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* From the Division of Thoracic Surgery, Toronto General Hospital, University of Toronto, Toronto, ON, Canada.
Correspondence to: Marc de Perrot, MD, MSc, Division of Thoracic Surgery, Toronto General Hospital, 9N-961, 200 Elizabeth St, Toronto, ON, M5G 2C4, Canada; e-mail: marc.deperrot{at}uhn.on.ca
Abstract
Background: Better knowledge of the evolution of persistent pulmonary hypertension after acute pulmonary embolism (PE) is required to optimize the indication and timing of pulmonary endarterectomy (PEA).
Methods: We reviewed our experience with 17 consecutive patients demonstrated to have persistent pulmonary hypertension after acute massive (n = 1), submassive (n = 7), or recurrent PE (n = 9).
Results: After a median of 18 weeks of anticoagulation (range, 12 to 30 weeks) since the last PE, 10 patients showed residual pulmonary artery systolic pressure (PAsP) > 50 mm Hg. These patients demonstrated a significant progression in PAsP over the ensuing 6 to 12 months, from 73 ± 14 to 101 ± 26 mm Hg (p = 0.005) [mean ± SD], and eight patients were found to be suitable candidates for PEA. In contrast, among seven patients with residual PAsP from 35 to 40 mm Hg (n = 3) and 41 to 50 mm Hg (n = 4), six patients had evidence of residual perfusion defects on the ventilation/perfusion scan and CT. The PAsP did not change significantly over the ensuing 6 to 12 months, except in two patients who had new episodes of acute PE.
Conclusions: Two groups of patients can be identified based on the degree of residual pulmonary hypertension after acute PE. Patients with residual PAsP > 50 mm Hg should be evaluated for PEA since their pulmonary artery pressures will significantly progress over the ensuing 6 to 12 months despite the absence of recurrent PE. In contrast, patients with PAsP from 35 to 50 mm Hg are at risk for severe pulmonary hypertension if new PE occurs, and should therefore be closely monitored.
Key Words: acute pulmonary emboli • chronic thromboembolic pulmonary hypertension • pulmonary thromboendarterectomy
Pulmonary thromboembolic disease has a wide variety of clinical presentations, with a spectrum of disease ranging from acute minor pulmonary embolism (PE) to chronic thromboembolic pulmonary hypertension (CTEPH).1 While the diagnosis and management of patients with acute PE is well characterized, the evaluation and outcome of patients with chronic disease are still unclear.23 Chronic thromboembolic disease refers to the development of pulmonary hypertension after an episode of PE associated with the persistent obstruction of some of the pulmonary artery branches despite adequate anticoagulation.
Studies456 suggest that 50 to 70% of patients demonstrate persistent abnormalities on CT pulmonary angiography (CTPA) several weeks after adequate anticoagulation following an acute PE, and that up to 43% of the patients presenting with acute PE have signs of persistent pulmonary hypertension on echocardiography at 1 year of follow-up. Approximately 5% will have significant residual pulmonary hypertension, and 3.8% of patients will eventually acquire symptomatic CTEPH.67
Most patients with CTEPH who are not candidate for pulmonary endarterectomy (PEA) die within 5 years after their diagnosis if the mean pulmonary artery pressure is > 30 mm Hg.89 The progression of the disease is usually related to the development of a distal vasculopathy similar to that observed in idiopathic pulmonary arterial hypertension or Eisenmenger syndrome and rarely to recurrent PE.10 Pulmonary hypertension can therefore progress despite adequate anticoagulation.
PEA is a potentially curative treatment for patients with CTEPH. The overall operative mortality is 5 to 10% in experienced centers. The risk is directly related to the severity of pulmonary hypertension, and the operative mortality can be reduced to < 5% if the pulmonary vascular resistance is < 600 dyne.s.cm-5 at the time of surgery.1112 The distal vasculopathy can lead to residual pulmonary hypertension postoperatively and increase the risk of postoperative complications and death. PEA should ideally be performed early in the course of the disease prior to the development of the distal vasculopathy and right ventricular (RV) dysfunction. Hence, better understanding of the risk for pulmonary hypertension and better knowledge of the rate of progression of the pulmonary hypertension in patients with chronic thromboembolic disease is required to optimize the timing of PEA.
