treatment of VTE. Although LMWH preparations are sometimes used for patients presenting with PE in the United States, and although clinical trials support this use, the FDA approvals read ‘‘established DVT with or without PE.’’ c The duration of warfarin therapy should be at least 6 to 12 months in patients with idiopathic venous thromboembolism.

with surgical embolectomy. Each approach has speciﬁc indications as well as advantages and disadvantages. Heparin and low-molecular-weight heparin The primary anticoagulants used to treat acute DVT or PE are unfractionated heparin and LMWH. These substances exert a prompt antithrombotic eﬀect by accelerating the action of antithrombin III, thus preventing thrombus extension. Although they do not directly dissolve thrombus or emboli, they allow the ﬁbrinolytic system to proceed unopposed and more readily reduce the size of the thromboembolic burden. Although thrombus growth can be prevented, early recurrence can sometimes develop even in the setting of therapeutic anticoagulation. LMWH preparations have substantial advantages over unfractionated heparin [57,58]. Because of these advantages, use of unfractionated heparin is becoming less common. When DVT or PE is diagnosed or strongly suspected, anticoagulation should be immediately instituted unless contraindications are present. Conﬁrmatory diagnostic testing should be arranged as soon as possible. When treatment with standard, unfractionated, intravenous heparin is initiated, the activated partial thromboplastin time

(aPTT) should be followed at 6-hour intervals until it is consistently in the therapeutic range of 1.5 to 2.0 times control values. This range corresponds to a heparin level of 0.2 to 0.4 U/mL as measured by protamine sulfate titration. Achieving a therapeutic aPTT within 24 hours after the onset of treatment of PE has been shown to reduce the recurrence rate, and it has become evident that the traditional heparin regimen consisting of a 5000-U bolus and 1000 U/h is inadequate in many patients. Heparin is administered as an intravenous bolus of 5000 U followed by a maintenance dose of at least 30,000 to 40,000 U/24 hours by continuous infusion [59]. The lower dose is administered if the patient is considered at high risk for bleeding. This aggressive approach decreases the risk of subtherapeutic anticoagulation. It is possible that early initiation of warfarin without heparin or LMWH may intensify hypercoagulability and increase the clot burden because of the short-half life of anticoagulation factors (factors C and S) that are also inhibited by warfarin. Factor VII is the primary clotting factor aﬀecting the prothrombin time and has a half-life of about 6 hours. Deﬁnitive anticoagulation requires the depletion of factor II (thrombin), which takes approximately 5 days. Thus, treatment with intravenous heparin or LMWH for at least 5 days is generally recommended. Heparin should be main-

V.F. Tapson / Cardiol Clin 22 (2004) 353–365

tained at a therapeutic level until two consecutive therapeutic international normalized ratio (INR) values of 2.0 to 3.0 have been documented at least 24 hours apart. The LMWH preparations have numerous advantages over unfractionated heparin and have dramatically changed treatment of thromboembolic disease. Among the diﬀerences between these two substances are the greater bioavailability of the LMWHs and more predictable dosing [57,58]. LMWHs can be subcutaneously administered once or twice daily even at therapeutic doses and do not require monitoring of the aPTT. Intravenous LMWH is not required in VTE. In addition, LMWHs have a more profound eﬀect in inhibiting clotting factor Xa relative to thrombin. The reduced frequency of heparin-induced thrombocytopenia with LMWH relative to unfractionated heparin is a compelling reason to use LMWH instead of unfractionated heparin whenever possible. Because of their eﬃcacy, safety, and convenience compared with standard heparin, these drugs are replacing standard heparin in many settings. A number of clinical trials and meta-analyses have strongly suggested the eﬃcacy and safety of LMWH for treatment of established acute proximal DVT using recurrent symptomatic VTE as the primary outcome measure [60–65]. The incidence of DVT and recurrent bleeding in these trials indicates that LMWH preparations are at least as eﬀective and as safe as unfractionated heparin. Meta-analytic data suggest that in the treatment of established proximal DVT the use of LMWH reduces bleeding rates and mortality compared with unfractionated heparin [65]. Monitoring anti-factor Xa levels seems reasonable in certain settings such as in morbidly obese patients, very small patients (<40 kg), pregnant patients, and patients with renal insuﬃciency. Because these drugs are renally metabolized, monitoring is important, particularly when the creatinine clearance is less than 30 mL/min. With severe renal insuﬃciency, standard heparin should be considered. There is not clear agreement on a weight limit above which LMWH should not be used, but some believe that an upper limit of approximately 120 to 150 kg is reasonable, with intravenous standard heparin being used in larger patients. It is unnecessary to monitor anti-factor Xa levels in other patients. Two pivotal trials published in the same issue of The New England Journal of Medicine in 1996 emphasized that therapy with LMWH could be

359

safely initiated at home or continued at home after a brief hospitalization [66,67]. In the United States, at the present time, two LMWH preparations (enoxaparin and tinzaparin) are approved by the Food and Drug Administration (FDA) for treating patients presenting with DVT with or without acute PE. The most widely used LMWH, enoxaparin, is approved for both inpatient and outpatient use at a dose of 1 mg/kg subcutaneously every 12 hours or at 1.5 mg/kg once daily for inpatient use. These regimens were proven eﬀective in a large study of inpatients in which both doses proved as eﬀective and as safe as unfractionated heparin. There is also experience with LMWH for treatment of patients presenting with PE [61]. Finally, a novel synthetic pentasaccharide anticoagulant, fondaparinux, has been studied in patients with acute DVT and PE and has proven eﬀective for these indications [68]. Although this drug is approved for prophylaxis in speciﬁc orthopedic populations, it is not approved by the FDA for therapy of acute VTE in the United States at the present time. It should be noted that the prophylactic doses of these agents diﬀer from the doses used for treating active disease. The characteristics of LMWHs compared with standard unfractionated heparin are shown in Table 4. Documented proximal DVT or PE should be treated for 3 to 6 months. Treatment over a more extended interval is appropriate when signiﬁcant risk factors persist, when thromboembolism is idiopathic, or when previous episodes of VTE have been documented.

Direct thrombin inhibitors Newer antithrombotic agents are being investigated. Whereas heparin and LMWH work indirectly, requiring antithrombin III as a cofactor, hirudin is a direct thrombin inhibitor that has several advantages over heparin, including eﬃcacy against ﬁbrin clot-bound thrombin. This drug, derived from the saliva of the medicinal leach (Hirudo medicinalis), does not require cofactors and is not inactivated by platelet factor 4 or plasma proteins. As with heparin, these direct thrombin inhibitors have narrow therapeutic indices. Currently, ximelagatran, an oral direct thrombin inhibitor, is being studied extensively and can simplify the acute as well as chronic treatment of VTE. It has proven eﬀective for treatment of VTE compared with placebo after extended warfarin therapy [69].

360

V.F. Tapson / Cardiol Clin 22 (2004) 353–365

Table 4 A comparison of LMWH with unfractionated heparin Characteristic Mean molecular weight Protein binding Anti-Xa activity Anti-Ila activity Administration (treatment) Administration (prophylaxis) Monitoring during treatment Outpatient therapy Incidence of HIT Reversibility with protamine

UFH

LMWH

12,000–15,000 substantial substantial substantial

4,000–6,000 minimala substantial minimal

intravenous

subcutaneous

subcutaneous aPTT every 6 hours diﬃcult 3% to 5%

subcutaneous none in most settingsb simpliﬁed <1%

complete

partial

PTT, activated partial thromboplastin time; HIT, heparin-induced thrombocytopenia; LMWH, lowmolecular-weight heparin; UFH, unfractionated heparin. a This implies signiﬁcantly superior bioavailability of LMWH relative to UFH. b LMWH requires monitoring in renal insuﬃciency (creatinine clearance <30 mL/min), signiﬁcant obesity (>150 kg), very small patients (<40 kg), and pregnant patients. Anti-Xa levels are followed, not the activated partial thromboplastin time.

Studies have been completed and are pending publication regarding the successful use of this drug compared with LMWH and warfarin in acute VTE [70]. Although ximelagatran is associated with transient elevation in hepatic transaminases between approximately 8 and 12 weeks, this elevation is generally transient and reversible even with continued exposure to the drug. Monitoring of liver function will probably be recommended, however, at least temporarily. The oral delivery, rapid onset, lack of signiﬁcant drug and food interactions, and lack of need for INR monitoring are among the advantages over warfarin. Bleeding is the major complication of anticoagulation therapy. The rates of major bleeding in recent trials using heparin administered by continuous infusion or high-dose subcutaneous injection are less than 5%. Heparin-induced thrombocytopenia (deﬁned as a platelet count drops to less than 100,000 to 150,000 mm3) typically develops 5 or more days after the initiation of heparin therapy and occurs in about 5% of patients [71]. The syndrome is caused by heparin-dependent IgG antibodies that activate platelets through their Fc receptors. If a patient is treated with heparin, and the platelet count pro-

gressively decreases to 100,000/mm3 or less, heparin should be discontinued. The formation of heparin-dependent IgG antibodies and the risk of thrombocytopenia are lower with LMWH than with standard heparin [71]. Both argatroban and lepirudin have been approved by the FDA for use in the setting of VTE with heparin-induced thrombocytopenia. The halflife of argatroban is 45 minutes, but it is prolonged in patients with hepatic dysfunction. Lepirudin is excreted by the kidneys, so the dosage must be reduced in patients with renal insuﬃciency. This drug has a short circulating half-life of 1.3 hours in patients with normal renal function, but the half-life may be as long as 2 days in patients with advanced renal failure. Although there is no antidote for lepirudin at present, the short half-life in patients with normal renal function allows rapid correction of prolonged aPTTs. A detailed discussion of heparin-induced thrombocytopenia is beyond the scope of this article. Bleeding related to warfarin therapy increases with intensity and duration of therapy. Warfarininduced skin necrosis is a rare but serious complication mandating immediate cessation of the drug. It is related, at least in some patients, to protein C or S deﬁciency. Warfarin crosses the placenta and may cause fetal malformations if used during pregnancy. Vena cava interruption When anticoagulation is contraindicated, a ﬁlter can be placed in the inferior vena cava to prevent lower-extremity thrombi from embolizing to the lungs. The primary indications for ﬁlter placement are contraindications to anticoagulation, recurrent embolism while receiving adequate therapy, and signiﬁcant bleeding complications during anticoagulation [72]. Filters are sometimes placed in the setting of massive PE when it is believed that any further emboli might be lethal, particularly if thrombolytic therapy is contraindicated. A number of ﬁlter designs exist but the Greenﬁeld ﬁlter has been most widely used. Filters can be inserted through the jugular or femoral vein. These devices are eﬀective, and complications, including insertion-related problems and migration, are unusual. More recently, temporary ﬁlters have been placed in patients in whom the risk of bleeding seems short term. Most of these devices can be removed up to 2 weeks later, and some may remain in place even longer with subsequent removal.

V.F. Tapson / Cardiol Clin 22 (2004) 353–365

Thrombolytic therapy Thrombolytic agents activate plasminogen to form plasmin that then results in ﬁbrinolysis as well as ﬁbrinogenolysis. These agents can dramatically accelerate clot lysis in acute PE (and DVT), and such an approach was ﬁrst documented more than several decades ago. Clinical trials have culminated in the approval of streptokinase, urokinase, and recombinant tissue-type plasminogen activator for the treatment of massive PE [73,74]. Although tenecteplase has been studied extensively in acute myocardial infarction and would be expected to be eﬀective in VTE, far fewer data are available for this agent. The speciﬁc FDA-approved regimens are shown in Box 2. For the past several decades the clearly accepted recommendation for thrombolytic therapy has been PE with hemodynamic instability (hypotension). Thrombolytic therapy should also be considered in patients with severely compromised oxygenation. Although thrombolytic therapy may result in rapid improvement of right ventricular function in patients with acute PE, there has been controversy as to whether patients with echocardiographic right ventricular dysfunction but without hypotension should receive this treatment. Several large studies have suggested that thrombolytic therapy should be considered in such patients, and a recent clinical trial indicated a less-frequent need for escalation of treatment when thrombolytic therapy was used in the setting of PE with right ventricular dysfunction [75]. The method of delivery of thrombolytic agents has also been investigated. Although standard- or low-dose intrapulmonary arterial thrombolytic infusions have been used to deliver a high concentration of drug in close proximity to the clot, intravenous therapy seems to be adequate in most cases [76]. More direct techniques, such as catheter-directed administration of intraembolic

361

thrombolytic therapy, have been used in small clinical studies, but the data are inadequate to formulate recommendations [77,78]. The use of thrombolytic therapy in patients with proximal occlusive DVT associated with signiﬁcant swelling and symptoms is increasing. Catheter-directed techniques are often employed [79]. In DVT, such aggressive therapy with thrombolytics may reduce the frequency of postphlebitic syndrome. Hemorrhage is the primary adverse eﬀect associated with thrombolytic therapy [80,81]. Both lysis of hemostatic ﬁbrin plugs and ﬁbrinogenolysis can lead to bleeding complications, which commonly occur at sites of invasive procedures such as pulmonary arteriography or arterial line placement. Invasive procedures should be minimized as much as possible. The most devastating complication associated with thrombolytic therapy is the development of intracranial hemorrhage, which occurs in less than 1% of patients. Retroperitoneal hemorrhage may result from a vascular puncture above the inguinal ligament and may be life threatening. The primary contraindications to thrombolytic therapy include active bleeding, surgery within the previous 1 to 2 weeks (depending on the speciﬁc procedure), intracranial pathology, or previous intracranial surgery. When patients seem to be at extraordinary risk of rapid death from PE, clinical judgment should be individualized with regard to contraindications. Management of unstable hemodynamics in massive pulmonary embolism Massive PE should always be suspected in the setting of the sudden onset of hypotension or extreme hypoxemia. The presence of electromechanical dissociation or sudden cardiac arrest should always make massive embolism a consideration. Once massive PE associated with

Box 2. Thrombolytic therapy for acute pulmonary embolism: approved regimens Streptokinase: 250,000 U intravenously (loading dose over 30 minutes); then 100,000 U/h for 24 hoursa Urokinase: 2000 U/lb intravenously (loading dose over 10 minutes); then 2000 U/pound/h for 12 to 24 hours Tissue-type plasminogen activator: 100 mg intravenously over 2 hours a Streptokinase administered over 24 to 72 hours at this loading dose and rate has also been approved for use in patients with extensive DVT.

362

V.F. Tapson / Cardiol Clin 22 (2004) 353–365

hypotension or severe hypoxemia is suspected, supportive vasoactive treatment is immediately initiated. Intravenous saline should be infused rapidly but cautiously, because right ventricular function is often markedly compromised. Dopamine or norepinephrine seem to be the favored choices of vasoactive therapy in massive PE and should be administered if the blood pressure is not rapidly restored [82]. Because death in this setting results from right ventricular failure, some have recommended dobutamine as a means to augment right ventricular output [83]. A vasopressor such as norepinephrine combined with dobutamine might oﬀer optimal results, and further exploration of such combined therapy would prove enlightening. Oxygen therapy is administered, and thrombolytic therapy is considered, as described previously. Pulmonary embolectomy may be appropriate in patients with massive embolism who cannot receive thrombolytic therapy. Prognosis The International Cooperative Pulmonary Embolism Registry included 2454 consecutive patients with a diagnosis of PE, and PE was the principal cause of death [84]. The 3-month mortality was 17.5%. In the PIOPED, the mortality rate was approximately 15%, but only 10% of deaths during the ﬁrst year of follow-up were attributed to PE [12]. Mean 1-month mortality rates of treated and untreated PE have been estimated at 8% and 30%, respectively. Although a small percentage of patients with acute PE ultimately develop chronic dyspnea and hypoxemia because of chronic thromboembolic pulmonary hypertension, most patients who survive the acute episode have no long-term pulmonary sequelae. Chronic leg pain and swelling from DVT (postphlebitic syndrome) may result in signiﬁcant morbidity, however. Prevention Measures to prevent VTE seem to be grossly underused [4,7]. A substantial reduction in the incidence of DVT can be achieved when patients at risk receive appropriate prophylaxis. For example, the risk of DVT after total hip or knee replacement is 50% or more without prophylaxis. The superiority of LMWH over unfractionated heparin has been demonstrated in these settings, and extending the duration of prophylaxis to approximately 1 month after surgery further re-

duces the DVT rate in total hip replacement [85,86]. Unfractionated heparin is not recommended in total joint replacement. In hospitalized general medical patients, anticoagulant prophylaxis should always be strongly considered because the rate of DVT, based upon a venographic endpoint, is as high as 15% in patients receiving placebo [31]. The rate of DVT, including proximal DVT, is statistically signiﬁcantly lower when enoxaparin is administered compared with placebo [31]. Either LMWH (enoxaparin, 40 mg, subcutaneously once daily) or subcutaneous heparin (5000 U every 8 hours) seems to be adequate for medical patient prophylaxis [87,88]. Although 5000 U of heparin every 12 hours has been commonly used, fewer data support this preventive regimen in medical patients. Intermittent pneumatic compression devices should be used when pharmacologic prophylaxis is contraindicated. Both methods combined are reasonable in patients deemed to be at exceptionally high risk, but an additional reduction in risk in such patients has not been well substantiated. Each hospitalized patient should be assessed for the need for such prophylactic measures, and all hospitals should strongly consider formulating written guidelines for each particular clinical setting, based upon the available medical literature [89]. References [1] Anderson FA, Wheeler HB. Venous thromboembolism: risk factors and prophylaxis. Clin Chest Med 1995;16:235–51. [2] Dalen JE, Alpert JS. Natural history of pulmonary embolism. Prog Cardiovasc Dis 1975;17:257–70. [3] Lindblad B, Eriksson A, Bergquist D. Autopsyveriﬁed pulmonary embolism in a surgical department: analysis of the period from 1951 to 1988. Br J Surg 1991;78:849–52. [4] Goldhaber SZ, Tapson VF. A prospective registry of 5,451 patients with ultrasound conﬁrmed deep vein thrombosis. Am J Cardiol 2004;93:259–62. [5] Coon WW. Risk factors in pulmonary embolism. Surg Gynecol Obstet 1976;143:385–90. [6] Kakkar VV, Howe CT, Nicolaides AN, et al. Deep vein thrombosis of the legs: is there a ‘‘high risk’’ group? Am J Surg 1970;120:527–30. [7] Bratzler DW, Raskob GE, Murray CK, et al. Underuse of venous thromboembolism prophylaxis for general surgery patients. Physician practices in the community hospital setting. Arch Intern Med 1998;158:1909–12. [8] von Virchow R. Weitere Untersuchungen ueber die Verstopfung der Lungenarterien und ihre Folge.

V.F. Tapson / Cardiol Clin 22 (2004) 353–365

[9] [10]

[11]

[12]

[13]

[14]

[15] [16]

[17]

[18]

[19]

[20]

[21]

[22]

[23]

[24]

[25] [26]

Traube’s Beitraege exp path u Physiol. Berlin 1846; 2:21–31. Goldhaber SZ. Pulmonary embolism. N Engl J Med 1998;339:93. McIntyre KM, Sasahara AA. The ratio of pulmonary artery pressure to pulmonary vascular obstruction. Chest 1977;71:692. Carson JL, Kelley MA, Duﬀy A, et al. The clinical course of pulmonary embolism. N Engl J Med 1992; 326:1240–5. The PIOPED investigators. Value of the ventilation/perfusion scan in acute pulmonary embolism. Results of the prospective investigation of pulmonary embolism diagnosis. JAMA 1990;263: 2753–2759. Stein PD, Terrin ML, Hales CA, et al. Clinical, laboratory, roentgenographic, and electrocardiographic ﬁndings in patients with acute pulmonary embolism and no pre-existing cardiac or pulmonary disease. Chest 1991;100:598–603. Clason S. Three cases of pulmonary embolism following conﬁnement, treated with heparin. Acta Med Scand 1941;107:131–5. Fitts WT Jr, Lehr HB, Bitner RL, et al. An analysis of 950 fatal injuries. Surgery 1964;56:663–8. Lamb GC, Tomski MH, Kaufman J, et al. Is chronic spinal cord injury associated with increased risk of venous thromboembolism? J Am Paraplegia Soc 1993;16:153–6. Fisher M, Michele A, McCann W. Thrombophlebitis and pulmonary infarction associated with fractured hip. Clin Res 1963;11:407. Clagett GP, Reisch JS. Prevention of venous thromboembolism in general surgical patients: Results of a meta-analysis. Ann Surg 1988;208: 227–40. Samama MM, Cohen AT, Darmon J-Y, et al. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. N Engl J Med 1999;341:793–800. Pineo GF, Brain MC, Gallus AS, et al. Tumors, mucus production and hypercoagulability. Ann N Y Acad Sci 1974;230:262–70. Rickles FR, Edwards RL. Activation of blood coagulation in cancer: Trousseau’s syndrome revisited. Blood 1983;62:14–31. Toglia MR, Weg JG. Current concepts: venous thromboembolism during pregnancy. N Engl J Med 1996;335:108–14. Handley AJ, Emerson PA, Fleming PR. Heparin in the prevention of deep vein thrombosis after myocardial infarction. BMJ 1972;2:436–8. Kraaijenhagen RA, Haverkamp D, Koopman MMW, et al. Travel and risk of venous thrombosis. Lancet 2000;356:1492–3. James PB. Jet ‘‘leg, ’’ pulmonary embolism, and hypoxia. Lancet 1996;347:1697. Bagshaw M. Jet ‘‘leg, ’’ pulmonary embolism, and hypoxia. Lancet 1996;348:415–6.

363

[27] Bounameaux H, Ciraﬁci P, DeMoerloose P, et al. Measurement of D-dimer in plasma as diagnostic aid in suspected pulmonary embolism. Lancet 1991;337: 196. [28] Wells PS, Anderson DR, Rodger M, et al. Excluding pulmonary embolism at the bedside without diagnostic imaging: management of patients with suspected pulmonary embolism presenting to the emergency department by using a simple clinical model and D-dimer. Ann Intern Med 2001; 135:98–107. [29] Egermayer P, Town GI, Turner JG, et al. Usefulness of D-dimer, blood gas, and respiratory rate measurements for excluding pulmonary embolism. Thorax 1998;53:830–4. [30] Ahearn GS, Bounameaux H. The role of the D-dimer in the diagnosis of venous thromboembolism. Semin Respir Crit Care Med 2000;21:521–36. [31] Meyer T, Binder L, Hruska N, et al. Cardiac troponin I elevation in acute pulmonary embolism is associated with right ventricular dysfunction. J Am Coll Cardiol 2000;36:1632–6. [32] Douketis JD, Crowther MA, Stanton EB, et al. Elevated cardiac troponin levels in patients with submassive pulmonary embolism. Arch Intern Med 2002;162:79–81. [33] Tapson VF. Diagnosing and managing acute pulmonary embolism: role of cardiac troponins. Am Heart J 2003;145:751–3. [34] Burke B, Sostman HD, Carroll BA, et al. The diagnostic approach to deep venous thrombosis: which technique? Clin Chest Med 1995;16:253–68. [35] Evans AJ, Tapson VF, Sostman HD, et al. The diagnosis of deep venous thrombosis: a prospective comparison of venography and magnetic resonance imaging. Chest 1992;102:120S. [36] Witty LA, Tapson VF, Evans AJ, et al. MRI versus ultrasound: a radiologic and clinical evaluation of DVT. Am Rev Respir Dis 1993;147:A998. [37] McNeill BJ, Hessel SJ, Branch WT, et al. Measures of clinical eﬃcacy: part 3: the value of the lung scan in the evaluation of young patients with pleuritic chest pain. J Nucl Med 1976;17:163–4. [38] Hull RD, Raskob G, Ginsberg JS, et al. A noninvasive strategy for the treatment of patients with suspected pulmonary embolism. Arch Intern Med 1994;154:289–97. [39] Stein PD, Athanasoulis C, Alavi A, et al. Complications and validity of pulmonary angiography in acute pulmonary embolism. Circulation 1992;85:462–8. [40] Remy-Jardin M, Remy J, Wattinne L, et al. Central pulmonary thromboembolism: diagnosis with spiral volumetric CT with the single-breath-hold technique. Comparison with pulmonary angiography. Radiology 1992;185:381–7. [41] Sostman HD, Layish DT, Tapson VF, et al. Prospective comparison of helical CT and MR imaging in clinically suspected acute pulmonary embolism. J Magn Reson Imaging 1996;6:275.

364

V.F. Tapson / Cardiol Clin 22 (2004) 353–365

[42] van Rossum AB, Pattynama PM, Treurniat FE, et al. Spiral CT angiography for detection of pulmonary embolism: validation in 124 patients. Radiology 1995;197(P):303. [43] Goodman LR, Curtin JJ, Mewissen MW, et al. Detection of pulmonary embolism in patients with unresolved clinical and scintigraphic diagnosis: helical CT versus angiography. AJR Am J Roentgenol 1995;164:1369–74. [44] Oser RF, Zuckerman DA, Gutirrez FR, et al. Anatomic distribution of pulmonary embolism at pulmonary arteriography: implications for spiral and electron-beam CT. Radiology 1996;199:31–5. [45] Teigen CL, Maus TP, Sheedy PF, et al. Pulmonary embolism: diagnosis with electron-beam CT. Radiology 1993;188:839–45. [46] Drucker EA, Rivitz SM, Shepard JO. Acute pulmonary embolism: assessment of helical CT. Radiology 1998;209:235–41. [47] van Rossum AB, Treurniat FE, Kieft GJ, et al. Role of spiral volumetric computed tomographic scanning in the assessment of patients with clinical suspicion of pulmonary embolism and an abnormal ventilation perfusion scan. Thorax 1996;51:23–8. [48] Ferretti GR, Bosson J-L, Buﬀaz P-D, et al. Acute pulmonary embolism: role of helical CT in 164 patients with intermediate probability at ventilation-perfusion scintigraphy and normal results at duplex US of the legs. Radiology 1997;205:453–8. [49] Perrier A, Howarth N, Didier D, et al. Performance of helical computed tomography in unselected outpatients with suspected pulmonary embolism. Ann Intern Med 2001;135:88–97. [50] Swensen SJ, Sheedy PF, Ryu JH, et al. Outcomes after withholding anticoagulation from patients with suspected acute pulmonary embolism and negative computed tomographic ﬁndings: a cohort study. Mayo Clin Proc 2002;77:130–8. [51] Garg K, Sieler H, Welsh CH, et al. Clinical validity of helical CT being interpreted as negative for pulmonary embolism: implications for patient treatment. AJR Am J Roentgenol 1999;172:1627–31. [52] Tapson VF. Pulmonary embolism—new diagnostic approaches. N Engl J Med 1997;336:1449–51. [53] Come PC. Echocardiographic evaluation of pulmonary embolism and its response to therapeutic interventions. Chest 1992;101:151–62S. [54] Goldhaber SZ, Haire WD, Feldstein ML, et al. Alteplase versus heparin in acute perfusion. Lancet 1993;341:507–10. [55] Tapson VF, Davidson CJ, Kisslo KB, et al. Rapid visualization of massive pulmonary emboli utilizing intravascular ultrasound. Chest 1994;105:888–90. [56] Tapson VF, Carroll BA, Davidson BL, et al. The diagnostic approach to pulmonary embolism: randomized trial assessing right ventricular function and pulmonary acute venous thromboembolism. Clinical Practice Guideline. American Thoracic Society. Am J Respir Crit Care Med 1999;160:1043–66.

[57] Tapson VF, Hull R. Management of venousthromboembolic disease: the impact of low- molecularweight heparin. Clin Chest Med 1995;16:281–94. [58] Tapson VF. Treatment of acute deep venous thrombosis and pulmonary embolism: use of low molecular weight heparin. Semin Respir Crit Care Med 2000;21:547–53. [59] Hull R, Raskob G, Rosenbloom D, et al. Optimal therapeutic level of heparin therapy in patients with venous thrombosis. Arch Intern Med 1992;152: 1589–95. [60] Merli G, Spiro T, Olsson C-G, et al. Subcutaneous enoxaparin once or twice daily compared with intravenous unfractionated heparin for treatment of venous thromboembolic disease. Ann Intern Med 2001;134:191–202. [61] Simmoneau G, Sors H, Charbonnier B, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism. The THESEE Study Group. N Engl J Med 1997;337:663–9. [62] Lensing AWA, Prins MH, Davidson BL, et al. Treatment of deep venous thrombosis with lowmolecular-weight heparins: a meta-analysis. Arch Intern Med 1995;155:601–7. [63] Leizorovicz A, Simonneau G, Decousus H, et al. Comparison of eﬃcacy and safety of low molecular weight heparins and unfractionated heparin in initial treatment of deep venous thrombosis. BMJ 1994;309:299–304. [64] Siragusa S, Cosmi B, Piovella F, et al. Lowmolecular-weight heparins and unfractionated heparin in the treatment of patients with acute venous thromboembolism: results of a meta-analysis. Am J Med 1996;100:269–77. [65] Dolovich LR, Ginsberg JS, Douketis JD, et al. A meta-analysis comparing low molecular weight heparins with unfractionated heparin in the treatment of venous thromboembolism. Arch Intern Med 2000;160:181–8. [66] Levine M, Gent M, Hirsh J, et al. A comparison of low molecular-weight-heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep vein thrombosis. N Engl J Med 1996;334:677–81. [67] Koopman MM, Prandoni P, Piovella F, et al. Low molecular-weight-heparin versus heparin for proximal deep vein thrombosis. N Engl J Med 1996;334: 682–7. [68] The Matisse Investigators. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med 2004;349:1695–702. [69] Schulman S, Wahlander K, Lundstrom T, et al. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor, ximelagatran. N Engl J Med 2003;349:1713–21. [70] Huisman MV, et al. Eﬃcacy and safety of the direct thrombin inhibitor ximelagatran compared with

V.F. Tapson / Cardiol Clin 22 (2004) 353–365

[71]

[72]

[73]

[74]

[75]

[76]

[77]

[78]

[79]

[80]

current standard therapy for acute, symptomatic deep vein thrombosis, with or without pulmonary embolism: A randomized, double-blind, multinational study. J Thromb Haemost 2003;suppl 1: abstract 0C003. Warkentin TE, Levine MN, Hirsh J, et al. Heparininduced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 1995;332:1330–5. Becker DM, Philbrick JT, Selby JB. Inferior vena cava ﬁlters: indications, safety, eﬀectiveness. Arch Intern Med 1992;152:1985–94. Thrombolytic therapy in thrombosis: a National Institutes of Health Consensus Development Conference. Ann Intern Med 1980;93:141–3. Goldhaber SZ. Evolving concepts in thrombolytic therapy for pulmonary embolism. Chest 1992;101: 183–5S. Konstantinides S, Geibel A, Huesel G, et al. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med 2002;347:1143–50. Verstraete M, Miller GAH, Bounameaux H, et al. Intravenous and intrapulmonary recombinant tissue-type plasminogen activator in the treatment of acute massive pulmonary embolism. Circulation 1988;77:353–60. Tapson VF, Witty LA. Massive pulmonary embolism: diagnostic and therapeutic strategies. Clin Chest Med 1996;16:329. Tapson VF, Gurbel PA, Royster R, et al. Pharmacomechanical thrombolysis of experimental pulmonary emboli: rapid low-dose intraembolic therapy. Chest 1994;106:1558–62. Semba CP, Dake MD. Iliofemoral deep venous thrombosis: aggressive therapy with catheterdirected thrombolysis. Radiology 1994;191:487–94. Sane DC, Caliﬀ RM, Topol EJ, et al. Bleeding during thrombolytic therapy for acute myocardial

[81] [82]

[83]

[84]

[85]

[86]

[87]

[88]

[89]

365

infarction: mechanisms and management. Ann Intern Med 1989;111:1010–22. Gore JM. Prevention of severe neurologic events in the thrombolytic era. Chest 1992;101:124–30S. Layish DT, Tapson VF. Pharmacologic hemodynamic support in massive pulmonary embolism. Chest 1997;111:218–24. Jardin F, Genevray B, Brun-ney D, et al. Dobutamine: a hemodynamic evaluation in pulmonary embolism shock. Crit Care Med 1985;13: 1009–12. Goldhaber SZ, Visani L. The International Cooperative Pulmonary Embolism Registry. Chest 1995;108:302. Bergqvist D, Benoni G, Bjorgello XX, Fredin H, et al. Low-molecular-weight heparin (enoxaparin) as prophylaxis against venous thromboembolism after total hip replacement. N Engl J Med 1996; 335:696–700. Comp PC, Spiro T, Friedman RJ, et al. Prolonged enoxaparin therapy to prevent venous thromboembolism after primary hip or knee replacement. J Bone Joint Surg [Am] 2001;83:336–45. Lechler E, Schramm W, Flosbach CW, et al. The venous thrombotic risk in nonsurgical patients: epidemiological data and eﬃcacy/safety proﬁle of a low molecular weight heparin (enoxaparin). Haemostasis 1996;26(Suppl 2):49–56. Kleber F, Witt C, Vogel G, et al. Randomized comparison of enoxaparin with unfractionated heparin for the prevention of venous thromboembolism in medical patients with heart failure or severe respiratory disease. Am Heart J 2003;145: 614–21. Geerts WH, Heit JA, Clagett GP, et al. Prevention of venous thromboembolism. Sixth American College of Chest Physicians Consensus Conference on Antithrombotic Therapy. Chest 2001;119:132–75S.

Cardiol Clin 22 (2004) 401–415

Cardiac catheterization techniques in pulmonary hypertension Paulo Guillinta, MD, Kirk L. Peterson, MD, Ori Ben-Yehuda, MD* Division of Cardiology, Department of Medicine, University of California, San Diego, 200 West Arbor Drive, San Diego, CA 92110, USA

Once considered dangerous and potentially life threatening, cardiac catheterization of the patient with pulmonary hypertension can be performed safely and provides essential information in the diagnosis and management of pulmonary hypertension. This article summarizes the modern techniques used for right-heart catheterization, selective pulmonary angiography, and pulmonary angioscopy in the evaluation of the patient with pulmonary hypertension or with suspected chronic thromboembolic disease. Cardiac catheterization of the patient with suspected pulmonary hypertension is essential to determine accurately the cause and extent of disease. In patients with suspected chronic thromboembolic pulmonary hypertension (CTEPH), pulmonary angiography remains an essential part of the diagnostic evaluation and selection of appropriate patients for surgical pulmonary thrombendarterectomy. Although historically pulmonary angiography has been considered contraindicated in the presence of severe pulmonary hypertension, advances in cardiac and pulmonary angiographic techniques allow this procedure to be performed in a safe manner with acceptable risk. In reviewing the technique of right-heart catheterization, pulmonary angiography, and angioscopy in the patient with pulmonary hypertension, the authors draw on the experience of more than 20 years of catheterization of patients with severe pulmonary hypertension at the University of California, San Diego (UCSD) Medical Center,

* Corresponding author. E-mail address: [email protected] (O. Ben-Yehuda).

where more than 2500 such procedures have been performed.

Indications and considerations for catheterization of the patient with pulmonary hypertension Catheterization plays an integral part in the evaluation of the patient with pulmonary hypertension. The primary goals of catheterization are to determine right ventricular and pulmonary artery hemodynamics, to exclude left-to-right cardiac shunts and any signiﬁcant left-sided cardiac disorder, to assist in the determination of the cause of pulmonary hypertension, and to test the response of therapeutic agents. In patients with suspected CTEPH, pulmonary angiography and angioscopy are used to assess clot location, extent, and size to determine candidacy for pulmonary thrombendarterectomy.

