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The Journal of Heart and Lung Transplantation
International Society for Heart and Lung Transplantation.

Combined pulmonary endarterectomy and balloon pulmonary angioplasty in patients with chronic thromboembolic pulmonary hypertension

Published:October 29, 2015DOI:https://doi.org/10.1016/j.healun.2015.10.030

      Background

      Pulmonary endarterectomy (PEA) is a curative treatment option for more than 60% of patients with chronic thromboembolic pulmonary hypertension (CTEPH). For selected inoperable patients, interventional balloon pulmonary angioplasty (BPA) has recently been established in addition to medical treatment. This approach disrupts scar tissue occluding the pulmonary arteries, leading to an improvement in parenchymal perfusion. CTEPH is occasionally heterogeneous, with operable disease on one side but peripheral, inoperable changes on the contralateral side. Performing unilateral PEA (on the operable side only) in these patients may lead to a worse hemodynamic outcome and increased mortality compared with patients who that can be surgically corrected bilaterally. We sought to determine the feasibility, safety, and benefits of BPA applied to the contralateral lung in several patients with predominantly unilateral disease that was amenable to treatment by PEA.

      Methods

      Standard unilateral PEA in deep hypothermic circulatory arrest was performed in 3 CTEPH patients with poor pulmonary hemodynamics, and inoperability of the contralateral pulmonary artery obstructions was confirmed. The inoperable side was treated by BPA. The intervention was performed during the rewarming phase of cardiopulmonary bypass.

      Results

      A dramatic improvement in pulmonary hemodynamics, with a mean reduction in pulmonary vascular resistance of 842 dyne · sec/cm5, was achieved in all patients. World Health Organization Functional Class was also significantly improved at the midterm follow-up.

      Conclusions

      The combination of surgical PEA and interventional BPA is a new treatment option for highly selected high-risk CTEPH patients. A multidisciplinary CTEPH expert team is a basic pre-requisite for this complex concept.