Few studies have systematically analyzed the clinical, radiologic, and echocardiographic findings after a period of at least 12 weeks of anticoagulation in patients presenting with a documented episode of acute PE.13 In this study, we review our experience with 17 consecutive patients demonstrated to have residual pulmonary hypertension after acute massive, submassive, or recurrent PE, and assess the degree and rate of progression of the pulmonary hypertension in association with the clinical and radiologic findings.
Materials and Methods
We reviewed a series of 17 consecutive patients demonstrated to have persistent pulmonary hypertension after acute massive, submassive, or recurrent PE between January 2005 and July 2006. None of these patients had significant cardiopulmonary disease or evidence of malignancy at the time of diagnosis of PE and thereafter. All patients remained on warfarin or low-molecular-weight heparin (LMWH) since their last episode of PE. The study was performed retrospectively after approval by the Toronto Academic Health Sciences Network Institutional Research Ethics Board.
Two patients presented with acute massive and submassive PE during the same time period but had normalization of their pulmonary artery pressures on echocardiography at 3 months follow-up and were therefore not included in this study. Six patients presented with acute submassive PE while undergoing chemotherapy or radiation therapy for malignancy and were therefore also excluded from the study.
PE was diagnosed using ventilation/perfusion (
/
) scan or CTPA, and was classified as acute if symptoms began < 2 weeks before diagnosis and subacute if the symptoms were ongoing for > 2 weeks before diagnosis. Patients were also classified as to whether they had a documented history of PE or not. PE was considered documented if confirmed by / scan, CTPA, or pulmonary angiography. Patients in cardiogenic shock were considered to have massive PE, and those with RV dysfunction only were considered to have submassive PE.
All patients were evaluated after at least 12 weeks of anticoagulation (median, 18 weeks; range, 12 to 30 weeks) with echocardiography, a / scan, and CTPA, and every 6 to 12 months thereafter. If patients had dyspnea (New York Heart Association [NYHA] class II or higher) after > 12 weeks of anticoagulation and persistently abnormal perfusion scan and/or CTPA, right-heart catheterization and pulmonary angiography were performed. Total pulmonary resistance (TPR) was calculated as follows: (mean pulmonary artery pressure/cardiac output) x 80. Preoperative TPR was calculated based on the last measurement before PEA, and postoperative TPR was calculated after PEA before removing the Swan-Ganz catheter (Edwards Lifesciences; Mississauga, ON, Canada).
Patients with CTEPH were evaluated for PEA, and surgical candidates then completed the preoperative evaluation with duplex vascular Doppler of the carotid and femoral vessels as well as coronary angiography in patients > 40 years old. Pulmonary function tests and arterial blood gas analysis were also systematically performed. PEA was performed according to the standardized technique previously described, with a period of circulatory arrest under deep hypothermia (18° to 20°C) for the right side and the left side.1112
All follow-up echocardiograms were performed by experienced cardiologists in our institution. The estimated pulmonary artery systolic pressure (PAsP) was calculated from the tricuspid regurgitation (TR) jet obtained under color flow imaging guidance. In all patients, the TR Doppler signal was obtained from the apical or modified low left parasternal four-chamber view. The simplified Bernoulli formula (peak gradient = 4·v2, where v is the peak TR velocity into the right atrium) was used to obtain the PAsP by adding the peak TR gradient to the estimated right atrial pressure. Right atrial pressure was estimated based on the degree of inspiratory collapse of the inferior vena cava.14
Pulmonary hypertension was defined as PAsP 
35 mm Hg. Patients were classified into three groups based on the degree of residual pulmonary hypertension after at least 12 weeks of anticoagulation: (1) PAsP 35 to 40 mm Hg, (2) PAsP 41 to 50 mm Hg, and (3) PAsP > 50 mm Hg.