Safety considerations Early case reports [1–4] of fatalities associated with pulmonary angiography in patients with pulmonary hypertension have led to a lingering perception that the procedure is associated with considerable risk, primarily because of acute right ventricular failure and arrhythmias. Even rightheart catheterization alone [5] was reported to be potentially dangerous. Larger series have since been published, both in acute and chronic pulmonary embolism and in mild as well as severe pulmonary hypertension. Mills et al [6] described three deaths in 1350 patients (incidence of 0.2%), all of whom had right ventricular end diastolic pressure of 20 mm Hg or higher. Nicod et al [7]

0733-8651/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ccl.2004.04.011

402

P. Guillinta et al / Cardiol Clin 22 (2004) 401–415

reported on the original series of 67 patients from UCSD undergoing CTEPH evaluation. Mean pulmonary arterial pressures (PAPs) were 47 13 mm Hg, with a right ventricular end diastolic pressure of 13 6 mm Hg and a cardiac index of 2.2 0.7 L/min. There were no deaths attributable to CTEPH. By 1991 this series had expanded to include more than 300 patients, without a death. Since then right-heart catheterization and pulmonary angiography have been performed in approximately 200 patients with severe pulmonary hypertension annually at UCSD, without a death related to the procedure (more than 2500 patients to date). There thus are no absolute contraindications to pulmonary angiography, and the procedure can be performed safely, provided certain precautions and advances in technique are employed. Nonfatal adverse reactions include transient hypotension and general catheterization-related adverse events such as inadvertent arterial puncture, oversedation, pneumothorax, and contrast agent–related nephropathy [8]. To minimize these risks, the authors use the following procedures at UCSD [9]: 1. Before the procedure echocardiography is performed, detecting potential clots in the right atrium or right ventricle or the presence of an atrial septal defect/patent foramen ovale. 2. Heart rate, rhythm, oxygen saturation, and systemic and PAP should be continuously monitored. Supplemental oxygen is provided to maintain oxygen saturation over 90%. 3. Access to the pulmonary vessels through the neck is preferred to avoid potential dislodgement of unsuspected venous thrombi involving the femoral vein, iliac vein, or inferior vena cava and to facilitate angioscopy. The authors prefer the internal jugular vein to the subclavian vein to reduce the risk of pneumothorax, which is likely to be poorly tolerated in these patients who are often hypoxemic. 4. Hemodynamics are assessed using a balloon ﬂotation catheter (Swan-Ganz catheter), at times stiffened with a 0.025-cm guide wire. This stiffening greatly facilitates the catheterization in these patients, who frequently have enlarged right ventricles, signiﬁcant tricuspid regurgitation, severely elevated PAPs, and low cardiac output. CO2 is used for balloon inﬂation to minimize the possi-

5.

6.

7.

8.

bility of paradoxical embolism in case of balloon rupture. A stiff, side-hole catheter such as a 7-F or 8-F NIH or Berman catheter is most commonly used to inject the pulmonary arteries. The injection through the side holes allows good opaciﬁcation with reduced injection velocity and pressure. Catheter retraction and whipping during injection are also minimized. Unilateral, sequential injection of the contrast agent in to each main pulmonary artery is preferred. Injection into the right atrium or right ventricle is avoided, thereby eliminating the possibility of intramyocardial injection. The catheter is positioned near the origin of the lower lobe vessels, and the contrast agent is allowed to ﬁll the upper lobes in retrograde fashion. Non-ionic contrast is preferred because fewer adverse reactions and minimal hemodynamic compromise are experienced [10,11]. Cardiac output and speed of run-off during small hand injection are used to determine the amount of contrast agent needed for assessment of the pulmonary vasculature anatomy. A smaller amount of contrast material is needed in patients with slow run-off or low cardiac output. At UCSD, the total amount of contrast medium used ranges from 20 to 65 mL. The usual injection is of 55 mL at a rate of 22 mL/second, with adjustments based on the patient’s cardiac output, assessment of the pulmonary vasculature during the hand injection, and pulmonary pressures. For example, the total occlusion of the main descending pulmonary artery after the takeoff of the upper lobe branch would necessitate a reduction of the total contrast to approximately 20 mL. Conversely, the presence of a brisk runoff during the hand injection coupled with a high cardiac output would lead to injection of more than the standard 55 mL.

Right-heart catheterization Evaluation of hemodynamics by right-heart catheterization plays an integral part of the evaluation of patients with pulmonary hypertension. The goals of right-sided catheterization are (1) to measure PAP directly and estimate pulmonary vascular resistance, (2) to evaluate for left-toright shunts, and (3) to test the response to therapeutic agents.

P. Guillinta et al / Cardiol Clin 22 (2004) 401–415

During right-heart catheterization by balloon ﬂotation catheter, rapid determination and continuous monitoring of pressures in the right ventricle, right atrium, and pulmonary artery and of postcapillary wedge pressure are possible. Understanding of normal and pathologic pressure waveforms is important to recognize certain cardiac disorders such as valvular and pericardial disease. In patients with primary pulmonary hypertension (PPH), particular attention should be paid to the right atrial pressure and right ventricle end-diastolic pressure. In the National Heart Lung and Blood Institute registry, mean right atrial pressure and decreased cardiac index were the most important predictive variables for survival in patients with PPH [12]. The patient with PPH commonly has elevated right atrial pressure, elevated mean PAP, reduced cardiac index, and low or normal postcapillary wedge pressure [8]. A postcapillary wedge pressure is obtained with an end-hole catheter positioned in a side branch of the pulmonary artery facing a pulmonary capillary bed. One pitfall to avoid is wedging the balloon too proximally, creating a hybrid tracing of pressures between actual PAP and postcapillary wedge pressure, resulting in an overestimation of the postcapillary wedge pressure (Fig. 1). Deﬂating the balloon to decrease its size will allow the catheter to be wedged in a smaller, more distal branch of the pulmonary artery. Caution should be taken to avoid overwedging and possible pulmonary artery rupture, a potentially lethal event. Fortunately in pulmonary hypertension the thickened, hypertrophied arterial wall provides some protection against rupture. When it is not clear whether a wedge tracing has been obtained, a blood sample is obtained through the distal port. In the wedge position arterial saturation should be present as blood from the capillary bed is aspirated. The authors have also found that typically the more narrow, tapering anatomy of the left pulmonary artery allows more reliable wedge determinations. The use of a J-tipped 0.25 wire to guide the Swan-Ganz catheter to the left pulmonary artery is essential. Typically patients with either PPH or CTEPH have low to normal wedge pressures. In the presence of substantially elevated postcapillary wedge pressure, left-heart catheterization should be performed to exclude pulmonary venoocclusive disease, mitral stenosis, or left ventricular dysfunction. Cardiac output is best determined by the Fick method in the setting of low cardiac output states or when there is signiﬁcant tricuspid regurgita-

403

tion. This method requires measuring oxygen consumption directly, because estimations of oxygen consumption may not apply to seriously ill patients with pulmonary hypertension and may introduce signiﬁcant calculation errors. In experienced hands, however, determination of cardiac output by thermodilution techniques is usually satisfactory for the adjustment of therapy in these patients [13].

Response of vasodilator challenge in the cardiac catheterization laboratory Vasoconstriction of the pulmonary vessels is one of the prominent pathologic features seen in patients with pulmonary hypertension of any cause, particularly in those with PPH [14]. Unfortunately, no hemodynamic or demographic characteristics exist to predict which patients are likely to beneﬁt from long-term vasodilator therapy [15,16]. In more recent studies, Groves et al [17] illustrated that the initial response to vasodilatory therapy accurately predicts the patient with PPH who is likely to beneﬁt from long-term oral therapy. In addition, patients who demonstrate a reduction in total pulmonary resistance index of more than 50% in response to short-term epoprostenol (prostacyclin, PGI2) challenge at the time of diagnosis had longer disease evolutions and better prognoses than patients with a lower vasodilator response [18,19]. For these reasons [3], it is important to assess the response to vasodilator therapy in patients with PPH in the cardiac catheterization laboratory. Nitric oxide and PGI2 are useful drugs to test pulmonary vasoreactivity because they are potent, short acting, and can be titrated. The acute eﬀects of inhaled nitric oxide and PGI2 on pulmonary artery pressure are similar [20,21]. Inhaled nitric oxide more consistently reﬂects the changes in pulmonary vascular tone and seems to be the better predictor of the long-term response to oral vasodilator treatment, making it the preferred agent for assessing pulmonary vasoreactivity [22]. Nitroprusside has fallen out of favor for assessing pulmonary vasoreactivity in patients with chronic pulmonary hypertension because this drug causes systemic hypotension compared with nitric oxide, at doses that cause similar degrees of pulmonary vasodilation [23]. Pulmonary arterial pressures, right ventricular pressures, cardiac output, and postcapillary wedge pressure are recorded during infusions of inhaled

404

P. Guillinta et al / Cardiol Clin 22 (2004) 401–415

Fig. 1. (A) Hybrid tracing of pulmonary artery pressure and wedge tracing overestimating wedge pressure. (B) Actual pulmonary capillary wedge pressure tracing once the balloon is deﬂated and allowed to wedge in a smaller, more distal branch of the pulmonary artery.

P. Guillinta et al / Cardiol Clin 22 (2004) 401–415

nitric oxide. Administration of inhaled nitric oxide with oxygen seems to be safe and provides additional pulmonary vasodilation in this patient population [24]. Pulmonary pressure are recorded during administration of 100% oxygen and inhaled nitric oxide dosed at 20 to 80 parts per million. The authors typically administer nitric oxide for 10 minutes, with repeat recordings obtained during the ﬁnal 5 minutes of the inhalation. Although a mild reduction in pulmonary vascular resistance (<20%) can be seen in most patients, even those with CTEPH, signiﬁcant reductions of more than 20% are seen in only one fourth of patients [25]. Pulmonary angiography: anatomy Accurate evaluation of the pulmonary angiogram requires knowledge of the pulmonary vas-

405

culature anatomy (Figs. 2 and 3). The main pulmonary artery arises from the pulmonary conus of the right ventricle, anterior and to the left of the aorta. It takes a posteromedial direction until its bifurcation into the right and left pulmonary arteries. The right pulmonary artery courses anterior to the right mainstem bronchus. It gives rise to the right upper lobe branch within the mediastinum. The left pulmonary artery passes over the left mainstem bronchus and descends posterior to the bronchus before the origin of the left upper lobe branch. The vessels then branch and are closely related to bronchial branching within the lung. Angiographic ﬁlms are taken using anteroposterior and lateral projections. The lateral projection is particularly helpful in separating the overlapping tributaries of the right middle and right lower lobe and left lingual and left lower lobe. It also allows a clear separation

Fig. 2. (A) Anteroposterior view of the anatomy of the right pulmonary artery. (B) Lateral view. (Reproduced from Peterson KL, Nicod P. Catheterization and angiography in pulmonary hypertension. In: Shure D, Auger W, Moser K, et al, editors. Cardiac catheterization: methods, diagnosis, and therapy. Philadelphia: W.B. Saunders; 1977. p. 404; with permission.)

406

P. Guillinta et al / Cardiol Clin 22 (2004) 401–415

Fig. 3. Anatomy of the left pulmonary artery in (A) anteroposterior and (B) lateral views. (Reproduced from Peterson KL, Nicod P. Catheterization and angiography in pulmonary hypertension. In: Shure D, Auger W, Moser K, et al, editors. Cardiac catheterization: methods, diagnosis, and therapy. Philadelphia: W.B. Saunders; 1977. p. 405; with permission).

between the superior segmental artery and the artery to the middle lobe.

Pulmonary angiography: interpretation in the patient with pulmonary hypertension Pulmonary angiography of the patient with pulmonary hypertension plays a central role in delineating the precapillary cause of elevated pulmonary pressures. Distinguishing major-vessel from small-vessel disease allows the correct therapeutic approach to be determined. Auger et al [26] described the angiographic patterns seen in patients with chronic thromboembolic disease. These patterns include pouching abnormalities, vascular webs or bandlike constrictions, intimal irregularities, abrupt narrowing of

major pulmonary vessels, and obstruction of major pulmonary vessels, most commonly at points of origin (Figs. 4–8). Although pulmonary arterial webs are typically seen in patients with chronic thromboemboli, they are also seen in congenital stenotic lesions of the pulmonary vessels and with vasculitides such as Takayasu’s arteritis [27,28]. Patients with congenital stenotic lesions of the pulmonary vasculature present at an early age and typically have coexisting cardiac abnormalities. Most Takayasu patients with pulmonary vessel involvement demonstrate systemic manifestations. Total obstruction or abrupt narrowing of the pulmonary vessel, typically seen in chronic thromboemboli, can also be seen in extrinsic compression from extensive mediastinal or hilar lymphadenopathy, ﬁbrosing mediastinitis, and pulmonary

P. Guillinta et al / Cardiol Clin 22 (2004) 401–415

407

Fig. 4. (A) The anteroposterior view of the right pulmonary artery in a patient with CTEPH. Note the marked hypovascularity, irregularity of the main descending pulmonary artery, and complete occlusion of most segmental branches. (B) The lateral view of the artery shown in 4A. Note the separation of the right middle lobe branches from the right lower lobe segments. In this view the middle lobe is perfused, as is the superior segment.

vascular or primary lung malignancies [29–32]. Chest CT aids in making the distinguishing these entities from chronic thromboembolic disease. Occasionally, several vascular abnormalities occur in the same patient. In this scenario, the pulmonary angiogram may aid in identifying the

Fig. 5. Right pulmonary angiogram shows central pulmonary artery enlargement and pouching abnormality in the right lower lobe vessel seen in chronic thromboembolic disease.

patient with acute on chronic thromboembolic disease (Fig. 9). Sharply deﬁned luminal defects are seen in small, acute emboli. Proximal pulmonary artery enlargement and bandlike abnormalities are typically seen in chronic thromboembolic disease but not in acute embolic disease. The hemodynamic data can also assist in distinguishing chronic from acute embolism. Pulmonary hypertension with mean PAPs above 35 mm Hg suggest chronicity, because the right ventricle in acute pulmonary embolism without previous pulmonary hypertension is incapable of generating such high pulmonary pressures [33]. The classic angiographic ﬁndings in patients with PPH include normal or dilated central arteries with pruning of the small, more distal, nonelastic arteries [8]. Pruning of the pulmonary vessels may also be seen with chronic thromboembolic disease, but in this scenario pruning is regional and more proximal [34]. A key question that the pulmonary angiogram addresses in patients with suspected CTEPH is the extent and surgical accessibility of chronic clot. The presence of bilateral disease and proximal involvement (main pulmonary trunks, lobar arteries, and segmental arteries) predicts surgical accessibility. Correlation with ﬁndings on the perfusion scan is essential, because the presence

408

P. Guillinta et al / Cardiol Clin 22 (2004) 401–415

Fig. 6. (A) Anteroposterior view of the right pulmonary artery demonstrating hypoperfusion of the lower lobe. (B) Only on the lateral ﬁlm does the extent of occlusion of the posterior basal segment and narrowing of the middle lobe branch become evident. The superior segment is also subtotally occluded.

of segmental defects is predictive of surgical success (see articles in this issue by Auger et al and Thistlethwaite et al).

When there is signiﬁcant proximal disease (eg, complete occlusions of lobar vessels), the inter-

pretation of pulmonary angiograms is straightforward. In the UCSD experience the pulmonary angiogram is suggestive but not deﬁnitive in about 20% to 25% of cases. The recanalization of chronic clot allows contrast to permeate through the lesions, and the pulmonary angiogram can underestimate disease just as the perfusion scan can. In addition, the presence of defects at the

Fig. 7. Abrupt narrowing of the pulmonary vessel seen in chronic thromboembolic disease.

Fig. 8. Anteroposterior projection shows complete obstruction of the right main pulmonary artery.

Pulmonary angioscopy

P. Guillinta et al / Cardiol Clin 22 (2004) 401–415

Fig. 9. Anteroposterior view demonstrates acute on chronic thromboemboli. Note the distinct numerous luminal ﬁlling defects (solid arrow) in a bandlike or web abnormality.

transition between segmental and subsegmental vessels may raise doubt regarding the surgical accessibility. In the patient with markedly elevated pulmonary hypertension (pulmonary vascular resistance >800 dynes/second/cm5) surgical risks rise signiﬁcantly if insigniﬁcant clot is removed during surgery, leaving the patient with severe pulmonary hypertension. Fiberoptic angioscopy, developed to allow direct visualization of the interior of the central pulmonary vessels up to the segmental and sub-

409

segmental levels, is used to deﬁne surgical accessibility better in borderline cases [35,36]. The challenges entailed in performing pulmonary angioscopy include the need to maneuver through an often hypertrophied right ventricle, the wide variation in pulmonary vessel size with varying anatomic branching, the large number of branches that require visualization, and the robust collateral circulation from the bronchial circulation. At UCSD pulmonary angioscopy has progressed through several stages of development over the past 20 years. The approach has been to use a balloon system to occlude blood ﬂow completely in the vessel that is being visualized, rather than a ﬂushing (hemodilution) approach as has been used in the coronary circulation. Hemodilution is not practicable in the large pulmonary arteries and would entail dangerous ﬂuid overload in these patients with right-heart failure. The angioscope presently used is a 120-cm ﬁberoptic device, 3 mm in diameter (Figs. 10 and 11). It can be ﬂexed 90( at the tip allowing navigation through the pulmonary tree. The occluding balloon is attached at a modiﬁed spool-like stainless steel lip, which allows secure tying of the disposable balloons. The balloon at the distal end is inﬂated with carbon dioxide to protect from air embolism in case of balloon rupture, a precaution of particular importance given the elevated rightsided pressures with potential for right- to-left embolism in patients with patent foramen ovale. The balloon is connected to a syringe by a tube in the angioscope, allowing deﬂation during the advancement of the catheter and inﬂation to occlude the vessel as well as allow ﬂotation further downstream.

Fig. 10. The pulmonary angioscope. (Courtesy of Olympus Corporation, Lake Success, NY.)

410

P. Guillinta et al / Cardiol Clin 22 (2004) 401–415

Fig. 11. Inﬂated balloon attached to the distal tip of the angioscope.

Because of the size of the angioscope (3 mm) an 11-F sheath is used. Although angioscopy can be accomplished from the femoral approach, it is much easier to navigate the instrument through the right ventricle using the internal jugular vein approach, particularly from the right. Two operators are needed to guide the angioscope, with one advancing and torquing the instrument and the other ﬂexing and extending it using the built-in deﬂectors. Angioscopy is most helpful in deﬁning the starting point of chronic thrombi and establishing whether they are within surgical reach. This procedure enables the examiner to determine operability of patients with chronic pulmonary thromboemboli in approximately 75% of the cases when the ﬁndings on the pulmonary angiogram are questionable [34]. A detailed map of the major pulmonary vessels can be performed safely within 20 minutes, without signiﬁcant morbidity, in this patient population. The main complications encountered have been transient ventricular ectopy during transit in the ventricle and minor local bleeding from the 11-F sheath site in the neck. During the procedure the ﬂuoroscopy images are recorded to localize the lesions seen on angioscopy and are correlated with the anatomy as deﬁned in the pulmonary angiogram. Normal pulmonary ﬁndings are of smooth, pale white, glistening intima (Fig. 12). Bifurcations are typically round and regular in appearance. In patients with pulmonary hypertension, either primary arterial hypertension or secondary to CTEPH, the arterial walls may demonstrate small, yellowish atheroscleroticlike plaques as well as more diﬀuse yellowish colorations (Figs. 13 and 14). Patients with chronic thrombi have irregular pulmonary arterial walls with transluminal bands

Fig. 12. Normal bifurcation of a pulmonary artery.

and obstructive lesions and irregular vessel ostia. Thin membranes can also be visualized. At times reddish-purplish subacute thrombi can be seen, which are distinct from the white ﬁbrotic lesions of chronic organized and recanalized clot. Small-vessel arteriopathy in patients with chronic thromboembolic pulmonary hypertension Although the main site of vasculopathy and increased resistance in CTEPH is in the large, elastic pulmonary arteries, a signiﬁcant number of patients have concomitant small-vessel arteriopathy that may persist despite the removal of proximal clot. These patients are at increased risk of persistent pulmonary hypertension after pulmonary thrombendarterectomy. Severe persistent pulmonary hypertension after surgery accounts for more than one third of perioperative mortality and up to 50% of long-term deaths. Recently the pulmonary artery occlusion technique [37] has been used to attempt to partition the pulmonary resistance into an upstream component (Rup) and downstream (small arterial plus venous) component. Using a standard Swan-Ganz catheter (Edwards Lifesciences Corporation, Irvine, CA) the pulmonary pressure signal is ﬁltered using a twopole digital low-pass ﬁlter with a cutoﬀ at 18 Hz. A biexponential ﬁtting of the pressure decay curve is then performed, which allows estimation of the derived occlusion pressure (Poccl). Rup is then calculated as follows: Rup mean pulmonary artery pressure Poccl ¼ ð%Þ mean pulmonary artery pressure Ppao where Ppao is the ﬁnal pulmonary artery occluded pressure (wedge pressure). In patients with

P. Guillinta et al / Cardiol Clin 22 (2004) 401–415

411

Fig. 13. Angioscopic ﬁndings in CTEPH. Note the ﬁbrotic white material with membranes, webs, and pitting.

Fig. 14. Angioscopic ﬁndings in CTEPH. Note the yellow plaque prominent in B, G, and K. Membranes, webs, and masslike ﬁbrotic tissue can be seen.

412

P. Guillinta et al / Cardiol Clin 22 (2004) 401–415

Fig. 15. Pulmonary artery pressure occlusion waveforms from two patients with (A) mainly upstream resistance and (B) mainly downstream resistance. In A the pressure drops more rapidly with balloon occlusion, resulting in lower Poccl and higher Rup%.

small-vessel arteriopathy the Poccl pressure is higher (a longer time is required for the pressure to reach Ppao), and therefore the Rup % is lower (Fig. 15). In a study [37] of 26 patients with suspected CTEPH, there was an excellent correlation between Rup % before pulmonary thrombendarterectomy and hemodynamic response to surgery. Moreover, all four patients with Rup % below 60 did not survive surgery (Fig. 16). Coronary arteriography Before pulmonary thrombendarterectomy the authors routinely perform coronary arteriography on all male patients above the age of 40 and female patients above the age of 45 and do so for

younger patients if ﬁndings are suggestive of coronary disease. In the presence of markedly enlarged proximal pulmonary arteries, the left main pulmonary artery may become compressed and give the appearance of ostial left main stenosis [38]. Best visualized in the let anterior oblique cranial view (Fig. 17), this ﬁnding is usually devoid of other evidence of atherosclerosis and is not in itself an indication for bypass surgery, especially if the patient’s pulmonary pressures decrease after surgery. Summary Cardiac catheterization of the patient with pulmonary hypertension plays an integral part in

P. Guillinta et al / Cardiol Clin 22 (2004) 401–415

413

Fig. 16. Correlation between preoperative Rup % and postoperative outcomes. (A) Postoperative pulmonary resistance (B) Mean postoperative pulmonary pressure. (Reproduced from Kim NH, Fesler P, Channick RN, et al. Preoperative pulmonary partitioning of pulmonary vascular resistance correlates with early outcome after thromboendarterectomy for chronic thromboembolic pulmonary hypertension circulation. 2004;109:19; with permission.)

414

P. Guillinta et al / Cardiol Clin 22 (2004) 401–415

Fig. 17. Left main ostial compression from an enlarged pulmonary artery. (Reproduced from Bonderman D, Fleischmann D, Prokop M, et al. Imges in cardiovascular medicine. Left main coronary artery compression by the pulmonary trunk in pulmonary hypertension. Circulation 2002;105:265; with permission.)

the diagnostic evaluation. Right-heart hemodynamics, pulmonary angiography, and pulmonary angioscopy oﬀer a way to determine the cause of disease safely and accurately and to oﬀer potentially life-saving therapies.

References [1] Dotter CT, Jackson FS. Death following angiocardiography. Radiology 1950;54:527–33. [2] Diamond EG, Gonlubol F. Death following angiocardiography: report of two cases after administration of diodrast and neo-iopax, respectively. N Engl J Med 1953;249:1029–31. [3] Alexander JK, Gonzales DA, Fred HL. Angiographic studies in cardiorespiratory diseases: special reference to thromboembolism. JAMA 1966;198: 575–8. [4] Snider GL, Ferris E, Gaensler EA, et al. Primary pulmonary hypertension: a fatality during pulmonary angiography. Chest 1973;64:628–35. [5] Caldini P, Gensini GG, Hoﬀman MS. Primary pulmonary hypertension with death during right heart catheterization. Am J Cardiol 1959;519–27. [6] Mills SR, Jackson DC, Older RA, et al. The incidence, etiologies, and avoidance of complications of pulmonary angiography in a large series. Radiology 1980;136:295–9. [7] Nicod P, Peterson KL, Levine M, et al. Pulmonary angiography in severe chronic pulmonary hypertension. Ann Intern Med 1987;107:565–8. [8] Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension: a national prospective study. Ann Intern Med 1987;107:216–23.

[9] Peterson KL, Nicod P. Catheterization and angiography in pulmonary hypertension. In: Shure D, Auger W, Moser K, et al, editors. Cardiac catheterization: methods, diagnosis, and therapy. Philadelphia: W.B. Saunders; 1977. p. 401–14. [10] Kumazaki T. Ioxaglate versus diatrizoate in selective pulmonary angiography. Part II: cardiovascular responses. Acta Radiol 1985;26:635. [11] Smith DC, Lois JF, Gomes AS, et al. Pulmonary angiography: comparison of cough stimulation eﬀects of diatrizoate and ioxaglate. Radiology 1987; 162:617–8. [12] D’Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension: result from a national prospective registry. Ann Intern Med 1991;115:343–9. [13] Rubin LW, Rich S. Primary pulmonary hypertension. In: Georgiou D, Cao T, Shapiro S, et al, editors. Hemodynamic evaluation in primary pulmonary hypertension. New York: Marcel Dekker; 1997. p. 253–86. [14] Wagenvoort CA. Vasoconstriction and medial hypertrophy in pulmonary hypertension. Circulation 1960;22:535–46. [15] Weir EK, Rubin LJ, Ayres SM, et al. The acute administration of vasodilator therapy in primary pulmonary hypertension: experience from the National Institute of Health Registry on Primary Pulmonary Hypertension. Am Rev Resp Dis 1989; 140:1623–40. [16] Weir EK. Acute vasodilator testing and pharmacological treatment of primary pulmonary hypertension. In: Fishman AP, editor. The pulmonary circulation: normal and abnormal: mechanisms, management and the national registry. Philadelphia: University of Pennsylvania Press; 1990. p. 485–99. [17] Groves BM, Badesch DB, Turkevich D, et al. Correlation of acute prostacyclin response in primary (unexplained) pulmonary hypertension with eﬃcacy of treatment with calcium channel blockers and survival. In: Hummes JR, Reeves JT, Weir EK, editors. Ion ﬂux in pulmonary vascular control. New York: Plenum Press; 1993. p. 317–30. [18] Rich S, Brundage BH. High-dose calcium channelblocking therapy for primary pulmonary hypertension: evidence of long-term reduction in pulmonary arterial hypertension and regression of right ventricular hypertrophy. Circulation 1987;76:135–41. [19] Olivier R, Re´za A, Franc¸ois B, et al. Clinical signiﬁcance of the pulmonary vasodilator response during short-term infusion of prostacyclin in primary pulmonary hypertension. Circulation 1996; 93:484–8. [20] Rich S, Kaufmann E, Levy PS. The eﬀects of high doses of calcium-channel blocker on survival in primary pulmonary hypertension. N Engl J Med 1992;327:76–81.

P. Guillinta et al / Cardiol Clin 22 (2004) 401–415 [21] Sitbon O, Brenot F, Denjean A, et al. Inhaled nitric oxide as a screening vasodilator agent in primary pulmonary hypertension. Am J Respir Crit Care Med 1995;151:384–9. [22] Morales-Blanhir J, Santos S, de Jover L, et al. Clinical value of vasodilator test with inhaled nitric oxide for predicting long-term response to oral vasodilators in pulmonary hypertension. Respir Med 2004;98:225–34. [23] Cockrill BA, Kacmarek RM, Fifer MA, et al. Comparison of eﬀects of nitric oxide, nitroprusside, and nifedipine on hemodynamics and right ventricular contractility in patient with chronic pulmonary hypertension. Chest 2001;119: 128–36. [24] Atz AM, Adatia I, Lock JE, et al. Combined eﬀects of nitric oxide and oxygen during acute pulmonary vasodilator testing. J Am Coll Cardiol 1999;33: 813–9. [25] Rich S, Kaufmann E, Levy PS. The eﬀect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med 1992;327:76. [26] Auger WR, Fedullo PF, Moser KM, et al. Chronic major-vessel thromboembolic pulmonary artery obstruction: appearance at angiography. Radiology 1992;182:393–8. [27] Peterson KL, Fred HL, Alexander JK. Pulmonary arterial webs: a new angiographic sign of previous thromboembolism. N Engl J Med 1967;277:33. [28] Haas A, Stiehm R. Takayasu’s arteritis presenting as pulmonary hypertension. Am J Dis Child 1986; 140:372–4. [29] Cho SR, Tisnado J, Cockrell CH, et al. Angiographic evaluation of patients with unilateral massive perfusion defects in the lung scan. Radiographics 1987;7:729–45.

415

[30] Arnett EN, Bacos JM, Macher AM, et al. Fibrosing mediastinitis causing pulmonary arterial hypertension without pulmonary venous hypertension. Am J Med 1977;63:634–43. [31] Carlin BW, Moser KM. Pulmonary artery obstruction due to malignant ﬁbrous histiocytoma. Chest 1987;92:173–5. [32] Schermoly M, Overman J, Pingleton SK. Pulmonary artery sarcoma—unusual pulmonary angiographic ﬁndings—a case report. Angiology 1987;38: 617–21. [33] Dalen JE, Banas JS, Brooks HL, et al. Resolution rate of acute pulmonary embolism in man. N Engl J Med 1969;280:1194–9. [34] Peterson KL, Nicod P. Cardiac catheterization: methods, diagnosis, and therapy. In: Shure D, Auger W, Moser K, et al, editors. Pulmonary angioscopy. Philadelphia: W.B. Saunders; 1997. p. 257–65. [35] Shure D, Gregoratos G, Moser KM. Fiberoptic angioscopy: role in the diagnosis of chronic pulmonary arterial obstruction. Ann Intern Med 1985;103:844–50. [36] Ricou F, Nicod PH, Moser KM, et al. Catheterbased intravascular ultrasound imaging of chronic thromboembolic pulmonary disease. Am J Cardiol 1991;67:749–52. [37] Kim NHS, Fesler P, Channick RN, et al. Preoperative partitioning of pulmonary vascular resistance correlates with early outcome after thromboendarterectomy for chronic thromboembolic pulmonary hypertension. Circulation 2004; 109:18–22. [38] Bonderman D, Fleischmann D, Mathias P, et al. Left main coronary artery compression by the pulmonary trunk in pulmonary hypertension. Circulation 2002;105:265.

Cardiol Clin 22 (2004) 453–466

Chronic thromboembolic pulmonary hypertension William R. Auger, MDa,*, Kim M. Kerr, MDa, Nick H.S. Kim, MDa, Ori Ben-Yehuda, MDb, Kirk U. Knowlton, MDb, Peter F. Fedullo, MDa a

Division of Pulmonary and Critical Care Medicine, University of California, San Diego, 9300 Campus Point Drive, La Jolla, CA 92037, USA b Division of Cardiology, University of California, San Diego, 200 West Arbor Drive, San Diego, CA 92103, USA

Throughout the late nineteenth and early twentieth century, several published autopsy reports described massive thrombosis of the major pulmonary vessels. These reports typically described organized thrombus in the pulmonary arteries in association with other diseases, such as tuberculosis, lung cancer, and congenital heart disease. Only rarely was organized thrombus in the pulmonary arteries appreciated in the absence of another pathologic condition [1]. Ante-mortem diagnosis and the description of the syndrome of chronic thrombotic obstruction of the major pulmonary arteries ﬁrst received attention in the 1950s [1–4]. Carroll and colleagues [4] were the ﬁrst to use ﬁrst cardiac catheterization and pulmonary angiography in the characterization of this unusual disease. In 1958, Hurwitt [5] reported the ﬁrst surgical attempt to remove the adherent thrombus from the vessel wall. Although the patient died, this operation provided the conceptual foundation for the distinction between acute and chronic thromboembolic disease of the pulmonary vascular bed and established that an endarterectomy, not an embolectomy, is necessary for a successful surgical remedy for this disease. The ﬁrst bilateral pulmonary thromboendarterectomy through a transverse sternotomy using cardiopulmonary bypass is credited to Houk and colleagues [6] in 1963. Reports describing the natural history and clinical characteristics of

* Corresponding author. E-mail address: [email protected] (W.R. Auger).

chronic thromboembolic disease and small, anecdotal series reporting surgical successes in the treatment of this disorder appeared with increasing frequency over the ensuing 2 decades [7–14]. A review of the world’s experience with pulmonary thromboendarterectomy up to 1985, however, showed an overall perioperative mortality rate of 22% in the 85 operated patients [15]. Consequently, although chronic thromboembolic pulmonary hypertension (CTEPH) was acknowledged as a potentially curable form of pulmonary hypertension, the operative risks, the limited availability of specialty diagnosticians and surgeons capable of evaluating and treating this disorder, and underrecognition of the disease by the worldwide medical community continued to relegate CTEPH to the realm of a medical oddity with a poor prognosis until the late 1980s. With improved diagnostic capabilities, surgical techniques, endarterectomy instrumentation, and postoperative management, Daily and Moser [16–19] at the University of California, San Diego (UCSD) subsequently published several reports heralding the advancements in managing CTEPH. In 1987, Moser and colleagues [17] reported the largest series of operated CTEPH patients at a single medical center to date (42 patients); in-hospital mortality was 16.6%. In addition, this publication documented the considerable postoperative improvements in pulmonary hemodynamics and functional capacity experienced by these patients, clinical gains that were sustained a year or more beyond surgery. During the past 2 decades, there has been a steady rise in the number of CTEPH patients

0733-8651/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ccl.2004.04.006

454

W.R. Auger et al / Cardiol Clin 22 (2004) 453–466

undergoing surgery and in the number of programs worldwide dedicated to the diagnosis and management of this patient population. At UCSD, more than 1600 patients from national and international referral sources have undergone pulmonary thromboendarterectomy between 1989 and 2003 [20]. Programs in North America, Europe, Japan, and Australia have evolved to manage an increasing medical need [21–30]. Although the growing number of CTEPH patients might seem to reﬂect an increasing prevalence of disease, the most likely explanation is greater physician recognition of this disorder. The rise in worldwide interest is further fueled by the understanding that medical management of CTEPH is ineﬀective in altering prognosis, that perioperative mortality rates are declining, and that pulmonary thromboendarterectomy can dramatically improve pulmonary hemodynamic status, functional outcome, and long-term survival.

