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Division of Pulmonary and Critical Care Medicine, University of California, San Diego, La Jolla, California
Correspondence and requests for reprints should be addressed to Nick H. S. Kim, M.D., Division of Pulmonary and Critical Care Medicine, University of California, San Diego, 9330 Campus Point Drive, MC 7381, La Jolla, CA 92037-7381. E-mail: h33kim{at}ucsd.edu
ABSTRACT
Pulmonary endarterectomy surgery (PEA) offers the possibility of a cure for patients suffering from chronic thromboembolic pulmonary hypertension (CTEPH). Despite growing experience worldwide, the approach and criteria for patient selection remain variable and center- or expert-dependent. A significant proportion of patients with CTEPH may be turned down for PEA for a number of reasons, most frequently over concerns of distal or inaccessible disease. Although traditional preoperative testing and currently available tools are adequate in identifying the presence of proximal disease in CTEPH, they provide only limited information on the status of the microvasculature. Because persistent pulmonary hypertension is the most important determinant of post-PEA outcome, the preoperative identification of patients with CTEPH with concomitant small-vessel disease and/or microvascular disease is crucial. Pulmonary vascular resistance (PVR) is a useful parameter for assessing potential concomitant small-vessel disease. By assessing the relative contribution of small vessels to the PVR, the pulmonary artery occlusion technique represents a promising tool for determining the risk of surgery in patients with high PVR. More information is required regarding the potential value or risk of preoperative medical therapies. Although traditional surgical classification of CTEPH takes place intraoperatively, there is a need for a preoperative classification system and consensus on operability. A preliminary preoperative classification system has been proposed.
Key Words: operability • preoperative classification system • pulmonary endarterectomy
Pulmonary endarterectomy (PEA) surgery remains the treatment of choice for patients with symptomatic chronic thromboembolic pulmonary hypertension (CTEPH) (1). Under optimal conditions (i.e., experienced centers and selected patients), PEA can be performed with low perioperative mortality, with profound improvements in hemodynamics, symptoms, and survival (2–5). However, depending on the center, anywhere from 10 to 50% of patients referred for PEA may be turned down for surgery, due either to distal location of chronic thromboembolic material deemed to be inaccessible, or to significant comorbidities thought to be associated with unacceptably high risk. In fact, persistent pulmonary hypertension (PH), likely due to concomitant small-vessel arteriopathy in addition to possibly distal thromboembolic disease (6, 7), is a critical and consistent determinant of perioperative risk (2, 3, 8). Therefore, proximal disease is not the sole determinant of whether a patient may benefit from surgery; and the preoperative assessment of the degree and contribution of small-vessel disease needs to be an equally important focus in determining operability. Secondly, although the treatment of choice for CTEPH has been PEA surgery, a preoperative classification system and general consensus among centers on patient selection remain lacking. This article explores some current issues in PEA evaluations, and proposes a preliminary, preoperative classification system incorporating a novel technique for assessing the status of small-vessel disease.
ASSESSMENT OF OPERABILITY
As with any surgery, a careful preoperative assessment is mandatory, and the decision for PEA must be tailored to individual patients. Once a diagnosis of CTEPH has been established, pulmonary angiography should be performed to assess disease location. Patients with CTEPH with main-, lobar-, or proximal segmental-level defects have been generally characterized as having proximal disease. The experience of the PEA team will, however, determine which lesions are considered as surgically treatable. Having disease that is accessible does not always mean the CTEPH is treatable—as in cases of significant concomitant small-vessel disease. Also, accessibility is dependent not solely on angiographic appearance, but also on the skill and experience of the surgeon. Indeed, even obstruction within segmental or subsegmental branches depicted in high-quality angiograms can be removed by surgeons with adequate experience (2).
In addition to defining the degree of proximal disease, another equally critical assessment is preoperative screening of microvascular disease. Traditionally, this screening has focused on a correlation between hemodynamic and radiographic findings. This approach relies on expert opinion and remains subjective, with criteria varying among centers and experts. The useful objective parameter in assessing potential concomitant small-vessel disease is pulmonary vascular resistance (PVR). Preoperative PVR in patients with CTEPH is determined by: chronic thromboembolic disease (either surgically accessible or inaccessible); concomitant small-vessel arteriopathy; and right-heart function (cardiac output). High PVR in the absence of substantial chronic thromboembolic disease on the angiogram suggests concomitant small-vessel disease, which increases the risk of persistent PH in the postoperative period and is associated with increased short- and long-term mortality (2).