      KeyWords

      Chronic thromboembolic pulmonary hypertension (CTEPH) is a common form of pulmonary hypertension.
      • Kim N.H.
      • Delcroix M.
      • Jenkins D.P.
      • et al.
      Chronic thromboembolic pulmonary hypertension.
      Up to 4% of patients who survive an episode of acute pulmonary embolism will develop CTEPH.
      • Pengo V.
      • Lensing A.
      • Prins M.
      • et al.
      Incidence of chronic thromboembolic pulmonary hypertension after a first episode of pulmonary embolism.
      • Guérin L.
      • Couturaud F.
      • Parent F.
      • et al.
      Prevalence of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism.
      Proximal and distal stenoses and occlusions of pulmonary artery (PA) branches lead to PH with consecutive deterioration of right ventricular (RV) function and right heart failure. Increased PA pressure (PAP) and hyperperfusion of the patent vessels cause a secondary microvasculopathy and further clinical deterioration.
      • Lang I.M.
      • Pesavento R.
      • Bonderman D.
      • Yuan J.X.
      Risk factors and basic mechanisms of chronic thromboembolic pulmonary hypertension: a current understanding.
      This vicious circle compromises the pulmonary and systemic circulation and is associated with a poor prognosis.
      Patients with CTEPH should be examined and treated in a high-volume center by a specialized team of experts.
      • Kim N.H.
      • Delcroix M.
      • Jenkins D.P.
      • et al.
      Chronic thromboembolic pulmonary hypertension.
      • Mayer E.
      Surgical and post-operative treatment of chronic thromboembolic pulmonary hypertension.
      • Thistlethwaite P.A.
      • Madani M.
      • Jamieson S.W.
      Outcomes of pulmonary endarterectomy surgery.
      • Pepke-Zaba J.
      • Delcroix M.
      • Lang I.
      • et al.
      Chronic thromboembolic pulmonary hypertension (CTEPH): results from an international prospective registry.
      • Mayer E.
      • Jenkins D.
      • Lindner J.
      • et al.
      Surgical management and outcome of patients with chronic thromboembolic pulmonary hypertension: results from an international prospective registry.
      • Jamieson S.W.
      • Kapelanski D.P.
      • Sakakibara N.
      • et al.
      Pulmonary endarterectomy: experience and lessons learned in 1,500 cases.
      The gold standard treatment for CTEPH is pulmonary endarterectomy (PEA). This complex surgical intervention is often curative, with post-operative normalization of the pulmonary hemodynamics, and can be accomplished with a low risk for the patients in experienced centers.
      • Mayer E.
      Surgical and post-operative treatment of chronic thromboembolic pulmonary hypertension.
      • Thistlethwaite P.A.
      • Madani M.
      • Jamieson S.W.
      Outcomes of pulmonary endarterectomy surgery.
      However, up to 37% of the patients are deemed inoperable.
      • Pepke-Zaba J.
      • Delcroix M.
      • Lang I.
      • et al.
      Chronic thromboembolic pulmonary hypertension (CTEPH): results from an international prospective registry.
      In many countries, medical treatment with the soluble guanylate cyclase stimulator riociguat has been approved for patients with inoperable CTEPH.
      • Ghofrani H.A.
      • D’Armini A.M.
      • Grimminger F.
      • et al.
      Riociguat for the treatment of chronic thromboembolic pulmonary hypertension.
      • Jaïs X.
      • D’Armini A.M.
      • Jansa P.
      • et al.
      Bosentan for treatment of inoperable chronic thromboembolic pulmonary hypertension: BENEFiT (Bosentan Effects in iNopErable Forms of chronIc Thromboembolic pulmonary hypertension), a randomized, placebo-controlled trial.
      In 2001, Feinstein et al
      • Feinstein J.A.
      • Goldhaber S.Z.
      • Lock J.E.
      • Ferndandes S.M.
      • Landzberg M.J.
      Balloon pulmonary angioplasty for treatment of chronic thromboembolic pulmonary hypertension.
      reported balloon pulmonary angioplasty (BPA) as a new treatment option for patients with inoperable CTEPH.
      • Feinstein J.A.
      • Goldhaber S.Z.
      • Lock J.E.
      • Ferndandes S.M.
      • Landzberg M.J.
      Balloon pulmonary angioplasty for treatment of chronic thromboembolic pulmonary hypertension.
      Recently, the procedure has been refined, mostly by Japanese centers, with improved clinical and hemodynamic results with a mean reduction of mean PAP (mPAP) from 43 mm Hg to 25 mm Hg.
      • Pitton M.B.
      • Herber S.
      • Mayer E.
      • Thelen M.
      Pulmonary balloon angioplasty of chronic thromboembolic pulmonary hypertension (CTEPH) in surgically inaccessible cases.
      • Sugimura K.
      • Fukumoto Y.
      • Satoh K.
      • et al.
      Percutaneous transluminal pulmonary angioplasty markedly improves pulmonary hemodynamics and long-term prognosis in patients with chronic thromboembolic pulmonary hypertension.
      • Mizoguchi H.
      • Ogawa A.
      • Munemasa M.
      • Mikouchi H.
      • Ito H.
      • Matsubara H.
      Refined balloon pulmonary angioplasty for inoperable patients with chronic thromboembolic pulmonary hypertension.
      • Kataoka M.
      • Inami T.
      • Hayashida K.
      • et al.
      Percutaneous transluminal pulmonary angioplasty for the treatment of chronic thromboembolic pulmonary hypertension.
      • Andreassen A.K.
      • Ragnarsson A.
      • Gude E.
      • Geiran O.
      • Andersen R.
      Balloon pulmonary angioplasty in patients with inoperable chronic thromboembolic pulmonary hypertension.
      BPA is performed as a staged procedure to reduce the risk of reperfusion edema and to minimize the amount of injected contrast medium, depending on the patient’s actual pulmonary hemodynamics and the number of PA lesions. However, BPA is not a competitive treatment option for operable CTEPH patients but seems to be a promising therapeutical tool for inoperable patients with sub-segmentally located net-like structures or strands (“webs and slits”) obstructing PA branches.
      • Mizoguchi H.
      • Ogawa A.
      • Munemasa M.
      • Mikouchi H.
      • Ito H.
      • Matsubara H.
      Refined balloon pulmonary angioplasty for inoperable patients with chronic thromboembolic pulmonary hypertension.
      • Kataoka M.
      • Inami T.
      • Hayashida K.
      • et al.
      Percutaneous transluminal pulmonary angioplasty for the treatment of chronic thromboembolic pulmonary hypertension.
      There are rare cases, however, of technically operable obstructions on one side (mostly right-sided) that could be treated surgically combined with distal contralateral lesions not amenable to surgery that could be target areas for BPA. Depending on the severity of PH, low-risk patients may undergo PEA, and if needed, BPA during follow-up. For patients with very poor pulmonary hemodynamics, however, a staged procedure might carry an extreme peri-operative risk of right heart complications and death. Therefore, PEA in combination with BPA of the inoperable side as a hybrid procedure might be a new therapeutic option for a carefully selected group of high-risk patients to instantly achieve a maximum reduction in RV afterload and to decrease the risk of RV failure after weaning from extracorporeal circulation. We report here 3 patients with severe CTEPH who were treated by combined PEA and BPA.