Natural history The pathophysiologic events leading to CTEPH are not entirely understood. Contributing to the gaps in the understanding of this process has been the typical presentation of patients late in the course of the disease, often without a history of a venous thromboembolic event or events. Consequently, a retrospective piecing together of historical and clinical clues, along with a knowledge of the natural history of acute thromboembolic events, has by necessity become the foundation of the understanding of the evolution of CTEPH. The development of CTEPH seems to be an extension of the natural history of acute pulmonary embolism, although it occurs in only a minority of patients. Although estimates vary, chronic thromboembolic disease of suﬃcient severity to require surgical intervention results in approximately 0.1% to 0.3% of patients surviving an acute embolic event [30,31]. Thrombus resolution with restoration of normal gas exchange and exercise tolerance occurs in most patients who experience an acute thromboembolic event. Recent data, however, suggest that incomplete anatomic and hemodynamic recovery occur more often than previously realized in patients who have been diagnosed with acute thromboembolic disease and who have received appropriate therapy, placing some of these patients at risk for developing CTEPH [32–34]. It is also apparent

that apparently acute pulmonary embolic events may be asymptomatic or may be misdiagnosed symptomatic embolic events [35,36], adding further to the pool of potential CTEPH candidates. In either scenario, inadequate thrombus resolution following one or more embolic events seems to be the inciting condition in most patients who eventually develop chronic thromboembolic disease of the major pulmonary vessels [37–39]. Deﬁning an underlying predisposition that might account for the aberrant pathway following a thromboembolic event or events has been elusive in most CTEPH patients. In a small number of patients with established disease, abnormal ﬁbrinolysis can be identiﬁed [40,41] or a prothrombotic risk factor can be detected. The presence of a lupus anticoagulant or anticardiolipin antibodies can be established in 10% to 24% of patients with chronic thromboembolic disease [42,43]. Hereditary thrombophilias such as protein C, protein S, and antithrombin III deﬁciencies cumulatively appear in less than 5% of patients [30]; factor VLeiden can be detected in 4% to 6.5% of CTEPH patients [43,44]. The incidence of other thrombophilic tendencies, such as the prothrombin gene mutation 20,210 G/A, elevated factor VII levels, and hyperhomocystinemia, have not been adequately established in this patient population [44]. A retrospective review of the clinical course of most CTEPH patients reveals that there is invariably an intervening period of months to years before cardiopulmonary complaints ﬁrst appear if the initial, suspected thromboembolic event was asymptomatic. For patients left with a modest degree of exercise intolerance after a pulmonary embolic event, a slow progression of symptoms is typically observed. During this period pulmonary hypertension and compensatory right ventricular changes slowly occur. Numerous factors probably aﬀect the progression of these changes and, therefore, the timing of patient presentation. For example, the patient’s age, previous physical health and state of conditioning, residence at altitude, and comorbid medical conditions (eg, chronic obstructive pulmonary disease [COPD], or coexisting coronary artery disease) seem to inﬂuence the clinical impact of chronic thromboembolic disease on any individual patient. What remains unclear is the pathophysiologic basis for the progression of pulmonary hypertension during this period. In certain patients, hemodynamic progression may involve thromboembolic recurrence or in situ pulmonary artery thrombosis. Small-vessel hypertensive arteriopathy, similar to

W.R. Auger et al / Cardiol Clin 22 (2004) 453–466

that seen in other forms of pulmonary hypertension, seems to develop in most CTEPH patients [45,46]. This supposition is supported by several observations in this patient population: (1) pulmonary hemodynamic progression typically occurs in the absence of recurrent pulmonary embolic events or in situ pulmonary artery thrombosis; (2) there is a poor correlation between the extent of central vessel occlusion and the degree of pulmonary hypertension, suggesting that a component of the increased pulmonary vascular resistance is from the unobstructed, distal vascular bed; and (3) histopathology demonstrates hypertensive arteriopathic changes in the resistance of vessels of lung regions both involved and uninvolved in proximal vessel–organized thromboembolic disease [45]. If CTEPH is left untreated, or should a patient’s cardiopulmonary symptoms go undiagnosed (or be misdiagnosed), progressive pulmonary hypertension, right ventricular failure, and ultimately death are the expected outcomes. Long-term survival of untreated CTEPH patients is poor and correlates with the degree of pulmonary hypertension at the time of presentation. Riedel and colleagues [37] demonstrated that the 10-year survival probability in thromboembolic patients with mean pulmonary pressure between 31 mm Hg and 40 mm Hg at the time of presentation is 50%. If the initial mean pulmonary artery pressure is 41 mm Hg to 50 mm Hg, survival probability declines to 20% over 10 years, and when the initial mean pulmonary pressure is above 50 mm Hg, 10-year survivorship is only 5%. A recent report from Poland reached similar conclusions [47]. In this study, 49 CTEPH patients deemed unsuitable for surgery were treated with anticoagulants only. Prognosis was adversely aﬀected by the presence of signiﬁcant pulmonary hypertension (mean pulmonary artery pressure > 30 mm Hg), coexisting chronic obstructive pulmonary disease, and poor exercise tolerance. Clinical presentation and patient evaluation At initial presentation, CTEPH patients most commonly complain of exertional dyspnea and an unexpected decline in exercise capabilities. Although individual tolerances vary, the physiologic basis for these complaints relates to limitations in cardiac performance caused by an elevated pulmonary vascular resistance and increased minute ventilatory needs from an elevated alveolar dead space. Patients can experience a nonproductive

455

cough, especially with exertion. Hemoptysis occurs rarely and is generally from a bronchial arterial source. Atypical chest pains are often pleuritic in nature, presumably because of peripherally infarcted lung. Exertion-related chest discomfort also occurs, however, and can often focus the initial patient evaluation on the status of the coronary vessels. This complaint typically occurs late in the course of CTEPH, as does exertionrelated presyncope, syncope, and resting dyspnea. At this point right ventricular function is unable to accommodate normal metabolic demands. The nonspeciﬁcity of these complaints contributes to the diagnostic delay experienced by most patients with chronic thromboembolic disease. Reports indicate that the delay from the onset of cardiopulmonary symptoms to the correct diagnosis can often range between 2 to 3 years [22,30]. The patient’s age, the presence or absence of coexisting cardiopulmonary disease, and prior level of physical conditioning (sedentary versus athletic) further complicate the timing and severity of symptoms at initial presentation. It is uncommon for a patient to present with a history and array of symptoms that immediately focus the diagnostician’s attention on the possibility of chronic thromboembolic disease. Consequently, during the course of their illness many CTEPH patients have been improperly labeled with alternative diagnoses, such as physical deconditioning, mild COPD, new-onset asthma, valvular heart disease, or, on occasion, psychogenic dyspnea. Findings on physical examination are generally most remarkable during the more advanced stages of disease. Even in the setting of severe pulmonary hypertension, patients can appear relatively well. The ﬁndings of pulmonary hypertension—a right ventricular lift, an accentuated pulmonic component of the second heart sound, a right ventricular S4 gallop, and tricuspid regurgitation—need to be carefully discerned. Only when signiﬁcant right ventricular dysfunction intervenes do severe tricuspid regurgitation, jugular venous distension, a right ventricular S3 gallop, hepatomegaly, ascites, peripheral edema, and cyanosis become evident. Lower-extremity examination may also disclose superﬁcial varicosities and venous stasis skin discoloration in patients with prior, symptomatic venous thrombosis. Unless there is coexisting parenchymal lung disease or airﬂow obstruction, auscultation of the lungs is typically normal. In approximately 30% of patients, a pulmonary ﬂow murmur can be auscultated over the lung ﬁelds [48]. Distinct from murmurs of

456

W.R. Auger et al / Cardiol Clin 22 (2004) 453–466

a cardiac origin, these vascular bruits arise from turbulent ﬂow across large, narrowed pulmonary vessels. Therefore they would not be present in a small-vessel pulmonary vascular disease such as idiopathic (primary) pulmonary arterial hypertension. These bruits, however, are not speciﬁc for CTEPH. They can be found in any disease state that is characterized by focal narrowing of major pulmonary vessels and have been described in congenital branch stenoses of the pulmonary arteries and large-vessel pulmonary vasculitis. Routine hematologic and blood chemistry tests can detect secondary organ dysfunction in the case of signiﬁcant right ventricular impairment. Longstanding hypoxemia may result in polycythemia; blood urea nitrogen, serum creatinine, and uric acid levels can be elevated as a result of a poor cardiac output and reduction in renal blood ﬂow; and hepatic congestion may result in signiﬁcantly abnormal liver function studies. Thrombocytopenia and a prolonged activated partial thromboplastin time in the absence of heparin anticoagulation should alert the clinician to the possible presence of a lupus anticoagulant. Pulmonary function testing, typically performed during an evaluation of a patient’s dyspnea, is most useful in deﬁning coexisting parenchymal lung disease or airﬂow obstruction. For patients with CTEPH alone, spirometry is generally unremarkable, although lung-volume measurements may disclose mild to moderate restrictive impairment caused by parenchymal scarring from prior lung infarction [49]. A mild to moderate reduction in single-breath diﬀusing capacity for carbon monoxide (DLCO) can be present in CTEPH. A normal value, however, does not exclude consideration of this diagnosis, and a severe reduction in DLCO suggests an alternative diagnosis that signiﬁcantly aﬀects the small pulmonary vascular bed [50–52]. Resting arterial blood gas analysis generally reveals a relatively normal oxygen level (PaO2), although, when measured, dead-space ventilation can be elevated. With exercise, CTEPH patients often exhibit a decline in PaO2 levels and an inappropriate increase in dead-space ventilation. These ﬁndings reﬂect ventilation-perfusion (V/Q) inequalities and an inappropriate cardiac output response to exercise; the latter manifests in a low mixed venous oxygen saturation [53]. Hypoxemia at rest suggests severe right ventricular dysfunction or the presence of a right-to-left shunt through a patent foramen ovale. Chest radiography can be deceptively normal in the early stages of CTEPH. With the develop-

ment of signiﬁcant pulmonary hypertension, enlargement of the right ventricle and pulmonary outﬂow tract can be observed. Dilatation of the central pulmonary vessels, which is occasionally mistaken for hilar adenopathy, is also a radiographic feature at this stage. Although symmetric dilatation is seen in patients with small-vessel pulmonary hypertension, CTEPH patients often demonstrate irregularly shaped and asymmetrically enlarged proximal vessels [54,55]. In the absence of coexisting parenchymal lung disease, inﬁltrates are not typical features of CTEPH, although hypo- and hyperperfused lung regions may be present. In poorly perfused lung, peripheral alveolar opacities and linear scarlike lesions from prior infarctions are commonly observed. Pleural eﬀusions, however, are uncommon unless right ventricular dysfunction, high right atrial pressure, volume overload, and ascites are clinically evident. The clinical presentation and results of the routine studies are occasionally suﬃcient to raise suspicions of a cardiac or pulmonary vascular cause for a patient’s complaints. These possibilities should also be entertained when a pulmonary diagnosis cannot be readily established as the basis for an individual’s exertional dyspnea. Transthoracic echocardiography then becomes a valuable study to suggest or conﬁrm elevated pulmonary pressures and to exclude primary pathology of the left ventricle, valvular disease, or intracardiac shunting as the cause for the pulmonary hypertension. Current technology allows an estimate of pulmonary artery systolic pressures with Doppler analysis of the degree of tricuspid regurgitation and an estimate of cardiac output. Right-heart chamber enlargement, abnormal right ventricular systolic function, paradoxical interventricular septal motion, and the impact of an enlarged right ventricle on left ventricular ﬁlling are additional echocardiographic ﬁndings in the setting of significant pulmonary hypertension [56]. The venous injection of contrast medium or agitated saline during echocardiography is of additional value in detecting a patent foramen ovale or a previously unsuspected septal defect. In symptomatic patients with echocardiographic evidence of only minimal pulmonary hypertension or modest right ventricular compromise at rest, a study obtained during exercise may document a substantial rise in pulmonary artery pressures along with an increase in right-heart size. This ﬁnding depicts the physiologic basis for a patient’s exertional dyspnea and underscores the observation that with chronic

W.R. Auger et al / Cardiol Clin 22 (2004) 453–466

thromboembolic obstruction of suﬃcient extent, the normal pulmonary vasodilatory response to exercise is abolished, and augmentation of cardiac output is accompanied by a nearly linear increase in pulmonary artery pressures [57]. Once the diagnosis of pulmonary hypertension has been established, radioisotopic V/Q scanning plays a pivotal role in distinguishing between large-vessel occlusive disease and small-vessel pulmonary vascular disease [55,58]. Patients with CTEPH invariably demonstrate one or more segmental or larger perfusion defects in lung regions with normal ventilation (Fig. 1). This ﬁnding is in contrast to the normal or mottled subsegmental perfusion pattern observed in idiopathic pulmonary arterial hypertension or in other forms of small-vessel pulmonary vascular disease [59,60]. The magnitude of perfusion defects in chronic thromboembolic disease often understates the actual degree of vascular obstruction as determined by angiography or at surgery [61]. During the process of organization proximal vessel thromboemboli may recanalize or narrow

Fig. 1. Lung perfusion study in a patient with chronic thromboembolic pulmonary hypertension. Ventilation scan was normal.

457

the vessel so that, to a limited degree, radiolabeled macroaggregated albumin may pass beyond the region of partial obstruction, thereby creating gray zones or areas of relative hypoperfusion on V/Q scan. Furthermore, mismatched segmental defects in patients with pulmonary hypertension are not speciﬁc for chronic thromboembolic disease. Extrinsic compression of proximal vessels (as seen with mediastinal adenopathy or ﬁbrosis, primary pulmonary vascular tumors, pulmonary veno-occlusive disease, and large-vessel pulmonary arteritis) may result in a V/Q appearance indistinguishable from CTEPH [62–64]. Consequently, additional imaging studies are typically necessary to establish diagnosis. Despite the increasing reliance on CT of the chest in the evaluation of the pulmonary vascular bed and thromboembolic disease, its role in patients with suspected CTEPH remains incompletely deﬁned. CT ﬁndings in chronic thromboembolic disease include mosaic perfusion of the lung parenchyma, central pulmonary vessel enlargement accompanied by variation in the size of segmental-level vessels (often diminutive in lung regions most involved with chronic thrombi), peripheral, scarlike densities in hypoattenuated lung regions, and the presence of mediastinal collateral vessels [65–68]. With contrast enhancement, organized thrombus often seems to line the larger pulmonary vessels in either a concentric or eccentric manner (Fig. 2). This appearance is to be distinguished from the intraluminal ﬁlling defects seen in acute thromboembolic disease. CT imaging is also valuable in providing information about the status of the lung parenchyma in patients with coexisting emphysematous or restrictive lung disease and in detecting mediastinal pathology that might account for occlusion of the central pulmonary arteries [69], particularly in patients with unilateral occlusion of a main pulmonary artery [70,71]. Thromboemboli may organize and become endothelialized in such a manner that their presence on CT angiography may not be apparent, however. Consequently, the absence of lining thrombus within the central pulmonary vessels does not exclude the diagnosis of chronic thromboembolic disease or the possibility of surgical intervention. Conversely, the demonstration of central thrombus has been described in primary pulmonary hypertension and other end-stage lung disorders [72,73]. Surgical endarterectomy in these cases involves a substantial perioperative mortality risk and is unlikely to mitigate the existing pulmonary hypertension. As

458

W.R. Auger et al / Cardiol Clin 22 (2004) 453–466

Fig. 2. Contrast chest CT scan in the patient shown in Fig. 1. Features of CTEPH include variable parenchymal perfusion (mosaic perfusion), web defects involving the right main pulmonary artery, irregularity and abrupt narrowing of the right descending pulmonary artery, intimal thickening of the left descending pulmonary artery, and bronchial collaterals.

a result, CT of the chest in the evaluation of the pulmonary hypertensive patient, although valuable in many respects, should not be the sole determinant in deciding whether or not a patient with suspected CTEPH is a candidate for surgical intervention. For patients with suspected chronic thromboembolic disease, right-heart catheterization and pulmonary angiography should be pursued. Pulmonary angiography, in most cases, is the most reliable means of deﬁning the extent and proximal location of organized thromboemboli. Several angiographic patterns have been found to correlate with the presence of chronic thromboembolic material at the time of surgery [74]. These patterns include vascular webs or bandlike narrowings, intimal irregularities, pouch defects, abrupt and often angular narrowing of major pulmonary arteries, and obstruction of pulmonary vessels, frequently at their point of origin. These ﬁndings are distinct from the intraluminal ﬁlling defects observed in acute pulmonary embolic disease, and in most patients with CTEPH two or more of these angiographic ﬁndings are present (Fig. 3), usually with bilateral involvement. Despite the value of pulmonary angiography, in a subgroup of patients the diagnosis of chronic thromboembolic disease and the surgical accessibility of the suspicious lesions by angiography

Fig. 3. Right pulmonary arteriogram of a patient with CTEPH in the anteroposterior and lateral projections. The anteroposterior projection demonstrates extensive areas of hypoperfusion with complete occlusion of a branch to the upper lobe and marked irregularity of the main descending pulmonary artery. The lateral projection shows a pouch occlusion of the descending pulmonary artery after the middle lobe of the right lung with absence of ﬂow to the entire right lower lobe. Because of overlap in the anteroposterior projection, the degree of chronic thromboembolic disease and its exact anatomic location are more clearly delineated in the lateral projection.

remain a question. Visualization of the vascular intima with a pulmonary angioscope has proven to be a useful in addressing this issue [75]. The angioscope, a ﬁberoptic device 120 cm in length and 3.0 mm in external diameter with 180( ﬂexion and extension capabilities at its tip, is introduced through an internal jugular vascular sheath and passed into the pulmonary arteries using ﬂuoroscopic guidance. Inﬂation of a balloon tied to the tip of the angioscope obstructs pulmonary artery blood ﬂow and allows visualization of the vessel lumen. Organized thromboemboli appear as irregularities or pitting of the intimal surface, as bands traversing the vascular lumen, as irregularly shaped vessel ostia, and as recanalization or multiple vascular channels where a single lumen should be present. At the University of California, San Diego (UCSD) Medical Center, angioscopy is performed in approximately 20% to 25% of patients undergoing an evaluation to determine their candidacy for pulmonary thromboendarterectomy. The procedure has proven most useful in predicting a beneﬁcial hemodynamic outcome in patients with relatively modest pulmonary hypertension in whom angiographic ﬁndings did not precisely deﬁne the proximal extent of the chronic

W.R. Auger et al / Cardiol Clin 22 (2004) 453–466

thromboembolic disease and in conﬁrming operability in patients with severe pulmonary hypertension who would not have been deemed surgical candidates based on angiographic ﬁndings alone [76]. The techniques of pulmonary angiography and angioscopy are described in greater detail in the article by Guillinta et al in this issue.

Surgical selection and preoperative management Patients with suspected chronic thromboembolic pulmonary hypertension undergo evaluation with the goals of establishing the need for surgical intervention, determining the surgical accessibility of the chronic thromboemboli, and estimating the risk of surgery and anticipated hemodynamic outcome for the individual patient. Most patients who ultimately go on to surgery exhibit a pulmonary vascular resistance greater than 300 dynes/ second/cmÿ5. At centers reporting their experience with pulmonary thromboendarterectomy, preoperative pulmonary vascular resistance is typically in the range of 700 to 1100 dynes/second/cmÿ5 [22–30]. At this level of pulmonary hypertension, patients can experience considerable impairment at rest and with exercise, and, in the absence of surgical intervention, prognosis is poor [37,47]. For patients with less severe pulmonary hypertension, surgery is considered based on individual circumstances. Included in this category are patients with chronic thromboemboli involving one main pulmonary artery, those with particularly vigorous lifestyle expectations (eg, professional athletes), and patients who live at altitude. Surgery would be performed to alleviate the exercise impairment associated with high dead space and minute ventilatory demands. Surgery is also occasionally oﬀered to patients with normal pulmonary hemodynamics or mild pulmonary hypertension at rest who have documented elevation of their pulmonary pressures with exertion. This group of patients has received increasing attention during the past several years because of growing concerns that their pulmonary hypertension is likely to progress in the absence of surgical intervention. An absolute criterion for surgery is the presence of accessible chronic thrombi as assessed by pulmonary angiography or angioscopy. The experience of the surgical team dictates what can be considered accessible. Current surgical techniques allow removal of organized thrombi in the main and lobar levels, extending to the proximal seg-

459

mental vessels. Dissection of segmental-level thrombus requires greater surgical skill and experience. In either situation, an accurate determination of accessible disease and a prediction that the removal of these lesions will reduce right ventricular afterload and pulmonary pressures are essential for a successful surgical outcome. In this assessment, the proximal location of the chronic thromboemboli is important, and a consideration of the extent of accessible disease in relation to the degree of pulmonary hypertension is critical. With experience, it has become apparent that the increase in pulmonary vascular resistance associated with chronic thromboembolic disease arises not only from the central, surgically accessible lesions but also from the distal, surgically inaccessible thromboemboli and the secondary, small-vessel arteriopathy. Pulmonary thromboendarterectomy relieves only the portion of the pulmonary vascular resistance arising from the accessible component of the chronic thromboembolic disease. Therefore, a focus of the preoperative evaluation is attempting to partition the proximal component of vascular resistance from that caused by distal disease. In patients with a signiﬁcant amount of coexisting distal disease, an endarterectomy of the proximal lesions theoretically will fail to mitigate pulmonary vascular resistance substantially. In patients with severe pulmonary hypertension and right ventricular dysfunction, this surgical outcome is associated with high risk of hemodynamic instability and death in the early postoperative period. Several techniques for evaluating the partitioning of the upstream and downstream components of pulmonary vascular resistance in the CTEPH patient are currently under investigation [77,78]. Kim and colleagues [79], using a pulmonary artery occlusion technique, have demonstrated that a preoperative upstream resistance of less than 60% correlated strongly with signiﬁcant pulmonary hypertension postoperatively and a higher incidence of postoperative death. The third consideration in assessing surgical candidacy is the presence of comorbid conditions that may adversely aﬀect perioperative mortality or morbidity. Coexisting coronary artery disease, parenchymal lung disease, renal insuﬃciency, hepatic dysfunction, or the presence of a hypercoagulable state may complicate patient management during the postoperative period. The reversal of pulmonary hypertension and right ventricular dysfunction with pulmonary thromboendarterectomy often improves hepatic and renal function postoperatively, however, and for

460

W.R. Auger et al / Cardiol Clin 22 (2004) 453–466

patients with coronary artery or valvular heart disease, coronary artery bypass grafting or valve replacement can be performed at the time of the pulmonary thromboendarterectomy without increasing surgical risk [80]. Consequently, advanced age or the presence of collateral disease is not an absolute contraindication to pulmonary thromboendarterectomy, although they do aﬀect risk assessment and postoperative management strategies. One exception seems to be the presence of severe parenchymal or obstructive lung disease. The postoperative course in these patients frequently is complicated by prolonged ventilatory support, and the cardiopulmonary beneﬁts of pulmonary thromboendarterectomy often result in minimal symptomatic improvement. Recent reports have suggested that the degree of pulmonary hypertension preoperatively correlates with a higher postendarterectomy mortality rate. Hartz et al [24] found that a preoperative pulmonary vascular resistance above1100 dynes/ second/cmÿ5 and a mean pulmonary artery pressure above 50 mm Hg predicted a higher operative mortality. Tscholl and colleagues [81] also showed that a pulmonary vascular resistance above 1136 dynes/second/cmÿ5 adversely inﬂuenced postoperative survivorship [81], and in a recent report of 500 operated patients by Jamieson et al [20], a preoperative pulmonary vascular above 1000 dynes/second/cmÿ5 was associated with a postoperative mortality rate of 10.1%, compared with 1.3% in patients with a preoperative pulmonary vascular resistance below 1000 dynes/second/ cmÿ5. Although these observations have not been substantiated by others [29], they have stimulated interest in the use of pulmonary vasodilator therapy in CTEPH patients before endarterectomy. It is hypothesized that with pulmonary vasodilator therapy the improved pulmonary hemodynamic proﬁle in patients with the severest form of CTEPH would lessen their perioperative mortality risk. Using intravenous prostacyclin for a period of 46 12 days before surgery, Nagaya and colleagues [82] demonstrated a 28% decrease in pulmonary vascular resistance (1510 53 to 1088 58 dynes/second/cmÿ5) and a reduction in brain natriuretic peptide levels in 12 CTEPH patients who ultimately went on to pulmonary thromboendarterectomy. Perioperative mortality in this patient group was 8.3%, compared with no deaths in the group of 21 CTEPH patients with a preoperative pulmonary vascular resistance of 1200 dynes/second/cmÿ5 or less. Postoperative hemodynamic improvement was comparable

between groups. This study, however, failed to determine whether the group with greater pulmonary hypertension would have achieved a similar outcome in the absence of pretreatment.

Pulmonary thromboendarterectomy Because the details of pulmonary thromboendarterectomy are reviewed by Thistlethwaite and Jamieson in an accompanying article in this issue and in other publications [20,83,84], only selected features of the operation are highlighted here. Surgical success requires a true endarterectomy to remove the organized thrombi, not an embolectomy. The chronic thromboembolic material is ﬁbrotic and is incorporated into the native vascular wall. An endarterectomy involves identiﬁcation of the pseudointima and creation of a dissection plane, often down to the media of the vessel, to free the thrombotic residua adequately from the central vascular bed. The removal of nonadherent, partially organized thrombus within the lumen of the central pulmonary arteries is ineﬀective in reducing right ventricular afterload. Creation of too deep a plane poses the risk of pulmonary artery perforation. The operation is performed through a median sternotomy, which allows access to the central pulmonary vessels of both lungs. Because patients with signiﬁcant CTEPH have bilateral disease, the advantages to this approach are evident. A sternotomy also avoids the pleural space and the potential to disrupt pleural adhesions and the extensive collateral bronchial circulation that develops as a result of chronically obstructed pulmonary arteries. Furthermore, this approach achieves adequate exposure if other cardiac procedures, such as coronary artery or valve surgery, are required. In a recent review of 1190 patients undergoing pulmonary thromboendarterectomy at UCSD Medical Center, 90 patients (7.6%) required a combined procedure (excluding closure of a patent foramen ovale, which occurs in approximately 30% of thromboendarterectomies). Eighty-three patients underwent coronary bypass graft surgery, three underwent tricuspid valve repair, two had mitral valve repair, and two required aortic valve replacement [80]. Cardiopulmonary bypass with periods of circulatory arrest is essential to ensure optimal exposure of the pulmonary vascular intima in a bloodless ﬁeld. The signiﬁcant back bleeding created by bronchial arterial blood ﬂow is mitigated by

W.R. Auger et al / Cardiol Clin 22 (2004) 453–466

interrupting the cardiopulmonary bypass. The periods of circulatory arrest are limited to 20 minutes, with resumption of blood ﬂow and restoration of mixed venous O2 saturation between each period of circulatory arrest. With experience, endarterectomy of either the right or left pulmonary vessel usually can be completed within one arrest period. This exposure allows the circumferential dissection of thromboembolic residua from the involved lobar, segmental, and subsegmental vessels. Over the past few years, modiﬁcations of the surgical approach have been suggested in an eﬀort to decrease risk and improve hemodynamic outcome. Dartevelle and colleagues [85] have suggested the use of intraoperative video-assisted angioscopy to increase visibility in the distal pulmonary arteries, allowing surgical intervention in patients with previously inaccessible disease. Zund et al [21] have advocated division rather than retraction of the superior vena cava to improve exposure of the right pulmonary artery. Selective antegrade cerebral perfusion during circulatory arrest has been proposed to decrease the risk of neurologic sequelae [86]. Outcome following pulmonary thromboendarterectomy Meticulous management of patients following pulmonary thromboendarterectomy and an understanding of the physiologic changes that occur postoperatively are essential to achieving successful outcomes [87]. In addition to complications seen in other forms of cardiac surgery involving cardiopulmonary bypass, such as arrhythmias, coagulation disorders, wound infections, delirium, and nosocomial pneumonia, postendarterectomy patients often experience two unique problems that adversely eﬀect oxygenation during the postoperative period: reperfusion lung injury and pulmonary artery steal. Reperfusion lung injury, clinically and biochemically, seems to be a form of high permeability, neutrophil-mediated lung damage. Leading to the need for prolonged mechanical ventilation (> 2 days) in up to one third of operated patients, severe reperfusion lung injury contributes to perioperative mortality in approximately half of the patients who die following pulmonary thromboendarterectomy. Although the exact pathophysiologic basis for this lung injury remains uncertain, its clinical behavior has been adequately described [88]. The onset of injury typically

461

occurs within the ﬁrst 24 hours postoperatively, although it may appear anytime up to 72 hours following surgery. Its severity is highly variable, ranging from mild to moderate hypoxemia in most aﬀected patients, to an acute, hemorrhagic and fatal form. Unique to this type of lung injury is that it is typically limited to endarterectomized lung regions. In these same lung regions, pulmonary arterial blood ﬂow is preferentially distributed, contributing to a greater degree of transpulmonary shunting and hypoxemia. The management of reperfusion lung edema is, to a large extent, supportive until resolution occurs. High-dose corticosteroids have been used to modulate the inﬂammatory component of the process, although their eﬀectiveness is unpredictable. Positional changes occasionally improve V/Q mismatch, although, again, these measures are not uniformly eﬀective. The use of inverseratio ventilation, a low-volume ventilatory strategy to minimize ongoing alveolar damage, and incremental levels of positive end-expiratory pressure have variably proved useful in improving ventilation–perfusion relationships and gas exchange. In a recent study of 47 patients undergoing pulmonary thromboendarterectomy, postoperative avoidance of inotropic catecholamines and vasodilators, along with a strategy of low-volume ventilation (<8 mL/kg), resulted in a lower incidence of reperfusion injury [89]. Inhaled nitric oxide has been reported to improve gas exchange, although experience has suggested that this eﬀect is transient and does not alter disease progression [90,91]. In extreme situations, extracorporeal support has been used successfully when aggressive conventional measures have been inadequate to maintain oxygenation. Further contributing to V/Q mismatching after endarterectomy is the occurrence of pulmonary artery steal, a postoperative redistribution of pulmonary blood ﬂow away from previously well-perfused lung segments and into newly endarterectomized lung regions. Although the basis for the shift in blood ﬂow is uncertain, clinical observations suggest that it occurs in most patients following pulmonary thromboendarterectomy, that it does not result from thrombosis of the nonoperated pulmonary segments, and that the distribution of pulmonary blood ﬂow improves over time in most patients [92,93]. In most CTEPH patients undergoing pulmonary thromboendarterectomy, both the shortterm and long-term hemodynamic outcomes have been favorable. With restoration of blood ﬂow to

462

W.R. Auger et al / Cardiol Clin 22 (2004) 453–466

previously occluded lung segments, an immediate reduction in right ventricular afterload occurs, resulting in a decline in pulmonary artery pressures and an augmentation in cardiac output. Since 1997, several groups have reported such improvements in pulmonary hemodynamics following surgery [20,25–29,81,85,89,94,95]. In 500 consecutive operated patients at the UCSD Medical Center between 1998 and 2002, the pre- and postoperative hemodynamic values were mean pulmonary artery pressures, 46 11.0 mm Hg to 28 10.1 mm Hg (P < 0.0001); cardiac output, 3.8 1.3 L/min to 5.5 1.5 L/min (P < 0.0001); and pulmonary vascular resistance, 893 443.5 dynes/second/cmÿ5 to 285 214.7 dynes/second/ cmÿ5 (P < 0.0001) [20]. Furthermore, this hemodynamic improvement has been sustained for months to years after endarterectomy, accompanied by substantial gains in functional status, gas exchange, and quality of life [23,96–101]. Not all CTEPH patients experience normalization or near-normalization of pulmonary hemodynamics after endarterectomy. Approximately 10% to 15% of postoperative patients are left with a residual pulmonary vascular resistance above 500 dynes/second/cmÿ5. Although in two thirds of these patients the postoperative hemodynamic improvement is signiﬁcant, approximately 3% to 5% of operated patients experience minimal to no hemodynamic beneﬁt from surgery. The basis for this lack of improvement relates to the presence of a distal vasculopathy in which the pulmonary pressures and cardiac function are unaﬀected by the removal of chronic thromboembolic material from the proximal vessel. These patients are particularly diﬃcult to manage during the postoperative period. Depending on the level of residual pulmonary hypertension, postsurgical hemodynamic instability may result from the persistently elevated right ventricular afterload and also from the physiologic consequences of cardiopulmonary bypass, deep hypothermia, residual metabolic acidosis, and hypoxemia. Management goals include minimizing systemic oxygen consumption, optimizing right ventricular preload, and providing inotropic support while avoiding systemic hypotension and a drop in coronary perfusion pressure. Pharmacologic attempts at reducing right ventricular afterload in these patients are often ineﬀectual, because pulmonary vascular resistance is ﬁxed, and there is a risk of provoking a decrease in systemic vascular resistance. Inhaled nitric oxide oﬀers a theoretic advantage with its pulmonary vasodilatory

properties and negligible systemic vascular eﬀects. Anecdotal experience with this approach in the setting of persistent postoperative pulmonary hypertension has been disappointing, however. If the patient survives the immediate postoperative period, long-term pulmonary vasodilator therapy, such as the use of intravenous epoprostenol or an endothelin antagonist, should be considered [102]. It has been estimated that more than 2500 pulmonary thromboendarterectomies have been performed worldwide since 1970 [30], approximately 1700 of them at UCSD Medical Center. In patient series reported since 1996, operative mortality rates have ranged between 4.4% and 24% [20,24–29,81,85,89,94,95]. Factors that contribute to perioperative mortality risks have not been completely elucidated, although New York Heart Association class IV functional status, age older than 70 years, the severity of preoperative pulmonary vascular resistance, the presence of right ventricular failure (correlated with high right atrial pressures), morbid obesity, and the duration of pulmonary hypertension have been to reported to aﬀect postoperative survival [20,24,81,103,104]. Attributable causes of death following pulmonary thromboendarterectomy are variable. Cardiac arrest, multiorgan failure, uncontrollable mediastinal bleeding, sepsis syndrome, and massive pulmonary hemorrhage are among the causes of death cited [24,26–29,81]. Severe reperfusion lung injury and residual pulmonary hypertension and right ventricular dysfunction are the leading contributors to perioperative mortality in larger patient series [20]. Since the inception of the pulmonary thromboendarterectomy program at UCSD in 1970, there has been a steady decline in operative mortality rates. For the ﬁrst 200 operated patients between 1970 and 1990, the in-hospital mortality rate was 17.0%. For the 500 patients undergoing pulmonary thromboendarterectomy between 1994 and 1998, the operative mortality rate was 8.8%, declining further to 4.4% for the 500 patients operated on between 1998 and 2002 [20]. Results from this same group have also shown that longterm survivorship following hospital discharge is dramatically improved relative to these patients’ expected longevity without surgical intervention. In a cohort of 532 patients followed postoperatively for up to 19 years, Archibald et al [100] demonstrated a 75% probability of survivorship beyond 6 years. These encouraging results bear testimony to the eﬀectiveness of pulmonary thromboendarterectomy for the treatment of

W.R. Auger et al / Cardiol Clin 22 (2004) 453–466

appropriately selected CTEPH patients. The declining perioperative mortality rates also possibly result from increasing physician awareness of the disease, prompting referrals to experienced surgical centers before the onset of the severe secondary peripheral arteriopathy and right-heart failure that can be so compromising to patient care. In pulmonary thromboendarterectomy, consistency of patient evaluation, surgical experience, and the knowledgeable delivery of postoperative care are of utmost importance in achieving sustained, positive outcomes.

[13]

[14]

[15]

[16]

References [1] Ball KP, Goodwin JF, Harrison CV. Massive thrombotic occlusion of the large pulmonary arteries. Circulation 1956;14:766–83. [2] Owen WR, Thomas WA, Castleman B, Bland EF. Unrecognized emboli to the lungs with subsequent cor pulmonale. N Engl J Med 1953;249:919–26. [3] Hollister LE, Cull VL. The syndrome of chronic thrombosis of the major pulmonary arteries. Am J Med 1956;21:312–20. [4] Carroll D. Chronic obstruction of major pulmonary arteries. Am J Med 1950;9:175–85. [5] Hurwitt ES, Schein CJ, Rifkin H, Lebendiger A. A surgical approach to the problem of chronic pulmonary artery obstruction due to thrombosis or stenosis. Ann Surg 1958;147:157–65. [6] Houk VN, Hufnagel CH, McClenathan JE, Moser KM. Chronic thrombotic obstruction of major pulmonary arteries: report of a case successfully treated by thromboendarterectomy and a review of the literature. Am J Med 1963;35:269–82. [7] Synder WA, Kent DC, Baisch BF. Successful endarterectomy of chronically occluded pulmonary artery: clinical report and physiologic studies. J Thorac Cardiovasc Surg 1963;45:482–9. [8] Castleman B, McNeeley BU, Scannell G. Case records of the Massachusetts General Hospital, Case 32–1964. N Engl J Med 1964;271:40–50. [9] Moser KM, Houk VN, Jones RC, Hufnagel CH. Chronic, massive thrombotic obstruction of pulmonary arteries: analysis of four operated cases. Circulation 1965;32:377–85. [10] Nash ES, Shapiro S, Landau A, Barnard CN. Successful thromboembolectomy in long-standing thromboembolic pulmonary hypertension. Thorax 1966;23:121–30. [11] Moor GF, Sabiston DC Jr. Embolectomy for chronic pulmonary embolism and pulmonary hypertension: case report and review of the problem. Circulation 1970;41:701–8. [12] Cabrol C, Cabrol A, Acar J, Gandjbakhch I, Guiraudon G, Laughlin L, et al. Surgical correction of chronic postembolic obstructions of the

[17]

[18]

[19]

[20]

[21]

[22]

[23]

[24]

[25]

[26]

463

pulmonary arteries. J Thorac Cardiovasc Surg 1978;76:620–8. Sabiston DC Jr, Wolfe WG, Oldham HN Jr, Wechsler AS, Crawford FA Jr, Jones KW, et al. Surgical management of chronic pulmonary embolism. Ann Surg 1977;185:699–712. Utley JR, Spragg RG, Long WB, Moser KM. Pulmonary endarterectomy for chronic thromboembolic obstruction: recent surgical experience. Surgery 1982;92:1096–102. Chitwood WR, Sabiston DC Jr, Wechsler AS. Surgical treatment of chronic unresolved pulmonary embolism. Clin Chest Med 1984;5:507–36. Daily PO, Dembitsky WP, Peterson KL, Moser KM. Modiﬁcations of techniques and early results of pulmonary thromboendarterectomy for chronic pulmonary embolism. J Thorac Cardiovasc Surg 1987;93:221–33. Moser KM, Daily PO, Peterson K, Dembitsky W, Vapnek JM, Shure D, et al. Thromboendarterectomy for chronic, major-vessel thromboembolic pulmonary hypertension: immediate and long-term results in 42 patients. Ann Intern Med 1987;107:560–5. Daily PO, Dembitsky WP, Iversen S. Technique of pulmonary thromboendarterectomy for chronic pulmonary embolism. J Card Surg 1989;4:10–24. Daily PO, Dembitsky WP, Daily RP. Dissectors for pulmonary thromboendarterectomy. Ann Thorac Surg 1991;51:842–3. Jamieson SW, Kapelanski DP, Sakakibara N, Manecke GR, Thistlethwaite PA, Kerr KM, et al. Pulmonary endarterectomy: experience and lessons learned in 1,500 cases. Ann Thorac Surg 2003;76:1457–64. Zund G, Pretre R, Niederhauser U, Vogt PR, Turina MI. Improved exposure of the pulmonary arteries for thromboendarterectomy. Ann Thorac Surg 1998;66:1821–3. Simonneau G, Azarian R, Brenot F, Dartevelle PG, Musset D, Duroux P. Surgical management of unresolved pulmonary embolism: a personal series of 72 patients. Chest 1995;107:52S–5S. Mayer E, Dahm M, Hake U, Schmid FX, Pitton M, Kupferwasser I, et al. Mid-term results of pulmonary thromboendarterectomy for chronic thromboembolic pulmonary hypertension. Ann Thorac Surg 1996;61:1788–92. Hartz RS, Byme JG, Levitsky S, Park J, Rich S. Predictors of mortality in pulmonary thromboendarterectomy. Ann Thorac Surg 1996;62:1255–9. Nakajima N, Masuda M, Mogi K. The surgical treatment for chronic pulmonary thromboembolism—our surgical experience and current review of the literature. Ann Thorac Cardiovasc Surg 1997;3:15–21. Gilbert TB, Gaine SP, Rubin LJ, Sequeira AJ. Short-term outcome and predictors of adverse events following pulmonary thromboendarterectomy. World J Surg 1998;22:1029–32.

