The outcome of reoperative pulmonary endarterectomy surgery

The outcome of reoperative pulmonary endarterectomy surgery Abstract OBJECTIVES Pulmonary endarterectomy (PEA) is the treatment of choice for patients with chronic thromboembolic pulmonary hypertension (PH). Despite excellent outcomes following PEA, a small proportion of patients have residual proximal disease or present with recurrent chronic thromboembolic PH and may benefit from further surgery. The aim of this study was to analyse outcomes following reoperative PEA at a high-volume national tertiary referral centre for the management of chronic thromboembolic PH. METHODS This retrospective analysis was performed using our prospectively maintained PH database to identify all patients who underwent reoperative PEA surgery between the commencement of the programme in 1997 and January 2017, and the patients' data were collected for analysis. RESULTS Twelve patients underwent reoperative PEA during the period of study. The mean interval between primary procedure and reoperative procedure was 6.3 years. Significant improvements were observed in pulmonary haemodynamics following reoperative PEA. Mean pulmonary arterial pressure decreased from 46.8 to 29.8 mmHg (P < 0.0001) and pulmonary vascular resistance decreased from 662 to 362 dyne·s·cm−5 (P = 0.0007). A significant functional improvement in the 6-min walking test distance was also observed, increasing from 327 to 460 m at 6 months postoperatively (P = 0.0018). Median length of hospital stay was 12 days. In-hospital mortality was 8.3% with 1-year survival of 83.3%. CONCLUSIONS Reoperative PEA is technically possible and relatively safe, achieving good functional and physiological outcomes. Patients must be carefully selected by a multidisciplinary team, and surgery should be performed in experienced centres. Chronic thromboembolic pulmonary hypertension, Pulmonary endarterectomy, Pulmonary thromboendarterectomy, Recurrent disease, Residual disease, Redo, Reoperation INTRODUCTION Chronic thromboembolic pulmonary hypertension (CTEPH) is often described as a potentially curable form of pulmonary hypertension (PH) in selected patients. Despite this, it remains an underdiagnosed and frequently overlooked entity [1]. CTEPH is characterized by the presence of occlusive thromboembolic material within the pulmonary arteries and is believed to be a late complication of acute pulmonary embolism with an incidence estimated to be between 0.57% and 8.8% [2]. Pulmonary endarterectomy (PEA, also known as a pulmonary thromboendarterectomy) surgery is the guideline-recommended treatment [3]. For those patients deemed operable, PEA offers excellent symptomatic and prognostic benefits in comparison with the 5-year mortality rate of 90% in patients who remain untreated [4, 5]. In high-volume centres, in-hospital mortality rates as low as 2.2% were achieved [6], and 3-year survival rates of up to 90% were reported [2, 7–9]. Despite excellent outcomes following PEA, some patients have residual PH after PEA [9]. The aetiology is multifactorial, but in many cases, it is due to small vessel vasculopathy. It can also be related to other causes such as unmasking PH related to left heart disease. Occasionally, residual PH following PEA is due to an incomplete surgical clearance. In addition, a small proportion of patients develop recurrent CTEPH either due to a new thromboembolism or in situ thrombosis. To be certain that obstructive vascular disease is truly recurrent one has to have evidence of improved imaging and haemodynamics following PEA, new symptoms and associated new pulmonary artery obstruction on imaging. The risk factors for development of recurrent CTEPH are poorly characterized but may be similar to the risk factors for the development of primary CTEPH, for example, thrombotic predisposition, antiphospholipid syndrome, splenectomy and presence of indwelling intravascular catheters [10]. In the UK, all patients are routinely reassessed following PEA, and follow-up is continued at a designated PH centre for at least 5 years. This provides a unique opportunity to assess this issue. On the basis of the excellent outcomes currently attained following PEA, those patients with recurrent CTEPH should be assessed to consider reoperation. There is only 1 historical report on reoperative PEA [11]. Now that alternative treatments for CTEPH are available, namely balloon pulmonary angioplasty (BPA) and licenced vasodilator drug therapy, the outcomes following contemporary reoperative PEA should be evaluated. The aim of this study was to analyse outcomes following reoperative PEA at a high-volume national tertiary referral centre for the management of CTEPH. METHODS This retrospective analysis was performed using our prospectively maintained PH database to identify all patients who underwent reoperative PEA surgery between the commencement of the programme in 1997 and January 2017. All patients with CTEPH are assessed for surgical intervention at the UK national PEA multidisciplinary team meeting where decision on operability is made based on 3 questions [12]: (i) Are chronic thrombotic lesions surgically accessible? (ii) Does the presence and severity of haemodynamic impairment correlate with the burden of thromboembolic disease? (iii) Do patient comorbidities preclude surgical consideration? Our surgical technique for PEA is now well established and has been previously reported [13, 14]. When considering reoperative surgery, there is a detailed multidisciplinary team (MDT) review where the original operative notes and specimen photo if available, serial and current pulmonary haemodynamics and serial imaging are carefully reviewed, and the relative risks and potential symptomatic and prognostic benefits are considered. All reoperative PEAs were performed by a single surgeon (D.P.J.). Patient demographics and intraoperative and postoperative characteristics were retrieved from the database. Data were cross-checked with the individual patient's notes, perfusion data records and the electronic intensive care information system. Right heart catheter studies were performed preoperatively and immediately postoperatively in the intensive care unit on Day 1. Data were analysed using the GraphPad Prism 5.03 (GraphPad Software, Inc., San Diego, CA, USA). The Kaplan–Meier method was used to plot survival rates of the patient. Paired data analysis was performed using the Student’s t-test, and the results were considered statistically significant at P-value <0.05. RESULTS Patient demographics Of the 1607 PEAs performed at our centre during the study period (to the end of January 2017), a total of 12 (0.7%) PEAs were reoperative procedures. Preoperative and postoperative characteristics are summarized in Tables 1 and 2. In this cohort, 5 patients were men and 7 were women. The