      Pre-operative assessment

      All patients were assessed by an experienced multidisciplinary team in an international CTEPH reference center. Clinical history, physical examination, 12-lead electrocardiogram, laboratory tests, echocardiography, cardiopulmonary exercise test, 6-minute walk distance, coronary angiography, right-sided heart catheterization, ventilation and perfusion scintigraphy, computed tomography (CT) angiography, and pulmonary angiography were performed. The results were assessed for all patients.
      The 3 patients had bilateral distal PA obstructions that were considered technically operable on the right side with a high likelihood of technical inoperability of the sub-segmental arteries of the left lower lobe. PEA was planned for all 3 patients with the possibility of combined BPA if surgical inaccessibility of the left-sided distal obstructions was confirmed.

      Patient 1

      A 68-year-old man with inoperable CTEPH was diagnosed in 2011, and combined PH-specific medication was initiated. After further clinical deterioration (World Health Organization Functional Class [WHO FC] IV), the patient was referred to our center for a second opinion. Pulmonary angiography showed lesions in almost every segmental branch of the right PA. On the left side, there were only a few subsegmental obstructions in the lower lobe. Right-sided heart catheterization revealed severe CTEPH (mPAP, 65 mm Hg; pulmonary vascular resistance [PVR], 1,600 dyne ∙ sec/cm5). The procedure was planned as an endarterectomy of the right PA branches and BPA of the left posterobasal segment if these lesions were deemed inoperable.

      Patient 2

      A 70-year-old woman with severe progressive dyspnea for 5 years was diagnosed with CTEPH in 2009. She denied further assessment of operability at that time, and PH-specific medication was initiated. Owing to further worsening of her clinical condition (WHO FC III), she was referred to our center. As in Patient 1, pulmonary angiography showed surgically accessible lesions in the right PA and sub-segmentally located obstructions in the left lower lobe with poor pulmonary hemodynamics (mPAP, 65 mm Hg; PVR, 1,630 dyne · sec/cm5). A complete endarterectomy of 7 segmental arteries of the right side and BPA of the anterobasal and posterobasal segments (8 and 10) of the left PA was planned.