Several studies have found that a high preoperative PVR is associated with increased PEA mortality (2, 3, 9) and poor hemodynamic outcome (8). Hartz and colleagues (9) found that PVR greater than 1,100 dynes · s · cm–5 was associated with 41% PEA mortality versus less than 6% in patients with PVR below 1,100 dynes · s · cm–5. This observation was supported by Dartevelle and colleagues (3), who reported an increased postoperative mortality of 10% in patients with preoperative PVR 900–1,200 dynes · s · cm–5, increasing to 20% mortality when PVR was above 1,200 dynes · s · cm–5. Similarly, in a large series of 500 patients with CTEPH who underwent PEA, Jamieson and colleagues (2) reported that patients with a preoperative PVR greater than 1,000 dynes · s · cm–5 had a significantly higher mortality rate than those with a preoperative PVR less than 1,000 dynes · s · cm–5 (10.1 vs. 1.4%; p < 0.0001). Although D'Armini and colleagues (10) have reported that PEA leads to hemodynamic recovery even in severely compromised patients with CTEPH, the balance of evidence indicates that high preoperative PVR has an unfavorable effect on outcome after PEA.
MICROVASCULAR DISEASE
Persistent PH after PEA is likely to reflect concomitant small-vessel or microvascular disease (2), and remains the most important determinant of postoperative mortality and long-term outcome (2). Indeed, among 500 patients with CTEPH who underwent PEA, those with a postoperative PVR greater than 500 dynes · s · cm–5 had a mortality rate of 30.6% compared with a mortality rate of only 0.9% in those with a postoperative PVR of less than 500 dynes · s · cm–5 (p < 0.0001) (2). Furthermore, nearly half of all long-term deaths following PEA were attributed to persistent PH (5).
Potential treatment of concomitant microvascular disease ideally starts with accurate preoperative identification of patients with CTEPH with significant small-vessel disease. It has been suggested that secondary vasculopathy can be avoided by early diagnosis of CTEPH and by PEA surgery; however, some patients with severe microvascular disease may have primary vasculopathy with secondary thrombosis. Controlled studies are needed to determine whether patients with CTEPH with a high preoperative PVR have a better surgical outcome if they receive preoperative medical therapy, such as prostanoids, endothelin receptor antagonists, or phosphodiesterase inhibitors. However, these studies need to weigh the risk of delaying potentially effective surgical treatment in these often severely compromised patients with CTEPH. In rare instances, lung transplantation may be appropriate in select patients if there is no viable alternative.
PREOPERATIVE TESTS
The tools and techniques that are currently available for patient assessment are covered in detail elsewhere in this issue (11). All patients with CTEPH need a right-heart catheterization before PEA. Obtaining an accurate pulmonary artery occluded or "wedge" pressure can be particularly challenging in CTEPH, and may reflect the irregular proximal vasculature. In some patients, a left-ventricular end-diastolic pressure measurement may be necessary in order to calculate the PVR. Ventilation–perfusion scintigraphy remains the screening test of choice to distinguish between CTEPH and other PH etiologies (12). Despite the technical progress that has been made with computer tomography and magnetic resonance imaging scanning, pulmonary angiography remains the gold standard for imaging. In the future, however, advances in computer tomography and magnetic resonance imaging may supplant selective angiography as the imaging standard in patients with CTEPH. Pulmonary angioscopy and intravascular ultrasound have not been widely available, but have been used in select centers to further assist with determining candidacy for PEA.
OTHER CONSIDERATIONS
Severe underlying chronic lung disease, either obstructive or restrictive, is a contraindication to PEA (13). Although the degree of lung function abnormality precluding PEA has not been well studied, revascularization of regions affected with either significant emphysema or interstitial lung disease can cause profound refractory hypoxemia, off-setting any hemodynamic benefits of PEA. Severe right ventricular failure, renal or hepatic insufficiency, and malignancy with reasonable life expectancy should be included in the risk assessment, but should not be regarded as absolute contraindications. Indeed, patients with the most severe right ventricular failure from CTEPH can often have the most dramatic and satisfying outcome after surgery. PEA has been successfully performed alongside other cardiac procedures, including valvular repair or replacement and coronary artery bypass grafting, with no apparent adverse effect on 1-yr survival and mean reduction in PVR (14). Advanced or young age should be included in the risk assessment, but neither characteristic is an absolute contraindication to PEA (15).
Significant risks are associated with PEA, and patients must be fully informed and accepting of the risks before surgery can be carried out. It is important to consider how information is presented to the patient to ensure that they are in the position to make a "reasonable" and informed decision with regard to surgery.