mean age at first operation was 34 (range 14–53) years and at reoperation 40 (range 20–56) years with a mean interval between operations of 6.3 (range 1.0–11.6) years. Half of the patients in this series underwent the primary procedure at another centre and were referred to our centre for consideration of reoperation. In 4 of the patients, it was believed that the disease represented residual material not cleared during the primary procedure. Thus, the incidence of the need for redo PEA surgery from our own experience was 6 of 1607 PEAs (0.4%). Table 1: Demographic details of patients undergoing reoperative pulmonary endarterectomy Patient Sex Age (years) Interval from first PEA (years) Haematological disorder IVC filter Anticoagulation Medication Recurrence/ residual 1 F 47 0.7 APS Yes Warfarin Bosentan Recurrence 2 F 56 3.2 Nil Yes Warfarin Nil Recurrence 3 M 34 7.8 Nil Yes Warfarin Sildenafil Recurrence 4 F 37 7.4 Anticardiolipin antibody No Warfarin Sildenafil Residual 5 M 20 7.6 Undetermined thrombophilia Yes Warfarin Nil Recurrence 6 M 40 6.6 APS, polycythemia No Warfarin Sildenafil Recurrence 7 M 51 9.9 Nil No Warfarin Sildenafil Residual 8 F 37 8.2 Prothrombin mutation, protein C deficiency No Warfarin Sildenafil Residual 9 F 45 4.3 APS Yes Rivaroxaban Bosentan Recurrence 10 F 29 6.4 Nil No Warfarin Bosentan Residual 11 M 50 1.5 Nil Yes Warfarin Sildenafil Recurrence 12 F 38 11.6 Nil Yes Warfarin Sildenafil and bosentan Recurrence Patient Sex Age (years) Interval from first PEA (years) Haematological disorder IVC filter Anticoagulation Medication Recurrence/ residual 1 F 47 0.7 APS Yes Warfarin Bosentan Recurrence 2 F 56 3.2 Nil Yes Warfarin Nil Recurrence 3 M 34 7.8 Nil Yes Warfarin Sildenafil Recurrence 4 F 37 7.4 Anticardiolipin antibody No Warfarin Sildenafil Residual 5 M 20 7.6 Undetermined thrombophilia Yes Warfarin Nil Recurrence 6 M 40 6.6 APS, polycythemia No Warfarin Sildenafil Recurrence 7 M 51 9.9 Nil No Warfarin Sildenafil Residual 8 F 37 8.2 Prothrombin mutation, protein C deficiency No Warfarin Sildenafil Residual 9 F 45 4.3 APS Yes Rivaroxaban Bosentan Recurrence 10 F 29 6.4 Nil No Warfarin Bosentan Residual 11 M 50 1.5 Nil Yes Warfarin Sildenafil Recurrence 12 F 38 11.6 Nil Yes Warfarin Sildenafil and bosentan Recurrence APS: antiphospholipid syndrome; F: female; IVC: inferior vena cava; M: male; PEA: pulmonary endarterectomy. Table 1: Demographic details of patients undergoing reoperative pulmonary endarterectomy Patient Sex Age (years) Interval from first PEA (years) Haematological disorder IVC filter Anticoagulation Medication Recurrence/ residual 1 F 47 0.7 APS Yes Warfarin Bosentan Recurrence 2 F 56 3.2 Nil Yes Warfarin Nil Recurrence 3 M 34 7.8 Nil Yes Warfarin Sildenafil Recurrence 4 F 37 7.4 Anticardiolipin antibody No Warfarin Sildenafil Residual 5 M 20 7.6 Undetermined thrombophilia Yes Warfarin Nil Recurrence 6 M 40 6.6 APS, polycythemia No Warfarin Sildenafil Recurrence 7 M 51 9.9 Nil No Warfarin Sildenafil Residual 8 F 37 8.2 Prothrombin mutation, protein C deficiency No Warfarin Sildenafil Residual 9 F 45 4.3 APS Yes Rivaroxaban Bosentan Recurrence 10 F 29 6.4 Nil No Warfarin Bosentan Residual 11 M 50 1.5 Nil Yes Warfarin Sildenafil Recurrence 12 F 38 11.6 Nil Yes Warfarin Sildenafil and bosentan Recurrence Patient Sex Age (years) Interval from first PEA (years) Haematological disorder IVC filter Anticoagulation Medication Recurrence/ residual 1 F 47 0.7 APS Yes Warfarin Bosentan Recurrence 2 F 56 3.2 Nil Yes Warfarin Nil Recurrence 3 M 34 7.8 Nil Yes Warfarin Sildenafil Recurrence 4 F 37 7.4 Anticardiolipin antibody No Warfarin Sildenafil Residual 5 M 20 7.6 Undetermined thrombophilia Yes Warfarin Nil Recurrence 6 M 40 6.6 APS, polycythemia No Warfarin Sildenafil Recurrence 7 M 51 9.9 Nil No Warfarin Sildenafil Residual 8 F 37 8.2 Prothrombin mutation, protein C deficiency No Warfarin Sildenafil Residual 9 F 45 4.3 APS Yes Rivaroxaban Bosentan Recurrence 10 F 29 6.4 Nil No Warfarin Bosentan Residual 11 M 50 1.5 Nil Yes Warfarin Sildenafil Recurrence 12 F 38 11.6 Nil Yes Warfarin Sildenafil and bosentan Recurrence APS: antiphospholipid syndrome; F: female; IVC: inferior vena cava; M: male; PEA: pulmonary endarterectomy. Table 2: Pre- and postoperative haemodynamic characteristics of patients undergoing reoperative pulmonary endarterectomy (postoperative indicates Day 1 while receiving inotropes and on ventilation in the ICU) Patient Preoperative PAP (mmHg) Postoperative PAP (mmHg) Preoperative PVR (dyne·s·cm−5) Postoperative PVR (dyne·s·cm−5) ICU LOS (days) Hospital LOS (days) Preoperative 6MWT (m) Postoperative 6MWT (m) Follow-up (years) Current status 1 77/23 (41) 56/21 (33) 692 564 2 16 323 436 11.40 Deceased 2 69/25 (39) 39/10 (21) 365 210 3 10 218 390 5.35 Alive 3 73/32 (47) 40/14 (23) 568 197 4 12 380 510 1.55 Alive 4 57/15 (31) 48/15 (22) 354 341 3 9 450 480 6.98 Alive 5 92/35 (59) 42/17 (27) 763 250 2 12 315 500 3.08 Alive 6 96/33 (57) 44/19 (29) 828 349 4 10 350 520 1.28 Alive 7 81/37 (54) 55/29 (40) 634 472 5 10 260 570 2.01 Alive 8 48/25 (33) 68/28 (41) 615 579 6 13 280 x 0.11 Deceased 9 99/43 (62) 52/24 (33) 1124 368 1 16 380 465 7.59 Alive 10 83/30 (48) 53/14 (27) 615 358 1 30 255 342 6.85 Deceased 11 58/24 (35) 40/27 (31) 489 145 3 12 333 658 5.23 Alive 12 90/26 (47) 66/26 (39) 897 515 57 57 450 x 0.15 Deceased Patient Preoperative PAP (mmHg) Postoperative PAP (mmHg) Preoperative PVR (dyne·s·cm−5) Postoperative PVR (dyne·s·cm−5) ICU LOS (days) Hospital LOS (days) Preoperative 6MWT (m) Postoperative 6MWT (m) Follow-up (years) Current status 1 77/23 (41) 56/21 (33) 692 564 2 16 323 436 11.40 Deceased 2 69/25 (39) 39/10 (21) 365 210 3 10 218 390 5.35 Alive 3 73/32 (47) 40/14 (23) 568 197 4 12 380 510 1.55 Alive 4 57/15 (31) 48/15 (22) 354 341 3 9 450 480 6.98 Alive 5 92/35 (59) 42/17 (27) 763 250 2 12 315 500 3.08 Alive 6 96/33 (57) 44/19 (29) 828 349 4 10 350 520 1.28 Alive 7 81/37 (54) 55/29 (40) 634 472 5 10 260 570 2.01 Alive 8 48/25 (33) 68/28 (41) 615 579 6 13 280 x 0.11 Deceased 9 99/43 (62) 52/24 (33) 1124 368 1 16 380 465 7.59 Alive 10 83/30 (48) 53/14 (27) 615 358 1 30 255 342 6.85 Deceased 11 58/24 (35) 40/27 (31) 489 145 3 12 333 658 5.23 Alive 12 90/26 (47) 66/26 (39) 897 515 57 57 450 x 0.15 Deceased 6MWT: 6-min walk test (postoperative indicates 6 months following discharge); ICU: intensive care unit; LOS: length of stay; PAP: pulmonary arterial pressure; PVR: pulmonary vascular resistance. Table 2: Pre- and postoperative haemodynamic characteristics of patients undergoing reoperative pulmonary endarterectomy (postoperative indicates Day 1 while receiving inotropes and on ventilation in the ICU) Patient Preoperative PAP (mmHg) Postoperative PAP (mmHg) Preoperative PVR (dyne·s·cm−5) Postoperative PVR (dyne·s·cm−5) ICU LOS (days) Hospital LOS (days) Preoperative 6MWT (m) Postoperative 6MWT (m) Follow-up (years) Current status 1 77/23 (41) 56/21 (33) 692 564 2 16 323 436 11.40 Deceased 2 69/25 (39) 39/10 (21) 365 210 3 10 218 390 5.35 Alive 3 73/32 (47) 40/14 (23) 568 197 4 12 380 510 1.55 Alive 4 57/15 (31) 48/15 (22) 354 341 3 9 450 480 6.98 Alive 5 92/35 (59) 42/17 (27) 763 250 2 12 315 500 3.08 Alive 6 96/33 (57) 44/19 (29) 828 349 4 10 350 520 1.28 Alive 7 81/37 (54) 55/29 (40) 634 472 5 10 260 570 2.01 Alive 8 48/25 (33) 68/28 (41) 615 579 6 13 280 x 0.11 Deceased 9 99/43 (62) 52/24 (33) 1124 368 1 16 380 465 7.59 Alive 10 83/30 (48) 53/14 (27) 615 358 1 30 255 342 6.85 Deceased 11 58/24 (35) 40/27 (31) 489 145 3 12 333 658 5.23 Alive 12 90/26 (47) 66/26 (39) 897 515 57 57 450 x 0.15 Deceased Patient Preoperative PAP (mmHg) Postoperative PAP (mmHg) Preoperative PVR (dyne·s·cm−5) Postoperative PVR (dyne·s·cm−5) ICU LOS (days) Hospital LOS (days) Preoperative 6MWT (m) Postoperative 6MWT (m) Follow-up (years) Current status 1 77/23 (41) 56/21 (33) 692 564 2 16 323 436 11.40 Deceased 2 69/25 (39) 39/10 (21) 365 210 3 10 218 390 5.35 Alive 3 73/32 (47) 40/14 (23) 568 197 4 12 380 510 1.55 Alive 4 57/15 (31) 48/15 (22) 354 341 3 9 450 480 6.98 Alive 5 92/35 (59) 42/17 (27) 763 250 2 12 315 500 3.08 Alive 6 96/33 (57) 44/19 (29) 828 349 4 10 350 520 1.28 Alive 7 81/37 (54) 55/29 (40) 634 472 5 10 260 570 2.01 Alive 8 48/25 (33) 68/28 (41) 615 579 6 13 280 x 0.11 Deceased 9 99/43 (62) 52/24 (33) 1124 368 1 16 380 465 7.59 Alive 10 83/30 (48) 53/14 (27) 615 358 1 30 255 342 6.85 Deceased 11 58/24 (35) 40/27 (31) 489 145 3 12 333 658 5.23 Alive 12 90/26 (47) 66/26 (39) 897 515 57 57 450 x 0.15 Deceased 6MWT: 6-min walk test (postoperative indicates 6 months following discharge); ICU: intensive care unit; LOS: length of stay; PAP: pulmonary arterial pressure; PVR: pulmonary vascular resistance. Five of the patients in this cohort did not have an inferior vena cava (IVC) filter in situ. Four patients were anticoagulated with warfarin and 1 patient received rivaroxaban. Poor compliance with anticoagulation was reported in 1 patient (patient 3). Seven of the patients experienced a predisposing haematological condition (Table 1). None of the patients had undergone splenectomy nor did they have any long-term indwelling intravascular catheters. None of the patients had a diagnosed episode of deep vein thrombosis or pulmonary embolism. Patients undergoing reoperative PEA were significantly functionally impaired by CTEPH, with 9 patients in the New York Heart Association (NYHA) Class III, 2 patients in Class IV and 1 patient in Class II. The mean 6-min walk test distance was 327 m (range 218–450 m). Ten of the patients were on pulmonary arterial hypertension vasodilator therapy at the time of surgery. Redo surgery Good surgical clearances were achieved in all patients, and a previous bilateral PA dissection was obvious in all patients (Fig. 1). PA dissection was more challenging than a standard dissection in all patients. The mean cardiopulmonary bypass time was 326 (range 276–388) min. The mean cumulative duration of aortic cross-clamp time was 75 (range 42–118) min, and deep hypothermic circulatory arrest was 39 (range 19–73) min. Four patients had Type 1 surgical disease, 5 patients had Type 2 disease and the remaining 3 patients had Type 3 disease [15]. Figure 1: View largeDownload slide Photographs of operative specimen at primary surgery and redo surgery in the same patient. Figure 1: View largeDownload slide Photographs of operative specimen at primary surgery and redo surgery in the same patient. Two patients in this series underwent a concomitant procedure at the time of the redo PEA. Patient 2 required concomitant mitral valve replacement, whereas patient 8 required tricuspid valve repair. Pulmonary haemodynamics Preoperative and immediately postoperative haemodynamic characteristics are listed in Tables 2 and 3. Significant improvements were observed in pulmonary haemodynamics following reoperative PEA. Mean pulmonary arterial pressure decreased from 46.8 ± 2.8 to 29.8 ± 1.8 mmHg (P < 0.0001); mean right atrial pressure decreased from 12.8 ± 2.1 to 7.7 ± 1.1 mmHg (P = 0.04) and pulmonary vascular resistance (PVR) decreased from 662 ± 63.6 to 362 ± 42.1 dyne·s·cm−5 (P = 0.0007). Four patients were discharged, with continued medical therapy for residual PH (3 patients on sildenafil and 1 patient on bosentan). The improvement in haemodynamics persisted following discharge, and repeat right heart catheterization at 6 months postoperatively confirmed an increase in mean PA pressure from 46.8 ± 2.8 to 37.1 ± 3.9 mmHg (P = 0.05) and PVR from 662 ± 63.6 to 472 ± 78.4 dyne·s·cm−5 (P = 0.07). Table 3: Comparison of preoperative and immediate postoperative haemodynamic characteristics on Day 1 in the intensive care unit and at outpatient follow-up 6 months postoperatively Preoperative Immediate postoperative P-value 6 months postoperative P-value Mean PAP (mmHg) 46.8 ± 2.8 29.8 ± 1.8 <0.001 37.1 ± 3.9 0.05 RAP (mmHg) 12.8 ± 2.1 7.7 ± 1.1 0.04 7.6 ± 1.6 0.07 CO (l·min−1) 4.28 ± 0.25 4.56 ± 0.21 0.41 4.78 ± 0.35 0.25 PVR (dyne·s·cm−5) [6] 662 ± 63.6 362 ± 42.1 <0.001 472.7 ± 78.4 0.07 6MWT (m) 327 ± 21.3 460 ± 33.5 0.002 Preoperative Immediate postoperative P-value 6 months postoperative P-value Mean PAP (mmHg) 46.8 ± 2.8 29.8 ± 1.8 <0.001 37.1 ± 3.9 0.05 RAP (mmHg) 12.8 ± 2.1 7.7 ± 1.1 0.04 7.6 ± 1.6 0.07 CO (l·min−1) 4.28 ± 0.25 4.56 ± 0.21 0.41 4.78 ± 0.35 0.25 PVR (dyne·s·cm−5) [6] 662 ± 63.6 362 ± 42.1 <0.001 472.7 ± 78.4 0.07 6MWT (m) 327 ± 21.3 460 ± 33.5 0.002 Values are presented as mean ± standard deviation. Bold values are those that are statistically significant. 6MWT: 6-min walk test (postoperative indicates 6 months following discharge); CO: cardiac output; PAP: pulmonary arterial pressure; PVR: pulmonary vascular resistance; RAP: right atrial pressure. Table 3: Comparison of preoperative and immediate postoperative haemodynamic characteristics on Day 1 in the intensive care unit and at outpatient follow-up 6 months postoperatively Preoperative Immediate postoperative P-value 6 months postoperative P-value Mean PAP (mmHg) 46.8 ± 2.8 29.8 ± 1.8 <0.001 37.1 ± 3.9 0.05 RAP (mmHg) 12.8 ± 2.1 7.7 ± 1.1 0.04 7.6 ± 1.6 0.07 CO (l·min−1) 4.28 ± 0.25 4.56 ± 0.21 0.41 4.78 ± 0.35 0.25 PVR (dyne·s·cm−5) [6] 662 ± 63.6 362 ± 42.1 <0.001 472.7 ± 78.4 0.07 6MWT (m) 327 ± 21.3 460 ± 33.5 0.002 Preoperative Immediate postoperative P-value 6 months postoperative P-value Mean PAP (mmHg) 46.8 ± 2.8 29.8 ± 1.8 <0.001 37.1 ± 3.9 0.05 RAP (mmHg) 12.8 ± 2.1 7.7 ± 1.1 0.04 7.6 ± 1.6 0.07 CO (l·min−1) 4.28 ± 0.25 4.56 ± 0.21 0.41 4.78 ± 0.35 0.25 PVR (dyne·s·cm−5) [6] 662 ± 63.6 362 ± 42.1 <0.001 472.7 ± 78.4 0.07 6MWT (m) 327 ± 21.3 460 ± 33.5 0.002 Values are presented as mean ± standard deviation. Bold values are those that are statistically significant. 