      Patient 3

      A 58-year-old man (WHO FC IV) was diagnosed with severe CTEPH (mPAP, 64 mm Hg; PVR 852 dyne · sec/cm5). Comorbidity was significant, with a history of stroke and coronary artery disease. Pulmonary angiography showed exclusively segmental obstructions of the right PA with sub-segmental lesions located in the left lower lobe and lingular PA branches (Figure 1). Endarterectomy of the right side for complete disobliteration with BPA of 3 segments of the left lower lobe (segment 8–10) and 1 lingular segment (segment 5 ) was planned. Coronary intervention or bypass was not indicated according to findings of the pre-operative coronary angiography.
      Figure thumbnail gr1
      Figure 1Pre-procedural pulmonary angiography (lateral projections) in Patient 3. (A) Right pulmonary artery with surgically removable lesions (arrows); (B) left side with very distally located lesions (arrows).

      Procedural characteristics

      All patients were repeatedly informed in detail about the planned treatment options and possible risks. All gave written consent and agreed to the analytic processing of their data. Surgery was accomplished using the San Diego technique, with periods of deep hypothermic circulatory arrest of up to 20 minutes. Right-sided PEA was successfully performed with circulatory arrest times of 43 minutes in 3 periods (Patient 1), 28 minutes in 2 periods (Patient 2), and 38 minutes in 2 periods (in Patient 3; Figure 2).
      Figure thumbnail gr2
      Figure 2The surgically removed obstructing tissue from the right pulmonary artery in Patient 2.
      The left PA was incised for inspection and eventual endarterectomy. Because an adequate endarterectomy plane could not be developed during another period of deep hypothermic circulatory arrest and the obstructions were located distally to the areas of visibility, endarterectomy was considered impossible and the PA incision was closed. Reperfusion was initiated and rewarming of the patient was started after release of the aortic cross clamp.
      BPA of the left PA branches was performed during rewarming (Figure 3). This phase generally takes between 1 and 1.5 hours, offering a useful time-slot for angioplasty. In all 3 patients, no further time was needed for the intervention. Two purse-string sutures were placed into the anterior pulmonary trunk, and a 6F sheath (Terumo) was inserted and navigated to the left main PA. A 6F multipurpose guiding catheter (Medtronic) was passed through the left PA to intubate the obstructed segments under fluoroscopy. The cardiopulmonary bypass flow was reduced to achieve a systolic pulmonary pressure of 30 mm Hg. At the same time, an inspiratory hold was generated by the ventilator.
      Figure thumbnail gr3
      Figure 3(A–D) Peri-procedural pulmonary angiography during balloon pulmonary angioplasty (BPA) of the left pulmonary artery in Patient 2.
      During angiography, guiding in a 30° lateral projection, 2 guidewires (Runthrough NS-PTCA Guide Wire, Terumo; Galeo ES PTCA Guide Wire, Biotronik) were placed into the subsegmental arteries that had been previously identified as target lesions for angioplasty, and the diseased sub-segmental branches were dilated by multiple balloon inflations (Emerge, 2.0/20 mm, 4.0/20 mm, and 5.0/20 mm; Boston Scientific; Figure 3). Balloon size had been determined before the procedure using CT imaging. As in conventional BPA, in case of uncertainty, the smaller-sized balloon was used. Two segmental arteries with their sub-segmental branches were dilated in Patients 1 and 2, and 4 segmental arteries were successfully treated in Patient 3. The final pulmonary angiography showed an improvement of parenchymal perfusion, with excellent run-off in the venous phase.
      After normal core temperature was re-established, patients were weaned from cardiopulmonary bypass, and the chest was closed according to standard clinical practice. Simultaneously, inhaled iloprost was administered and continued for the first 6 hours after surgery,
      • Kramm T.
      • Eberle B.
      • Guth S.
      • Mayer E.
      Inhaled iloprost to control residual pulmonary hypertension following pulmonary endarterectomy.
      which follows our standard protocol for patients with high pre-operative PVR and poor RV function.