464

W.R. Auger et al / Cardiol Clin 22 (2004) 453–466

[27] Ando M, Okita Y, Tagusari O, Kitamura S, Nakanishi N, Kyotani S. Surgical treatment for chronic thromboembolic pulmonary hypertension under profound hypothermia and circulatory arrest in 24 patients. J Card Surg 1999;14:377–85. [28] Rubens F, Wells P, Bencze S, Bourke M. Surgical treatment of chronic thromboembolic pulmonary hypertension. Can Respir J 2000;7:49–57. [29] D’Armini AM, Cattadori B, Monterosso C, Klersy C, Emmi V, Piovella F, et al. Pulmonary thromboendarterectomy in patients with chronic pulmonary hypertension: hemodynamic characteristics and changes. Eur J Cardiothorac Surg 2000;18: 696–702. [30] Fedullo PF, Auger WR, Kerr KM, Kim NH. Chronic thromboembolic pulmonary hypertension. Seminars in Respiratory and Critical Care Medicine 2003;24:273–85. [31] Dalen JE, Albert JS. Natural history of pulmonary embolism. Prog Cardiovasc Dis 1975;17:259–70. [32] Ribeiro A, Lindmarker P, Johnsson H, JuhlinDannfelt A, Jorfeldt L. Pulmonary embolism. One-year follow-up with echocardiography Doppler and ﬁve-year survival analysis. Circulation 1999;99:1325–30. [33] Peterson KL. Acute pulmonary embolism: has its evolution been redeﬁned?. Circulation 1999;99: 1280–3. [34] Wartski M, Collignon M-A. Incomplete recovery of lung perfusion after 3 months in patients with acute pulmonary embolism treated with antithrombotic agents. J Nucl Med 2000;41:1043–8. [35] Meignan M, Rosso J, Gauthier H, Brunengo F, Claudel S, Sagnard L, et al. Systematic lung scans reveal a high frequency of silent pulmonary embolism in patients with proximal deep venous thrombosis. Arch Intern Med 2000;160:159–64. [36] Ryu JH, Olson EJ, Pellikka PA. Clinical recognition of pulmonary embolism: problem of unrecognized and asymptomatic cases. Mayo Clin Proc 1998;73:873–9. [37] Riedel M, Stanek V, Widimsky J, Prerovsky I. Longterm follow-up of patients with pulmonary thromboembolism: late prognosis and evolution of hemodynamic and respiratory data. Chest 1982; 81:151–8. [38] Fedullo PF, Rubin LJ, Kerr KM, Auger WR, Channick RN. The natural history of acute and chronic thromboembolic disease: the search for the missing link. Eur Resp J 2000;15:435–7. [39] Egermayer P, Peacock AJ. Is pulmonary embolism a common cause of pulmonary hypertension? Limitations of the embolic hypothesis. Eur Resp J 2000;15:440–8. [40] Rich S, Levitsky S, Brundage BH. Pulmonary hypertension from chronic pulmonary thromboembolism. Ann Intern Med 1988;108:425–34. [41] Olman MA, Marsh JJ, Lang IM, Moser KM, Binder BR, Schleef RR. The endogenous ﬁbrino-

[42]

[43]

[44]

[45]

[46]

[47]

[48]

[49]

[50]

[51]

[52]

[53]

lytic system in chronic large-vessel thromboembolic pulmonary hypertension. Circulation 1992; 86:1241–8. Auger WR, Permpikul P, Moser KM. Lupus anticoagulant, heparin use, and thrombocytopenia in patients with chronic thromboembolic pulmonary hypertension: a preliminary report. Am J Med 1995;99:392–6. Wolf M, Soyer-Neumann C, Parent F, Eschwege V, Jaillet H, Meyer D, et al. Thrombotic risk factors in pulmonary hypertension. Eur Respir J 2000;15:395–9. Sompradeekul S, Fedullo PF, Le DT. Congenital and acquired thrombophilias in patients with chronic thromboembolic pulmonary hypertension [abstract]. Am J Respir Crit Care Med 1999;159: A358. Moser KM, Bloor CM. Pulmonary vascular lesions occurring in patients with chronic major vessel thromboembolic pulmonary hypertension. Chest 1993;103:685–92. Kim H, Yung GL, Marsh JJ, Konopka RG, Pedersen CA, Chiles PG, et al. Pulmonary vascular remodeling distal to pulmonary artery ligation is accompanied by upregulation of endothelin receptors and nitric oxide synthase. Exp Lung Res 2000;26:287–301. Lewczuk J, Piszko P, Jagas J, Porada A, Wojciak S, Sobkowicz B, et al. Prognostic factors in medically treated patients with chronic pulmonary embolism. Chest 2001;119:818–23. Auger WR, Moser KM. Pulmonary ﬂow murmurs: a distinctive physical sign found in chronic pulmonary thromboembolic disease [abstract]. Clin Res 1989;37:145A. Morris TA, Auger WR, Ysrael MZ, Olson LK, Channick RN, Fedullo PF, et al. Parenchymal scarring is associated with restrictive spirometric defects in patients with chronic thromboembolic pulmonary hypertension. Chest 1996;110: 399–403. Steenhuis LH, Groen HJM, Koeter GH, van der Mark THW. Diﬀusion capacity and haemodynamics in primary and chronic thromboembolic pulmonary hypertension. Eur Respir J 2000;16: 276–81. Elliott CG, Colby TV, Hill T, Crapo RO. Pulmonary veno-occlusive disease associated with severe reduction of single-breath carbon monoxide diﬀusing capacity. Respiration (Herrlisheim) 1988; 53:262–6. Steen VD, Graham G, Conte C, Owens G, Medsger TA Jr. Isolated diﬀusing capacity reduction in systemic sclerosis. Arthritis Rheum 1992;35:765–70. Kapitan KS, Buchbinder M, Wagner PD, Moser KM. Mechanisms of hypoxemia in chronic thromboembolic pulmonary hypertension. Am Rev Respir Dis 1989;139:1149–54.

W.R. Auger et al / Cardiol Clin 22 (2004) 453–466 [54] Woodruﬀ WW III, Hoeck BE, Chitwood WR Jr, Lyerly HK, Sabiston DC Jr, Chen JT. Radiographic ﬁndings in pulmonary hypertension from unresolved embolism. AJR Am J Roentgenol 1985;144:681–6. [55] D’Alonzo GE, Bower JS, Dantzker DR. Diﬀerentiation of patients with primary and thromboembolic pulmonary hypertension. Chest 1984;85: 457–61. [56] Dittrich HC, McCann HA, Blanchard DG. Cardiac structure and function in chronic thromboembolic pulmonary hypertension. Am J Card Imaging 1994;8:18–27. [57] Fedullo PF, Auger WR, Moser KM, Watt CN, Buchbinder M, Peterson KL. Hemodynamic response to exercise in patients with chronic, major vessel thromboembolic pulmonary hypertension. Am Rev Respir Dis 1990;141:A890. [58] Lisbona R, Kreisman H, Novales-Diaz J, Derbekyan V. Perfusion lung scanning: diﬀerentiation of primary from thromboembolic pulmonary hypertension. AJR Am J Roentgenol 1985; 144:27–30. [59] Rich S, Pietra GG, Kieras K, Hart K, Brundage BH. Primary pulmonary hypertension: radiographic and scintigraphic patterns of histologic subtypes. Ann Intern Med 1986;105:499–502. [60] Powe JE, Palevsky HI, McCarthy KE, Alavi A. Pulmonary arterial hypertension: value of perfusion scintigraphy. Radiology 1987;164:727–30. [61] Ryan KL, Fedullo PF, Davis GB, Vasquez TE, Moser KM. Perfusion scan ﬁndings understate the severity of angiographic and hemodynamic compromise in chronic thromboembolic pulmonary hypertension. Chest 1988;93:1180–5. [62] Bailey CL, Channick RN, Auger WR, Fedullo PF, Kerr KM, Yung GL, et al. ‘‘High probability’’ perfusion lung scans in pulmonary venoocclusive disease. Am J Respir Crit Care Med 2000;162: 1974–8. [63] Cook DJ, Tanser PH, Dobranowski J, Tuttle RJ. Primary pulmonary artery sarcoma mimicking pulmonary thromboembolism. Can J Cardiol 1988;4:393–6. [64] Palevsky HI, Cone L, Alavi A. A case of ‘‘falsepositive’’ high probability ventilation-perfusion lung scan due to tuberculous adenopathy with a discussion of other causes of ‘‘false-positive’’ high probability ventilation-perfusion lung scans. J Nucl Med 1991;32:512–7. [65] King MA, Bergin CJ, Yeung D, Belezzouli E, Olson L, Ashburn W, et al. Chronic pulmonary thromboembolism: detection of regional hypoperfusion with CT. Radiology 1994;191:359–63. [66] Schwickert HC, Schweden F, Schild HH, Piepenburg R, Duber C, Kauczor H-U, et al. Pulmonary arteries and lung parenchyma in chronic pulmonary embolism: preoperative and postoperative CT ﬁndings. Radiology 1994;191:351–7.

465

[67] Tardivon AA, Musset D, Maitre S, Brenot F, Dartevelle P, Simonneau G, et al. Role of CT in chronic pulmonary embolism: comparison with pulmonary angiography. J Comput Assist Tomogr 1993;17:345–52. [68] Bergin CJ. Chronic thromboembolic pulmonary hypertension: the disease, the diagnosis, and the treatment. Semin Ultrasound CT MR 1997;18: 383–91. [69] Berry PF, Buccigrossi D, Peabody J, Peterson KL, Moser KM. Pulmonary vascular occlusion and ﬁbrosing mediastinitis. Chest 1986;89:296–301. [70] Bergin CJ, Hauschildt JP, Brown MA, Channick RN, Fedullo PF. Identifying the cause of unilateral hypoperfusion in patients suspected to have chronic pulmonary thrombo-embolism: diagnostic accuracy of helical CT and conventional angiography. Radiology 1999;213:743–9. [71] Cho SR, Tisnado J, Cockrell CH, Beachley MC, Fratkin MJ, Henry DA. Angiographic evaluation of patients with unilateral massive perfusion defects on the lung scan. Radiographics 1987;7: 729–45. [72] Moser KM, Fedullo PF, Finkbeiner WE, Golden J. Do patients with primary pulmonary hypertension develop extensive central thrombi? Circulation 1995;91:741–5. [73] Russo A, De Luca M, Vigna C, De Rito V, Pacilli M, Lombardo A, et al. Central pulmonary artery lesions in chronic obstructive pulmonary disease. A transesophageal echocardiographic study. Circulation 1999;100:1808–15. [74] Auger WR, Fedullo PF, Moser KM, Buchbinder M, Peterson KL. Chronic major-vessel thromboembolic pulmonary artery obstruction: appearance at angiography. Radiology 1992;182:393–8. [75] Shure D, Gregoratos G, Moser KM. Fiberoptic angioscopy: role in the diagnosis of chronic pulmonary arterial obstruction. Ann Intern Med 1985;103:844–50. [76] Sompradeekul S, Fedullo PF, Kerr KM, Channick RN, Auger WR. The role of pulmonary angioscopy in the preoperative assessment of patients with thromboembolic pulmonary hypertension (CTEPH) [abstract]. Am J Respir Crit Care Med 1999;159:A456. [77] Bergin CJ, Sirlin C, Deutsch R, Fedullo P, Hauschildt J, Huynh T, et al. Predictors of patient response to pulmonary thromboendarterectomy. AJR Am J Roentgenol 2000;174:509–15. [78] Fesler P, Kim HS, Channick RN, Rubin LJ, Naeije R. Partition of pulmonary vascular resistance in chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med 2002; 165:A332. [79] Kim HS, Fesler P, Channick RN, Knowlton KU, Ben-Yehuda O, Lee SH, et al. Preoperative partitioning of pulmonary vascular resistance correlates with early outcome after thromboen-

466

[80]

[81]

[82]

[83]

[84]

[85]

[86]

[87]

[88]

[89]

[90]

[91]

W.R. Auger et al / Cardiol Clin 22 (2004) 453–466 darterectomy for chronic thromboembolic pulmonary hypertension. Circulation 2004;109:18–22. Thistlethwaite PA, Auger WR, Madani MM, Pradhan S, Kapelanski DP, Jamieson SW. Pulmonary thromboendarterectomy combined with other cardiac operations: indications, surgical approach, and outcome. Ann Thorac Surg 2001; 72:13–9. Tscholl D, Langer F, Wendler O, Wilkens H, Georg T, Schafers H-J. Pulmonary thromboendarterectomy – risk factors for early survival and hemodynamic improvement. Eur J Cardiothorac Surg 2001;19:771–6. Nagaya N, Sasaki N, Ando M, Ogino H, Sakamaki F, Kyotani S, et al. Prostacyclin therapy before pulmonary thromboendarterectomy in patients with chronic thromboembolic pulmonary hypertension. Chest 2003;123:338–43. Daily PO, Dembitsky WP, Jamieson SW. The evolution and the current state of the art of pulmonary thromboendarterectomy. Semin Thorac Cardiovasc Surg 1999;11:152–63. Jamieson SW, Kapelanski DP. Pulmonary thromboendarterectomy. Curr Probl Surg 2000;37: 165–252. Dartevelle P, Fadel E, Chapelier A, Macchiarini P, Cerrina J, Parquin F, et al. Angioscopic videoassisted pulmonary endarterectomy for post-embolic pulmonary hypertension. Eur J Cardiothorac Surg 1999;16:38–43. Zeebregts CJ, Dossche KM, Morshuis WJ, Knaepen PJ, Schepens MA. Surgical thromboendarterectomy for chronic thromboembolic pulmonary hypertension using circulatory arrest with selective antegrade cerebral perfusion. Acta Chir Belg 1998;98:95–7. Fedullo PF, Auger WR, Dembitsky WP. Postoperative management of the patient undergoing pulmonary thromboendaterectomy. Semin Thorac Cardiovasc Surg 1999;11:172–8. Levinson RM, Shure D, Moser KM. Reperfusion pulmonary edema after pulmonary thromboendarterectomy. Am Rev Respir Dis 1986;134: 1241–5. Mares P, Gilbert TB, Tschernko EM, Hiesmayr M, Muhm M, Herneth A, et al. Pulmonary artery thromboendarterectomy: a comparison of two diﬀerent postoperative treatment strategies. Anesth Analg 2000;90:267–73. Pinelli G, Mertes PM, Carteaux JP, Hubert T, Dopﬀ C, Burtin P, et al. Inhaled nitric oxide as an adjunct to pulmonary thromboendarterectomy. Ann Thorac Surg 1996;61:227–9. Gardeback M, Larsen FF, Radegran K. Nitric oxide improves hypoxaemia following reperfusion

[92]

[93]

[94]

[95]

[96]

[97]

[98]

[99]

[100]

[101]

[102]

[103]

[104]

oedema after pulmonary thromboendarterectomy. Br J Anaesth 1995;75:798–800. Olman MA, Auger WR, Fedullo PF, Moser KM. Pulmonary vascular steal in chronic thromboembolic pulmonary hypertension. Chest 1990;98: 1430–4. Moser KM, Metersky ML, Auger WR, Fedullo PF. Resolution of vascular steal after pulmonary thromboendarterectomy. Chest 1993;104:1441–4. Mayer E, Kramm T, Dahm M, Moersig W, Eberle B, Duber C, et al. Early results of pulmonary thromboendarterectomy in chronic thromboembolic pulmonary hypertension. Z Kardiol 1997;86: 920–7. Masuda M, Nakajima N. Our experience of surgical treatment for chronic pulmonary thromboembolism. Ann Thorac Cardiovasc Surg 2001;7: 261–5. Moser KM, Auger WR, Fedullo PF, Jamieson SW. Chronic thromboembolic pulmonary hypertension: clinical picture and surgical treatment. Eur Respir J 1992;5:334–42. Kramm T, Mayer E, Dahm M, Guth S, Menzel T, Pitton M, et al. Long-term results after thromboendarterectomy for chronic pulmonary embolism. Eur J Cardiothorac Surg 1999;15:579–84. Kapitan KS, Clausen JL, Moser KM. Gas exchange in chronic thromboembolism after pulmonary thromboendarterectomy. Chest 1990;98: 14–9. Tanabe N, Okada O, Nakagawa Y, Masuda M, Kato K, Nakajima N, et al. The eﬃcacy of pulmonary thromboendarterectomy on long-term gas exchange. Eur Respir J 1997;10:2066–72. Archibald CJ, Auger WR, Fedullo PF, Channick RN, Kerr KM, Jamieson SW, et al. Long-term outcome after pulmonary thromboendarterectomy. Am J Respir Crit Care Med 1999;160:523–8. Zoia MC, D’Armini AM, Beccaria M, and the Pavia Thromboendarterectomy Group. Mid-term eﬀects of pulmonary thromboendarterectomy on clinical and cardiopulmonary functional status. Thorax 2002;57:608–12. McLaughlin VV, Genthner DE, Panella MM, Hess DM, Rich S. Compassionate use of continuous prostacyclin in the management of secondary pulmonary hypertension: a case series. Ann Intern Med 1999;130:740–3. Daily PO, Dembitsky WP, Iversen S, Moser KM, Auger W. Risk factors for pulmonary thromboendarterectomy. J Thorac Cardiovasc Surg 1990;99: 670–8. Moser KM, Auger WR, Fedullo PF. Chronic major vessel thromboembolic pulmonary hypertension. Circulation 1990;81:1735–43.

Cardiol Clin 22 (2004) 327–341

Classiﬁcation and epidemiology of pulmonary hypertension Vallerie V. McLaughlin, MD Pulmonary Hypertension Program, Division of Cardiovascular Medicine, University of Michigan, Woman’s RM. L3119, 1500 E. Medical Center Drive, Ann Arbor, MI 48109-0273, USA

In 1951, Dresdale et al [1], having collected data on 39 patients with unexplained pulmonary hypertension, coined the term primary pulmonary hypertension (PPH). Eight years later, Wood [2] described the clinical features of this disease in a series of 17 patients, and by 1971 more than 600 cases had been reported. Meanwhile, in 1967, cardiac catheterization laboratories in Switzerland noted an abrupt increase in the incidence of pulmonary hypertension for which neither a cardiac nor pulmonary cause could be found, and such patients were ultimately diagnosed as having PPH [3]. Shortly thereafter, similar reports from Germany and Austria implicated the popular overthe-counter appetite suppressant, aminorex, as the causative agent. Withdrawal of aminorex from the market was followed by a subsidence of the epidemic. Prompted by this outbreak and the many questions it raised, the World Health Organization (WHO) convened a meeting in 1973 in Geneva, Switzerland, and invited a small group of clinical cardiologists, clinical investigators, and pathologists to assess the understanding of PPH [4]. This meeting marked the beginning of attempts to classify this complex disease. With the widespread acceptance of PPH as a unique disease entity, all other forms of pulmonary hypertension were collectively referred to as secondary pulmonary hypertension. The remarkable advances in knowledge about pulmonary hypertension during the ensuing 25 years led to the second WHO cosponsored symposium on pulmonary hypertension in Evian, France,

E-mail address: [email protected]

in 1998. Larger and more diverse than the 1973 meeting, the Evian meeting addressed a broad array of topics including the nomenclature and classiﬁcation of all pulmonary hypertensive diseases. Fueled by the frustration that had arisen from the categorizing of a vast array of diﬀerent diseases as secondary pulmonary hypertension and the realization that pulmonary hypertension related to certain speciﬁc diseases is clinically and pathologically similar to PPH, new nomenclature, known as the Evian classiﬁcation, was proposed (Box 1). This classiﬁcation focused on the biologic expression of the disease and etiologic factors in an attempt to group these illnesses on the basis of clinical similarities. It served as a useful guide to the clinician both in terms of the diagnostic evaluation and the treatment algorithm. Category I, pulmonary arterial hypertension (PAH) included PPH, and also pulmonary hypertension associated with other disease entities that clinically appears similar to PPH in presentation and response to treatment. In addition, a functional classiﬁcation patterned after the New York Heart Association functional classiﬁcation for heart disease was developed to allow comparisons of patients with respect to the clinical severity of the disease process (Box 2). The main diﬀerence between the WHO functional classiﬁcation of pulmonary hypertension and the New York Heart Association functional classiﬁcation is the inclusion of patients with syncope as functional class IV in the former. The Evian classiﬁcation became well accepted by clinicians and has even been adapted by regulatory authorities for the purposes of drug registration, with both bosentan and treprostinil approved by the Food

0733-8651/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ccl.2004.04.001

328

V.V. McLaughlin / Cardiol Clin 22 (2004) 327–341

Box 1. The Evian clinical classification of pulmonary arterial hypertension Pulmonary arterial hypertension (PAH) 1. Primary pulmonary hypertension Familial pulmonary hypertension 2. Primary pulmonary hypertension associated with Connective tissue disease Congenital heart disease Portal hypertension HIV infection Drugs /toxins (a) Anorexigens (b) Other agents

3. Persistent pulmonary hypertension of the newborn 4. Pulmonary veno-occlusive disease 5. Pulmonary capillary hemangiomatosis Pulmonary venous hypertension 1. Left-sided atrial or ventricular heart disease 2. Left-sided valvular heart disease 3. Extrinsic compression of central pulmonary veins Fibrosing mediastinitis Adenopathy/tumors 4. Other Pulmonary hypertension associated with disorders of the respiratory system or hypoxemia 1. Chronic obstructive pulmonary disease 2. Interstitial lung disease 3. Sleep-disordered breathing 4. Alveolar hypoventilation disorders 5. Chronic exposure to high altitude 6. Neonatal lung disease 7. Alveolar-capillary dysplasia 8. Other Pulmonary hypertension caused by chronic thrombotic or embolic disease 1. Thromboembolic obstruction of proximal pulmonary arteries 2. Thromboembolic obstruction of the distal pulmonary arteries 3. Pulmonary embolism (tumor, ova parasites, foreign material) Pulmonary hypertension due to disorders directly affecting the pulmonary vasculature 1. Inflammatory Schistosomiasis Sarcoidosis Histocytosis X Other Modified from Rich S, editor. Primary pulmonary hypertension: executive summary from the World Symposium – Primary Pulmonary Hypertension 1998. Available at: http://www.who.int/ncd/cvd/pph.html

and Drug Administration for the treatment of PAH. Although the Evian classiﬁcation has served the pulmonary hypertension community well, minor

modiﬁcations were proposed at the Third World Symposium on Pulmonary Arterial Hypertension, held in Venice, Italy, in 2003. Perhaps the most signiﬁcant change was to the nomenclature of PPH.

V.V. McLaughlin / Cardiol Clin 22 (2004) 327–341

329

Pulmonary arterial hypertension Box 2. WHO functional classification of pulmonary hypertension Class I – Patients with pulmonary hypertension but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or syncope. Class II – Patients with pulmonary hypertension resulting in slight limitation of physical activity who are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope. Class III – Patients with pulmonary hypertension resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope. Class IV – patients with pulmonary hypertension with inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnea and/or fatigue may even be present at rest. Discomfort is increased by any physical activity. Modified from Rich S, editor. Primary pulmonary hypertension: executive summary from the world symposium – Primary Pulmonary Hypertension 1998. Available at: http://www.who.int/ncd/cvd/pph.html)

The term primary pulmonary hypertension has been abandon in favor of sporadic or idiopathic PAH, so category I consists of sporadic PAH (IPAH), familial PAH (FPAH), and PAH related to connective tissue disease, congenital heart disease, portal hypertension, HIV infection, drugs and toxins, and other causes (Box 3). Additionally, pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH) have been categorized as a subgroup of PAH, because the clinical presentation of and risk factors for these entities are similar. This article focuses on class I, PAH.

Sporadic pulmonary arterial hypertension Although IPAH (formerly referred to as PPH) is the best studied entity in this category, validated indices commonly used to quantify the occurrence of the disease in the population, such as incidence, prevalence, and mortality, are not available in the literature. Nevertheless, the incidence (number of new cases per year in a welldeﬁned population) has been estimated to vary from approximately one to two per 1 million inhabitants in countries such as the United States, France, and Israel [5,6]. Considering the rarity, subtle presentation, and diagnostic dilemma commonly posed by this disease, underdiagnosis and underreporting are probably widespread, making a true calculation of incidence diﬃcult. Lilienfeld and Rubin [7] examined the annual age-adjusted mortality rates for blacks and whites in the United States from 1979 to 1996. The highest mortality rates were noted among infants, whereas children in general experienced the lowest death rates. After childhood, death rates increased with age and were greater among women than men and among blacks than whites. The average annual age-adjusted mortality per 1 million persons from 1979 to 1996 was two for white men, ﬁve for black men, three for white women, and nine for black women. These authors also noted a temporal rise in mortality, which may indicate either better diagnosis of cases with no change in the underlying incidence or a real increase in the incidence of the disease. The largest natural history study of IPAH was the National Institutes of Health (NIH) Registry on PPH, which recruited 187 patients from 32 centers from 1981 to 1987 [8]. In this registry, IPAH was deﬁned as a mean pulmonary artery pressure (mPAP) of greater than 25 mm Hg at rest or 30 mm Hg with exercise, in the absence of another cause for the pulmonary hypertension. The mean age of patients enrolled was 36.4 years, with the highest frequency being in the third decade for female patients and in the fourth decade for male patients. Nine percent of patients were more than 60 years of age. The female-to-male ratio was 1.7:1 and was relatively constant throughout age groups. The distribution of patients by race was similar to that of the general population: 12.3% were black, and 2.3% were Hispanic. There was a greater female-to-male preponderance in the black population, at 4.3:1.

330

V.V. McLaughlin / Cardiol Clin 22 (2004) 327–341

Box 3. Revised* clinical and classification of pulmonary hypertension (Venice 2003) Pulmonary arterial hypertension (PAH) 1. *Idiopathic (IPAH) 2. Familial (FPAH) 3. PAH associated with Collagen vascular disease Congenital systemic to pulmonary shunts Portal hypertension HIV infection Drugs and toxins *Other (thyroid disorders, glycogen storage disease, Gaucher’s disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders, splenectomy) 4. Associated with significant venous or capillary involvement Pulmonary veno-occlusive disease (PVOD) Pulmonary capillary hemangiomatosis (PCH) 5. Persistent pulmonary hypertension of the Newborn *Pulmonary venous hypertension 1. Left-sided atrial or ventricular heart disease 2. Left-sided valvular heart disease *Pulmonary hypertension associated with hypoxemia 1. Chronic obstructive pulmonary disease 2. Interstitial lung disease 3. Sleep-disordered breathing 4. Alveolar hypoventilation disorders 5. Chronic exposure to high altitude 6. Developmental abnormalities *Pulmonary hypertension caused by chronic thrombotic or embolic disease 1. Thromboembolic obstruction of proximal pulmonary arteries 2. Thromboembolic obstruction of distal pulmonary arteries 3. Pulmonary embolism (tumor, parasites, foreign material) Miscellaneous: sarcoidosis, histiocytosis x, lymphangiomatosis, compression of pulmonary vessels (adenopathy, tumor, fibrosing mediastinitis) *Modifications from the Evian classification.

The most common presenting symptom was dyspnea (60%), with fatigue (19%), chest pain (7%), syncope (8%), near syncope (5%), palpitations (5%), and leg edema (3%) occurring less commonly at presentation. The mean time from the onset of symptoms to diagnosis was 2.03 4.9 years with a median time of 1.27 years. The mean right atrial pressure (mRAP) at diagnosis was 9.7 6 mm Hg, mPAP was 60 18 mm Hg, and the cardiac index was 2.3 0.9 L/min/m2. A subsequent survival analysis of 194 patients from the NIH registry documented a median survival of 2.8 years [9]. Survival rates at 1, 3,

and 5 years were 68%, 48%, and 34%, respectively. Advanced New York Heart Association functional class was associated with a poor survival, as were three hemodynamic variables: elevated mRAP, decreased cardiac index, and elevated mPAP. An equation to predict survival based on these three hemodynamic factors was formulated and was subsequently validated in an independent group of 61 patients [10]. Age and gender were not predictive of survival. Other retrospective series have documented similar demographics. The mean age of 44 patients diagnosed with IPAH in Israel from 1988 to 1997

V.V. McLaughlin / Cardiol Clin 22 (2004) 327–341

was 43 13 years, and the female-to-male ratio was 3.4:1 [5]. The mean and median time from onset of symptoms to diagnosis was 2.9 and 2 years, respectively. In a retrospective series of 61 IPAH patients in India, the mean age was 22.3 years with a female-to-male ratio of 1:1. The mean duration of symptoms before diagnosis was 2.5 years [11]. The mean age of 223 IPAH patients diagnosed in Japan between 1980 and 1990 was 28.4 17.0 years, and the female-to-male ration was 1.82:1. The mean time from the onset of symptoms until the diagnosis was 2.27 3.05 years [12].

Familial pulmonary arterial hypertension Within 3 years of Dresdale’s original description of IPAH in 1951, he recorded the occurrence of the disease in several members of one family [13]. It became apparent that this familial condition was more common than initially believed but had been unrecognized, in part because of patient and physician unawareness and in part because of the markedly reduced penetrance of the genetic defects. A pioneering report by Loyd et al [14] in 1984 indicated that some of the cases of IPAH had been mislabeled as a result of incomplete family histories. Although the true incidence of FPAH is unknown, initial series suggested that the incidence was rather low. In the NIH registry, there were 12 cases (6%) of familial pulmonary hypertension, deﬁned as disease aﬀecting a ﬁrstorder blood relative, 7 in men and 5 in women [8]. It was noted that patients who had a positive family history were usually diagnosed sooner after the onset of symptoms than were other registry patients (0.68 years compared with 2.56 years; P = 0.0002). Heightened patient and physician awareness in these cases may have led to earlier diagnosis. Notably, there were no diﬀerences in age, hemodynamic data, or symptoms among the familial and sporadic patients in the NIH registry. In a large series of IPAH patients treated with intravenous epoprostenol reported many years later, in 2002, 22 of 162 patients (13.6%) were reported as having familial disease [15]. It is more likely that this ﬁnding represents better recognition of FPAH rather than an increase in the incidence of the disease. FPAH segregates as an autosomal dominant trait but with markedly reduced penetrance [14]. The gene for FPAH has been localized using linkage analysis to chromosome 2q31-33 and has been designated as PPH1 [16]. The bone morphogenetic

331

protein receptor type II (BMPR-II) gene (BMPR2), coding for a receptor member of the transforming growth factor beta family (TGF-b), has been identiﬁed as causative of FPAH [17,18]. BMPR-II is a ubiquitously expressed receptor for a family of secreted growth factors named for the bone morphogenetic proteins (BMPs) [19]. Part of the TGFb superfamily, BMPs were originally identiﬁed as proteins regulating growth and diﬀerentiation of bone and cartilage. More recently studies have demonstrated that these multifunctional cytokines regulate growth, diﬀerentiation, and apoptosis of various cell types. Based on analyses of multiple FPAH pedigrees, the FPAH gene seems to be transmitted as an autosomal dominant trait with incomplete penetrance [14,20]. Although vertical transmission, suggestive of a single dominant gene, is evident, the disease may skip generations or aﬀect only a few individuals among several members at risk. It has been estimated that the overall penetrance of the gene is approximately 10% to 20%. The reduced penetrance points to the likely requirement for additional factors, either environmental or genetic, in the pathogenesis of the disease. The worsening of familial disease in subsequent generations is known as genetic anticipation. This phenomenon has been well described in fragile X syndrome and in several dominantly inherited neurologic diseases such as myotonic dystrophy and Huntington’s disease. Genetic anticipation in FPAH was conﬁrmed by Loyd et al [21], who showed that the age at death was 45.6 14.4, 36.3 12.6, and 24.2 11 years in successive generations. Two recent studies have suggested that some cases of so-called IPAH may represent unidentiﬁed familial cases. Having evaluated several American families, Newman et al [22] uncovered a kindred aﬀected by FPAH that spans seven generations and involves ﬁve subfamilies initially not known to be related. This kindred included 12 aﬀected members who were initially thought to have IPAH and seven aﬀected members whose conditions were ﬁrst misdiagnosed as other cardiopulmonary diseases. Mutational analysis of the BMPR2 gene in six aﬀected members revealed the same missense mutation in exon 6. Detailed genealogic investigations revealed that these families were indeed related with common ancestors born in the nineteenth century. This ﬁnding supports the hypothesis that the incidence of FPAH is underestimated, with FPAH patients being categorized as having

332

V.V. McLaughlin / Cardiol Clin 22 (2004) 327–341

IPAH, particularly when detailed and accurate family histories are not available. Because resolution of this issue has important implications, Thomson et al [23] investigated the BMPR2 gene in a cohort of 50 unrelated patients with a clinical diagnosis of IPAH and no identiﬁable family history of the disease. Eleven diﬀerent heterozygous germline mutations of the BMPR2 gene were identiﬁed in 13 of the 50 patients studied. This ﬁnding suggests that molecular description of IPAH patients, based upon the presence or absence of BMPR2 mutations, may have important implications and further supports the theory that the true incidence of FPAH is higher than previously described. Now that the PPH1 gene has been identiﬁed, screening patients with IPAH or FPAH and family members of patients with FPAH is scientiﬁcally possible, but the appropriate use of this technique remains controversial. A commercially available, sensitive assay to detect mutations in the BMPR2 gene will undoubtedly be expensive and technically diﬃcult because of the size of the gene and the wide variety of sequence variants that have been shown to cause disease. Although families of FPAH patients may request genetic analysis, those carrying the mutation will not necessarily develop the disease, because the penetrance is low. The psychologic and ﬁnancial impact of this knowledge must be considered before testing, and appropriate genetic counseling must be provided. At this point, the role of genetic testing for this disease remains to be deﬁned.