6MWT: 6-min walk test (postoperative indicates 6 months following discharge); CO: cardiac output; PAP: pulmonary arterial pressure; PVR: pulmonary vascular resistance; RAP: right atrial pressure. Functional outcomes All patients surviving to 6 months had an improved functional outcome, with an increase in the proportion of patients in NHYA Class I or II from 8.3% preoperatively to 100% postoperatively (Fig. 2). Functional outcome was also assessed by means of the 6-min walk test. A significant increase in mean distance was observed from 327 ± 21.3 m preoperatively to 460 ± 33.5 m at 6 months postoperatively (P = 0.0018). Figure 2: View largeDownload slide Functional improvement in the NYHA class following redo pulmonary endarterectomy. NYHA: New York Heart Association. Figure 2: View largeDownload slide Functional improvement in the NYHA class following redo pulmonary endarterectomy. NYHA: New York Heart Association. Patient outcomes Median length of stay in the intensive care unit following reoperative PEA was 3 (range 1–57) days, and median length of hospital stay was 12 (range 9–57) days. In-hospital mortality was 8.3%, and 1 patient died on postoperative Day 57. Median follow-up of these patients was 6.3 years (Table 4 and Fig. 3). Both the 1- and 5-year survival rates were 83.3%, with 1 death following hospital discharge. Table 4: Summary of postoperative outcome measures ICU length of stay (days), median (range) 3 (1–57) Hospital length of stay (days), median (range) 12 (9–57) In-hospital mortality, n (%) 1 (8.3) 1-year survival (%) 83.3 Median follow-up (years) 6.3 ICU length of stay (days), median (range) 3 (1–57) Hospital length of stay (days), median (range) 12 (9–57) In-hospital mortality, n (%) 1 (8.3) 1-year survival (%) 83.3 Median follow-up (years) 6.3 ICU: intensive care unit. Table 4: Summary of postoperative outcome measures ICU length of stay (days), median (range) 3 (1–57) Hospital length of stay (days), median (range) 12 (9–57) In-hospital mortality, n (%) 1 (8.3) 1-year survival (%) 83.3 Median follow-up (years) 6.3 ICU length of stay (days), median (range) 3 (1–57) Hospital length of stay (days), median (range) 12 (9–57) In-hospital mortality, n (%) 1 (8.3) 1-year survival (%) 83.3 Median follow-up (years) 6.3 ICU: intensive care unit. Figure 3: View largeDownload slide Patient survival following redo pulmonary endarterectomy. Figure 3: View largeDownload slide Patient survival following redo pulmonary endarterectomy. There were 2 perioperative deaths in this series. One patient died in the hospital (patient 12) following a very complicated postoperative course. Before redo surgery, she was dependent on IV prostacyclin infusion and continuous oxygen with a PVR of 897 dyne·s·cm−5 during treatment. She was slow to wake after sedation withdrawal, and a computed tomography brain scan revealed a previously unknown large cystic lesion in the left cerebral hemisphere with significant bleeding around it, creating a mass effect. She was transferred to the hospital for immediate neurosurgical intervention on Day 5, and craniectomy decompression was performed. Subsequently she developed sepsis and renal failure and also had 2 late airway bleeds requiring periods of venovenous extracorporeal membrane oxygenation. She developed a cerebral abscess, and active treatment was withdrawn on Day 57 following further neurological deterioration and the development of multiorgan failure. The second patient underwent a successful surgery, an uneventful initial recovery and was discharged from hospital on postoperative Day 14. Unfortunately, she died on postoperative Day 39 at home due to unexplained circumstances. There have been 2 late deaths in this cohort, both more than 6 years following the redo surgery. DISCUSSION PEA is now established as the guideline-recommended treatment for patients with operable CTEPH and offers excellent symptomatic and prognostic benefits [3]. Our results demonstrate that reoperative PEA is rarely necessary if a good primary operation is performed, but is technically possible, and that good functional and physiological outcomes can be achieved in selected patients. Following PEA, there is an immediate improvement in haemodynamic function with a decrease in pulmonary arterial pressure and PVR. For primary PEA, significant reproducible improvements are reported [16]. A large series from the University of California at San Diego reported a reduction in mean PA pressure from 46.1 ± 11.4 to 28.1 ± 10.1 mmHg and a reduction in PVR from 861.2 ± 446.2 to 294.8 ± 204.2  dyne·s·cm−5 [6]. The haemodynamic improvements observed in our reoperative series are not as significant as with primary surgery but are comparable. The mean cumulative period of deep hypothermic circulatory arrest of 39 min is comparable with the 35 min reported in an international registry for first-time PEA [17]. Despite the magnitude of the intervention, in-hospital mortality rates for first-time PEA range between 2.2% and 4.7% at experienced centres [6, 18]. The in-hospital mortality rate in our series is higher than this, although the number of patients is small and includes 2 patients who had concomitant valve surgery. In general, most reoperative cardiac surgery is associated with a higher perioperative risk [19, 20]. It should be highlighted that patients undergoing reoperative PEA were specially selected and younger than the patients in our overall series (mean age of 40 years compared with 62 years). Therefore, the functional and physiological results achieved in this series will not be generalizable to all patients with residual PH following PEA. Patients undergoing reoperative PEA comprised 2 groups: patients who developed true recurrent CTEPH following a good original surgical clearance and patients in whom it was believed that their presentation was with residual CTEPH following the initial PEA operation. Residual proximal CTEPH is due to a technically incomplete surgical clearance at the primary operation. Three of the 4 patients with residual CTEPH in this series had undergone initial surgery at a low-volume centre. This observation, together with reports confirming improved outcomes, is achieved at high-volume centres and supports the argument that PEA should only be performed by experienced surgeons at high-volume centres [12]. It should be emphasized that the residual PH is relatively common after PEA [9], but this is due to small vessel vasculopathy in the majority of cases, and if a good technical clearance of macroscopic disease has been performed, there is no role for attempted repeat surgery. The remaining patients developed recurrent CTEPH following a good surgical clearance at the first operation. It is not clear whether recurrent CTEPH develops following a subsequent pulmonary embolic event or in situ thrombosis within the endarterectomized