      Post-procedural observations

      On the first post-operative day, pulmonary hemodynamic variables were measured at 07:00 a.m., before removal of the PA catheter. A mean reduction of PVR of 842 dyne · sec/cm5 was observed (Table 1). All patients were extubated on the morning of the first post-operative day. Radiographic signs of reperfusion edema in the endarterectomized lung (in all 3 patients) and also in the interventionally treated lung in Patient 3 were seen within the first 4 post-operative days. Two patients required non-invasive ventilation for 2 and 3 days, respectively. In addition, 2 patients developed intermittent atrial fibrillation, which was treated medically. No further complications were observed.
      Table 1Pulmonary Hemodynamics and World Health Organization Functional Classes of All Patients
      Hemodynamic variables were assessed in the initial phases of the operation (“pre”) and on postoperative day 1 (“post“), with the difference in the PVR values (Δ-PVR) indicated. The WHO Functional Class assessed preoperatively (“pre”) months after the procedure (“post”), as indicated.
      Mean PAP (mm Hg)PVR (dyne · sec/cm5)WHO Functional Class
      PatientPrePostPrePostΔ-PVRPrePost (months)
      165381,60060599542 (10)
      265451,6306011,02931 (9)
      3643085235050241 (6)
      PAP, pulmonary artery pressure; PVR, pulmonary vascular resistance; WHO, World Health Organization
      a Hemodynamic variables were assessed in the initial phases of the operation (“pre”) and on postoperative day 1 (“post“), with the difference in the PVR values (Δ-PVR) indicated. The WHO Functional Class assessed preoperatively (“pre”) months after the procedure (“post”), as indicated.
      All patients were discharged from hospital after 14 days in good general condition. At 10 (Patient 1), 9 (Patient 2), and 6 (Patient 3) months after the intervention, all patients are alive with a significant improvement of exercise capacity (WHO FC II [Patient 1] and I [Patients 2 and 3]). To date, no further interventional treatment has been performed.