Pulmonary arterial hypertension related to connective tissue disease PAH is a well-known complication of connective tissue diseases such as systemic sclerosis, systemic lupus erythematosus, mixed connective tissue disease, and, to a lesser extent, rheumatoid arthritis, dermatopolymyositis, and primary Sjo¨gren’s syndrome [24–30]. PAH occurs most commonly in association with the scleroderma spectrum of diseases and is the leading cause of scleroderma-related deaths in such patients [31]. Histopathologic changes in PAH associated with connective tissue disease are generally indistinguishable from those of classic IPAH [32]. Evaluating dyspnea in scleroderma patients and distinguishing PAH from pulmonary ﬁbrosis can sometimes present a diagnostic dilemma. Pioneering work by Steen and colleagues [33,34] has

demonstrated that patients with a decreasing or very low (<55%) diﬀusing capacity of carbon monoxide have a high likelihood of developing PAH. A reduction in diﬀusing capacity of carbon monoxide out of proportion to the reduction in vital capacity over time should prompt an evaluation for PAH in a scleroderma patient. Also, when evaluating dyspnea in this patient population, it is also important to exclude other potential confounding factors such as left ventricular dysfunction (both systolic and diastolic) and thromboembolic disease. Although the incidence of PAH in association with the scleroderma spectrum of disease has been estimated to be in the range of 30% to 50% based on echocardiographic studies, a more recent study using right heart catheterization as the basis of diagnosis has demonstrated an incidence of approximately 12%. Mukerjee et al [35] prospectively studied 722 patients with systemic sclerosis and conﬁrmed PAH by right-heart catheterization in 89 patients (12%). The mean age in the patients with PAH was 66 7 years, and there was a 4:1 preponderance of women, a ﬁnding consistent with previous data suggesting that patients with scleroderma-associated PAH tend to be older and that the female-to-male ratio is higher than in patients with IPAH. These investigators also noted an increased incidence of anticentromere antibody positivity in scleroderma patients with PAH. The mean time between the diagnosis of scleroderma and the diagnosis of PAH was 14 5 years. This landmark series also evaluated survival and prognostic factors in scleroderma-associated PAH. The 1-, 2-, and 3-year survival Rates were 81%, 63%, and 56%, respectively. Patients were enrolled in this registry between March 1998 and September 2002, and many received state-ofthe-art medical therapies. Of all the hemodynamic predictors of survival, the only one with independent predictive value was mRAP, for which the hazard ratio was 20.7 (P = 0.0001). In PAH associated with connective tissue disease, unlike IPAH, response to acute vasodilators did not inﬂuence survival. Patients with PAH associated with connective tissue disease may have a poorer prognosis than IPAH patients despite medical therapies. Although similar hemodynamic and exercise endurance beneﬁts were noted in the 12-week, randomized, openlabel trials with epoprostenol in both populations, a survival beneﬁt was noted only in the IPAH group [36,37]. In a large series of PAH patients treated with epoprostenol, Kuhn et al [38] demonstrated

V.V. McLaughlin / Cardiol Clin 22 (2004) 327–341

a higher mortality among patients with an underlying diagnosis of scleroderma than in patients with IPAH, congenital heart disease (CHD), or other PAH etiologies [38]. Kawut et al [39] compared outcomes of a cohort of 22 patients with scleroderma-related PAH with 33 patients with either IPAH, FPAH, or anorexigen-related PAH. Despite similar hemodynamics and treatment strategies, mortality was higher in the group with scleroderma-related PAH. The unadjusted hazard ratio was 2.9 (95% conﬁdence interval [CI], 1.1–7.8; P = 0.03), and the risk seemed to persist after adjustment for a variety of demographic, hemodynamic, and treatment variables.

Pulmonary arterial hypertension related to congenital heart disease Eisenmenger [40] ﬁrst described a patient with cyanosis and dyspnea since infancy who died of massive hemoptysis at the age of 32 years. Postmortem examination demonstrated a ventricular septal defect and severe pulmonary vascular disease. Subsequently, Wood [41] coined the term Eisenmenger syndrome to include all systemic-topulmonary arterial connections leading to pulmonary hypertension and resulting in a right-to-left or bidirectional shunt. The pulmonary vascular involvement from CHD generally follows a period of reduced pulmonary vascular resistance and high pulmonary blood ﬂow that occurs as the result of a large left-to-right shunt. Morphologic changes of the pulmonary vasculature over time include medial hypertrophy of the pulmonary arterioles, intimal proliferation and ﬁbrosis, occlusion of small arterioles, and, eventually, plexiform lesions, all of which are indistinguishable from the morphologic changes found in IPAH. As the pulmonary vascular resistance approaches or exceeds the systemic vascular resistance, the shunt is reversed, and blood ﬂows from right to left. The development of PAH in CHD seems to be related to the size of the defect. Although only 3% of patients with small to moderate-sized ventricular septal defects develop PAH, approximately 50% of those with ventricular septal defects greater than 1.5 cm in diameter develop PAH [42,43]. The type of defect is also important. About twice as many patients with any size ventricular septal defects than with atrial septal defects develop PAH [44,45]. Among those with large defects, almost all patients with truncus arteriosus, 50%

333

of those with ventricular septal defects, and 10% of those with atrial septal defects develop PAH [46]. Among those with atrial septal defects, the incidence of PAH is greater in patients with sinus venosus defects (16%) than in patients with ostium secundum defects (4%) [47]. In fact, the debate continues as to whether a patient with a small atrial septal defect and PAH truly has PAH related to CHD or in fact has IPAH. Some patients are diagnosed with severe PAH years after ‘‘successful’’ correction of the congenital defect. In most instances, it remains unclear whether irreversible pulmonary vascular disease was present before the surgical intervention or the pulmonary vascular disease progressed despite the correction. Although the clinical manifestations of PAH associated with CHD include dyspnea and chest pain and in many respects are similar to IPAH, there are some important diﬀerences. Cyanosis may be present as a result of the right-to-left shunt. Although some patients may not appear cyanotic at rest, substantial exercise desaturation suggests a right-to-left shunt. Hemoptysis may occur because of rupture of dilated bronchial arteries. Blood dyscrasias including polycythemia, abnormal hemostasis, and a tendency toward thrombosis are common. Paradoxical embolization across the defect may result in cerebrovascular accidents. Perhaps because of the longstanding nature of the disease, these patients tend to be well compensated, and heart failure is uncommon. Survival in patients with PAH associated with CHD is better than in patients with IPAH. Hopkins and coworkers evaluated 100 patients with either IPAH or PAH related to CHD who underwent evaluation for lung transplantation but did not undergo the procedure [48]. The 1-, 2- and 3-year survival rates were 97%, 89%, and 77%, respectively, in the group with CHD-associated PAH and were 77%, 69%, and 35%, respectively in the IPAH group. Similarly, in a cohort of patients with PAH treated with epoprostenol, survival was greater for those with CHD than for those with IPAH [38].

Pulmonary arterial hypertension related to portal hypertension The recognition of the association of portal and pulmonary hypertension dates back to 1951 [49]. Since then, a number of case series have validated this observation [50–53]. Portal hypertension rather than the hepatic disorder itself seems to be the

334

V.V. McLaughlin / Cardiol Clin 22 (2004) 327–341

main determining risk factor for developing pulmonary hypertension, leading to the term portopulmonary hypertension [50,54]. Although liver disease is by far the most common cause of portal hypertension complicated by pulmonary hypertension, a minority of patients have portal hypertension secondary to nonhepatic causes such as biliary atresia, extraheptic portal vein obstruction, noncirrhotic portal ﬁbrosis, and idiopathic portal hypertension. The mechanism by which portal hypertension facilitates the development of pulmonary hypertension remains unknown. The presence of a porto-systemic shunt might allow vasoconstrictive and vasoproliferative substances, including serotonin, normally cleared by the liver, to reach the pulmonary circulation. Again, histologically, the disease is indistinguishable from IPAH. Pulmonary arterial hypertension is an uncommon complication of portal hypertension. In a large autopsy series, ﬁndings consistent with PAH were present in 0.73% of patients with cirrhosis compared with 0.13% in unselected autopsied patients [55]. Later studies based on right-heart catheterization data have suggested prevalence between 2% and 5% [52,56,57]. In patients with portal hypertension undergoing evaluation for liver transplantation, the prevalence of PAH has ranged from 3.5% to 8.5% [58– 60]. On average, the diagnosis of PAH is made 4 to 7 years after the diagnosis of portal hypertension, and the risk of developing PAH increases with the duration of portal hypertension [52,61]. Whether the severity of portal hypertension inﬂuences the development of PAH is controversial. The mean age at presentation, in the ﬁfth decade, tends to be slightly greater than that of IPAH patients, and the gender distribution is equal [52–54,62]. Although often the presenting symptoms are similar to IPAH, with dyspnea, chest pain, fatigue, and syncope, some patients are diagnosed serendipitously as they undergo evaluation for liver transplantation. Hemodynamically, compared with IPAH patients, patients with portopulmonary hypertension tend to have a higher cardiac output and lower systemic and pulmonary vascular resistance. When the PAH is untreated, the prognosis is poor, with a mean survival of 15 months after diagnosis [53]. Although patients with portopulmonary hypertension have been excluded from every clinical drug trial to date, some evidence suggests that epoprostenol may be an eﬀective treatment for such patients [63]. Although portopulmonary hypertension is a contraindication to liver transplantation in most instances, in highly

selected individuals the procedure has been shown to reverse the pulmonary vascular disease [64].

Pulmonary arterial hypertension related to HIV infection During the initial years of the HIV epidemic, noninfectious complications of the disease remained undetectable because they were overshadowed by the opportunistic infections and malignancies. With the advent of highly active antiretroviral therapy and the improved prognosis, noninfectious complications have emerged and are now well described in the literature. The ﬁrst case of PAH associated with HIV was reported in 1987 in a 40-year-old homosexual man with HIV and membranoproliferative glomerulonephritis [65]. One year later, Goldsmith et al [66] reported a series of ﬁve HIV-infected hemophiliacs with socalled PPH. Subsequently, two groups each reported series of six cases of PAH from cohorts of 1200 HIV-infected individuals; both groups estimated a cumulative incidence of 0.5% [67,68]. The Swiss HIV Cohort, a large case-control study involving 3349 HIV-infected patients over a period of 5.5 years, demonstrated a cumulative incidence of PAH of 0.57% (19 cases), resulting in an annual incidence of 0.1% [69]. Thus, compared with the annual incidence of IPAH in the general population, HIV infection carries a relative risk for the development of PAH of more than 600. Although every group at risk for HIV infection can be aﬀected, intravenous drug users seem to predominate in the published series. In two series of 86 and 82 patients, intravenous drug users accounted for 42% and 59% of the patients, respectively, whereas this risk factor is observed in approximately one third of the overall HIV population in developed countries [70,71]. Intravenous drug users may have additional risk factors for the development of PAH including foreign particle pulmonary emboli, portal hypertension, and substance abuse (eg, amphetamines and cocaine). The cause of the association remains unclear. The hypothesis of a direct infection of the pulmonary vascular wall has not been conﬁrmed [72,73]. This lack of understanding has led to as-yet-unproven speculation that HIV has an indirect eﬀect on the production of cytokines and growth factors by activated macrophages and lymphocytes. Interestingly, human herpes virus 8 has been implicated in HIV-related Kaposi sarcoma pathogenesis, and recently, an association between

V.V. McLaughlin / Cardiol Clin 22 (2004) 327–341

human herpes virus 8 and IPAH has been described [74]. Another report suggests that HIV-associated PAH may reﬂect a host response to HIV determined by one or more human leukocyte antigen-DR alleles located within the major histocompatibility complex [75]. The clinical and hemodynamic features of HIV-associated PAH are similar to those of IPAH. Survival in patients with HIV-associated PAH seems similar to that in the IPAH population. Opravil et al [69] performed a prospective, case-controlled, single-center study in 19 patients with HIV-associated PAH. The probability of surviving was signiﬁcantly decreased in patients with PAH compared with the control subjects (median survival, 1.3 versus 2.6 years). In a retrospective, uncontrolled, single-center study, Petitpretz and coworkers [76] identiﬁed 20 patients with HIV-associated PAH and compared their outcomes with those of 93 patients with IPAH identiﬁed between 1987 and 1992. Overall survival was poor and was not signiﬁcantly diﬀerent between the groups with HIV-associated PAH and IPAH (46% and 53% survival rates, respectively, at 2 years). Most of the deaths in the HIV group were related to PAH. More recently, Nunes and coworkers [71] reported overall 1-, 2-, and 3-year survival rates of 73%, 60%, and 47%, respectively, among 82 patients with HIV-associated PAH treated at a single center. Univariate analysis indicated that CD4 lymphocyte count of more than 212 cells/mm3, the use of combination antiretroviral therapy, and epoprostenol infusion were related to a better survival.

Pulmonary arterial hypertension related to drugs and toxins The epidemic that followed the introduction of aminorex fumarate has been well documented in the literature. The increase in incidence of pulmonary hypertension in the late 1960s was reported in Switzerland, Austria, and West Germany [3,77,78]. Although only 2% of the population that had taken aminorex developed pulmonary arterial hypertension, 61% of the 582 patients who were identiﬁed as new cases of PPH reported a history of aminorex intake. The relative risk for developing pulmonary hypertension in aminorex users was estimated to be 52:1 compared with patients without any exposure to the drug. Fenﬂuramine derivatives have been prescribed widely as anorectic agents since the early 1960s. Brenot

335

and colleagues [79] studied a group of 73 patients with PPH and found that approximately 25% had been exposed to fenﬂuramine. Based on this observation, the International Primary Pulmonary Hypertension Study (IPPHS) was performed [80]. This study found a clear association between appetite suppressants and pulmonary hypertension (odds ratio, 6.3, 95% CI, 3–13.2). Ninety percent of the cases in which use of a speciﬁc product could be conﬁrmed had used a fenﬂuramine derivative. Observations in this trial also indicated that the risk of developing PAH increased markedly with the duration of use, with the relative risk being 23.1 for individuals who took the drug for more than 3 months. Although it is clear that there is a relationship between duration of use and relative risk, reports of individuals developing the disease after as little as 23 days of exposure have been documented [81]. The surveillance of North American Pulmonary Hypertension Study recently conﬁrmed this clear association between fenﬂuramine derivatives and pulmonary hypertension [82]. It also documented a high use of anorexigen among patients with PAH associated with other underlying conditions, such as connective tissue diseases. The withdrawal of these agents from the United States market in September 1997 may have well averted an incipient epidemic in the United States. The exact pathogenetic mechanism of PAH associated with fenﬂuramine derivatives remains unknown. One hypothesis is that alteration of the serotonin pathway might be the common denominator. Serotonin acts as a potent vasoconstrictor, can induce platelet aggregation, and is a potent factor stimulating pulmonary smooth muscle proliferation. The relationship between other amphetamine derivatives and PAH is less clear. The syndrome of pulmonary hypertension as a result of exposure to toxic rapeseed oil was ﬁrst suggested in Spain in early 1981 with the recognition of a multisystem disease that included pulmonary inﬁltrates [83]. Pulmonary hypertension was found in approximately 20% of hospitalized patients in the second through fourth month following the onset of the disease. Alonso-Ruiz et al [84] followed 332 cases of toxic oil syndrome for up to 8 years and found that 8.1% developed PAH. Although the condition regressed in most patients, some developed the more severe form of PAH. Microcystoscopic examination of the lungs of such patients demonstrated pulmonary hypertensive arteriopathy including medial hypertrophy, intimal ﬁbrosis, and plexiform lesions.

336

V.V. McLaughlin / Cardiol Clin 22 (2004) 327–341

The association of illicit substances with PAH is less clear. In the IPPHS study, use of intravenous drugs or cocaine was associated with an increased risk of the development of PAH (odds ratio, 2.9) but the numbers were small [80]. Interpretation of such data is also clouded by the known risk factors for PAH such as HIV infection and liver disease, which are prevalent in such a patient population. Use of oral contraceptives and antidepressants has not been associated with the development of PAH in well-designed epidemiologic studies. Pulmonary arterial hypertension related to other disease entities Type Ia glycogen storage disease is an autosomal or recessive disorder that is caused by a deﬁciency of glucose-6-phosphatase. It is a rare disease with an estimated incidence of 1 per 100,000; however, since 1980, seven cases of severe PAH have been described in patients with type I glycogen storage disease [85]. It has been suggested that this relationship might result from an abnormal production of vasoconstrictive amines such as serotonin. Again, the pulmonary histology was typical of PAH; however, the clinical course was that of rapidly worsening disease. PAH has been described in association with a variety of hematologic disorders. Primary pulmonary hypertension has been described in a patient with familial platelet storage pool disease [86]. Pulmonary hypertension has long been recognized as a complication of sickle cell hemoglobinopathy, although one must always consider left ventricular diastolic dysfunction in this particular patient population [87]. Other disorders of hemoglobin that have been associated with PPH include the beta-chain Hb Warsaw and Hb Washtenaw resulting in abnormally low oxygen aﬃnity [88,89]. A unifying mechanism for PAH in the hemoglobinopathies has not yet been identiﬁed. A clear association of PAH in the setting of hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) has been described. This syndrome is an autosomal dominant vascular dysplasia characterized by mucocutaneous telangiectasias aﬀecting primarily the nasal and gastrointestinal mucosa. Arterial venous malformations, particularly in the pulmonary, hepatic, and cerebral circulations, have been described. Although pulmonary arteriovenous malformations may produce clinically signiﬁcant right-to-left shunts and pulmonary hypertension related to a high ﬂow state, some patients develop PAH that is clinically

and histologically indistinguishable from IPAH. Genetic analysis has demonstrated that genes encoding TGF-b receptor proteins, including ALK-1, endoglin, and BMPR2, allow the demonstration of PAH in association with hereditary hemorrhagic telangiectasia [90]. Pulmonary veno-occlusive disease PVOD is a rare form of IPAH. The histopathologic diagnosis is based on the presence of obstructive eccentric ﬁbrous intimal pads within the pulmonary veins and venules. This obstruction may result in arterialization of the pulmonary veins and subsequent alveolar capillary congestion. Other histopathologic features of IPAH, such as medial hypertrophy and muscularization of the arterials with eccentric intimal ﬁbrosis, may also be seen. The pulmonary venous obstruction explains the increase in pulmonary capillary wedge pressure that may be observed in such patients. The disease tends to be patchy and may aﬀect some segments of the lungs and not others. The clinical ﬁndings, along with the ventilationperfusion scan showing diﬀuse, patchy, nonsegmental abnormalities, suggests the diagnosis on a clinical basis [91,92]. CT scans are commonly helpful and may demonstrate smooth interlobular septal thickening, ground-glass opacities, and a mosaic attenuation pattern. Unfortunately, the treatment of PVOD is diﬃcult. Anecdotal reports of the success of calcium-channel blockers in epoprostenol have been tempered by reports of these same treatments producing pulmonary edema. Early referral for lung transplantation should be strongly considered. Pulmonary capillary hemangiomatosis PCH was ﬁrst described in 1978 as a very rare cause of IPAH [93]. Unfortunately there are few reports in the medical literature, and it is diﬃcult to characterize the disease. The typical chest radiograph demonstrates a diﬀuse bilateral reticular nodular pattern associated with enlarged central pulmonary arteries [94]. Ventilation perfusion scans are often abnormal and may show both matched and unmatched defects. Characteristic high-resolution CT ﬁndings include diﬀuse bilateral thickening of the intralobular septae and small, centrilobular, poorly circumscribed, nodular opacities in addition to ground-glass opacities [95]. Histologically the disease consists of small irregular nodular foci of thin-walled, capillary-sized vessels that diﬀusely invade the lung parenchyma, the

V.V. McLaughlin / Cardiol Clin 22 (2004) 327–341

bronchiolar walls, and the adventitia of large vessels. These nodular lesions are commonly associated with alveolar hemorrhage. Changes of hypertensive arteriopathy, including intimal ﬁbrosis and medial smooth muscle cell hypertrophy, are also common. Many patients are young and present similarly to patients with IPAH, although hemoptysis may be more common. It is diﬃcult to distinguish PCH from IPAH clinically. Unfortunately the clinical course is usually one of progressive deterioration, leading to severe pulmonary hypertension, right-sided heart failure, and death. Again there are reports of intravenous epoprostenol being used; however, it may also be associated with the development of severe pulmonary edema [96]. Again, the only deﬁnitive therapy for these patients is bilateral lung transplantation. Persistent pulmonary hypertension of the newborn Persistent pulmonary hypertension of the newborn (PPHN) has been characterized as hypertrophic, hypoplastic, and reactive. In hypertrophic PPHN, the muscular tissue of the pulmonary arteries is hypertrophied and extends peripherally into the acini. PPHN is believed to result from sustained fetal hypertension from chronic vasoconstriction caused by chronic fetal distress. In hypoplastic PPHN, the lungs and pulmonary arteries are underdeveloped, usually as a result of congenital diaphragmatic hernia or prolonged leakage of the amniotic ﬂuid. In reactive PPHN, lung histology is presumably normal, but vasoconstriction causes pulmonary hypertension. High levels of vasoconstrictive mediators such as thromboxane, norepinephrine, and leukotrienes may be contributing factors. Although PPHN can vary in severity, severe cases are usually life threatening. PPHN is commonly associated with severe hypoxemia and the need for mechanical ventilation. Right-to-left shunting at the level of the ductus arteriosus or foramen ovale is common. Inhaled nitric oxide improves oxygenation and the disease course in such patients [97].

Pulmonary venous hypertension Pulmonary venous hypertension is deﬁned most commonly as pulmonary hypertension in the setting of elevated left-heart ﬁlling pressures. A wide variety of cardiac causes such as left ventricular systolic and diastolic dysfunction, mitral valve disease, aortic valve disease, restrictive myopathies,

337

and constrictive pericarditis may result in pulmonary venous hypertension. At times patients may present with symptoms similar to PAH, including dyspnea on exertion, fatigue, chest pain, and lower extremity edema. Other cardinal symptoms of pulmonary venous hypertension include paroxysmal nocturnal dyspnea and orthopnea. Treatment of the underlying cardiac disorder is paramount to treating the pulmonary hypertension. Pulmonary hypertension associated with disorders of the respiratory system, or hypoxemia Numerous pulmonary disorders have been associated with pulmonary hypertension, and in such cases pulmonary hypertension tends to be modest, at much lower levels than seen in pulmonary arterial hypertension. Box 3 lists pulmonary disorders of the respiratory system that may be associated with pulmonary hypertension that are classiﬁed under this category. Again, treatment of the underlying disease is paramount to treatment of the pulmonary hypertension. Pulmonary hypertension caused by chronic thrombotic or embolic disease Pulmonary hypertension may be caused by chronic thrombotic or embolic obstruction of the pulmonary vasculature. This group of disorders is categorized as those caused by obstruction of the proximal pulmonary arteries, by obstruction of the distal pulmonary arteries, and by pulmonary embolism. The obstruction may be caused by tumor, parasites, or foreign material. This group of disorders is discussed extensively elsewhere in this issue and is not discussed further here. Miscellaneous causes of pulmonary hypertension Although sarcoidosis is considered a multisystem granulomatous disorder of unknown origin primarily aﬀecting the lung parenchyma, cardiac involvement may be present in up to a third of the cases. Pulmonary hypertension is most commonly the result of severe chronic ﬁbrocystic sarcoidosis and tends to be milder than in patients with pulmonary hypertension of other origins. A small subset of patients with sarcoidosis, however, may present with severe pulmonary hypertension believed to result from direct pulmonary vascular involvement. These patients, like those with

338

V.V. McLaughlin / Cardiol Clin 22 (2004) 327–341

pulmonary hypertension associated with other diseases, seem to be predisposed to the development of pulmonary vascular disease that is triggered in some way by the sarcoid disease process. Some patients with severe pulmonary hypertension have been treated with intravenous epoprostenol. Although this treatment may be eﬀective in treating right-sided heart failure and in improving pulmonary hemodynamics, it will have no eﬀect on underlying ﬁbrotic lung disease that may still render the patient symptomatic [98]. Other rare causes of pulmonary hypertension that are included in this miscellaneous category include histiocytosis x, ﬁbrosing mediastinitis, adenopathy, persistent pulmonary hypertension of the newborn, and tumors and lymphangiomatosis.

References [1] Dresdale D, Schultz M, Michtom R. Primary pulmonary hypertension: I. Clinical and hemodynamic study. Am J Med 1951;11:686–94. [2] Wood P. Pulmonary hypertension with special reference to the vasoconstrictive factor. Br Heart J 1959;21:557–70. [3] Gurtner H. Pulmonary hypertension, ‘‘plexogenic pulmonary arteriopathy’’ and the appetite depressant drug aminorex: post or propter? Bull Eur Physiopathol Respir 1979;15:897. [4] Hantano S, Strasser T, editors. Primary pulmonary hypertension. Report of the WHO meeting. Geneva: World Health Organization; 1975. [5] Appelbaum L, Yigla M, Bendayan D, et al. Primary pulmonary hypertension in Israel. A national survey. Chest 2001;119(6):1801–6. [6] The International Primary Pulmonary Hypertension Study Group. The International Primary Pulmonary Hypertension Study (IPPHS). Chest 1994;105(Suppl):37S–41S. [7] Lilienfeld D, Rubin L. Mortality from primary pulmonary hypertension in the United States, 1979– 1996. Chest 2000;117:796–800. [8] Rich S, Dantzker R, Ayres S, et al. Primary pulmonary hypertension: a national prospective study. Ann Intern Med 1987;107:216–23. [9] D’Alonzo G, Barst R, Ayres S, et al. Survival in patients with primary pulmonary hypertension: results from a national prospective registry. Ann Intern Med 1991;115:343–9. [10] Sandoval J, Bauerle O, Palomar A, et al. Survival in primary pulmonary hypertension. Validation of a prognostic equation. Circulation 1994;89: 1733–44. [11] Rajasekhar D, Balakrishnan KG, Venkitachalam CG, et al. Primary pulmonary hypertension: natural

[12]

[13]

[14]

[15]

[16]

[17]

[18]

[19] [20] [21]

[22]

[23]

[24]

[25]

[26]

history and prognostic factors. Indian Heart J 1994; 46(3):165–70. Okada O, Tanabe N, Yasuda J, et al. Prediction of life expectancy in patients with primary pulmonary hypertension. A retrospective nationwide survey from 1980–1990. Intern Med 1999;38(1):12–6. Dresdale D, Michtom R, Schultz M. Recent studies in primary pulmonary hypertension, including pharmacodynamic observations on pulmonary vascular resistance. Bull N Y Acad Med 1954;30:195. Loyd J, Primm R, Newman J. Transmission of familial primary pulmonary hypertension. Am Rev Respir Dis 1984;129:194–7. McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation 2002;106(12): 1477–82. Nichols WC, Koller DL, Slovis B, et al. Localization of the gene for familial primary pulmonary hypertension to chromosome 2q31–32. Nat Genet 1997;15(3):277–80. Lane KB, Machado RD, Pauciulo MW, et al. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. The International PPH Consortium. Nat Genet 2000;26(1):81–4. Deng Z, Morse JH, Slager SL, et al. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet 2000;67(3):737–44. Massague J, Chen YG. Controlling TGF-beta signaling. Genes Dev 2000;14(6):627–44. Loyd J, Newman J. Familial primary pulmonary hypertension. New York: Marcel Dekker; 1997. Loyd JE, Butler MG, Foroud TM, et al. Genetic anticipation and abnormal gender ratio at birth in familial primary pulmonary hypertension. Am J Respir Crit Care Med 1995;152(1):93–7. Newman J, Wheeler L, Lane K, et al. Mutation in the gene for bone morphogenetic protein receptor II as a cause of primary pulmonary hypertension in a large kindred. N Engl J Med 2001;345(5):319–24. Thomson JR, Machado RD, Pauciulo MW, et al. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family. J Med Genet 2000;37(10):741–5. Koh ET, Lee P, Gladman DD, Abu-Shakra M. Pulmonary hypertension in systemic sclerosis: an analysis of 17 patients. Br J Rheumatol 1996;35(10): 989–93. Salerni R, Rodnan GP, Leon DF, et al. Pulmonary hypertension in the CREST syndrome variant of progressive systemic sclerosis (scleroderma). Ann Intern Med 1977;86(4):394–9. Stupi AM, Steen VD, Owens GR, et al. Pulmonary hypertension in the CREST syndrome variant of systemic sclerosis. Arthritis Rheum 1986;29(4): 515–24.

V.V. McLaughlin / Cardiol Clin 22 (2004) 327–341 [27] Ungerer RG, Tashkin DP, Furst D, et al. Prevalence and clinical correlates of pulmonary arterial hypertension in progressive systemic sclerosis. Am J Med 1983;75(1):65–74. [28] Asherson RA, Higenbottam TW, Dinh Xuan AT, et al. Pulmonary hypertension in a lupus clinic: experience with twenty-four patients. J Rheumatol 1990;17(10):1292–8. [29] Simonson JS, Schiller NB, Petri M, et al. Pulmonary hypertension in systemic lupus erythematosus. J Rheumatol 1989;16(7):918–25. [30] Sullivan WD, Hurst DJ, Harmon CE, et al. A prospective evaluation emphasizing pulmonary involvement in patients with mixed connective tissue disease. Medicine (Baltimore) 1984;63(2):92–107. [31] Silver RM. Scleroderma. Clinical problems. The lungs. Rheum Dis Clin North Am 1996;22(4): 825–40. [32] Yousem SA. The pulmonary pathologic manifestations of the CREST syndrome. Hum Pathol 1990; 21(5):467–74. [33] Steen VD, Graham G, Conte C, et al. Isolated diﬀusing capacity reduction in systemic sclerosis. Arthritis Rheum 1992;35(7):765–70. [34] Steen V, Medsger TA Jr. Predictors of isolated pulmonary hypertension in patients with systemic sclerosis and limited cutaneous involvement. Arthritis Rheum 2003;48(2):516–22. [35] Mukerjee D, St George D, Coleiro B, et al. Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: application of a registry approach. Ann Rheum Dis 2003;62(11):1088–93. [36] Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N Engl J Med 1996; 334(5):296–302. [37] Badesch D, Tapson V, McGoon M, et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. Ann Intern Med 2000;132:425–34. [38] Kuhn K, Byrne D, PG A, et al. Outcome in 91 consecutive patients with pulmonary arterial hypertension receiving epoprostenol. Am J Respir Crit Care Med 2003;167(4):580–6. [39] Kawut SM, Taichman DB, Archer-Chicko CL, et al. Hemodynamics and survival in patients with pulmonary arterial hypertension related to systemic sclerosis. Chest 2003;123(2):344–50. [40] Eisenmenger V. Die angeboren Defects des Kammerscheidewand des Herzen. Z Klin Med 1897(32): 1–28. [41] Wood P. The Eisenmenger syndrome, or pulmonary hypertension with reversed central shunt. BMJ 1958;2:755. [42] Kidd L, Driscoll DJ, Gersony WM, et al. Second natural history study of congenital heart defects.

[43]

[44] [45]

[46]

[47]

[48]

[49]

[50]

[51]

[52]

[53]

[54]

[55]

[56]

[57]

[58]

339

Results of treatment of patients with ventricular septal defects. Circulation 1993;87(2 Suppl):I38–51. Neumayer U, Stone S, Somerville J. Small ventricular septal defects in adults. Eur Heart J 1998; 19(10):1573–82. Besterman E. Atrial septal defects with pulmonary hypertension. Br Heart J 1961;(23):587–98. Hoﬀman JI, Rudolph AM. The natural history of ventricular septal defects in infancy. Am J Cardiol 1965;16(5):634–53. Steele PM, Fuster V, Cohen M, et al. Isolated atrial septal defect with pulmonary vascular obstructive disease–long-term follow-up and prediction of outcome after surgical correction. Circulation 1987; 76(5):1037–42. Vogel M, Berger F, Kramer A, et al. Incidence of secondary pulmonary hypertension in adults with atrial septal or sinus venosus defects. Heart 1999; 82(1):30–3. Hopkins W, Ochoa L, Richardson G, et al. Comparison of the hemodynamics and survival of adults with severe primary pulmonary hypertension or Eisenmenger syndrome. J Heart Lung Transplant 1996;15:100–5. Mantz F, Craig E. Portal axis thrombosis with spontaneous portacaval shunt and resultant cor pulmonale. Arch Pathol Lab Med 1951;(52):91–7. Lebrec D, Capron JP, Dhumeaux D, et al. Pulmonary hypertension complicating portal hypertension. Am Rev Respir Dis 1979;120(4): 849–56. Edwards BS, Weir EK, Edwards WD, et al. Coexistent pulmonary and portal hypertension: morphologic and clinical features. J Am Coll Cardiol 1987;10(6):1233–8. Hadengue A, Benhayoun MK, Lebrec D, et al. Pulmonary hypertension complicating portal hypertension: prevalence and relation to splanchnic hemodynamics. Gastroenterology 1991;100(2): 520–8. Robalino B, Moodie D. Association between primary pulmonary hypertension and portal hypertension: analysis of its pathophysiology and clinical, laboratory and hemodynamic manifestations. J Am Coll Cardiol 1991;17:492. Herve´ P, Lebrec D, Brenot F, et al. Pulmonary vascular disorders in portal hypertension. Eur Respir J 1998;11:1153–66. McDonnell P, Roye P, Hutchins G. Primary pulmonary hypertension and cirrhosis: are they related? Am Rev Respir Dis 1986;127:437. Sen S, Biswas PK, Biswas J, et al. Primary pulmonary hypertension in cirrhosis of liver. Indian J Gastroenterol 1999;18(4):158–60. Yang YY, Lin HC, Lee WC, et al. Portopulmonary hypertension: distinctive hemodynamic and clinical manifestations. J Gastroenterol 2001;36(3):181–6. Taura P, Garcia-Valdecasas JC, Beltran J, et al. Moderate primary pulmonary hypertension in

340

[59]

[60]

[61]

[62]

[63]

[64]

[65]

[66]

[67]

[68]

[69]

[70]

[71]

[72]

V.V. McLaughlin / Cardiol Clin 22 (2004) 327–341 patients undergoing liver transplantation. Anesth Analg 1996;83(4):675–80. Castro M, Krowka MJ, Schroeder DR, et al. Frequency and clinical implications of increased pulmonary artery pressures in liver transplant patients. Mayo Clin Proc 1996;71(6):543–51. Ramsay MA, Simpson BR, Nguyen AT, et al. Severe pulmonary hypertension in liver transplant candidates. Liver Transpl Surg 1997;3(5):494–500. Auletta M, Oliviero U, Iasiuolo L, et al. Pulmonary hypertension associated with liver cirrhosis: an echocardiographic study. Angiology 2000;51(12): 1013–20. Kuo P, Plotkin J, Johnson L, et al. Distinctive clinical features of portopulmonary hypertension. Chest 1997;112:980–6. Krowka MJ, Frantz RP, McGoon MD, et al. Improvement in pulmonary hemodynamics during intravenous epoprostenol (prostacyclin): a study of 15 patients with moderate to severe portopulmonary hypertension. Hepatology 1999;30(3):641–8. Krowka MJ, Plevak DJ, Findlay JY, et al. Pulmonary hemodynamics and perioperative cardiopulmonary-related mortality in patients with portopulmonary hypertension undergoing liver transplantation. Liver Transpl 2000;6(4):443–50. Kim KK, Factor SM. Membranoproliferative glomerulonephritis and plexogenic pulmonary arteriopathy in a homosexual man with acquired immunodeﬁciency syndrome. Hum Pathol 1987; 18(12):1293–6. Goldsmith GH Jr, Baily RG, Brettler DB, et al. Primary pulmonary hypertension in patients with classic hemophilia. Ann Intern Med 1988;108(6): 797–9. Himelman RB, Dohrmann M, Goodman P, et al. Severe pulmonary hypertension and cor pulmonale in the acquired immunodeﬁciency syndrome. Am J Cardiol 1989;64(19):1396–9. Speich R, Jenni R, Opravil M, et al. Primary pulmonary hypertension in HIV infection. Chest 1991;100:1268–71. Opravil M, Peche`re M, Speich R, et al. HIVassociated primary pulmonary hypertension: a case control study. Am J Respir Crit Care Med 1997; 155:990–5. Mesa R, Edell E, Dunn W, et al. Human immunodeﬁciency virus infection and pulmonary hypertension: two new cases and a review of 86 reported cases. Mayo Clin Proc 1998;73:37–45. Nunes H, Humbert M, Sitbon O, et al. Prognositc factors for survival in human immunodeﬁciency virus–associated pulmonary arterial hypertension. Am J Respir Crit Care Med 2003;167:1433–9. Humbert M, Monti G, Fartoukh M, et al. Plateletderived growth factor expression in primary pulmonary hypertension: comparison of HIV seropositive and HIV seronegative patients. Eur Respir J 1998;11:554–9.