pulmonary arterial tree. None of the patients reported a clinical episode of pulmonary embolism, although there is the possibility of an occult event [2, 17]. Reviewing the patients in this series, the majority had at least 1 recognized risk factor for the development of thrombosis or embolic disease. Seven of the 12 patients were known to have a coagulation disorder with a thrombophilic tendency and 4 patients had confirmed antiphospholipid syndrome, which is known to predispose to CTEPH development. In 1 additional patient, the history of poor compliance with anticoagulation was reported. This incidence of thrombotic risk factors of 58% in this series is far higher when compared with a CTEPH population undergoing primary PEA surgery. The European registry reported an incidence of thrombotic risk factors of 27.7% [17]. Hence, the presence of thrombotic risk factors, and APLS in particular, may be a risk factor for recurrent disease [10]. The utility of long-term vena caval filtration in CTEPH is controversial. Five of the patients in this series did not have an IVC filter. Previously, IVC filters were routinely placed in patients due to undergo PEA in keeping with the recommendations on the management of pulmonary thromboembolism [13, 21]. However, large randomized controlled trials demonstrating no significant improvement in survival or episodes of recurrent PE in patients with IVC filters have resulted in reduced interest [22, 23], especially with data revealing late complications of IVC filter placement such as IVC erosion, thrombosis and filter displacement or migration [24]. As a result, most centres no longer routinely use IVC filters in patients undergoing PEA [16]. One previous study has reported on outcomes following reoperative PEA in 1999 [11]. This group similarly observed a high proportion of patients having had an initial operation elsewhere. They observed functional and physiological improvements in patients following reoperative PEA and similar mortality. It is worth noting that more than half of their reoperative patients had previously undergone unilateral PEA at another low-volume centre. Bilateral exploration and dissection are always recommended [16]. This is a single-centre experience, although from a national referral centre with one of the highest PEA volumes worldwide. CTEPH is a relatively rare disease, and recurrent CTEPH is even rarer, so the number of patients reported is necessarily low. The patients included in this report of redo PEA were specially selected and noted to have significant symptomatic and prognostic benefits from repeat surgery. The results reported herein may not be generalizable to older patients or less experienced centres. Although this series confirms reoperative PEA to be technically feasible with good outcomes, the future role for reoperative PEA is unclear with emerging therapies that may allow for less invasive management of patients with recurrent CTEPH. The soluble guanylate cyclase stimulator, Riociguat, has been shown to improve exercise capacity and symptoms in patients with persistent or recurrent PH after PEA [25, 26]. However, it is too early to report whether this drug will lead to improved longer term outcomes for patients with recurrent CTEPH. A second therapy, percutaneous transcatheter BPA, may also have a role to play in recurrent CTEPH [27]. BPA uses a similar technology when compared with coronary angioplasty to dilate obstructed pulmonary arteries using selective angiography. To date, BPA has mostly been utilized in patients deemed inoperable for PEA, but encouraging results have been reported [28, 29], and this modality may become an alternative approach to reoperative PEA for some patients presenting with recurrent CTEPH due to segmental and subsegmental web lesions but would not be suitable for true occlusive disease [30]. It is thus important that patients are assessed by an experienced CTEPH team with the availability of all modalities for CTEPH treatment, so the best decision can be made for each individual patient. This is especially important for this rare patient group that has already undergone a PEA operation. Conflict of interest: none declared. REFERENCES 1 Ali JM , Hardman G , Page A , Jenkins DP. Chronic thromboembolic pulmonary hypertension: an underdiagnosed entity? Hosp Pract 2012 ; 40 : 71 – 9 . Google Scholar CrossRef Search ADS 2 Poch DS , Auger WR. Chronic thromboembolic pulmonary hypertension: detection, medical and surgical treatment approach, and current outcomes . Heart Fail Rev 2016 ; 21 : 309 – 22 . Google Scholar CrossRef Search ADS PubMed 3 Galie N , Humbert M , Vachiery JL , Gibbs S , Lang I , Torbicki A et al. . 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the joint task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT) . Eur Heart J 2016 ; 37 : 67 – 119 . Google Scholar CrossRef Search ADS PubMed 4 Dalen JE. Pulmonary embolism: what have we learned since Virchow? Natural history, pathophysiology, and diagnosis . Chest 2002 ; 122 : 1440 – 56 . Google Scholar CrossRef Search ADS PubMed 5 Jenkins D. Pulmonary endarterectomy: the potentially curative treatment for patients with chronic thromboembolic pulmonary hypertension . Eur Resp Rev 2015 ; 24 : 263 – 71 . Google Scholar CrossRef Search ADS 6 Madani MM , Auger WR , Pretorius V , Sakakibara N , Kerr KM , Kim NH et al. . Pulmonary endarterectomy: recent changes in a single institution’s experience of more than 2, 700 patients . Ann Thorac Surg 2012 ; 94 : 97 – 103 ; discussion 03. Google Scholar CrossRef Search ADS PubMed 7 Freed DH , Thomson BM , Tsui SS , Dunning JJ , Sheares KK , Pepke-Zaba J et al. . Functional and haemodynamic outcome 1 year after pulmonary thromboendarterectomy . Eur J Cardiothorac Surg 2008 ; 34 : 525 – 9 ; discussion 29–30. Google Scholar CrossRef Search ADS PubMed 8 Delcroix M , Lang I , Pepke-Zaba J , Jansa P , D’Armini AM , Snijder R et al. . Long-term outcome of patients with chronic thromboembolic pulmonary hypertension: results from an international prospective registry . Circulation 2016 ; 133 : 859 – 71 . Google Scholar CrossRef Search ADS PubMed 9 Cannon JE , Su L , Kiely DG , Page K , Toshner M , Swietlik E et al. . Dynamic risk stratification of patient long-term outcome after pulmonary endarterectomy: results from the United Kingdom National Cohort . Circulation 2016 ; 133 : 1761 – 71 . Google Scholar CrossRef Search ADS PubMed 10 Sharma S , Lang IM. Current understanding of the pathophysiology of chronic thromboembolic pulmonary hypertension . Thromb Res 2017 ;pii: S0049-3848(17) 30375 – 4 . 