Data are expressed as mean ± SD or as median and range. Student t test was used to test differences between continuous variables, and 
2 was used for categorical variables. Statistical software (Graphpad; San Diego, CA) was used for all analyses; p < 0.05 was considered significant.
Results
Nine patients presented with their first episode of PE. One of them had massive PE and underwent thrombolysis, whereas the remaining eight patients presented with submassive PE and were treated with heparin only during the acute phase. The PAsP was elevated (mean, 74 ± 20 mm Hg) at the time of PE diagnosis and decreased after 12 to 16 weeks of anticoagulation (mean, 53 ± 16 mm Hg; p = 0.03). After at least 12 weeks of anticoagulation (median, 14 weeks; range, 12 to 16 weeks), residual PAsP was > 50 mm Hg in four patients, from 41 to 50 mm Hg in three patients, and from 35 to 40 mm Hg in two patients (Table 1 ).
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/ scan and CTPA. As noted, two of these patients had dramatic deterioration of their pulmonary pressures over the ensuing 12 months that was related to recurrent PE despite warfarin therapy. The remaining five patients had minimal or no progression of PAsP over the ensuing 6 to 12 months (Fig 1
). Two patients in NYHA class II had small deterioration in the PAsP over 12 months, from 42 to 47 mm Hg in the first patient, and from 36 to 41 mm Hg in the second patient.
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/ scan and CTPA results associated with NYHA class II limitations. Significant aggravation of the PAsP from 73 ± 14 to 101 ± 26 mm Hg was observed after 6 to 12 months of follow-up despite adequate anticoagulation and no evidence of recurrent PE (Fig 1). All patients were evaluated for PEA, and eight were found to be suitable candidates. The two remaining patients were started on therapy with an endothelin antagonist, and one of them was listed for bilateral lung transplant. Eight patients underwent PEA in our institution (Table 3 ). The mean TPR decreased from 1,114 ± 662 dyne.s.cm-5 preoperatively to 388 ± 181 dyne.s.cm-5 postoperatively (p = 0.007). The total circulatory arrest time ranged from 23 to 51 min (median, 28 min). The endarterectomy specimens were classified according to the Jamieson classification. Two patients presenting with subacute PE were classified as Jamieson class I because of the presence of residual thrombi in the main pulmonary artery branches, whereas four of six patients presenting with recurrent PE were classified as Jamieson class II since only residual fibrotic tissue was present (Fig 2 ). All patients survived the surgery and were discharged from hospital alive. Extubation was performed after a median of 2 days (range, 1 to 20 days), and patients were discharged from hospital after a median of 20 days (range, 10 to 41 days). The NYHA class significantly improved from 3.4 ± 0.7 preoperatively to 1.5 ± 0.5 postoperatively at the 3-month follow-up.
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This study suggests that patients presenting with massive, submassive, or recurrent PE should be evaluated with serial echocardiograms. It also emphasizes that the presence of pulmonary hypertension on an echocardiogram after 12 weeks of anticoagulation should lead to further investigation with a / scan and CTPA. In our study, all patients with a PAsP > 50 mm Hg despite 12 weeks of anticoagulation had evidence of chronic thromboembolic disease on pulmonary angiography. In addition, these patients had significant progression of their pulmonary hypertension on repeat echocardiography performed 6 to 12 months later.