[73] Mette S, Palevsky H, Pietra G, et al. Primary pulmonary hypertension in association with human immunodeﬁciency virus infection. Am Rev Respir Dis 1992;145:1196. [74] Cool CD, Rai PR, Yeager ME, et al. Expression of human herpesvirus 8 in primary pulmonary hypertension. N Engl J Med 2003;349(12):1113–22. [75] Morse JH, Barst RJ, Itescu S, et al. Primary pulmonary hypertension in HIV infection: an outcome determined by particular HLA class II alleles. Am J Respir Crit Care Med 1996;153(4 Pt 1): 1299–301. [76] Petitpretz P, Brenot F, Azarian R, et al. Pulmonary hypertension in patients with human immunodeﬁciency virus infection. Comparison with primary pulmonary hypertension. Circulation 1994;89(6): 2722–7. [77] Gurtner HP. Aminorex and pulmonary hypertension. A review. Cor Vasa 1985;27(2–3):160–71. [78] Kay JM, Smith P, Heath D. Aminorex and the pulmonary circulation. Thorax 1971;26(3):262–70. [79] Brenot F, Herve P, Pettipretz P. Primary pulmonary hypertension and fenﬂuramine use. Br Heart J 1993;70:537–41. [80] Abenhaim L, Moride Y, Brenot F, et al. Appetitesuppressant drugs and the risk of primary pulmonary hypertension. N Engl J Med 1996;335: 609–16. [81] Mark E, Patalas E, Chang H, et al. Fatal pulmonary hypertension associated with short-term use of fenﬂuramine and phentermine. N Engl J Med 1997;337(9):602–6. [82] Rich S, Rubin L, Walker A, et al. Anorexigens and pulmonary hypertension in the United States: results from the surveillance of North American pulmonary hypertension. Chest 2000;117(3):870–4. [83] Kilbourne EM, Rigau-Perez JG, Heath Jr CW, et al. Clinical epidemiology of toxic-oil syndrome. Manifestations of a new illness. N Engl J Med 1983; 309(23):1408–14. [84] Alonso-Ruiz A, Calabozo M, Perez-Ruiz F, et al. Toxic oil syndrome. A long-term follow-up of a cohort of 332 patients. Medicine (Baltimore) 1993;72(5):285–95. [85] Pizzo CJ. Type I glycogen storage disease with focal nodular hyperplasia of the liver and vasoconstrictive pulmonary hypertension. Pediatrics 1980;65(2): 341–3. [86] Herve P, Drouet L, Dosquet C, et al. Primary pulmonary hypertension in a patient with a familial platelet storage pool disease: role of serotonin. Am J Med 1990;89:117–20. [87] Collins FS, Orringer EP. Pulmonary hypertension and cor pulmonale in the sickle hemoglobinopathies. Am J Med 1982;73(6):814–21. [88] Rich S, Hart K. Familial pulmonary hypertension in association with an abnormal hemoglobin. Insights into the pathogenesis of primary pulmonary hypertension. Chest 1991;99(5):1208–10.

V.V. McLaughlin / Cardiol Clin 22 (2004) 327–341 [89] Wille RT, Krishnan K, Cooney KA, et al. Familial association of primary pulmonary hypertension and a new low-oxygen aﬃnity beta-chain hemofglobinopathy, Hb Washtenaw. Chest 1996;109(3): 848–50. [90] Trembath R, Thomson J, Machado R, et al. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N Engl J Med 2001; 345(5):325–34. [91] Swensen S, Tashjian J, Myers J, et al. Pulmonary venoocclusive disease: CT ﬁndings in eight patients. AJR Am J Roentgenol 1996;167:937–40. [92] Valdes L, Gonzalez-Juanatey J, Alvarez D, et al. Diagnosis of pulmonary veno-occlusive disease: new criteria for biopsy. Respir Med 1998;92:979–83. [93] Masur Y, Remberger K, Hoefer M. Pulmonary capillary hemangiomatosis as a rare cause of pulmonary hypertension [published erratum appears in Pathol Res Pract 1996;192:646]. Pathol Res Pract 1996;192(3):290–5.

341

[94] Lippert J, White C, Cameron E, et al. Pulmonary capillary hemangiomatosis: radiographic appearance. J Thorac Imaging 1998;13:49–51. [95] Dufour B, Maitre S, Humbert M, et al. Highresolution CT of the chest in four patients with pulmonary capillary hemangiomatosis or pulmonary venoocclusive disease. AJR Am J Roentgenol 1998;171:1321–4. [96] Humbert M, Maıˆ tre S, Capron F, et al. Pulmonary edema complicating continuous intravenous prostacyclin in pulmonary capillary hemangiomatosis. Am J Respir Crit Care Med 1998;157:1681–5. [97] Roberts J, Fineman III J, Morin III FC, et al. Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. N Engl J Med 1997; 336:605–10. [98] McLaughlin VV, Genthner DE, Panella MM, et al. Compassionate use of continuous prostacyclin in the management of secondary pulmonary hypertension: a case series. Ann Intern Med 1999;130(9): 740–3.

Cardiol Clin 22 (2004) 367–373

Diagnosis and evaluation of the patient with pulmonary hypertension Nick H.S. Kim, MD a

Division of Pulmonary and Critical Care Medicine, University of California, San Diego, 9300 Campus Point Drive, La Jolla, CA 92037, USA

Deﬁnitions Pulmonary hypertension is deﬁned as mean pulmonary artery pressure greater than 25 mm Hg at rest or greater than 30 mm Hg with exercise [1]. The normal pulmonary circulation is a highcapacitance, low-resistance system; hence, the right ventricle is normally accustomed to relatively low after-load, even during exercise [2]. In pulmonary hypertension, persistent elevation of right ventricular after-load leads over time to right ventricular hypertrophy, enlargement, and ultimately failure. Early attempts at organizing the heterogeneous causes of pulmonary hypertension included anatomically and pathologically based classiﬁcation systems [3]. Although descriptive, these classiﬁcation systems lacked clinical practicality. Instead, clinicians often separated pulmonary hypertension simply into primary (idiopathic) and secondary causes. This division did not address the problem of diagnostic and treatment heterogeneity of the more common causes of pulmonary hypertension represented in the secondary group. The current classiﬁcation system for pulmonary hypertension categorizes pulmonary hypertension by shared clinical attributes [4]. The system oﬀers a more practical approach to diagnosis and classiﬁcation than earlier anatomically or pathologically based versions. Although the system was revised in 2003 at the Third World Symposium on PAH in Venice, Italy, it has maintained its structure and roots in clinical

E-mail address: [email protected]

utility. Pulmonary hypertension is now classiﬁed into ﬁve categories based largely on diagnostic and treatment implications: 1. Pulmonary arterial hypertension (PAH) 2. Pulmonary hypertension related to left-heart disease 3. Pulmonary hypertension related to lung disease or hypoxemia 4. Chronic thrombotic or embolic pulmonary hypertension 5. Miscellaneous McLaughlin’s review of pulmonary hypertension classiﬁcation in this issue gives a more detailed analysis.

Presentation Although presenting symptoms can vary depending on the cause of pulmonary hypertension, dyspnea and fatigue are the most common. In a National Institutes of Health (NIH) registry of 187 patients with PAH, dyspnea was present in 98% of patients and fatigue in 73% by the time of diagnosis [1]. Chest pain related to pulmonary hypertension was present in 47% of this cohort and can mimic angina pectoris. The cause of chest pain is likely from supply–demand mismatch of the right ventricle. Patients can also present with near syncope or syncope, edema, and ascites, all indicative of impaired cardiac output. Right upper quadrant pain can result from hepatic congestion. Hoarseness has been described from the enlarged left pulmonary artery impinging on the recurrent laryngeal nerve (Ortner’s sign).

0733-8651/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ccl.2004.04.003

368

N.H.S. Kim / Cardiol Clin 22 (2004) 367–373

Nonproductive cough and palpitations are also frequently reported. Productive cough, orthopnea, and wheezing are atypical and should alert the clinician to underlying respiratory disease or congestive heart failure. A careful history and physical examination can often direct the clinician to the cause of pulmonary hypertension. A thorough history should cover potential risk factors and associated conditions: 1. Family history of pulmonary hypertension 2. Current or remote use of anorexigens, amphetamines, or other illicit drugs 3. Connective tissue disease 4. Liver disease 5. HIV 6. Left-heart failure 7. Valvular disease 8. Chronic obstructive pulmonary disease (COPD), interstitial lung disease, or sleep apnea 9. Deep vein thrombosis or pulmonary embolism, thrombophilia There is a female preponderance in idiopathic PAH. Median age at presentation is in the 30s [1]. Familial PAH accounted for 6% of idiopathic PAH in a NIH registry of 187 cases; this number is probably an underestimation of actual prevalence. PAH is seen more frequently in patients who have used appetite suppressants and stimulants. The risk of developing PAH seems to be associated with duration of use [5]. Cocaine and methamphetamine use have also been associated with PAH [6]. PAH has been reported in 0.5% of HIVinfected patients [7]. Portopulmonary hypertension has been reported in 1% to 6% of patients with advanced liver disease [8–10]. PAH has also been seen in patients with liver disease without evidence of cirrhosis or portal hypertension [11]. Congenital heart diseases with systemic to pulmonary shunts can present with Eisenmenger’s complex with right-to-left shunting. These patients can have severely elevated pulmonary pressures (exceeding systemic pressures), often with compensated right-heart function. Connective tissue disease remains the most common cause of PAH. As many as 50% of patients with limited scleroderma (or CREST syndrome) have PAH [12]. Patients with diﬀuse scleroderma more frequently have pulmonary hypertension related to pulmonary ﬁbrosis [13]. An estimated 14% of patients with systemic lupus

erythematosus and 29% of patients with of mixed connective tissue disease have PAH [14,15]. Unlike PAH related to scleroderma, immunosuppression therapy has resulted in pulmonary hypertension improvement in select patients with PAH associated with systemic lupus erythematosus [16,17]. PAH also has been reported in patients with polymyositis, dermatomyositis, and rheumatoid arthritis [18,19]. Chronic thromboembolic pulmonary hypertension (CTEPH) is a potentially curable cause of severe pulmonary hypertension [20]. Representing an insidious sequela of pulmonary embolism, CTEPH has an estimated incidence ranging from 500 to 2500 new cases per year in the United States. Patients with CTEPH typically present with progressive dyspnea similar to patients with PAH. Evidence of prior deep venous thrombosis by duplex ultrasound is present in less than half of CTEPH patients. Unlike PAH, the primary treatment for CTEPH remains surgical (pulmonary thromboendarterectomy), often with rapid clinical improvement and recovery of normal right heart function. (See the discussions of CTEPH by Auger et al and of pulmonary thromboendarterectomy by Thisteltwaite et al in this issue.) At autopsy as many as 40% of patients with COPD have evidence of right-heart enlargement [21]. Pulmonary hypertension (deﬁned in these earlier reports as mean pulmonary arterial pressure >20 mm Hg) can be found in 40% and 70% of COPD patients with a forced expiratory volumes in 1 second of less than 1 L and less than 0.6L, respectively [22,23]. Pulmonary hypertension can be seen in patients with restrictive ventilatory diseases and is typically associated with severely reduced vital capacity and chronic respiratory acidosis on blood gas analysis. Rightheart dysfunction was found in 18% of patients with obstructive sleep apnea (OSA) [24]. Only half of these patients had pulmonary hypertension conﬁrmed by right-heart catheterization (RHC), suggesting the causes of right-heart dysfunction in OSA may be multifactorial. Elevated left atrial pressure and diastolic dysfunction may contribute to pulmonary hypertension seen in OSA [25,26]. Although the presence of pulmonary hypertension in OSA seems to correlate with severity of nocturnal desaturation and the presence of daytime hypoxia, the severity of apnea-hypopnea index does not seem to correlate with the presence of pulmonary hypertension [26–28]. With the exception of patients with severe interstitial lung diseases, the degree of pulmonary pressure

N.H.S. Kim / Cardiol Clin 22 (2004) 367–373

elevation in patients with underlying lung or ventilatory disease tends to be mild or moderate. In pulmonary hypertension, ﬁndings on physical examination can be subtle. Vital signs may reveal resting tachycardia and reduced systemic pulse pressure. Central cyanosis is present in Eisenmenger’s complex and in pulmonary hypertension with shunting through a patent foramen ovale (PFO). Isolated peripheral cyanosis suggests low cardiac output. Lung examination in PAH and CTEPH is typically normal. Signiﬁcant crackles, evidence of mitral or aortic valve dysfunction, wheezing, or thoracic deformities should suggest underlying lung or left heart disease as the cause of pulmonary hypertension. Jugular venous distention, accentuated pulmonic component of the second heart sound, and tricuspid regurgitation louder with inspiration are characteristic cardiac examination ﬁndings in pulmonary hypertension. Additional signs of right ventricular dysfunction may include edema, ascites, hepatomegaly, and audible right-sided gallop. Diagnostic step 1: suspect pulmonary hypertension The ﬁrst and most important step in successfully making the diagnosis of pulmonary hypertension is considering it in the diﬀerential diagnosis. Pulmonary hypertension should be considered in any patient with persistent dyspnea, fatigue, or exercise intolerance without a readily attributable cause. Pulmonary hypertension should also be considered in any patient with symptoms of cardiopulmonary insuﬃciency who has not demonstrated improvement despite therapy for an initial working, but ultimately incorrect, diagnosis. Once pulmonary hypertension is considered, diagnostic investigation should begin by considering pulmonary hypertension related to left-heart or chronic lung disease. ECG and chest radiographs are two readily available, often valuable initial screening tests for chronic lung disease or left-heart disease. In PAH or CTEPH, ECG may reveal evidence of right ventricular hypertrophy, right atrial enlargement, rightward axis deviation, and right bundle branch block. Presence of P wave of 2.5 mm or greater in lead II and QR pattern in lead V1 were both associated with worsened survival in 51 PAH patients [29]. These ECG ﬁndings may not be present in early pulmonary hypertension [30]. In a cohort of 61 PAH patients, ECG was normal in 13% [31]. Chest radiographs are usually clear of parenchymal disease in PAH. Evidence of

369

parenchymal infarct, scarring, or mosaic perfusion pattern may be seen in CTEPH [32]. On upright, posterior-anterior projection, a right descending pulmonary artery greater than 16 mm in width and a left main pulmonary artery greater than 18 mm in width suggest pulmonary hypertension [33]. Pruning of pulmonary arteries distal to the centrally enlarged vessels can be found in both PAH and CTEPH. The cardiac silhouette is often enlarged, particularly with prominence of right heart contour. Diagnostic step 2: echocardiogram and pulmonary function tests Transthoracic echocardiogram is the preferred test for screening for pulmonary hypertension and also for excluding signiﬁcant left-heart or valvular disease. The pulmonary artery systolic pressure (PASP) can be estimated in 59% to 72% of patients using Doppler interrogation of tricuspid regurgitation [34–36]. In patients with signiﬁcant lung disease, the PASP is often overestimated [37]. The presence of enlarged or hypertrophied right ventricle should also raise suspicion of pulmonary hypertension. Additional ﬁndings on echocardiography may include ﬂattening of the intraventricular septum, reduced respiratory variation of the vena cava, pericardial eﬀusion, and PFO [38]. The left ventricle systolic function is typically normal in PAH and CTEPH. Diastolic dysfunction in PAH and CTEPH is usually the result of impairment from an enlarged right heart. Evidence of signiﬁcant left atrial enlargement, leftsided valvular dysfunction or abnormality, or left ventricular systolic dysfunction warrants further investigation. (Daniels et al present a detailed review of echocardiography in pulmonary vascular disease elsewhere in this issue.) Complete pulmonary function testing (PFT) should be obtained in patients with persistent dyspnea and suspicion of pulmonary hypertension. The typical pattern on PFT of patients with PAH and CTEPH is mild restriction with reduced diﬀusion capacity for carbon monoxide (mean 60%) [39]. Normal PFT, however, does not rule out possible pulmonary hypertension. Analysis of arterial blood gases typically reveals chronic respiratory alkalosis and widened A-a gradient. Severe hypoxemia in the absence of pulmonary inﬁltrates suggests intracardiac shunting through a PFO (present in 24% of cases) [38]. Severely reduced diﬀusion abnormality on PFT should be investigated with a high-resolution CT scan

370

N.H.S. Kim / Cardiol Clin 22 (2004) 367–373

Step 1. Suspect PH -persistent dyspnea, fatigue -risk factors or associated conditions -exam suggestive -obtain CXR, ECG

PH suspected Step 2. Echocardiogram and PFTs -estimate PA pressure -evaluate right heart size/function -screen for left heart/valvular diseaseA -screen for lung diseaseA -consider sleep test/high resolution CTA pulmonary vascular cause suspected

Step 3. Lung ventilation-perfusion scan -screen for CTEPHB -consider angiogram

PAH suspected

Step 4. Right heart catheterization -confirm PH -screen for left heart/valvular diseaseA -prognostic data -guide treatment decisions Fig. 1. Simpliﬁed four-step diagnostic algorithm for pulmonary hypertension. (A) Further investigate and treat left heart disease or lung-ventilatory disease causing PH. (B) Conﬁrm CTEPH with RHC-angiogram or refer to pulmonary thromboendarterectomy center.

screening for interstitial lung disease. Patients with history of excessive daytime somnolence or witnessed apneas should be tested with overnight oximetry or polysomnogram to rule out pulmonary hypertension related to sleep-disordered breathing. Although the severity of daytime hypoxia correlates with pulmonary hypertension, daytime hypoxia may not always be present. Although cardiopulmonary exercise testing has not been routinely obtained in patients with established pulmonary hypertension, it may be valuable in screening early-stage disease and pro-

vide additional prognostic data [40,41]. Reductions in Vo2max, anaerobic threshold, and ventilatory eﬃciency have been described and shown to correlate with pulmonary hypertension severity [42].

Diagnostic step 3: lung ventilation-perfusion scan Once an isolated vascular cause of pulmonary hypertension is suspected, a ventilation-perfusion scan should be obtained. Perfusion scan ﬁndings

N.H.S. Kim / Cardiol Clin 22 (2004) 367–373

in PAH fall in three categories: (1) normal, (2) a heterogeneous or mottled pattern, with no defects larger than subsegment in size, or (3) preferential ﬂow to the posterior bases, which can be misinterpreted as CTEPH with upper-lobes involvement [32]. The second and third categories may warrant additional conﬁrmatory testing such as pulmonary angiogram or angioscopy. Although CT angiography has replaced the VQ scans in many centers as the diagnostic tool for detecting pulmonary embolism, the VQ scan remains the preferred screening test in CTEPH.

Diagnostic step 4: right-heart catheterization RHC provides the deﬁnitive diagnosis of pulmonary hypertension and should be obtained in all patients with PAH before treatment. RHC can also provide other diagnostic information and important prognostic data [43]. Obtaining a hepatic occlusion pressure with comparison to inferior vena cava pressure can screen for portal hypertension. In addition to estimating left atrial pressure, RHC can also detect mitral regurgitation and screen for intracardiac shunting. RHC is also required for acute vasodilator testing and, in select patients, for obtaining exercise hemodynamics and early response/titration of epoprostenol therapy. Lastly, RHC data are invaluable when considering treatment decisions from an ever-growing armament of pulmonary hypertension therapeutics (see the review of PAH by Williamson and Channick in this issue). Lung biopsy in pulmonary hypertension is risky and currently is not recommended for almost all cases of pulmonary hypertension. Screening serologic tests (antinuclear antibodies, HIV) and liver function tests should be obtained in patients suspected of having PAH. Although substantial progress has been made in recent years in the area of pulmonary hypertension–related genetics, a genetic screening test is currently not recommended or available for general diagnostic purposes [44,45].

Summary With a thorough history and a few tests, the nature and degree of pulmonary hypertension can be determined eﬃciently (Fig. 1). A high index of suspicion and a step-wise evaluation approach are necessary for accurate and timely diagnosis of pulmonary hypertension.

371

References [1] Rich S, Dantzker DR, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, et al. Primary pulmonary hypertension. A national prospective study. Ann Intern Med 1987;107:216–23. [2] Reeves JT, Dempsey JA, Grover RF. In: Weir EK, Reeves JT, editors. Pulmonary vascular physiology and pathophysiology: lung biology in health and disease series, Vol. 38. New York: Marcel Dekker; 1989. p. 107–34. [3] D’Alonzo GE, Dantzker DR. In: Rubin LJ, Rich S, editors. Primary pulmonary hypertension: lung biology in health and disease series, vol. 99. New York: Marcel Dekker; 1997. p. 227–52. [4] Rich S. Executive summary of the World Symposium on PPH. 1999. Available at: http://www.who.int/ ncd/cvd/pph.html. Accessed October 9, 2001. [5] Abenheim L, Moride Y, Brenot F, Rich S, Benichou J, Kurz X, et al. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. N Engl J Med 1996;335:609–16. [6] Schaiberger PH, Kennedy TC, Miller FC, Gal J, Petty TL. Pulmonary hypertension associated with long-term inhalation of crank methamphetamine. Chest 1993;104:614–6. [7] Speich R, Jenni R, Opravil M, Pfab M, Russi EW. Primary pulmonary hypertension in HIV infection. Chest 1991;100:1268–71. [8] McDonnell PJ, Toye PA, Hutchins GM. Primary pulmonary hypertension and cirrhosis: are they related? Am Rev Respir Dis 1983;127:437–41. [9] Torregrosa M, Genesca J, Gonzalez A, Evangelista A, Mora A, Margarit C, et al. Role of Doppler echocardiography in the assessment of portopulmonary hypertension in liver transplantation candidates. Transplantation 2001;71:572–4. [10] Colle IO, Moreau R, Godinho E, Belghiti J, Ettori F, Choen-Solal A, et al. Diagnosis of portopulmonary hypertension in candidates for liver transplantation: a prospective study. Hepatology 2003; 37:401–9. [11] Auletta M, Oliviero U, Iasiuolo L, Scherillo G, Antoniello S. Pulmonary hypertension associated with liver cirrhosis: an echocardiographic study. Angiology 2000;51:1013–20. [12] Ungerer RG, Tashkin DP, Furst D. Prevalence and clinical correlates of pulmonary arterial hypertension in progressive systemic sclerosis. Am J Med 1983;75:65–74. [13] Tanoue LT. Pulmonary hypertension in the collagen vascular diseases. Semin Resp Crit Care Med 2003;24:287–95. [14] Simonson JS, Schiller NB, Petri M, Hellmann DB. Pulmonary hypertension in systemic lupus erythematosus. J Rheumatol 1989;16:918–25. [15] Sullivan WD, Hurst DJ, Harmon CE, Esther JH, Agia GA, Maltby JD, et al. A prospective evaluation emphasizing pulmonary involvement in

372

[16]

[17]

[18]

[19]

[20]

[21]

[22]

[23]

[24]

[25]

[26]

[27]

[28]

[29]

N.H.S. Kim / Cardiol Clin 22 (2004) 367–373 patients with mixed connective tissue disease. Medicine 1984;63:92–107. Goupille P, Fauchier L, Babuty D, Fauchier JP, Valat JP. Precapillary pulmonary hypertension dramatically improved with high doses of corticosteroids during systemic lupus erythematosus. J Rheumatol 1994;21:1976–7. Groen H, Bootsma H, Postma DS, Kallenberg CG. Primary pulmonary hypertension in a patient with systemic lupus erythematosus: partial improvement with cyclophosphamide. J Rheumatol 1993;20: 1055–7. Palevsky HI, Gurughagavatula I. Pulmonary hypertension in collagen vascular disease. Comp Ther 1999;25:133–43. Dawson JK, Goodson NG, Graham DR, Lynch MP. Raised pulmonary artery pressures measured with Doppler echocardiography in rheumatoid arthritis patients. Rheumatol 2000;39:1320–5. Fedullo PF, Auger WR, Kerr KM, Rubin LJ. Chronic thromboembolic pulmonary hypertension. N Engl J Med 2001;345:1465–72. Heath D, Brewer D, Hicken P. Mechanisms and pathology. In: Thomas CC, editor. Cor pulmonale in emphysema. Springﬁeld (IL): Thomas; 1968. p. 1–37. Mitchell RS, Vincent TN, Filley GF. Chronic obstructive bronchopulmonary disease, IV: the clinical and physiological diﬀerential of chronic bronchitis and emphysema. Am J Med Sci 1964; 247:513–7. Renzetti AD Jr, McClement JH, Litt BD. The Veterans Administration cooperative study of pulmonary function, III: mortality in relation to respiratory function in chronic obstructive pulmonary disease. Am J Med 1966;41:115–9. Sanner BM, Konermann M, Strum A, Muller HJ, Zidek W. Right ventricular dysfunction in patients with obstructive sleep apnoea syndrome. Eur Respir J 1997;10:2079–83. Hetzel M, Kochs M, Marx N, Woehrle H, Mobarak I, Hombach V, et al. Pulmonary hemodynamics in obstructive sleep apnea: frequency and causes of pulmonary hypertension. Lung 2003;181:157–66. Sanner BM, Doberauer C, Konermann M, Sturm A, Zidek W. Pulmonary hypertension in patients with obstructive sleep apnea syndrome. Arch Intern Med 1997;157:2483–7. Sajkov D, Cowie RJ, Thornton AT, Espinoza HA, McEvoy RD. Pulmonary hypertension and hypoxemia in obstructive sleep apnea syndrome. Am J Respir Crit Care Med 1994;149:416–22. Bady E, Achkar A, Pascal S, Orvoen-Frija E, Laaban JP. Pulmonary arterial hypertension in patients with sleep apnoea syndrome. Thorax 2000; 55:934–9. Bossone 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.

[30] Kanemoto N. Electrocardiographic and hemodynamic correlations in primary pulmonary hypertension. Angiology 1988;39:781–7. [31] Ahearn GS, Tapson VF, Rebeiz A, Greenﬁeld JC Jr. Electrocardiography to deﬁne clinical status in primary pulmonary hypertension and pulmonary arterial hypertension secondary to collagen vascular disease. Chest 2002;122:524–7. [32] Fedullo PF, Auger WR, Channick RN, Kerr KM, Rubin LJ. Chronic thromboembolic pulmonary hypertension. Clin Chest Med 2001;22:561–81. [33] Matthay RA, Schwarz MI, Ellis JH, Steele PP, Siebert PE, Durrance JR, et al. Pulmonary artery hypertension in chronic obstructive pulmonary disease: determination by chest radiography. Invest Radiol 1981;16:95–100. [34] Berger M, Haimowitz A, Van Tosh A, Berdoﬀ RL, Goldberg E. Quantitative assessment of pulmonary hypertension in patients with tricuspid regurgitation using continuous wave Doppler ultrasound. J Am Coll Cardiol 1985;6:359–65. [35] Denton CP, Cailes JB, Phillips GD, Wells AU, Black CM, Bois RM. Comparison of Doppler echocardiography and right heart catheterization to assess pulmonary hypertension in systemic sclerosis. Br J Rheumatol 1997;36:239–43. [36] Chan KL, Currie PJ, Seward JB, Hagler DJ, Mair DD, Tajik AJ. Comparison of three Doppler ultrasound methods in the prediction of pulmonary artery pressure. J Am Coll Cardiol 1987; 9:549–54. [37] Arcasoy SM, Christie JD, Ferrari VA, Sutton MS, Zisman DA, Blumenthal NP, et al. Echocardiographic assessment of pulmonary hypertension in patients with advanced lung disease. Am J Respir Crit Care Med 2003 1;167(5):735–40. [38] Bossone E, Duong-Wagner TH, Paciocco G, Oral H, Ricciardi M, Bach DS, et al. Echocardiographic features of primary pulmonary hypertension. J Am Soc Echocardiogr 1999;12:655–62. [39] Steenhuis LH, Groen HJ, Koeter GH, van der Mark TW. Diﬀusion capacity and haemodynamics in primary and chronic thromboembolic pulmonary hypertension. Eur Respir J 2000;16:276–81. [40] Sun XG, Hansen JE, Oudiz RJ, Wasserman K. Pulmonary function in primary pulmonary hypertension. J Am Coll Cardiol 2003;41:1028–35. [41] Wensel R, Opitz CF, Anker SD, Winkler J, Hoﬀken G, Kleber FX, et al. Assessment of survival in patients with primary pulmonary hypertension: importance of cardiopulmonary exercise testing. Circulation 2002;106:319–24. [42] Sun XG, Hansen JE, Oudiz RJ, Wasserman K. Exercise pathophysiology in patients with primary pulmonary hypertension. Circulation 2001;104: 429–35. [43] D’Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, et al. Survival in patients with primary pulmonary hypertension. Results

N.H.S. Kim / Cardiol Clin 22 (2004) 367–373 from a national prospective registry. Ann Intern Med 1991;115:343–9. [44] Humbert M, Trembath RC. Genetics of pulmonary hypertension: from bench to bedside. Eur Respir J 2002;20:741–9.

373

[45] Grunig E, Janssen B, Merles D, Barth U, Borst MM, Vogt IR, et al. Abnormal pulmonary artery pressure response in asymptomatic carriers of primary pulmonary hypertension gene. Circulation 2000;102:1145–50.

Cardiol Clin 22 (2004) 441–452

Diagnosis and treatment of pulmonary arterial hypertension Richard Channick, MDa,*, Timothy L. Williamson, MDb a

Division of Pulmonary and Critical Care, University of California, San Diego, 9300 Campus Point Drive, La Jolla, CA 92037, USA b Division of Pulmonary and Critical Medicine Care Medicine, University of Kansas Hospital, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA

Pulmonary arterial hypertension (PAH) is characterized by an elevated pulmonary vascular resistance (PVR) that, in the absence of intervention, progresses to right ventricular failure and death. When deﬁned clinically as a mean pulmonary artery pressure greater than or equal to 25 mm Hg at rest or 30 mm Hg with exercise, idiopathic PAH has been estimated to aﬀect at least 1 to 2 persons per million population [1], although secondary forms of the disease are much more common. The World Health Organization (WHO) classiﬁcation of pulmonary hypertension (PH) is reviewed in detail in the article by McLaughlin et al. This classiﬁcation is based on expert consensus opinion reached at the WHO Symposium on Pulmonary Hypertension in Evian, France in 1998. It divides PH into ﬁve categories, including PAH, pulmonary venous hypertension, PH associated with respiratory diseases, PH associated with embolic disease, and PH caused by diseases that directly aﬀect the pulmonary vasculature, such as sarcoidosis. Experts recently convened again in Venice, Italy in 2003 [1]. Among the modiﬁcations from the Venice meeting is that pulmonary hypertension without a known association or cause is no longer referred to as primary pulmonary hypertension (PPH), but instead as idiopathic (sporadic) PAH (IPAH) with a separate category for familial PAH (FPAH). Because of the body of literature * Corresponding author. E-mail address: [email protected] (R. Channick).

that has employed the term PPH, this article uses both terms interchangeably. In addition to IPAH, PAH can occur in association with other conditions such as connective tissue disease, congenital heart disease, portal hypertension, HIV, and prior ingestion of stimulant drugs such as fenﬂuramines, amphetamines, or cocaine. Of the various categories, only PAH is discussed in this article. The evaluation of pulmonary hypertension, however, should ascertain its proper cause and classiﬁcation, because many of the treatment options for PAH discussed here are not necessarily eﬃcacious and may be deleterious in patients with pulmonary hypertension secondary to other disorders. Although long considered a disease of pulmonary vasoconstriction, PAH should now more correctly be considered a disease of proliferation. Voelkel and Cool further review the pathology of this disorder elsewhere in this issue. Brieﬂy, PAH is characterized by increased pulmonary arterial thickness, dilated capillaries, and plexiform lesions that obstruct the vessel lumen [2]. Additionally, patients are at risk for in situ thrombosis secondary to increased platelet aggregation as a consequence of decreased nitric oxide and prostacyclin production [3]. Survival in PAH without intervention is dismal. A National Institutes of Health registry followed patients with PPH (idiopathic PAH) between 1985 and 1988, in an era that preceded currently available therapeutic agents [4]. Survival rates at 1, 3, and 5 years were 68%, 48% and 34%, respectively, with a median survival from diagnosis of 2.8 years.

0733-8651/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ccl.2004.04.004

442

R. Channick, T.L. Williamson / Cardiol Clin 22 (2004) 441–452

Findings correlated with poorer prognosis included WHO functional class III or class IV (Box 1), presence of Raynaud’s phenomenon, increased right atrial pressure, increased pulmonary artery pressure, decreased cardiac index, and decreased diﬀusion [4]. In another study multivariate analysis suggested pericardial eﬀusion, enlarged right atrium, 6-minute walk distance, and mixed venous oxygen saturation as predictors of adverse outcomes [5]. Not all causes of PAH portend the same survival. Patients with PAH associated with the scleroderma spectrum of diseases, for example, have a worse prognosis than those with idiopathic PAH (PPH) [6]. Pulmonary veno-occlusive disease is associated with perhaps the worst survival, with 1-year mortality following diagnosis exceeding 70% [7]. Diagnosis The diagnosis of PAH requires a high index of suspicion, because presenting symptoms are often protean and common to a multitude of cardiopulmonary disorders. The goals of the PAH evaluation are severalfold: to establish the correct cause of dyspnea, to exclude treatable causes of PAH, to document the presence and severity of pulmonary hypertension and right ventricular dysfunction, to recognize the extent of functional impairment, and to use this information to help formulate a therapeutic regimen. The tools for accomplishing these tasks are largely those used daily by physicians to quantify and qualify other cardiopulmonary disorders, namely clinical ﬁndings, lung function testing, radiographic studies, echocardiograms, heart catheterization, and exercise testing. During the diagnostic process special

attention should be paid to excluding chronic thromboembolic disease, because a potentially corrective surgical procedure exists for this disorder [8,9]. The symptoms of PAH are nonspeciﬁc. Dyspnea is nearly universal as the disease progresses, but fatigue, chest pain, syncope, and near syncope are also common [10]. Given the vague nature of symptoms, it is not surprising that the time from symptom onset to deﬁnitive diagnosis averages 2 or more years [10]. The cardinal ﬁndings on physical examination in PAH are an accentuated second heart sound and a tricuspid regurgitation murmur, but both ﬁndings may be variably present. As pulmonary hypertension progresses, signs of right-heart failure may ensue as evidenced by jugular venous distention, a right ventricular heave, lower extremity edema, hepatomegaly, and ascites. During the physical examination particular attention should also be paid to ﬁndings suggestive of diseases known to be associated with PAH, such as collagen vascular disorders and chronic liver disease, because prognosis and treatment may vary by underlying cause. Additionally, the presence or absence of pulmonary ﬂow murmurs should be noted, because these murmurs are highly suggestive of chronic thromboembolic disease, pulmonary vasculitis, or pulmonic stenosis, and have not been reported in PAH from other causes [9]. Pulmonary function tests are often obtained during the course of an evaluation of dyspnea but have no ﬁndings speciﬁc for PAH. Diﬀusion is often only modestly decreased (69 25) [10]; more severe diﬀusion defects may indicate concurrent parenchymal disease. A pattern of mild

Box 1. World Health Organization functional class in pulmonary artery hypertension Class I: Patients in with pulmonary hypertension, but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near syncope. Class II: Patients with pulmonary hypertension resulting in slight limitation of physical activity. Patients are comfortable at rest, but ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope. Class III: Patients with pulmonary hypertension resulting in marked limitation of physical activity. Patients are comfortable at rest, but less than ordinary physical activity cause undue dyspnea or fatigue, chest pain, or near syncope. Class IV: Patients with pulmonary hypertension resulting in inability to perform any physical activity without symptoms. Patients manifest signs of right heart failure. Dyspnea and/or fatigue may be present at rest, and discomfort is increased by any physical activity.