11 Mo M , Kapelanski DP , Mitruka SN , Auger WR , Fedullo PF , Channick RN et al. . Reoperative pulmonary thromboendarterectomy . Ann Thorac Surg 1999 ; 68 : 1770 – 6 ; discussion 76. Google Scholar CrossRef Search ADS PubMed 12 Jenkins DP , Biederman A , D’Armini AM , Dartevelle PG , Gan HL , Klepetko W et al. . Operability assessment in CTEPH: lessons from the CHEST-1 study . J Thorac Cardiovasc Surg 2016 ; 152 : 669 – 74.e3 . Google Scholar CrossRef Search ADS PubMed 13 Jenkins DP , Madani M , Mayer E , Kerr K , Kim N , Klepetko W et al. . Surgical treatment of chronic thromboembolic pulmonary hypertension . Eur Respir J 2013 ; 41 : 735 – 42 . Google Scholar CrossRef Search ADS PubMed 14 Vuylsteke A , Sharples L , Charman G , Kneeshaw J , Tsui S , Dunning J et al. . Circulatory arrest versus cerebral perfusion during pulmonary endarterectomy surgery (PEACOG): a randomised controlled trial . Lancet 2011 ; 378 : 1379 – 87 . Google Scholar CrossRef Search ADS PubMed 15 Thistlethwaite PA , Mo M , Madani MM , Deutsch R , Blanchard D , Kapelanski DP et al. . Operative classification of thromboembolic disease determines outcome after pulmonary endarterectomy . J Thorac Cardiovasc Surg 2002 ; 124 : 1203 – 11 . Google Scholar CrossRef Search ADS PubMed 16 Jenkins D , Madani M , Fadel E , D’Armini AM , Mayer E. Pulmonary endarterectomy in the management of chronic thromboembolic pulmonary hypertension . Eur Respir Rev 2017 ; 26 : 143 . 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A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. Prevention du Risque d’Embolie Pulmonaire par Interruption Cave Study Group . N Engl J Med 1998 ; 338 : 409 – 15 . Google Scholar CrossRef Search ADS PubMed 24 Geffroy S , Furber A , L’Hoste P , Abraham P , Geslin P. [Very long-term outcome of 68 vena cava filters percutaneously implanted] . Arch Mal Coeur Vaiss 2002 ; 95 : 38 – 44 . Google Scholar PubMed 25 Ghofrani HA , D’Armini AM , Grimminger F , Hoeper MM , Jansa P , Kim NH et al. . Riociguat for the treatment of chronic thromboembolic pulmonary hypertension . N Engl J Med 2013 ; 369 : 319 – 29 . Google Scholar CrossRef Search ADS PubMed 26 Simonneau G , D’Armini AM , Ghofrani H-A , Grimminger F , Hoeper MM , Jansa P et al. . Riociguat for the treatment of chronic thromboembolic pulmonary hypertension: a long-term extension study (CHEST-2) . Eur Respir J 2015 ; 45 : 1293 – 302 . Google Scholar CrossRef Search ADS PubMed 27 Satoh T , Kataoka M , Inami T , Ishiguro H , Yanagisawa R , Shimura N et al. . Endovascular treatment for chronic pulmonary hypertension: a focus on angioplasty for chronic thromboembolic pulmonary hypertension . Exp Rev Cardiovasc Ther 2016 ; 14 : 1089 – 94 . Google Scholar CrossRef Search ADS 28 Inami T , Kataoka M , Yanagisawa R , Ishiguro H , Shimura N , Fukuda K et al. . Long-term outcomes after percutaneous transluminal pulmonary angioplasty for chronic thromboembolic pulmonary hypertension . Circulation 2016 ; 134 : 2030 – 2 . Google Scholar CrossRef Search ADS PubMed 29 Mizoguchi H , Ogawa A , Munemasa M , Mikouchi H , Ito H , Matsubara H. Refined balloon pulmonary angioplasty for inoperable patients with chronic thromboembolic pulmonary hypertension . Circ Cardiovasc Interv 2012 ; 5 : 748 – 55 . Google Scholar CrossRef Search ADS PubMed 30 Shimura N , Kataoka M , Inami T , Yanagisawa R , Ishiguro H , Kawakami T et al. . Additional percutaneous transluminal pulmonary angioplasty for residual or recurrent pulmonary hypertension after pulmonary endarterectomy . Int J Cardiol 2015 ; 183 : 138 – 42 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Interactive CardioVascular and Thoracic Surgery Oxford University Press

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
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Abstract

Abstract OBJECTIVES Pulmonary endarterectomy (PEA) is the treatment of choice for patients with chronic thromboembolic pulmonary hypertension (PH). Despite excellent outcomes following PEA, a small proportion of patients have residual proximal disease or present with recurrent chronic thromboembolic PH and may benefit from further surgery. The aim of this study was to analyse outcomes following reoperative PEA at a high-volume national tertiary referral centre for the management of chronic thromboembolic PH. METHODS This retrospective analysis was performed using our prospectively maintained PH database to identify all patients who underwent reoperative PEA surgery between the commencement of the programme in 1997 and January 2017, and the patients' data were collected for analysis. RESULTS Twelve patients underwent reoperative PEA during the period of study. The mean interval between primary procedure and reoperative procedure was 6.3 years. Significant improvements were observed in pulmonary haemodynamics following reoperative PEA. Mean pulmonary arterial pressure decreased from 46.8 to 29.8 mmHg (P < 0.0001) and pulmonary vascular resistance decreased from 662 to 362 dyne·s·cm−5 (P = 0.0007). A significant functional improvement in the 6-min walking test distance was also observed, increasing from 327 to 460 m at 6 months postoperatively (P = 0.0018). Median length of hospital stay was 12 days. In-hospital mortality was 8.3% with 1-year survival of 83.3%. CONCLUSIONS Reoperative PEA is technically possible and relatively safe, achieving good functional and physiological outcomes. Patients must be carefully selected by a multidisciplinary team, and surgery should be performed in experienced centres. Chronic thromboembolic pulmonary hypertension, Pulmonary endarterectomy, Pulmonary thromboendarterectomy, Recurrent disease, Residual disease, Redo, Reoperation INTRODUCTION Chronic thromboembolic pulmonary hypertension (CTEPH) is often described as a potentially curable form of pulmonary hypertension (PH) in selected patients. Despite this, it remains an underdiagnosed and frequently overlooked entity [1]. CTEPH is characterized by the presence of occlusive thromboembolic material within the pulmonary arteries and is believed to be a late complication of acute pulmonary embolism with an incidence estimated to be between 0.57% and 8.8% [2]. Pulmonary endarterectomy (PEA, also known as a pulmonary thromboendarterectomy) surgery is the guideline-recommended treatment [3]. For those patients deemed operable, PEA offers excellent symptomatic and prognostic benefits in comparison with the 5-year mortality rate of 90% in patients who remain untreated [4, 5]. In high-volume centres, in-hospital mortality rates as low as 2.2% were achieved [6], and 3-year survival rates of up to 90% were reported [2, 7–9]. Despite excellent outcomes following PEA, some patients have residual PH after PEA [9]. The aetiology is multifactorial, but in many cases, it is due to small vessel vasculopathy. It can also be related to other causes such as unmasking PH related to left heart disease. Occasionally, residual PH following PEA is due to an incomplete surgical clearance. In addition, a small proportion of patients develop recurrent CTEPH either due to a new thromboembolism or in situ thrombosis. To