      Discussion

      We report use of a hybrid procedure combining PEA and BPA to treat 3 patients with CTEPH. Experience in both therapeutic strategies is limited to very few centers worldwide.
      Operability assessment is the key point in the management of CTEPH patients. The pattern of PA obstructions and the impairment of right heart function and pulmonary hemodynamics are of particular importance. Early mortality after PEA is increased in patients with high pre-operative PVR
      • Mayer E.
      • Jenkins D.
      • Lindner J.
      • et al.
      Surgical management and outcome of patients with chronic thromboembolic pulmonary hypertension: results from an international prospective registry.
      • Dartevelle P.
      • Fadel E.
      • Mussot S.
      • et al.
      Chronic thromboembolic pulmonary hypertension.
      or post-operative PVR > 500 dyne · sec/cm5.
      • Jamieson S.W.
      • Kapelanski D.P.
      • Sakakibara N.
      • et al.
      Pulmonary endarterectomy: experience and lessons learned in 1,500 cases.
      De Perrot et al
      • De Perrot M.
      • Thenganatt J.
      • McRae K.
      • et al.
      Pulmonary endarterectomy in severe chronic thromboembolic pulmonary hypertension.
      recently reported an elevated risk for PEA in patients with poor RV function.
      Patients with obstructions amenable to surgery on one side and only sub-segmental lesions (i.e., surgically inaccessible) on the opposite side are rare. In 2014, 220 CTEPH patients were evaluated in our department: 152 were considered operable, and 8 with poor pulmonary hemodynamics were classified as possible hybrid candidates. All of these patients underwent surgery, and only in the 3 patients presented here was a unilateral PEA with intraoperative BPA on the opposite side performed. A complete bilateral PEA was possible in the remaining 5 patients considered for the hybrid procedure.
      The use of PEA and BPA as a hybrid procedure is a completely new approach for severely ill CTEPH patients with poor hemodynamics and PA obstructions that are only partially accessible by surgery. This approach might reduce the early mortality rate in this high-risk group of patients. The decision for such a procedure certainly depends on the experience of the center. Because surgical removal of the obstructive material was not possible in all 3 patients, BPA was considered as the best option for an additional RV afterload reduction.
      The overall survival among patients with severe CTEPH is similar to that of a malignant disease.
      • 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.
      For operable patients, PEA provides a safe and often curative treatment option.
      • Pepke-Zaba J.
      • Delcroix M.
      • Lang I.
      • et al.
      Chronic thromboembolic pulmonary hypertension (CTEPH): results from an international prospective registry.
      Most patients with inoperable disease are treated medically for PH, and there is a wide spectrum of treatment outcomes.
      • Wilkens H.
      • Lang I.
      • Behr J.
      • et al.
      Chronic thromboembolic pulmonary hypertension (CTEPH): updated Recommendations of the Cologne Consensus Conference 2011.
      In specialized centers, inoperable CTEPH patients are screened for the additional treatment option of BPA. In selected cases, BPA might be a promising therapeutic option with a limited peri-procedural risk. To date, however, there are only limited studies that have addressed the outcome of BPA,
      • Sugimura K.
      • Fukumoto Y.
      • Satoh K.
      • et al.
      Percutaneous transluminal pulmonary angioplasty markedly improves pulmonary hemodynamics and long-term prognosis in patients with chronic thromboembolic pulmonary hypertension.
      • Mizoguchi H.
      • Ogawa A.
      • Munemasa M.
      • Mikouchi H.
      • Ito H.
      • Matsubara H.
      Refined balloon pulmonary angioplasty for inoperable patients with chronic thromboembolic pulmonary hypertension.
      • Kataoka M.
      • Inami T.
      • Hayashida K.
      • et al.
      Percutaneous transluminal pulmonary angioplasty for the treatment of chronic thromboembolic pulmonary hypertension.
      • Andreassen A.K.
      • Ragnarsson A.
      • Gude E.
      • Geiran O.
      • Andersen R.
      Balloon pulmonary angioplasty in patients with inoperable chronic thromboembolic pulmonary hypertension.
      and long-term data are lacking.
      The indication for treatment in the patients presented here was based on an interdisciplinary decision considering the localization of the obstructions in the PAs shown by pulmonary angiography and CT scan and the severity of PH. It was assumed that PEA alone might not lead to sufficient reduction in RV afterload, with a high risk of post-operative right heart failure and death, because one side was rated as inoperable in all 3 patients due to a high amount of peripheral occlusions. The combined removal of obstructive tissue within segmental vessels on one side and the interventional opening of sub-segmental arterial branches in more peripheral territories on the contralateral side was expected to result in a sufficient decrease in RV afterload. The intraoperative situation (invasive ventilation, cardiopulmonary bypass, possibility of inspiratory hold, no coughing, adjustable flow conditions in the PA, direct access to the PA) presents ideal conditions for BPA. The risk of vascular injury might also be reduced due to low pressures in the pulmonary vasculature.
      The risk of post-interventional reperfusion edema is probably lower than in conventional BPA because of the expected abrupt improvement in pulmonary hemodynamics after contralateral PEA and the continual invasive ventilation with high positive end-expiratory pressure during the first night. For this reason, more target areas can be treated in the same session. The concept of image-guided BPA was preferred to direct BPA with an open PA because more precise deployment of the balloon catheter within the sub-segmental branches of the left lower lobe arteries was possible.
      The hybrid procedure of PEA and BPA for well-selected, high-risk CTEPH patients may be a useful addition to the surgical and interventional spectrum of procedures in experienced CTEPH centers. Centrally localized thromboembolic material can still be targeted for surgical removal, and peripheral lesions can be dilated during the same session. Vessels that have been previously insufficiently surgically treated should not be dilated due to the increased risk of bleeding from guidewire perforation. An experienced multidisciplinary CTEPH team is mandatory for this complex procedure.

      Disclosure statement

      None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.
      The authors are grateful to Elizabeth Martinson, PhD, from the KHFI Editorial Office, for her editorial assistance.

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