R. Channick, T.L. Williamson / Cardiol Clin 22 (2004) 441–452

obstructive lung disease has been described in severe PAH [11]. Radiographic studies may be most useful to exclude competing explanations for dyspnea and, if PAH is present, to aid in excluding secondary causes. Chest radiographs may suggest interstitial or obstructive lung disease and demonstrate enlarged pulmonary arteries or cardiomegaly. CT scans may likewise exhibit enlarged pulmonary arteries and parenchymal lung disease but may also help detect chronic thromboembolic pulmonary hypertension, pulmonary veno-occlusive disease, pulmonary vascular tumors, or extrinsic compression of the pulmonary vessels. Lung perfusion scanning has a pivotal role in the evaluation of PAH, because it may reveal segmental and subsegmental defects consistent with chronic thromboembolic disease, prompting further evaluation by pulmonary angiography. High-probability perfusion scans, although highly suggestive of possible chronic thromboembolic disease, have also been reported in pulmonary veno-occlusive disease [12]. In contrast, lung perfusion scans in PAH are either normal or demonstrate a diﬀuse, mottled appearance. Echocardiography Echocardiography is a relatively inexpensive, noninvasive tool for estimating pulmonary artery pressures and detailing cardiovascular anatomy and function. In addition to providing an estimation of peak pulmonary artery pressure, echocardiography may provide useful assessments of chamber and valve morphology, presence of congenital heart disease, left ventricular systolic and diastolic function, and intracardiac or intrapulmonary shunting [13]. Pericardial eﬀusions are common (present in more than half of patients with severe PAH), and although they often are not hemodynamically signiﬁcant, they may carry prognostic signiﬁcance, with an association with right-heart failure, impaired exercise tolerance, and a poor 1-year survival [14]. Typical ﬁndings in severe PAH may include tricuspid regurgitation, right ventricular or atrial enlargement, and elevated pulmonary artery pressures. Several studies, however, have shown that the accuracy of echocardiography is limited when compared with direct measurement of pulmonary artery pressure by right-heart catheterization. Arcasoy and colleagues [15] examined 374 lung transplant candidates who underwent both procedures. Estimation of systolic pulmonary artery pressures by

443

echocardiography was possible in only 44% of the patients, with a correlation coeﬃcient of 0.69. In 52% of patients studied, the diﬀerences between measurements on right-heart catheterization and echocardiography were greater than 10 mm Hg, and 48% of patients classiﬁed as having pulmonary hypertension on echocardiography were found to be misclassiﬁed after right-heart catheterization. Similarly, Cotton et al [16] looked at 78 liver transplant candidates. Systolic pulmonary artery pressures were signiﬁcantly higher when measured by echocardiography than when measured by right-heart catheterization, with a correlation coeﬃcient of only 0.46, and a positive predictive value of 37.5%. Negative predictive value, however, was nearly 92%. Daniels et al present a full discussion of echocardiography in pulmonary vascular disease elsewhere in this issue. Right-heart catheterization Given its limitations, echocardiography should not be used to diagnose PAH deﬁnitively. Rightheart catheterization remains the standard for determining pulmonary artery pressures and should always be performed before initiation of costly or invasive therapy. In addition to direct quantiﬁcation of pulmonary hemodynamics (which are correlated with prognosis [4]), rightheart catheterization may help exclude congenital heart disease, establish the presence and contribution of left-sided heart disease, and quantify vasodilator reserve (discussed further in the section on calcium-channel blockers). The details of the right-heart catheterization procedure are discussed elsewhere in this issue. Functional assessment Functional impairment in PAH may be identiﬁed subjectively or objectively. Subjectively, the WHO functional classiﬁcation detailed in Box 1 categorizes patients by reported exercise tolerance. Although this classiﬁcation system is not perfect, most PAH practitioners are familiar with its application, and it is widely used in research and therapeutic algorithms. Cardiopulmonary exercise testing provides an objective assessment of functional status correlates closely with mortality: a peak VO2max less than 10.4 mL/kg/min independently predicts decreased survival [17]. Cardiopulmonary exercise testing, however, is expensive, time consuming, diﬃcult to perform for many patients with advanced disease, and not universally available. For these reasons submaximal

444

R. Channick, T.L. Williamson / Cardiol Clin 22 (2004) 441–452

exercise testing to determine functional status is desirable. The 6-minute walk has been used as a reliable, well-validated examination in assessing exercise capacity. Simply, patients walk a premeasured course, at their own pace and without encouragement or direction from technicians, and the distance walked is measured. The 6-minute walk distance has been shown to be correlated with survival, with a distance less than 332 m associated with increased mortality [18]. The test is inexpensive, widely available, not overly burdensome to patients or providers, and reproducible. Six-minute walk testing has often served as the primary outcome endpoint in clinical trials of new therapies for PAH.

increase morbidity or mortality. This disease often aﬄicts women of childbearing age, and these patients should be strongly counseled to avoid pregnancy, because the mortality in patients with PAH who become pregnant has been reported to be as high as 30% to 56% [19,20]. Patients are often concerned about the level of activity that they are allowed to undertake. In general, patients should be encouraged to stay active to prevent deconditioning but cautioned to not overexert themselves to the point of severe dyspnea, chest pain, or syncope. Given the adverse eﬀect of altitude on the pulmonary vasculature, patients with PAH should avoid altitudes higher than approximately 4000 feet.

Treatment

Supportive therapies Despite limited evidence of their value, a number of nonspeciﬁc supportive therapies are frequently used in PAH, especially as right-heart failure ensues. The decision to initiate any of these treatments must be made on an individualized basis.

In the past 2 decades an exponential growth of interest and research in PAH has engendered several therapeutic options that were not available as recently as 5 years ago. The ideal goals of treatment are to improve symptoms and survival using the least invasive therapies possible. Given the expanding therapeutic options in PAH, it is important to understand which patients are appropriate for which therapy. Used inappropriately, many of the available PAH therapies have the potential for adversely aﬀecting patient outcome, so the dictum of primum non nocere must be paramount. For example, using PAH medications in patients with even modest degrees of left ventricular systolic or diastolic dysfunction can worsen clinical status. It is recommended that right-heart catheterization be performed before initiating therapy with most agents speciﬁc for the treatment of PAH, because right-heart catheterization is a powerful resource to determine contributions of left-sided heart disease and also provides indirect evidence of right ventricular compensation, knowledge that is useful in selecting the appropriate therapeutic regimen. Patients with WHO functional class III and class IV symptoms should be considered for referral to a center with speciﬁc focus and expertise in the management of pulmonary vascular disorders. General treatments Lifestyle modiﬁcation Treatment should be directed toward both pharmacologic interventions and lifestyle modiﬁcation, with avoidance of behaviors that might

Oxygen. Hypoxemia should be recognized and treated, both at rest and with exercise. When given acutely, 100% oxygen has been demonstrated to reduce mean pulmonary artery pressure and PVR modestly and to increase the cardiac index [21]. Few data exist regarding the long-term beneﬁts of oxygen in this disorder, but extrapolating the positive eﬀect of oxygen therapy on survival in patients with chronic obstructive pulmonary disorder [22], it seems reasonable that hypoxemia should be recognized and treated at rest and with exercise. Additionally, nocturnal oxygen desaturation is common in PAH [23], even in the absence of concurrent sleep-disordered breathing, and adequate oxygenation at night should be assured as well. Wafarin. Warfarin therapy is standard in patients with IPAH (PPH) and is often recommended in other forms of PAH based on two retrospective studies demonstrating a modest survival beneﬁt. PAH may be complicated by in situ thrombosis, and low-level anticoagulation with warfarin is often used in an eﬀort to help prevent this process. Two studies have established a beneﬁcial eﬀect on mortality [24,25]; one of these studies also exhibited improvement in quality-of-life indices [24]. Patients with chronic indwelling intravenous catheters and right-to-left intracardiac shunting may

R. Channick, T.L. Williamson / Cardiol Clin 22 (2004) 441–452

be especially strong candidates for chronic anticoagulation. Digoxin. Digoxin is often added to the regimen of patients with right-heart failure. In 17 patients examined in the catheterization laboratory, digoxin was shown to improve cardiac output somewhat and to decrease norepinephrine levels [26]. Long-term data on its eﬃcacy in PAH are lacking, however. Diuretics. Diuretics are also commonly used in PAH to decrease intravascular volume and to improve dyspnea. It is postulated that improvements in right ventricular geometry may decrease septal intrusion into the left ventricle, improving left-ventricular function as well.

Speciﬁc therapies In properly selected patients the therapies discussed here have been shown to modify the course of PAH signiﬁcantly and to improve symptoms, hemodynamics, and survival. Calcium-channel blockade Acute vasodilator challenge testing during right-heart catheterization may identify the small percentage of patients with PAH who have disease characterized primarily by vasoconstriction. Appropriate testing agents include inhaled nitric oxide, adenosine, and prostacyclin. The deﬁnition of a vasodilator responder has varied, but using a deﬁnition of a decrease in PVR of greater than 20%, Rich and colleagues [25] found 26% of patients to be responders. These patients were treated for up to 5 years with high doses of calcium-channel blockers (nifedipine with an average daily dose of 172 mg and diltiazem with an average daily dose of 720 mg). At 5 years 94% of responding patients were alive, compared with 55% of patients who were not responders. A recent retrospective study by Sitbon et al [27] suggests that only half of acute vasodilator responders will beneﬁt long term. In this study only 6% of all patients did well functionally when treated with calcium-channel blockers alone. These patients were those who achieved nearly normal pulmonary arterial pressures (mean, <37 mm Hg) and PVR (<5 Wood units) with adequate cardiac output during the vasodilator test. Similarly, Raﬀy et al [28] examined 91 consecutive patients undergoing vasodilator challenge with epoprostenol. Patients were classiﬁed by the magnitude of

445

their response in depression of total pulmonary resistance: those with a depression of less than 20% were categorized as nonresponding, those with a depression of 20% to 50% as moderately responding, and those with a depression above 50% as highly responding. Two-year survival rates for these groups were 38%, 47%, and 62%, respectively (P < 0.05). Use of calcium-channel blockers for PAH should be reserved for the small subset of patients who exhibit near normalization of pulmonary artery pressures during vasodilator challenge with a preserved cardiac output. Long-term clinical response should be closely monitored, and treatment should be escalated if deterioration occurs. It thus seems that calcium-channel blockers are rarely beneﬁcial and should be used only in patients with a signiﬁcant acute vasodilator response and never in nonresponders. Calciumchannel blockers with signiﬁcant negative inotropic eﬀect, such as verapamil, should be avoided. Treatment with calcium-channel blockade should be avoided in patients who do not respond at vasodilator challenge, because serious adverse events have been reported in these patients [29]. Systemic hypotension in the setting of a ﬁxed right ventricular cardiac output may lead to decreased right coronary perfusion, with potential to cause syncope, chest pain, or even death. Treatment sequence Currently, the WHO functional class of patients largely guides therapy. Supportive therapy is used as indicated. In patients with functional class I and class II symptoms, speciﬁc therapy is not indicated, because the cost and risk of therapy in these patients has not been justiﬁed. Patients who are WHO functional class III should be considered for oral therapy, and patients whose disease progresses on oral therapy and patients with advanced class IV symptoms should be considered for intervention with prostacyclin. Unfortunately, cost and insurance coverage can also inﬂuence the selection of available agents: the cost of bosentan therapy can exceed US $25,000 per year, and the costs of epoprostenol and treprostinil therapy can each exceed US $100,000 per year. Although interest is growing in testing combination therapy, limited data are currently available. Endothelin receptor antagonists Endothelin is a smooth muscle mitogen and vasoconstrictive agent. Its production is increased in pulmonary hypertension [30] and is strongly

446

R. Channick, T.L. Williamson / Cardiol Clin 22 (2004) 441–452

correlated with pulmonary hemodynamics and 6-minute walk data [31]. Eﬀects are mediated through endothelin-A and endothelin-B receptors that are variably distributed throughout the lung. Both receptors may contribute to pulmonary artery smooth muscle cell proliferation and vascular remodeling [32]. Blockade of these receptors has generated signiﬁcant interest as a therapeutic target. Bosentan (Tracleer) is a nonselective endothelin receptor antagonist that has proven eﬃcacy in two double-blinded, multicenter, placebocontrolled trials. It is currently the only oral medication approved in the United States for PAH. In a pilot study, Channick and colleagues [33] randomly assigned 32 patients with idiopathic PAH or PAH associated with the scleroderma spectrum of disease to treatment with bosentan (62.5 mg twice daily for 1 month followed by 125 mg twice daily) or placebo in a study lasting 12 weeks. Six-minute walk distance improved by 70 m in the treatment group but declined by 6 m in the placebo group. Cardiac index improved, and PVR decreased, with associated improvements in Borg Dyspnea Index scores and functional class. Three patients in the placebo group withdrew from the study because of worsening clinical status. A larger follow-up study (BREATHE-1, the Bosentan Randomized Trial of Endothelin Antagonist Therapy) enrolled 213 WHO functional class III or class IV patients with idiopathic PAH or PAH associated with connective tissue disease and followed them for 16 weeks [34]. Six-minute walk distances again improved, as did Borg Dyspnea Index scores and WHO functional class. Although the preliminary study exhibited adverse events that did not diﬀer from placebo [33], BREATHE-1 found that some patients suﬀered a signiﬁcant elevation of hepatic transaminases [34]. These elevations resolved in all patients with dose reduction or discontinuation of bosentan, but the ﬁnding reﬂects the need for at least monthly monitoring of liver function tests in patients who receive this drug. When bosentan was introduced as a treatment for PAH, there was concern that delaying therapy with prostacyclin would adversely aﬀect survival. Recent survival data with bosentan oﬀer some reassurance that this is not the case. McLaughlin and colleagues [35] reported long-term follow-up of 169 patients with PPH who had been enrolled in the initial bosentan trials. Observed survival was compared with predicted survival using an equation based on initial NIH registry data

encompassing variables such as cardiac index, mean pulmonary artery pressure, and mean right atrial pressure. Actual survival in patients receiving bosentan at 1, 2, and 3 years was 96%, 89% and 86%, respectively, compared with predicted survivals of 69%, 57%, and 48%, respectively, at the same time intervals. Bosentan (Actelion Pharmaceuticals Ltd., Allschwil, Switzerland, 2003) is a class X drug in pregnancy, because animal studies have identiﬁed it as a teratogen. Female patients of childbearing age should be tested for pregnancy before starting treatment with bosentan and should use two forms of contraception, including a barrier method, because bosentan may aﬀect the eﬃcacy of oral contraceptive. Patients taking bosentan should not receive concurrent glyburide because an increased risk for elevations in transaminases has been associated with this combination, and they should not receive concurrent cyclosporine because markedly elevated bosentan levels have been reported with coadministration of both drugs. The Food and Drug Administration (FDA) approved bosentan for use in WHO functional class III or class IV patients. Eﬃcacy of this drug may not be seen for 2 to 3 months after initiation of therapy, and it should not be used as sole therapy for patients with advanced class IV disease who need a more immediate response. Bosetan is, however, the only currently approved oral therapy for PAH and should be considered ﬁrst-line therapy for patients with WHO functional class III symptoms. Prostacyclins Prostacyclin (PGI2) is produced by the vascular endothelium and has important vasodilatory, antiplatelet aggregation, and antiproliferative eﬀects. The production of prostacyclin synthase, the enzyme necessary for prostacyclin synthesis, is decreased in patients with PAH [3], as is the excretion of stable metabolites of PGI2 [36]. Replacement of prostacyclin, therefore, is a reasonable therapeutic option from a pathophysiologic standpoint. The agent with which there is the most experience is epoprostenol (Flolan). Epoprostenol is a synthetic salt of prostacyclin that has an extremely short half-life, 3 to 5 minuets, on average. Because of its short half-life, it must be given by continuous infusion through an indwelling venous catheter. In addition to the previously mentioned eﬀects of endogenous prostacyclin, chronic epoprostenol administration also improves right ventricular function and geometry

R. Channick, T.L. Williamson / Cardiol Clin 22 (2004) 441–452

[37] and improves the net balance between pulmonary endothelin-1 clearance and release [38]. Epoprostenol has been investigated in a variety of patient populations. In 81 patients with idiopathic PAH (PPH) and WHO functional class III and class IV symptoms followed for a 12-week period, epoprostenol improved 6-minute walk distances from 315 to 362 m, whereas patients in the control group deteriorated from 270 to 204 m over the study period [39]. Quality-of-life indices were improved, as were pulmonary hemodynamics, albeit modestly. There were eight deaths, all in the placebo group. The response to epoprostenol of patients with PAH associated with the scleroderma spectrum of disease has also been examined in a randomized, controlled fashion in 111 patients, also over a 12-week period [40]. Exercise capacity, dyspnea scores, and functional class improved in the treatment group. There was no demonstrated diﬀerence in survival, although the study was not powered to do so. A recent Cochrane review synthesized the results of seven randomized, controlled trials using intravenous prostacyclin or one of its analogues and found that over a 12-week period prostaglandins seem to improve exercise capacity, functional class, and several cardiopulmonary hemodynamic variables [41]. In addition to these beneﬁcial eﬀects, epoprostenol has been shown to aﬀect survival positively in studies involving both adults and children [42–44]. Epoprostenol, however, has a number of unfavorable characteristics that limit more widespread applicability. Its short half-life requires continuous intravenous administration, necessitating indwelling central venous access and the associated risks of catheter-related sepsis, cellulitis, thrombosis, pneumothorax, catheter dislodgement, and hemorrhage [39,40]. Additionally, adverse eﬀects related to the drug itself are common and include jaw pain, diarrhea, ﬂushing, headaches, nausea, vomiting, and anorexia [39,40]. Caution should be exercised when considering epoprostenol administration for subsets of PAH patients who have a signiﬁcant ﬁxed downstream obstruction such as pulmonary venoocclusive disease or pulmonary capillary hemangiomatosis. Case reports in both disorders report pulmonary edema that complicates epoprostenol delivery [45,46]. Despite its signiﬁcant drawbacks, epoprostenol is potentially life saving and is among the quickest acting of agents currently available. In the treat-

447

ment algorithm described later, it is reserved for WHO functional class IV patients and (rarely) for WHO functional class III patients who are not candidates for less-invasive therapy. Because the instability of epoprostenol requires placement of an indwelling catheter for continuous infusion, with the subsequent risk of complications, there is much interest in providing prostacyclin therapy through alternate mechanisms of delivery. Treprostinil (Remodulin) is a prostaglandin analogue that is stable at room temperature (unlike epoprostenol, which must be kept cool) and has a much longer half-life than epoprostenol that permits subcutaneous administration of this drug. Treprostinil is delivered by continuous subcutaneous infusion in a manner similar to continuous insulin administration. The delivery pump is roughly the size of a pager and can be worn inconspicuously by the patient. Two studies have demonstrated the safety and eﬃcacy of treprostinil. Initial pilot studies compared intravenous treprostinil with intravenous epoprostenol, subcutaneous treprostinil with intravenous treprostinil, and subcutaneous treprostinil with placebo [47]. Intravenous treprostinil, subcutaneous treprostinil, and epoprostenol produced similar reductions in PVR (approximately 20%). When compared with placebo, subcutaneous treprostinil produced statistically signiﬁcant improvement in 6-minute walk distance (increase of 37 17 m versus a decline of 6 28 m in the placebo arm) and trends toward improved cardiac index and reduced PVR. A larger multicenter, randomized trial focused on 470 patients with idiopathic PAH, PAH associated with connective tissue disease, and PAH associated with congenital systemic to pulmonary shunts [48]. Patients with WHO class II, class III, or class IV symptoms were enrolled. After 12 weeks there was a 16-m diﬀerence in median 6-minute walk distances between treatment and placebo groups, and dyspnea indices improved in treated patients. Eighty-ﬁve percent of patients, however, reported signiﬁcant pain at the infusion site, and 8% of patients withdrew from the study because of pain. Other typical adverse eﬀects common to prostacyclin analogues, such as diarrhea, jaw pain, ﬂushing, and lower extremity pain, were also reported. In the United States, the FDA has approved treprostinil for patients with PAH characterized by WHO class II, class III, and class IV symptoms. Improvements in 6-minute walk distances, however, do not reach the magnitude demonstrated by

448

R. Channick, T.L. Williamson / Cardiol Clin 22 (2004) 441–452

epoprostenol, and to the authors’ knowledge, no signiﬁcant improvement in mortality has been demonstrated with treprostinil. Site pain is a signiﬁcant problem for patients receiving this drug and limits its utility in the management of PAH. Although approved for most classes of symptoms, treprostinil should primarily be reserved for patients with class IV symptoms who are not candidates for continuous intravenous infusion of epoprostenol and for patients with class III symptoms for whom treatment with currently available oral therapies is not appropriate. Two other prostacyclin analogues have been investigated and used outside the United States, but neither is currently available in the United States. Iloprost is a nebulized prostaglandin with demonstrated beneﬁcial eﬀects on functional class, 6-minute walk distance, and hemodynamics [49–51]. A mild cough, minor headache, jaw pain, and nausea were reported adverse eﬀects in these studies. Because of its short half-life, iloprost must be administered six to nine times per day. Beraprost is an oral prostacyclin analogue that is approved in Japan for PAH patients. The largest trial examined 130 WHO functional class II and class III patients and showed a diﬀerence in 6minute walk distance of 25.1 m between treatment and placebo groups, improved Borg dyspnea index, and no change in hemodynamics or functional class [52]. Adverse eﬀects included headache, ﬂushing, jaw pain, diarrhea, leg pain, and nausea. Table 1 summarizes the drugs used in treating PAH. Experimental therapies A number of therapies for PAH have shown promise in anecdotal case reports, small case

series, or preliminary studies but have not yet been examined in a large-scale randomized trial and have not received FDA approval. Two endothelin receptor antagonists fall into this category. Sitaxsentan is an endothelin-A receptor antagonist investigated by Barst and colleagues [53] in a pilot study involving patients with idiopathic PAH or PAH associated with collagen vascular disease or congenital systemic to pulmonary shunts. Six-minute walk distances improved from 466 132 m to 515 141 m (P = 0.006), and there were modest improvements in mean positive airway pressure and PVR. There were, however, two cases of acute hepatitis, one of which was fatal. A larger, randomized trial is ongoing at this time. Other experimental endothelin antagonists, such as ambrisentan, are also in the preliminary phases of investigation. Sildenaﬁl (Viagra) is a phosphodiesterase-5 inhibitor that is gaining increasing attention for the treatment of pulmonary vascular disease. Sildenaﬁl has potential vasodilatory properties mediated through cyclic GMP and cyclic AMP systems. Several small studies, short-term hemodynamic studies, and case reports have suggested beneﬁcial results in pulmonary hypertension of various origins, with improvement in hemodynamics, exercise capacity, functional class, and dyspnea indices [54–58]. Sildenaﬁl has also been used in combination with prostacyclins in small case series and in hemodynamic studies, also with encouraging results [59–61]. In a small open-label study, 16 patients with pulmonary ﬁbrosis and pulmonary hypertension were randomly assigned to intravenous epoprostenol or sildenaﬁl [62]. Both epoprostenol and sildenaﬁl were found to reduce PVR, but epoprostenol in this setting

Table 1 Drugs used in treating pulmonary arterial hypertension Drug

Route

Epoprostenol

Intravenous (continuous)

Treprostinil

Subcutaneous (continuous)

Iloprost Beraprost Bosentan Sitaxsentan Ambrisentan Sildenaﬁl

Inhaled (6–9 times/d) By mouth (4 times/d) By mouth (2 tunes/d) By mouth (1 time/d) By mouth (1 time/d) By mouth (3 times/d)

FDA Approval

Available in United States

Yes—WHO class III/IV Yes—WHO class II/III/IV No No Yes No No Not for PAH

Yes Yes No No Yes No No Yes

Notes Infection, catheter complications, rebound Infusion site pain Frequent inhalation Hepatic toxicity Experimental Experimental Oﬀ-label/experimental use

Abbreviations: FDA, Food and Drug Administration; PAH, pulmonary arterial hypertension.

R. Channick, T.L. Williamson / Cardiol Clin 22 (2004) 441–452

increased ventilation/perfusion mismatch and adversely aﬀected arterial oxygenation. Sildenaﬁl, in contrast, maintained ventilation/perfusion matching and raised arterial oxygenation. In original studies in patients with erectile dysfunction, the drug has been shown to be relatively safe, with headache, ﬂushing, and dyspepsia the most commonly reported adverse eﬀects [63]. Visual disturbances were also reported in this same series. Phase III trials are currently ongoing with sildenaﬁl in the setting of PAH. For the time being, its use should be considered investigational. A myriad of pathophysiologic defects in PAH are potential therapeutic targets, and it is conceivable that combination therapy acting on two or more targets could improve outcomes in this disease. Ongoing studies are scrutinizing this hypothesis. A number of novel therapies have been suggested in PAH in animal models or small case reports. They include aerosolized adrenomedullin [64], oral dehydroepiandrosterone (DHEA) [65], simvastatin [66], and vasoactive intestinal peptide [67]. All are in the most preliminary stages of investigation and warrant further study before widespread clinical application. Surgical options in pulmonary hypertension Chronic thromboembolic pulmonary hypertension should be diﬀerentiated from pulmonary hypertension of other causes, because a potentially curative operative procedure exists for this entity. Chronic thromboembolic pulmonary hypertension and the surgery to treat it, namely pulmonary thromboendarterectomy, are beyond the scope of this article and are reviewed elsewhere in this issue. Atrial septostomy was ﬁrst described in 1983 [68] and is an option in patients with severe PAH who do not respond to maximal medical therapies. Sandoval and colleagues [69] reported their experiences with the procedure in a series of 15 such patients who underwent graded balloon dilation atrial septostomy. In the 14 patients who survived the procedure, right ventricular end diastolic procedure was immediately decreased, and cardiac output was improved, although at the expense of systemic oxygen desaturation secondary to the increased right to left shunting. Functional class and exercise capacity were improved as well. Atrial septostomy should be considered in patients with severe PAH and recurrent syncope or progressive right

449

ventricular failure despite maximal medical therapy, as a bridge to transplantation if maximal medical therapy has failed, and as a palliative procedure when no other option exists [1]. It should be attempted only in institutions with experience in its use. Contraindications include patients with impending death, receiving maximal cardiopulmonary support, or with preprocedure systemic oxygen saturations of less than 90% [1]. PAH is a declining indication for lung and heart-lung transplantation compared with other indications for transplantation (constituting 4.5% of procedures over a 7-year period [70]), probably because of advances in the medical management of the disease. In the United States, most transplant centers perform bilateral single-lung transplantations for PAH, although a small percentage of centers perform single-lung transplantation for this disorder. Heart-lung transplantation is reserved for patients with PAH secondary to congenital systemic-to-pulmonary shunts that cannot be surgically corrected by isolated lung transplantation. Heart-lung transplantation in PAH is more frequently employed in Europe [70]. Early mortality is higher in patients with PAH than that in patients with other indications for transplantation, but overall survival approximates 83%, 73%, 57%, 45%, and 23% at 3 months, 1 year, 3 years, 5 years, and 10 years, respectively [70]. Timing of lung transplantation is problematic. There is currently, in the United States, no priority for severity of patient illness, and priority is strictly related to time accrued while waiting for transplantation. Wait times average approximately 17 months but can be 36 months or longer [71]. Heart-lung transplant lists may have even longer wait times. Therefore, if a physician waits to refer a patient with severe PAH until the patient is in extremis, it is unlikely that the patient will survive to transplantation. Although the decision to refer for lung transplantation must be individualized to each patient, in general consideration for referral should be given to the patient who has ‘‘symptomatic, progressive disease which, despite medical or surgical treatment, leaves the patient in NYHA III or NYHA IV’’ [72]. From a practical standpoint, because the clinical course of patients with PAH can be quite variable, the authors refer patients for lung transplant evaluation if medical management necessitates the initiation of intravenous or subcutaneous prostaglandin administration.

450

R. Channick, T.L. Williamson / Cardiol Clin 22 (2004) 441–452

Summary The diagnosis of pulmonary hypertension requires a high index of suspicion and careful attention to assessing the severity and classiﬁcation of disease. Proper evaluation and understanding of determinants of severity in PAH are necessary to guide appropriate therapy. There are now highly eﬀective therapies for PAH that have meaningfully improved the outcome for patients, and it likely that that the future is even brighter, with development of combination regimens and additional therapies that attack speciﬁc targets within the pulmonary vasculature and right ventricle. Despite the increasing availability of oral therapies for PAH, consideration should be given to referral of patients with functional class III and IV symptoms to specialized PAH centers that may have additional experience in the timing and nature of escalation of therapy when needed. Referral also may help concentrate a fairly rare population of patients to facilitate research that, one hopes, may lead to continued advances in the management of this disease. Although survival remains limited, the authors are encouraged by the interest and commitment to this disease that has engendered continued progress in the development of an armamentarium to ﬁght it. References [1] Simonneau G, Galie` N, Rubin L, Langleben D, Seeger W, Domenighetti G, et al. Clinical classiﬁcation of pulmonary hypertension. J Am Coll Cardiol 2004;43:55–125. [2] Meyrick B. The pathology of pulmonary artery hypertension. Clin Chest Med 2001;22:393. [3] Tuder RM, Cool CD, Geraci MW, et al. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med 1999;159:1925. [4] D’Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med 1991;115:343. [5] Raymond RJ, Hinderliter AL, Willis PW, et al. Echocardiographic predictors of adverse outcomes in primary pulmonary hypertension. J Am Coll Cardiol 2002;39:1214. [6] Kawut SM, Taichman DB, Archer-Chicko CL, et al. Hemodynamics and survival in patients with pulmonary arterial hypertension related to systemic sclerosis. Chest 2003;123:344. [7] Holcomb BW Jr, Loyd JE, Ely EW, et al. Pulmonary veno-occlusive disease: a case series and new observations. Chest 2000;118:1671.

[8] Daily PO, Dembitzsky WP, Iversen S, et al. Current early results of pulmonary thromboendarterectomy for chronic pulmonary embolism. Eur J Cardiothorac Surg 1990;4:117. [9] Fedullo PF, Auger WR, Kerr KM, et al. Chronic thromboembolic pulmonary hypertension. N Engl J Med 2001;345:1465. [10] Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension. A national prospective study. Ann Intern Med 1987;107:216. [11] Meyer FJ, Ewert R, Hoeper MM, et al. Peripheral airway obstruction in primary pulmonary hypertension. Thorax 2002;57:473. [12] Bailey CL, Channick R, Auger W, et al. ‘‘High probability’’ perfusion lung scans in pulmonary venoocclusive disease. Am J Respir Crit Care Med 2000;162:1974. [13] McGoon MD. The assessment of pulmonary hypertension. Clin Chest Med 2001;22:493. [14] Hinderliter AL, Willis PWt, Long W, et al. Frequency and prognostic signiﬁcance of pericardial eﬀusion in primary pulmonary hypertension. PPH Study Group. Am J Cardiol 1999;84:481. [15] Arcasoy SM, Christie JD, Ferrari VA, et al. Echocardiographic assessment of pulmonary hypertension in patients with advanced lung disease. Am J Respir Crit Care Med 2003;167:735. [16] Cotton CL, Gandhi S, Vaitkus PT, et al. Role of echocardiography in detecting portopulmonary hypertension in liver transplant candidates. Liver Transpl 2002;8:1051. [17] Wensel R, Opitz CF, Anker SD, et al. Assessment of survival in patients with primary pulmonary hypertension: importance of cardiopulmonary exercise testing. Circulation 2002;106:319. [18] Miyamoto S, Nagaya N, Satoh T, et al. Clinical correlates and prognostic signiﬁcance of six-minute walk test in patients with primary pulmonary hypertension. Comparison with cardiopulmonary exercise testing. Am J Respir Crit Care Med 2000; 161:487. [19] McCaﬀrey RN, Dunn LJ. Primary pulmonary hypertension in pregnancy. Obstet Gynecol Surv 1964;19:567. [20] Weiss BM, Zemp L, Seifert B, et al. Outcome of pulmonary vascular disease in pregnancy: a systematic overview from 1978 through 1996. J Am Coll Cardiol 1998;31:1650. [21] Roberts DH, Lepore JJ, Maroo A, et al. Oxygen therapy improves cardiac index and pulmonary vascular resistance in patients with pulmonary hypertension. Chest 2001;120:1547. [22] Group NOTT. Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: a clinical trial. Ann Intern Med 1980;93: 391. [23] Rafanan AL, Golish JA, Dinner DS, et al. Nocturnal hypoxemia is common in primary pulmonary hypertension. Chest 2001;120:894.

R. Channick, T.L. Williamson / Cardiol Clin 22 (2004) 441–452 [24] Frank H, Mlczoch J, Huber K, et al. The eﬀect of anticoagulant therapy in primary and anorectic drug-induced pulmonary hypertension. Chest 1997; 112:714. [25] Rich S, Kaufmann E, Levy PS. The eﬀect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med 1992;327:76. [26] Rich S, Seidlitz M, Dodin E, et al. The short-term eﬀects of digoxin in patients with right ventricular dysfunction from pulmonary hypertension. Chest 1998;114:787. [27] Sitbon O, Humbert M, Jais X, Ioos V, Hamid AM, Parent F, et al. Acute vasodilator responsiveness and long-term response to calcium-channel blockers in diﬀerent forms of pulmonary artery hypertension [abstract A86]. In: Programs and abstracts of the 100th International Conference of the American Thoracic Society. Orlando, Florida: 2004. p. A210. [28] Raﬀy O, Azarian R, Brenot F, et al. Clinical signiﬁcance of the pulmonary vasodilator response during short-term infusion of prostacyclin in primary pulmonary hypertension. Circulation 1996;93:484. [29] Sitbon O, Humbert M, Jagot JL, et al. Inhaled nitric oxide as a screening agent for safely identifying responders to oral calcium-channel blockers in primary pulmonary hypertension. Eur Respir J 1998;12:265. [30] Stewart DJ, Levy RD, Cernacek P, et al. Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease? Ann Intern Med 1991;114:464. [31] Rubens C, Ewert R, Halank M, et al. Big endothelin-1 and endothelin-1 plasma levels are correlated with the severity of primary pulmonary hypertension. Chest 2001;120:1562. [32] Davie N, Haleen SJ, Upton PD, et al. ET(A) and ET(B) receptors modulate the proliferation of human pulmonary artery smooth muscle cells. Am J Respir Crit Care Med 2002;165:398. [33] Channick RN, Simonneau G, Sitbon O, et al. Eﬀects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet 2001;358:1119. [34] Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002;346:896. [35] McLaughlin V, Sitbon O, Rubin LJ, et al. The eﬀect of ﬁrst line bosentan on survival of patients with primary pulmonary hypertension. Abstract, American Thoracic Society, 2003. [36] Christman BW, McPherson CD, Newman JH, et al. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med 1992;327:70. [37] Hinderliter AL, Willis PWT, Barst RJ, et al. Eﬀects of long-term infusion of prostacyclin (epoprostenol) on echocardiographic measures of right ventricular

[38]

[39]

[40]

[41]

[42]

[43]

[44]

[45]

[46]

[47]

[48]

[49]

[50]

451

structure and function in primary pulmonary hypertension. Primary Pulmonary Hypertension Study Group. Circulation 1997;95:1479. Langleben D, Barst RJ, Badesch D, et al. Continuous infusion of epoprostenol improves the net balance between pulmonary endothelin-1 clearance and release in primary pulmonary hypertension. Circulation 1999;99:3266. Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N Engl J Med 1996; 334:296. Badesch DB, Tapson VF, McGoon MD, 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. Paramothayan NS, Lasserson TJ, Wells AU, et al. Prostacyclin for pulmonary hypertension. Cochrane Database Syst Rev CD002994, 2003. Barst RJ, Maislin G, Fishman AP. Vasodilator therapy for primary pulmonary hypertension in children. Circulation 1999;99:1197. Kuhn KP, Byrne DW, Arbogast PG, et al. Outcome in 91 consecutive patients with pulmonary arterial hypertension receiving epoprostenol. Am J Respir Crit Care Med 2003;167:580. Sitbon O, Humbert M, Nunes H, et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol 2002;40:780. Humbert M, Maitre S, Capron F, et al. Pulmonary edema complicating continuous intravenous prostacyclin in pulmonary capillary hemangiomatosis. Am J Respir Crit Care Med 1998;157:1681. Palmer SM, Robinson LJ, Wang A, et al. Massive pulmonary edema and death after prostacyclin infusion in a patient with pulmonary veno-occlusive disease. Chest 1998;113:237. McLaughlin VV, Gaine SP, Barst RJ, et al. Eﬃcacy and safety of treprostinil: an epoprostenol analog for primary pulmonary hypertension. J Cardiovasc Pharmacol 2003;41:293. Simonneau G, Barst RJ, Galie N, et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med 2002;165:800. Hoeper MM, Schwarze M, Ehlerding S, et al. Longterm treatment of primary pulmonary hypertension with aerosolized iloprost, a prostacyclin analogue. N Engl J Med 2000;342:1866. Olschewski H, Ghofrani HA, Schmehl T, et al. Inhaled iloprost to treat severe pulmonary hypertension. An uncontrolled trial. German PPH Study Group. Ann Intern Med 2000;132:435.