be certain that obstructive vascular disease is truly recurrent one has to have evidence of improved imaging and haemodynamics following PEA, new symptoms and associated new pulmonary artery obstruction on imaging. The risk factors for development of recurrent CTEPH are poorly characterized but may be similar to the risk factors for the development of primary CTEPH, for example, thrombotic predisposition, antiphospholipid syndrome, splenectomy and presence of indwelling intravascular catheters [10]. In the UK, all patients are routinely reassessed following PEA, and follow-up is continued at a designated PH centre for at least 5 years. This provides a unique opportunity to assess this issue. On the basis of the excellent outcomes currently attained following PEA, those patients with recurrent CTEPH should be assessed to consider reoperation. There is only 1 historical report on reoperative PEA [11]. Now that alternative treatments for CTEPH are available, namely balloon pulmonary angioplasty (BPA) and licenced vasodilator drug therapy, the outcomes following contemporary reoperative PEA should be evaluated. The aim of this study was to analyse outcomes following reoperative PEA at a high-volume national tertiary referral centre for the management of CTEPH. METHODS This retrospective analysis was performed using our prospectively maintained PH database to identify all patients who underwent reoperative PEA surgery between the commencement of the programme in 1997 and January 2017. All patients with CTEPH are assessed for surgical intervention at the UK national PEA multidisciplinary team meeting where decision on operability is made based on 3 questions [12]: (i) Are chronic thrombotic lesions surgically accessible? (ii) Does the presence and severity of haemodynamic impairment correlate with the burden of thromboembolic disease? (iii) Do patient comorbidities preclude surgical consideration? Our surgical technique for PEA is now well established and has been previously reported [13, 14]. When considering reoperative surgery, there is a detailed multidisciplinary team (MDT) review where the original operative notes and specimen photo if available, serial and current pulmonary haemodynamics and serial imaging are carefully reviewed, and the relative risks and potential symptomatic and prognostic benefits are considered. All reoperative PEAs were performed by a single surgeon (D.P.J.). Patient demographics and intraoperative and postoperative characteristics were retrieved from the database. Data were cross-checked with the individual patient's notes, perfusion data records and the electronic intensive care information system. Right heart catheter studies were performed preoperatively and immediately postoperatively in the intensive care unit on Day 1. Data were analysed using the GraphPad Prism 5.03 (GraphPad Software, Inc., San Diego, CA, USA). The Kaplan–Meier method was used to plot survival rates of the patient. Paired data analysis was performed using the Student’s t-test, and the results were considered statistically significant at P-value <0.05. RESULTS Patient demographics Of the 1607 PEAs performed at our centre during the study period (to the end of January 2017), a total of 12 (0.7%) PEAs were reoperative procedures. Preoperative and postoperative characteristics are summarized in Tables 1 and 2. In this cohort, 5 patients were men and 7 were women. The mean age at first operation was 34 (range 14–53) years and at reoperation 40 (range 20–56) years with a mean interval between operations of 6.3 (range 1.0–11.6) years. Half of the patients in this series underwent the primary procedure at another centre and were referred to our centre for consideration of reoperation. In 4 of the patients, it was believed that the disease represented residual material not cleared during the primary procedure. Thus, the incidence of the need for redo PEA surgery from our own experience was 6 of 1607 PEAs (0.4%). Table 1: Demographic details of patients undergoing reoperative pulmonary endarterectomy Patient Sex Age (years) Interval from first PEA (years) Haematological disorder IVC filter Anticoagulation Medication Recurrence/ residual 1 F 47 0.7 APS Yes Warfarin Bosentan Recurrence 2 F 56 3.2 Nil Yes Warfarin Nil Recurrence 3 M 34 7.8 Nil Yes Warfarin Sildenafil Recurrence 4 F 37 7.4 Anticardiolipin antibody No Warfarin Sildenafil Residual 5 M 20 7.6 Undetermined thrombophilia Yes Warfarin Nil Recurrence 6 M 40 6.6 APS, polycythemia No Warfarin Sildenafil Recurrence 7 M 51 9.9 Nil No Warfarin Sildenafil Residual 8 F 37 8.2 Prothrombin mutation, protein C deficiency No Warfarin Sildenafil Residual 9 F 45 4.3 APS Yes Rivaroxaban Bosentan Recurrence 10 F 29 6.4 Nil No Warfarin Bosentan Residual 11 M 50 1.5 Nil Yes Warfarin Sildenafil Recurrence 12 F 38 11.6 Nil Yes Warfarin Sildenafil and bosentan Recurrence Patient Sex Age (years) Interval from first PEA (years) Haematological disorder IVC filter Anticoagulation Medication Recurrence/ residual 1 F 47 0.7 APS Yes Warfarin Bosentan Recurrence 2 F 56 3.2 Nil Yes Warfarin Nil Recurrence 3 M 34 7.8 Nil Yes Warfarin Sildenafil Recurrence 4 F 37 7.4 Anticardiolipin antibody No Warfarin Sildenafil Residual 5 M 20 7.6 Undetermined thrombophilia Yes Warfarin Nil Recurrence 6 M 40 6.6 APS, polycythemia No Warfarin Sildenafil Recurrence 7 M 51 9.9 Nil No Warfarin Sildenafil Residual 8 F 37 8.2 Prothrombin mutation, protein C deficiency No Warfarin Sildenafil Residual 9 F 45 4.3 APS Yes Rivaroxaban Bosentan Recurrence 10 F 29 6.4 Nil No Warfarin Bosentan Residual 11 M 50 1.5 Nil Yes Warfarin Sildenafil Recurrence 12 F 38 11.6 Nil Yes Warfarin Sildenafil and bosentan Recurrence APS: antiphospholipid syndrome; F: female; IVC: inferior vena cava; M: male; PEA: pulmonary endarterectomy. Table 1: Demographic details of patients undergoing reoperative pulmonary endarterectomy Patient Sex Age (years) Interval from first PEA (years) Haematological disorder IVC filter Anticoagulation Medication Recurrence/ residual 1 F 47 0.7 APS Yes Warfarin Bosentan Recurrence 2 F 56 3.2 Nil Yes Warfarin Nil Recurrence 3 M 34 7.8 Nil Yes Warfarin Sildenafil Recurrence 4 F 37 7.4 Anticardiolipin antibody No Warfarin Sildenafil Residual 5 M 20 7.6 Undetermined thrombophilia Yes Warfarin Nil Recurrence 6 M 40 6.6 APS, polycythemia No Warfarin Sildenafil Recurrence 7 M 51 9.9 Nil No Warfarin Sildenafil Residual 8 F 37 8.2 Prothrombin mutation, protein C deficiency No Warfarin Sildenafil Residual 9 F 45 4.3 APS Yes Rivaroxaban Bosentan Recurrence 10 F 29 6.4 Nil No Warfarin Bosentan Residual 11 M 50 1.5 Nil Yes Warfarin Sildenafil Recurrence 12 F 38 11.6 Nil Yes Warfarin Sildenafil and bosentan Recurrence Patient Sex Age (years) Interval from first PEA (years) Haematological disorder IVC filter Anticoagulation Medication Recurrence/ residual 1 F 