SURGICAL CLASSIFICATION
Currently, classification of CTEPH cases is restricted to an (intra)operative classification system that categorizes patients according to surgical specimen type (type 1: fresh thrombus in main-lobar pulmonary arteries; type 2: intimal thickening and fibrosis proximal to the segmental arteries; type 3: disease within distal segmental arteries only; type 4: distal arteriolar vasculopathy without visible thromboembolic disease) (15). Using this system, patients with thromboembolic disease proximal to segmental arteries (type 1 or type 2 disease) have been shown to have the most favorable hemodynamic outcome from PEA, whereas patients with disease limited to the segmental pulmonary arteries have a higher surgical risk and a poorer prognosis (Table 1) (16).
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PREOPERATIVE ASSESSMENT OF MICROVASCULAR DISEASE
A promising tool to determine the risk of surgery in patients with a highly elevated PVR is the pulmonary artery occlusion technique. Based on the assumption that the decaying pulmonary arterial occlusion pressure waveform can estimate precapillary pressures (occlusion pressure), the PVR can then be partitioned into large arterial (upstream) and small arterial plus venous (downstream) components (17, 18). Representative pulmonary artery pressure occlusion waveforms from patients with primarily upstream resistance (Rup) and significant downstream resistance are displayed in Figures 1A and 1B, respectively. In a series of 26 patients, there was good correlation demonstrated between preoperative measurement of Rup and postoperative total pulmonary resistance index (R2=0.79) and mean pulmonary artery pressure (R2=0.75) (Figure 2). In this cohort, the only postoperative deaths occurred in patients with Rup preoperatively estimated at less than 60%, indicating significant downstream, inoperable, small-vessel involvement (18). Moreover, nonsurvivors had the highest total pulmonary resistance index and mean pulmonary artery pressure. Thus, patients with lower Rup appear to be at high risk for persistent PH and death after PEA. It is unclear, however, whether patients with seemingly distal CTEPH (by conventional evaluation) and high Rup values should be considered for PEA. Lesions that are upstream according to the occlusion technique may still be too distal for successful PEA. Furthermore, clinical experience with this technique is limited.
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Despite the growth in both expertise and number of PEA centers worldwide, we still lack a standardized preoperative classification system, as found in many other disease states, that define and separate patients into being either surgically amenable or inoperable (e.g., solid malignancies). With the expansion and availability of effective medical therapies for pulmonary arterial hypertension, a pertinent question in the preoperative assessment of patients with CTEPH is the presence of significant small-vessel disease, which may be more amenable to medical therapy, either in lieu of or before surgery. Table 2 shows a preliminary PEA classification system, which is presented as a template for discussion and future modifications. Classes A, B, and C all have CTEPH based on abnormal ventilation–perfusion scan with associated abnormal angiography. Class A patients have PVR (
1,100 dynes · s · cm–5) in the range associated with lower postoperative mortality from multiple centers (8, 9). Class B and C patients have higher PVR (> 1,100 dynes · s · cm–5), compelling additional investigation into the status of the microvasculature. Although preliminary, the pulmonary artery occlusion technique is currently the only objective test to assess the contribution of small-vessels in CTEPH. Class C patients have lower Rup estimated by the occlusion technique and are at higher risk for persistent PH and death after PEA. This may represent a group in which medical therapy, either before or in lieu of PEA, should be considered and tested. The cut-off levels for both preoperative PVR and Rup need to be further validated and revised based on new data.
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PEA remains the treatment of choice for CTEPH, and assessment of operability must be an interdisciplinary process for each individual patient. The importance of preoperative high-quality pulmonary angiography and hemodynamic data cannot be overemphasized. Surgical classification of CTEPH is not a preoperative assessment, and therefore cannot be applied in the preoperative period to predict surgical success. There is a need for a preoperative assessment tool(s) that can be used to accurately assess surgical risk and expected outcome after PEA surgery. Surgical variables of operability include surgical expertise, lesion location, and consistency between PH and extent of proximal chronic thromboembolic disease. Severe underlying chronic lung disease is a contraindication for PEA. More information is required regarding the value of lowering PVR preoperatively. Improvements in preoperative evaluation, such as partitioning PVR, may better identify those select patients that may benefit from medical treatment, either before or in lieu of PEA. A preliminary preoperative classification system has been proposed.
FOOTNOTES
Supported by an unrestricted educational grant from Actelion Pharmaceuticals.
Conflict of Interest Statement: N.H.S.K. has received consultancy and speaker's fees from Actelion ($38,000), Encysive ($4,200), Cotherix ($1,500), and Schering ($2,000).
(Received in original form May 2, 2006; accepted in final form June 19, 2006)
REFERENCES
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