452

R. Channick, T.L. Williamson / Cardiol Clin 22 (2004) 441–452

[51] Olschewski H, Simonneau G, Galie N, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 2002;347:322. [52] Galie N, Humbert M, Vachiery JL, et al. Eﬀects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled trial. J Am Coll Cardiol 2002;39:1496. [53] Barst RJ, Rich S, Widlitz A, et al. Clinical eﬃcacy of sitaxsentan, an endothelin-A receptor antagonist, in patients with pulmonary arterial hypertension: open-label pilot study. Chest 121:1860;2002. [54] Bharani A, Mathew V, Sahu A, et al. The eﬃcacy and tolerability of sildenaﬁl in patients with moderate-to-severe pulmonary hypertension. Indian Heart J 2003;55:55. [55] Ghofrani HA, Schermuly RT, Rose F, et al. Sildenaﬁl for long-term treatment of nonoperable chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med 2003;167:1139. [56] Michelakis E, Tymchak W, Lien D, et al. Oral sildenaﬁl is an eﬀective and speciﬁc pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide. Circulation 2002;105:2398. [57] Molina J, Lucero E, Luluaga S, et al. Systemic lupus erythematosus-associated pulmonary hypertension: good outcome following sildenaﬁl therapy. Lupus 2003;12:321. [58] Sastry BK, Narasimhan C, Reddy NK, et al. A study of clinical eﬃcacy of sildenaﬁl in patients with primary pulmonary hypertension. Indian Heart J 2002;54:410. [59] Ghofrani HA, Rose F, Schermuly RT, et al. Oral sildenaﬁl as long-term adjunct therapy to inhaled iloprost in severe pulmonary arterial hypertension. J Am Coll Cardiol 2003;42:158. [60] Ghofrani HA, Wiedemann R, Rose F, et al. Combination therapy with oral sildenaﬁl and inhaled iloprost for severe pulmonary hypertension. Ann Intern Med 2002;136:515. [61] Stiebellehner L, Petkov V, Vonbank K, et al. Longterm treatment with oral sildenaﬁl in addition to continuous IV epoprostenol in patients with pulmonary arterial hypertension. Chest 2003;123:1293.

[62] Ghofrani HA, Wiedemann R, Rose F, et al. Sildenaﬁl for treatment of lung ﬁbrosis and pulmonary hypertension: a randomised controlled trial. Lancet 2002;360:895. [63] Goldstein I, Lue TF, Padma-Nathan H, et al. Oral sildenaﬁl in the treatment of erectile dysfunction. Sildenaﬁl study group. N Engl J Med 1998;338:1397. [64] Kandler MA, Von Der Hardt K, Mahfoud S, et al. Pilot intervention: aerosolized adrenomedullin reduces pulmonary hypertension. J Pharmacol Exp Ther 2003;306:1021. [65] Bonnet S, Dumas-de-La-Roque E, Begueret H, et al. Dehydroepiandrosterone (DHEA) prevents and reverses chronic hypoxic pulmonary hypertension. Proc Natl Acad Sci U S A 2003;100:9488. [66] Girgis RE, Li D, Zhan X, et al. Attenuation of chronic hypoxic pulmonary hypertension by simvastatin. Am J Physiol Heart Circ Physiol 2003;285: H938. [67] Petkov V, Mosgoeller W, Ziesche R, et al. Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary hypertension. J Clin Invest 2003;111:1339. [68] Rich S, Lam W. Atrial septostomy as palliative therapy for refractory primary pulmonary hypertension. Am J Cardiol 1983;51:1560. [69] Sandoval J, Gaspar J, Pulido T, et al. Graded balloon dilation atrial septostomy in severe primary pulmonary hypertension. A therapeutic alternative for patients nonresponsive to vasodilator treatment. J Am Coll Cardiol 1998;32:297. [70] Trulock E, Edwards L, Taylor D, et al. The registry of the International Society for Heart and Lung Transplantation: Twentieth Oﬃcial Adult Lung and Heart-lung Transplant Report–2003. J Heart Lung Transplant 2003;22:625. [71] Pielsticker EJ, Martinez FJ, Rubenﬁre M. Lung and heart-lung transplant practice patterns in pulmonary hypertension centers. J Heart Lung Transplant 2001;20:1297. [72] Physicians American Society for Transplant Physiciano, American Thoracic Society, European Respiratory Society, et al. International guidelines for the selection of lung transplant candidates. Am J Respir Crit Care Med 1998;158:335.

Cardiol Clin 22 (2004) 383–399

Echocardiography in pulmonary vascular disease Lori B. Daniels, MDa,b, David E. Krummen, MDa,b, Daniel G. Blanchard, MD, FACCa,b,* a

Division of Cardiology, Department of Medicine, University of California, San Diego School of Medicine, University of California, San Diego, 200 West Arbor Drive, San Diego, CA 92103, USA b University of California, San Diego Medical Center, 200 West Arbor Drive San Diego, CA 92103, USA

The assessment of pulmonary artery pressure, right ventricular function, right ventricular ﬁlling pressure, and tricuspid regurgitation provides invaluable information in the care of patients with pulmonary vascular disease. Echocardiography provides a rapid, noninvasive, portable, and accurate method to evaluate these parameters and also provides information on left ventricular and valvular function. Echocardiography has therefore become one of the most commonly performed diagnostic studies in patients with pulmonary vascular disease, and the technique’s applications in this area are likely to grow. This article presents an overview of the current uses of echocardiography in pulmonary vascular disease and pulmonary hypertension.

Echocardiographic measurements in pulmonary hypertension Measurement of right ventricular volume and function Measurement of right ventricular volume and function is important in making the diagnosis of pulmonary hypertension, but, because of the complex three-dimensional shape of the right ventricle, accurate measurement of right ventricular size and ejection fraction is diﬃcult. In the apical four-chamber view, enlargement of the right ventricle can be determined qualitatively * Corresponding author. UCSD Medical Center, 200 W. Arbor Drive, #8411, San Diego, CA 92103. E-mail address: [email protected] (D.G. Blanchard).

when its chamber cross-sectional area exceeds that of the left ventricle (Fig. 1). In addition, right ventricular enlargement is present when the distal portion of the right ventricle shares space with the left ventricle at the cardiac apex in the apical four-chamber view. Normally, the cardiac apex is exclusively composed of left ventricular myocardium. Quantitative measurements of right ventricle size, thickness, and cross-sectional area can also be obtained [1]. Right ventricular systolic function can be expressed as the percent of change in right ventricular area during the cardiac cycle: ð½EDA ESA EDAÞ 100% EDA is the right ventricular area from the apical four-chamber view at end-diastole, and ESA is the right ventricular area at end-systole. Normal right ventricular fractional area change is 40% to 45% [2]. Because right ventricular functional measurement is highly dependent upon afterload and transseptal pressure gradients, the percent of change in cross-sectional area is not routinely quantiﬁed [3]. Tricuspid regurgitation Tricuspid regurgitation is often present in the setting of pulmonary hypertension and ranges from mild to severe. Tricuspid regurgitation may be caused by dilatation of the tricuspid annulus and morphologic alteration of right ventricular geometry [4] as well as by chordal traction of the valve leaﬂets [5]. Although the severity of tricuspid regurgitation does not necessarily correlate with the degree of pulmonary hypertension, reversal of pulmonary hypertension leads to

0733-8651/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ccl.2004.04.007

384

L.B. Daniels et al / Cardiol Clin 22 (2004) 383–399

artery systolic pressure is ﬁrst to record the maximum tricuspid regurgitant jet velocity (VTR). This velocity can then be translated into the pressure gradient between the right ventricle and right atrium using the modiﬁed Bernoulli equation. The accuracy of this method depends on obtaining the true maximum VTR. The interrogating Doppler ultrasound beam must be parallel (or nearly so) to the direction of blood ﬂow in the jet of TR (Fig. 2). The apical or right ventricular inﬂow views are most commonly used for this analysis. The peak right ventricular and pulmonary artery systolic pressure can then be calculated (in the absence of pulmonic stenosis) as Fig. 1. Apical four-chamber view in severe pulmonary hypertension. The right atrium (RA) and ventricle are markedly enlarged, and the right ventricle (RV) is hypertrophied. The interventricular septum is shifted leftward, and the left-heart chambers appear compressed.

signiﬁcantly decreased tricuspid regurgitation in many cases, especially when the tricuspid regurgitation is caused by annular dilatation [6]. Estimation of pulmonary arterial pressure by the Bernoulli equation Transthoracic echocardiography (TTE) provides a readily available, noninvasive assessment of right-sided intracardiac pressures. The most reliable approach for approximating pulmonary

Pulmonary artery pressure ¼ 4VTR2 þ right atrial pressure ½7: Right atrial pressure can be estimated from the size and variation in the inferior vena cava (IVC) during quiet respiration. Best visualized from a subcostal window, the IVC normally has a diameter of 1.2 to 2.3 cm (Fig. 3) and should collapse by at least 50% during inspiration [8]. IVC dilation (or lack of collapse during inspiration) correlates with a higher right atrial pressure (eg, 10–15 mm Hg) [7]. In the setting of a dilated IVC, a complete lack of variation in IVC diameter with quick inspiration (a sniﬀ) suggests a right atrial pressure of at least 20 mm Hg. Pulmonary artery diastolic pressure also can be estimated from the velocities of the pulmonic

Fig. 2. Continuous-wave spectral Doppler tracing of tricuspid regurgitation (TR) recorded in a modiﬁed apical fourchamber plane. The peak velocity of the TR jet is 5.2 m/s, suggesting a gradient of 108 mm Hg.

L.B. Daniels et al / Cardiol Clin 22 (2004) 383–399

385

nary hypertension include a decrease in the velocity-time integral of ﬂow through the pulmonic valve and a shortening of the acceleration time (measured from beginning of ﬂow through the pulmonic valve to peak velocity.) The acceleration time (AT, in milliseconds) can be used to estimate the mean pulmonary artery pressure in mm Hg [11,12] according to the equation Mean pulmonary artery pressure ¼ 80 ðAT=2Þ:

Acute pulmonary embolus Fig. 3. Subcostal view of the inferior vena cava (IVC) emptying into the right atrium (RA). A hepatic vein is also visible (arrow).

regurgitant Doppler tracing [9,10] (Fig. 4). Again, using the modiﬁed Bernoulli equation, the enddiastolic velocity of the pulmonic regurgitation jet can be used to calculate the instantaneous gradient between the pulmonary artery and the right ventricle. The pulmonary artery diastolic pressure is obtained by adding this calculated gradient to the estimated right atrial pressure. Other ﬁndings in right ventricular dysfunction and pulmonary hypertension Other characteristic Doppler abnormalities seen in right ventricular dysfunction and pulmo-

Typical ﬁndings on transthoracic echocardiography Depending on the size of the thromboembolus, patients with acute pulmonary embolism may have a number of abnormalities on TTE. Rarely, a large thrombus may be directly visualized in a proximal pulmonary artery or in transit in the right-heart chambers (Fig. 5A–C) [13]. The most common echocardiographic ﬁndings, however, are caused by acute right-sided pressure overload. With acute massive pulmonary embolism, the right ventricle dilates and becomes markedly hypokinetic. Abnormal motion of the interventricular septum with ﬂattening or bulging toward the left ventricle in diastole may be seen (Fig. 6). Such paradoxical septal motion can result in left ventricular diastolic impairment, with decreased early diastolic ﬁlling

Fig. 4. Spectral Continuous-Wave Doppler tracing of pulmonic insuﬃciency (measured in the parasternal short-axis view at the base of the heart). The end-diastolic velocity is 2.2 m/s, suggesting a gradient between the pulmonary artery and right ventricle of 19 mm Hg at end-diastole.

Fig. 5. (A) Parasternal short-axis transthoracic echo image of a large thrombus (T) lodged in the bifurcation of the right and left main pulmonary arteries. Ao, ascending aorta; PA, main pulmonary artery. (B) Subcostal four-chamber view of a serpentine right atrial thrombus (**). On real-time imaging, the thrombus was very mobile. LV, left ventricle; RV, right ventricle. (C) Transesophageal image of a thrombus in transit. A venous thromboembolus has traveled to the right atrium (RA) and is lodged in a patent foramen ovale. A portion of the thrombus extends into the left atrium (LA).

L.B. Daniels et al / Cardiol Clin 22 (2004) 383–399

and increased reliance on the atrial kick (this process has been called the reverse Bernheim phenomenon) [14,15]. On Doppler examination of transmitral diastolic blood ﬂow, this phenomenon is seen as a decrease in the early rapid ﬁlling velocity (E wave) and an increase in the atrial contraction velocity (A wave). This septal impairment of left ventricular diastolic ﬁlling may further contribute to the low cardiac output seen in cases of massive pulmonary embolism. A ratio of right ventricle–to–left ventricle enddiastolic diameter (measured in the parasternal or subcostal view) greater than the upper normal limit of 0.6 helps indicate right ventricular dysfunction and may distinguish between massive and nonmassive pulmonary embolism [16,17]. In addition, tricuspid regurgitation is common in acute pulmonary embolism (Fig. 7) and provides a useful way to assess pulmonary artery pressure. The right atrium and the IVC often dilate in acute massive pulmonary embolism, reﬂecting elevated right-sided pressures, and the IVC fails to collapse normally during inspiration. Interatrial shunting can occur if a patent foramen ovale is present and right ventricular pressure is signiﬁcantly elevated. Unfortunately, the Doppler and two-dimensional echocardiographic ﬁndings of right ventricular dysfunction and right-sided pressure overload are not speciﬁc for pulmonary embolism: other diseases, including primary pulmonary hypertension, right ventricular myocardial infarction, cardiomyopathy, or right ventricular dysplasia, or acute exacerbations of obstructive pulmonary dis-

387

ease may produce similar ﬁndings. Hypokinesis of the right ventricle free wall with sparing of apical function (McConnell’s sign) has been proposed as a relatively speciﬁc sign of right ventricular dysfunction caused by acute pulmonary embolism rather than other causes, but the overall clinical utility of this observation is debatable [18]. The degree of pulmonary hypertension seen with acute pulmonary embolism is usually mild to moderate, but right ventricular dysfunction is not universally present in acute pulmonary embolism [19]. Approximately 20% of patients with acute pulmonary embolism conﬁrmed by ventilationperfusion (V/Q) scan or angiography may have normal ﬁndings on TTE [20,21]. Visualization of the right and left pulmonary arteries is sometimes diﬃcult, and detection of pulmonary thromboemboli is unusual in most cases of pulmonary embolism. Furthermore, echocardiographic images may be of limited usefulness in patients who are obese, have hyperinﬂated lungs, or are immobile (including those on mechanical ventilators). Because of these limitations, TTE is not recommended as a primary diagnostic tool in acute pulmonary embolism. Nonetheless, it may be helpful in diagnosing or excluding alternative causes of sudden hemodynamic instability, including cardiac tamponade, aortic dissection, and acute valvular insuﬃciency [22]. Typical ﬁndings on transesophageal echocardiography Transesophageal echocardiography (TEE) can detect all the ﬁndings detected by TTE but is much more eﬀective in the direct visualization of thrombi in the central pulmonary arteries. TEE visualizes the main pulmonary artery and the right pulmonary artery well, although the intervening left main bronchus may obscure the left pulmonary artery In the appropriate clinical setting, the ﬁnding of an intraluminal pulmonary artery mass is reasonably speciﬁc for the diagnosis of acute pulmonary embolism [7–9,23,24]. The sensitivity of TEE in acute pulmonary embolism varies among studies and depends on operator expertise and patient selection. False-positive results, however, are distinctly unusual [7–9,24]. Uses of echocardiography in acute pulmonary embolism

Fig. 6. Short-axis view in right ventricular overload. The interventricular septum is ﬂattened and pushed toward the left ventricle. LV, left ventricle; RV, right ventricle.

Although TTE is not the recommended diagnostic test for pulmonary embolism, it nonetheless can play a major role in the assessment of

388

L.B. Daniels et al / Cardiol Clin 22 (2004) 383–399

Fig. 7. Short-axis view through the base of the heart showing signiﬁcant tricuspid regurgitation. A multicolored jet of tricuspid regurgitation is seen in the right atrium (RA) during systole. LV, left ventricle; RV, right ventricle.

prognosis and management of this condition. Echocardiographic analysis of right ventricular function has proven useful in the risk stratiﬁcation of patients with pulmonary embolism. In a recent study of 209 consecutive patients with pulmonary embolism, the 65 who were hemodynamically stable but had right ventricular dysfunction on TTE had an in-hospital mortality rate of 5% versus 0% in those without right ventricular dysfunction [25]. In another study of 126 consecutive pulmonary embolism patients, echocardiography emerged as the strongest predictor of in-hospital mortality, because the risk of in-hospital death was six times greater for the patients with right ventricular dysfunction than for those with normal right ventricular function [21]. At 1-year follow-up, there was still a 2.4 relative risk of mortality associated with right ventricular dysfunction. In patients without an underlying malignancy, the pulmonary embolism mortality rate was 7.7% in patients with right ventricular hypokinesis but 0% in those without right ventricular dysfunction. Right ventricular hypokinesis on baseline echocardiography was also an important predictor of increased mortality in the International Cooperative Pulmonary Embolism Registry. Right ventricular hypokinesis was associated with a twofold increase in mortality and was as important a predictor of poor outcome as advanced age, cancer, congestive heart failure, and renal insuﬃciency [26]. Finally, in the Manage-

ment, Strategy and Prognosis of Pulmonary Embolism Registry (MAPPET) study of 1001 patients, right ventricular dysfunction was an independent and signiﬁcant marker of increased mortality [27]. Whether right ventricular dysfunction should be used to determine which patients receive thrombolytic therapy remains controversial. There is a general consensus that thrombolysis is the treatment of choice in patients with massive pulmonary embolism accompanied by hemodynamic collapse, and in these patients echocardiography is useful for monitoring changes in cardiac function with treatment [28]. There is, however, a signiﬁcant subset of patients with acute pulmonary embolism (as high as 40%) who do not have signiﬁcant hemodynamic compromise but still exhibit right ventricular dysfunction on TTE [25,26]. These patients may beneﬁt from thrombolytic therapy. In a randomized trial of thrombolysis plus anticoagulation versus anticoagulation alone, Goldhaber et al [28] found that 5 of 23 patients with right ventricular hypokinesis and dilatation had recurrent pulmonary embolism after receiving intravenous heparin alone, whereas pulmonary embolism did not recur in any of the 23 patients with right ventricular dysfunction who received thrombolytics. Patients given thrombolytics also had greater recovery of right ventricular function at 24 hours, improved absolute pulmonary perfusion, and decreased right ventricular end-diastolic

L.B. Daniels et al / Cardiol Clin 22 (2004) 383–399

area, though overall mortality was unchanged [28]. In the MAPPET registry, Konstantinides et al [27,29] found a lower 30-day mortality in subgroup of 719 normotensive patients with pulmonary embolism and right ventricular overload who were treated with thrombolytics than in those treated with intravenous heparin alone (4.7% mortality in the 169 patients initially treated with thrombolytics versus 11.1% in the 550 patients who initially received anticoagulation alone, P = 0.016). Other studies, however, have had conﬂicting results. A recent study by Hamel et al [30] assessed 128 patients with massive pulmonary embolism, stable hemodynamics, and right ventricular dysfunction. In their analysis, treatment with low-molecular-weight heparin resulted in a trend toward decreased mortality compared with treatment with thrombolytics (0% versus 6.3%, P = 0.12), with fewer major bleeding events. Overall, it seems that patients with acute pulmonary embolism and right ventricular dysfunction detected on echocardiography represent a group at higher risk [31]. These patients merit aggressive therapy, but it is not completely clear whether the addition of thrombolytics decreases the risk of early death. Another subgroup of patients who may beneﬁt from echocardiography is those presenting with acute pulmonary embolism and signiﬁcant pulmonary hypertension (pulmonary artery systolic pressure >50 mm Hg). In a 5-year study of 78 patients with pulmonary embolism, Ribeiro et al [32] found that this degree of initial pulmonary hypertension conferred an odds ratio of 3.3 for persistent pulmonary hypertension or right ventricular dysfunction. They reported an early exponential rate of decline in pulmonary artery pressures, followed by a stable period after 6 weeks. In this study, 5% of patients with acute pulmonary embolism developed persistent cardiopulmonary disability and chronic right-heart dysfunction, a percentage higher than previously estimated [33–35]. Thus, follow-up echocardiography at 6 weeks can identify the high-risk subgroup of patients with persistent pulmonary hypertension and right ventricular dysfunction who are potential candidates for pulmonary thromboendarterectomy [36]. Recommendations for transthoracic echocardiography in acute pulmonary embolism As discussed previously, many patients with acute pulmonary embolism have normal echocar-

389

diograms, and the routine use of TTE for diagnosis of pulmonary embolism is not recommended. Echocardiography may be appropriate, however, when the diagnosis is in question. In such cases, pulmonary embolism may be conﬁrmed or another cause of the patient’s symptoms may be detected. Additionally, TTE is indicated in patients with conﬁrmed pulmonary embolism, because the ﬁnding of right atrial or right ventricular thrombi often mandates the use of thrombolytics to prevent recurrent and potentially fatal pulmonary embolism. In hemodynamically unstable patients with suspected pulmonary embolism, TTE can be used as a rapid initial test. If signiﬁcant right ventricular dysfunction is present, pulmonary embolism is likely. Finally, echocardiography can help monitor treatment response in patients with documented acute pulmonary embolism. Serial echocardiography can predict the development of CTEPH and canassesssuitabilityforfuturepulmonarythromboendarterectomy. Use of transesophageal echocardiography Only a few studies have examined the role of TEE in acute pulmonary embolism. In patients with suspected acute pulmonary embolism who present with shock or recent cardiopulmonary resuscitation, completion of standard diagnostic tests such as V/Q scanning, CT, and pulmonary angiography can be diﬃcult. In these critically ill patients, bedside TEE may be useful. For example, a study of TEE in 25 patients presenting with pulseless electrical activity found that 14 had isolated right ventricular enlargement. Of these, 9 had acute pulmonary emboli [37]. One recent report by Krivec et al [38] examined 24 critically ill patients with unexplained shock and jugular venous distention. They found that 17 patients (70%) had right ventricular dilatation with global hypokinesis. TEE examination detected proximal pulmonary emboli in 12 of these patients and reduced right pulmonary artery ﬂow in one additional patient. Of these 13 patients, 12 eventually had documentation of massive pulmonary embolism (either by V/Q scan or post mortem study). The few studies available suggest that TEE can provide direct visualization of proximal pulmonary arterial thrombi and so can be useful for determining surgical accessibility in patients with massive pulmonary embolism and refractory circulatory collapse.

390

L.B. Daniels et al / Cardiol Clin 22 (2004) 383–399

Echocardiography in chronic right ventricular overload and pulmonary hypertension The nonspeciﬁc nature of symptoms from chronic pulmonary hypertension often impedes the early diagnosis of the condition. For example, Rubin et al [39] reported a mean time from presentation to diagnosis of approximately 2 years in patients with pulmonary hypertension. In general, pulmonary vascular disease should be suspected when symptoms of dyspnea cannot be easily explained. When pulmonary hypertension is suspected from physical examination or screening tests (such as electrocardiography or chest radiographs), Doppler echocardiography is the best subsequent test to evaluate right-heart function and pressure. In many cases, TTE is the ﬁrst test to detect an elevation of right ventricular pressure [40]. TTE also provides important information about prognosis and response to treatment in these patients [3,41]. Echocardiographic features of chronic pulmonary hypertension Tricuspid valve As noted previously, tricuspid regurgitation is common in the setting of pulmonary hypertension but may regress with reversal of the pressure overload. A recent study by Sadeghi et al [42] evaluated patients with CTEPH and severe tricuspid regurgitation who subsequently underwent pulmonary thromboendarterectomy. Seventy per-

cent of the patients had resolution of tricuspid regurgitation after pulmonary thromboendarterectomy, often despite persistent tricuspid annular dilation. The 30% of patients with persistent severe tricuspid regurgitation had less postoperative decrease in pulmonary artery pressure. Thistlethwaite et al [43] reported that intraoperative classiﬁcation of pulmonary thromboembolic disease helps predict successful decreases in pulmonary artery pressure and tricuspid regurgitation severity in patients with CTEPH: those with thrombus in the main lobar pulmonary arteries had the greatest improvement in these parameters following pulmonary thromboendarterectomy. Inferior vena cava and right-heart chambers As described previously, the right atrium and IVC are commonly dilated in patients with pulmonary hypertension (Fig. 8). This dilation is generally a manifestation of signiﬁcant tricuspid regurgitation, elevated right ventricular diastolic pressure, or both. Additionally, elevation of right atrial pressure may cause the interatrial septum to bulge toward the left atrium. Right atrial pressure in chronic pulmonary hypertension can be estimated by means similar to the method described for acute pulmonary embolism. The pulmonary artery is often dilated in the setting of chronic pulmonary hypertension and right ventricular hypertrophy. Pulmonic valvular regurgitation frequently occurs as well, and, as noted previously, the regurgitant ﬂow velocity can

Fig. 8. Subcostal view demonstrating a dilated inferior vena cava (IVC). Diameter of the IVC is more than 2.5 cm. LA, left atrium; RA, right atrium.

L.B. Daniels et al / Cardiol Clin 22 (2004) 383–399

be used to estimate the pulmonary artery diastolic pressure [9,10]. M-mode examination of the pulmonic valve in pulmonary hypertension may show a characteristic W-shaped motion of the valve leaﬂet during systole [44–46]. This midsystolic closure of the valve and partial reopening in late systole, sometimes called the ﬂying-W sign (Fig. 9), is probably caused by elevated pulmonary vascular resistance and early reﬂection of the systolic pressure wave within the proximal pulmonary arteries [47]. There also may be a loss of the normal presystolic opening of the pulmonic valve with atrial contraction (the ‘‘a’’ dip). Because of the large diﬀerence between right ventricular pressure and pulmonary artery pressure throughout diastole, the pressure generated by the atrial kick is insuﬃcient to open the pulmonic valve even partially. Chronic pulmonary hypertension ultimately leads to right ventricular hypertrophy, enlargement, and depressed systolic function. Echocardiographic measurements of right ventricle wall thickness can be performed from the parasternal and subcostal views, and a value of more than 5 mm is diagnostic for right ventricular hypertrophy [48]. In the setting of right ventricular hypertrophy, the moderator band is often hypertrophied and thickened as well [3]. Left-heart chambers and interventricular septum The left ventricle size is normal to small in severe pulmonary hypertension and right ventric-

391

ular hypertrophy [49]. Left ventricular diastolic dysfunction often occurs in right ventricular hypertrophy and reﬂects the degree of right ventricular overload and septal distortion seen with pulmonary hypertension. This diastolic left ventricular dysfunction may be caused by abnormal relaxation of the interventricular septum, which, in cases of severe pulmonary hypertension, functions as part of the right ventricle rather than as part of the left ventricle. More recent studies, however, suggest that the abnormal diastolic transmitral Doppler ﬂow patterns may stem from relative underﬁlling of the left ventricle in the setting of low right ventricular cardiac output [50]. In addition, the transmitral Doppler diastolic E to A ratio seems to correlate directly with cardiac output and inversely with pulmonary artery pressure (Fig. 10A, B) [50]. As with pulmonary embolism, in right ventricular overload with CTEPH the interventricular septum is often ﬂattened in the parasternal shortaxis TTE view and may actually bulge into the left ventricle. The timing of this septal distortion helps distinguish between pressure and volume right ventricular overload. In pure right ventricular volume overload, the right ventricular diastolic pressure may equal or exceed that within the left ventricle, whereas the systolic pressure of the left ventricle greatly exceeds that of the right ventricle. Therefore, the interventricular septum ﬂattens during diastole but returns to its normal curvature

Fig. 9. M-mode echocardiogram of the pulmonic valve in severe pulmonary hypertension. A characteristic W-shaped motion of the valve (the ﬂying-W sign) is present during systole.

392

L.B. Daniels et al / Cardiol Clin 22 (2004) 383–399

Fig. 10. (A) Inverse correlation between transmitral E/A ratio and mean pulmonary artery (PA) pressure in patients before and after pulmonary thromboendarterectomy. (B) Direct correlation between transmitral E/A ratio and cardiac output (CO) in patients before and after pulmonary thromboendarterectomy. (From Mahmud E, Raisinghani A, Hassankhani A, Sadeghi SM, Strachen GM, Auger A, et al. Correlation of left ventricular diastolic ﬁlling characteristics with right ventricular overload and pulmonary artery pressure in chronic thromboembolic pulmonary hypertension. J Am Coll Cardiol 2002;40:318–24; with permission).

during systole (Fig. 11A, B). With right ventricular pressure overload, however, the abnormally high right ventricular pressures persist through the entire cardiac cycle, and the interventricular septum remains deformed during both systole and diastole (Fig. 12A, B) [51]. This septal distortion can be quantiﬁed using the eccentricity index, a ratio of the two minor axes of the left ventricle measured in the parasternal short-axis plane. Normally, the left ventricle eccentricity index is 1.0 during both systole and diastole (ie, the left ventricle is circular in cross-section throughout

the cardiac cycle). In cases of right ventricular volume overload, the eccentricity index is abnormal during diastole (when the interventricular septum bulges toward the left ventricle) but returns to normal during systole. In right ventricular pressure overload, the eccentricity index is abnormal throughout the cardiac cycle, reﬂecting persistent septal deformation. The left atrium may appear compressed in the transverse plane because of leftward bulging of the interatrial septum. The mitral valve annulus may also be distorted by enlargement of the right

L.B. Daniels et al / Cardiol Clin 22 (2004) 383–399

393

Fig. 11. (A) Parasternal short-axis diastolic image in right ventricular volume overload. The interventricular septum is ﬂattened and bulges toward the left. LV, left ventricle; RV, right ventricle. (B) Parasternal short-axis systolic image in right ventricular volume overload. The interventricular septum appears normal and is rounded toward the right, reﬂecting the much higher pressure in the left ventricle (LV) compared with the right ventricle (RV).

ventricle, and the mitral valve may sometimes prolapse into the left atrium during systole (even though the mitral valve is morphologically normal). Relief of pulmonary hypertension often eliminates this ﬁnding of pseudoprolapse [52].

coronary sinus dilation frequently accompanies pulmonary hypertension, correlating with right atrial pressure and size [54].

Diﬀerential diagnosis of chronic pulmonary hypertension Pericardium A signiﬁcant proportion of patients with chronic pulmonary hypertension have pericardial eﬀusions. Eﬀusion size has been linked with right atrial pressure and is probably cause by impaired lymphatic and venous drainage [53]. Similarly,

Echocardiography can reliably diﬀerentiate various causes of pulmonary hypertension secondary to elevated left atrial pressure, including mitral and aortic valvular disease, cardiomyopathy, constrictive pericarditis, and cor triatriatum. In addition, contrast echocardiography using

394

L.B. Daniels et al / Cardiol Clin 22 (2004) 383–399

Fig. 12. (A) Parasternal short-axis diastolic image in right ventricular pressure overload. The interventricular septum is ﬂattened and bulges toward the left. LV, left ventricle; RV, right ventricle. (B) Parasternal short-axis systolic image in right ventricular pressure overload. The interventricular septum remains ﬂattened and continues to bulge toward the left, reﬂecting the abnormally elevated pressure in the right ventricle (RV) during systole. LV, left ventricle.

intravenous agitated saline can detect intracardiac shunts leading to pulmonary hypertension. In the absence of left-heart disease or intracardiac shunts, chronic pulmonary hypertension is most often caused by either idiopathic pulmonary arterial hypertension (sporadic/familial or associated with diseases such as HIV or collagen vascular disease) or CTEPH. Echocardiographic diﬀerentiation between these two entities is problematic.

Several studies have shown diﬀerent characteristics in these two patient groups using echocardiographic variables [55,56] and high-ﬁdelity pulmonary artery pressure waveforms [57–59], but in a prospective evaluation of 142 consecutive admissions for undiﬀerentiated symptomatic pulmonary hypertension, echocardiography was unable to distinguish one group from the other reliably [60]. Therefore, other diagnostic tests such as V/Q

L.B. Daniels et al / Cardiol Clin 22 (2004) 383–399

scanning, spiral CT, and pulmonary angiography are recommended for deﬁnitive diagnosis of CTEPH versus pulmonary arterial hypertension. Utility of echocardiography for prognosis and treatment of chronic pulmonary hypertension Echocardiography plays an important role in predicting the prognosis of patients with pulmonary hypertension. For example, Raymond et al [2] found that pericardial eﬀusion, right atrial enlargement and interventricular septal distortion predicted adverse outcomes in primary pulmonary hypertension. Similarly, D’Alonzo et al [61] reported a worsened survival in patients with pulmonary arterial hypertension, with elevated pulmonary artery pressure, right atrial pressure, and decreased cardiac output found on echocardiographic examination. Eysmann [62] added a shortened pulmonary artery Doppler acceleration time to the list of echocardiographic parameters associated with poor survival in pulmonary arterial hypertension. Pulmonary arterial hypertension: use of echocardiography in diagnosis and management Pulmonary arterial hypertension remains a difﬁcult disease to manage despite recent advances in drug therapy including intravenous epoprostenol [63] and, more recently, inhaled iloprost [64] and oral bosentan [65]. Preliminary studies also suggest an adjunctive role for oral sildenaﬁl [66]. Prognosis remains poor, but echocardiography has proven useful in assessing response to therapy. In a study by Hinderliter et al [67] the echocardiographic characteristics of 81 patients with severe pulmonary arterial hypertension were followed prospectively for 12 weeks. Baseline echocardiographic measures of right ventricular end-diastolic area, eccentricity index, pericardial eﬀusion size, and tricuspid regurgitation jet area were inversely correlated with baseline exercise capacity. After 12 weeks of intravenous prostacyclin infusion, right ventricular end-diastolic area, systolic and diastolic eccentricity index, and maximal VTR were improved. Quality of life was not signiﬁcantly associated with echocardiographic ﬁndings, however, and Doppler echocardiography was unable to quantify accurately small changes in pulmonary artery pressure associated with prostacyclin therapy in individual patients. Despite these limitations, it seems reasonable that patients with primary pulmonary hypertension should undergo echocardiography at regular

395

intervals to detect markers of poor prognosis. More aggressive therapy and lung transplant evaluation would then be indicated for these patients [2]. Chronic thromboembolic pulmonary hypertension In contrast to idiopathic pulmonary arterial hypertension (primary pulmonary hypertension), CTEPH is often markedly improved by pulmonary thromboendarterectomy. Several studies have demonstrated that the changes in the anatomic and physiologic abnormalities of pulmonary hypertension can be monitored by echocardiography. As mentioned previously, Sadeghi et al [42] found that the severity of tricuspid regurgitation generally lessened after pulmonary thromboendarterectomy, most notably in patients with marked decreases in pulmonary artery pressure. Additionally, measurements of right ventricular area and systolic function (eg, fractional area change) improve when right ventricular afterload is decreased by pulmonary thromboendarterectomy [4]. Some of these anatomic changes occur immediately after pulmonary thromboendarterectomy, but additional improvements are seen over time as the right ventricle remodels [3]. Right atrial size decreases signiﬁcantly after pulmonary thromboendarterectomy [68], and both IVC diameter and pulmonary artery size return to nearly normal within 2 weeks after successful surgery [65,68]. The left ventricular eccentricity index returns to approximately 1.0 after pulmonary thromboendarterectomy, and both the E/A ratio and isovolumetric relaxation time normalize. Cardiac output increases signiﬁcantly after surgery [4,50,69]. Mahmud et al [50] found that the transmitral E/A ratio can be used as a noninvasive marker of successful pulmonary thromboendarterectomy, because a postoperative E/A ratio of more than 1.5 correlates with both normal cardiac output and pulmonary artery pressure. Mild pulmonary hypertension The long-term prognosis of mild pulmonary hypertension is diﬃcult to predict and varies with the causative factor. Therefore, a complete evaluation is recommended to exclude correctable causes in asymptomatic patients who are serendipitously diagnosed with mild pulmonary hypertension. In patients with unexplained mild pulmonary hypertension, serial echocardiographic examinations at 6- to 12-month intervals seem

396

L.B. Daniels et al / Cardiol Clin 22 (2004) 383–399

prudent; earlier evaluation is warranted i