Seven patients showed residual PAsP from 35 to 50 mm Hg after at least 12 weeks of anticoagulation, and all but one patient had a residual perfusion defect of their pulmonary vascular tree on the / scan and CTPA. These patients are potentially at risk for severe pulmonary hypertension and RV failure over time, particularly if new PE develops, and should, in our opinion, remain on life-long anticoagulation. de Soyza and Murphy15 observed that a large proportion of patients with a history of PE and residual PAsP from 30 to 50 mm Hg had disproportionate elevation of the pulmonary artery pressures during exercise compared to the increase in cardiac output. These patients can potentially remain stable for many years after the initial PE if a new episode of PE does not develop.8
Ribeiro et al6 demonstrated that the PAsP decreased within the first 6 weeks after an episode of acute PE and reached a plateau afterwards. Approximately 43% of their patients had some residual pulmonary hypertension after 1-year follow-up on echocardiography. However, only 5% had a residual PAsP > 40 mm Hg and were at risk for progressive RV dysfunction. Ribeiro et al6 report that three of the four patients presenting with a PAsP > 40 mm Hg at 1 year follow-up underwent PEA due to progressive RV failure, whereas none of the patients with PAsP < 40 mm Hg underwent surgery.
The distinction between acute and chronic disease on initial presentation can be difficult.16 Measurement of the pulmonary artery pressures is the most reliable way to differentiate between acute and chronic PE. Previous studies1718 have shown that a PAsP > 70 mm Hg or a mean pulmonary artery pressure > 40 mm Hg at the time of diagnosis of an acute PE demonstrate the presence of a chronic component to the acute PE. Indeed, a normal right ventricle is unable to generate such high pressures unless there is some degree of chronic emboli in addition to the acute emboli.
From our study, we can estimate that the presence of a residual PAsP > 50 mm Hg on follow-up echocardiography after at least 12 weeks of anticoagulation following an episode of PE is diagnostic of chronic PE. These patients should therefore undergo right-heart catheterization, and if the right heart catheterization confirms that the PAsP is > 50 mm Hg, they should be evaluated for PEA even though they may have improved clinically during the first few weeks after starting the anticoagulation as the acute component of the PE improved. Residual pulmonary hypertension will persist and the symptoms worsen in a second phase despite adequate anticoagulation and the absence of recurrent PE. The transitory phase of improvement before further deterioration is typical of the "honeymoon" period.1219
This study is limited by the small number of patients, and the results need to be confirmed in a large cohort of patients evaluated prospectively after acute PE. However, based on our experience and that of the literature, we think it is important to differentiate three groups of patients in the recovery phase, 12 weeks from acute PE. The first group includes patients with a PAsP < 35 mm Hg who can be estimated to have fully recovered from the PE. The second group includes patients with a residual PAsP from 35 to 50 mm Hg. This group of patients often has persistent pulmonary vascular obstruction and is at risk for severe pulmonary hypertension, particularly if new PE occurs. These patients should therefore be closely monitored with an echocardiography every 6 months and, in our opinion, maintain on anticoagulation. The third group includes patients with a PAsP > 50 mm Hg. This group of patients is at risk for progressive aggravation of their pulmonary hypertension within 6 to 12 months despite adequate anticoagulation and should be assessed for PEA with a right-heart catheterization and pulmonary angiography. This evaluation at 12 weeks after acute PE should also help to characterize the natural history of CTEPH in the future.
In conclusion, patients showing signs of residual pulmonary hypertension on echocardiography after 12 weeks of anticoagulation should be closely evaluated. Patients presenting with a residual PAsP > 50 mm Hg should be evaluated for PEA because the pulmonary hypertension will typically progress over the following 6 to 12 months in this group of patients. In contrast, patients with a PAsP from 35 to 50 mm Hg can have mild-to-moderate symptoms associated with residual perfusion defects on the / scan and CTPA. These patients are at risk for pulmonary hypertension and RV failure over time, particularly if new PE occurs, and should therefore be closely monitored.
Footnotes
Abbreviations: CTEPH = chronic thromboembolic pulmonary hypertension; CTPA = CT pulmonary angiography; LMWH = low-molecular-weight heparin; NYHA = New York Heart Association; PAsP = pulmonary artery systolic pressure; PE = pulmonary embolism; PEA = pulmonary endarterectomy; RV = right ventricular; TPR = total pulmonary resistance; TR = tricuspid regurgitation; / = ventilation/perfusion
None of the authors have any conflicts of interest to disclose.
Received for publication October 12, 2006. Accepted for publication February 13, 2007.
References
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