47 0.7 APS Yes Warfarin Bosentan Recurrence 2 F 56 3.2 Nil Yes Warfarin Nil Recurrence 3 M 34 7.8 Nil Yes Warfarin Sildenafil Recurrence 4 F 37 7.4 Anticardiolipin antibody No Warfarin Sildenafil Residual 5 M 20 7.6 Undetermined thrombophilia Yes Warfarin Nil Recurrence 6 M 40 6.6 APS, polycythemia No Warfarin Sildenafil Recurrence 7 M 51 9.9 Nil No Warfarin Sildenafil Residual 8 F 37 8.2 Prothrombin mutation, protein C deficiency No Warfarin Sildenafil Residual 9 F 45 4.3 APS Yes Rivaroxaban Bosentan Recurrence 10 F 29 6.4 Nil No Warfarin Bosentan Residual 11 M 50 1.5 Nil Yes Warfarin Sildenafil Recurrence 12 F 38 11.6 Nil Yes Warfarin Sildenafil and bosentan Recurrence APS: antiphospholipid syndrome; F: female; IVC: inferior vena cava; M: male; PEA: pulmonary endarterectomy. Table 2: Pre- and postoperative haemodynamic characteristics of patients undergoing reoperative pulmonary endarterectomy (postoperative indicates Day 1 while receiving inotropes and on ventilation in the ICU) Patient Preoperative PAP (mmHg) Postoperative PAP (mmHg) Preoperative PVR (dyne·s·cm−5) Postoperative PVR (dyne·s·cm−5) ICU LOS (days) Hospital LOS (days) Preoperative 6MWT (m) Postoperative 6MWT (m) Follow-up (years) Current status 1 77/23 (41) 56/21 (33) 692 564 2 16 323 436 11.40 Deceased 2 69/25 (39) 39/10 (21) 365 210 3 10 218 390 5.35 Alive 3 73/32 (47) 40/14 (23) 568 197 4 12 380 510 1.55 Alive 4 57/15 (31) 48/15 (22) 354 341 3 9 450 480 6.98 Alive 5 92/35 (59) 42/17 (27) 763 250 2 12 315 500 3.08 Alive 6 96/33 (57) 44/19 (29) 828 349 4 10 350 520 1.28 Alive 7 81/37 (54) 55/29 (40) 634 472 5 10 260 570 2.01 Alive 8 48/25 (33) 68/28 (41) 615 579 6 13 280 x 0.11 Deceased 9 99/43 (62) 52/24 (33) 1124 368 1 16 380 465 7.59 Alive 10 83/30 (48) 53/14 (27) 615 358 1 30 255 342 6.85 Deceased 11 58/24 (35) 40/27 (31) 489 145 3 12 333 658 5.23 Alive 12 90/26 (47) 66/26 (39) 897 515 57 57 450 x 0.15 Deceased Patient Preoperative PAP (mmHg) Postoperative PAP (mmHg) Preoperative PVR (dyne·s·cm−5) Postoperative PVR (dyne·s·cm−5) ICU LOS (days) Hospital LOS (days) Preoperative 6MWT (m) Postoperative 6MWT (m) Follow-up (years) Current status 1 77/23 (41) 56/21 (33) 692 564 2 16 323 436 11.40 Deceased 2 69/25 (39) 39/10 (21) 365 210 3 10 218 390 5.35 Alive 3 73/32 (47) 40/14 (23) 568 197 4 12 380 510 1.55 Alive 4 57/15 (31) 48/15 (22) 354 341 3 9 450 480 6.98 Alive 5 92/35 (59) 42/17 (27) 763 250 2 12 315 500 3.08 Alive 6 96/33 (57) 44/19 (29) 828 349 4 10 350 520 1.28 Alive 7 81/37 (54) 55/29 (40) 634 472 5 10 260 570 2.01 Alive 8 48/25 (33) 68/28 (41) 615 579 6 13 280 x 0.11 Deceased 9 99/43 (62) 52/24 (33) 1124 368 1 16 380 465 7.59 Alive 10 83/30 (48) 53/14 (27) 615 358 1 30 255 342 6.85 Deceased 11 58/24 (35) 40/27 (31) 489 145 3 12 333 658 5.23 Alive 12 90/26 (47) 66/26 (39) 897 515 57 57 450 x 0.15 Deceased 6MWT: 6-min walk test (postoperative indicates 6 months following discharge); ICU: intensive care unit; LOS: length of stay; PAP: pulmonary arterial pressure; PVR: pulmonary vascular resistance. Table 2: Pre- and postoperative haemodynamic characteristics of patients undergoing reoperative pulmonary endarterectomy (postoperative indicates Day 1 while receiving inotropes and on ventilation in the ICU) Patient Preoperative PAP (mmHg) Postoperative PAP (mmHg) Preoperative PVR (dyne·s·cm−5) Postoperative PVR (dyne·s·cm−5) ICU LOS (days) Hospital LOS (days) Preoperative 6MWT (m) Postoperative 6MWT (m) Follow-up (years) Current status 1 77/23 (41) 56/21 (33) 692 564 2 16 323 436 11.40 Deceased 2 69/25 (39) 39/10 (21) 365 210 3 10 218 390 5.35 Alive 3 73/32 (47) 40/14 (23) 568 197 4 12 380 510 1.55 Alive 4 57/15 (31) 48/15 (22) 354 341 3 9 450 480 6.98 Alive 5 92/35 (59) 42/17 (27) 763 250 2 12 315 500 3.08 Alive 6 96/33 (57) 44/19 (29) 828 349 4 10 350 520 1.28 Alive 7 81/37 (54) 55/29 (40) 634 472 5 10 260 570 2.01 Alive 8 48/25 (33) 68/28 (41) 615 579 6 13 280 x 0.11 Deceased 9 99/43 (62) 52/24 (33) 1124 368 1 16 380 465 7.59 Alive 10 83/30 (48) 53/14 (27) 615 358 1 30 255 342 6.85 Deceased 11 58/24 (35) 40/27 (31) 489 145 3 12 333 658 5.23 Alive 12 90/26 (47) 66/26 (39) 897 515 57 57 450 x 0.15 Deceased Patient Preoperative PAP (mmHg) Postoperative PAP (mmHg) Preoperative PVR (dyne·s·cm−5) Postoperative PVR (dyne·s·cm−5) ICU LOS (days) Hospital LOS (days) Preoperative 6MWT (m) Postoperative 6MWT (m) Follow-up (years) Current status 1 77/23 (41) 56/21 (33) 692 564 2 16 323 436 11.40 Deceased 2 69/25 (39) 39/10 (21) 365 210 3 10 218 390 5.35 Alive 3 73/32 (47) 40/14 (23) 568 197 4 12 380 510 1.55 Alive 4 57/15 (31) 48/15 (22) 354 341 3 9 450 480 6.98 Alive 5 92/35 (59) 42/17 (27) 763 250 2 12 315 500 3.08 Alive 6 96/33 (57) 44/19 (29) 828 349 4 10 350 520 1.28 Alive 7 81/37 (54) 55/29 (40) 634 472 5 10 260 570 2.01 Alive 8 48/25 (33) 68/28 (41) 615 579 6 13 280 x 0.11 Deceased 9 99/43 (62) 52/24 (33) 1124 368 1 16 380 465 7.59 Alive 10 83/30 (48) 53/14 (27) 615 358 1 30 255 342 6.85 Deceased 11 58/24 (35) 40/27 (31) 489 145 3 12 333 658 5.23 Alive 12 90/26 (47) 66/26 (39) 897 515 57 57 450 x 0.15 Deceased 6MWT: 6-min walk test (postoperative indicates 6 months following discharge); ICU: intensive care unit; LOS: length of stay; PAP: pulmonary arterial pressure; PVR: pulmonary vascular resistance. Five of the patients in this cohort did not have an inferior vena cava (IVC) filter in situ. Four patients were anticoagulated with warfarin and 1 patient received rivaroxaban. Poor compliance with anticoagulation was reported in 1 patient (patient 3). Seven of the patients experienced a predisposing haematological condition (Table 1). None of the patients had undergone splenectomy nor did they have any long-term indwelling intravascular catheters. None of the patients had a diagnosed episode of deep vein thrombosis or pulmonary embolism. Patients undergoing reoperative PEA were significantly functionally impaired by CTEPH, with 9 patients in the New York Heart Association (NYHA) Class III, 2 patients in Class IV and 1 patient in Class II. The mean 6-min walk test distance was 327 m (range 218–450 m). Ten of the patients were on pulmonary arterial hypertension vasodilator therapy at the time of surgery. Redo surgery Good surgical clearances were achieved in all patients, and a previous bilateral PA dissection was obvious in all patients (Fig. 1). PA dissection was more challenging than a standard dissection in all patients. The mean cardiopulmonary bypass time was 326 (range 276–388) min. The mean cumulative duration of aortic cross-clamp time was 75 (range 42–118) min, and deep hypothermic circulatory arrest was 39 (range 19–73) min. Four patients had Type 1 surgical disease, 5 patients had Type 2 disease and the remaining 3 patients had Type 3 disease [15]. Figure 1: View largeDownload slide Photographs of operative specimen at primary surgery and redo surgery in the same patient. Figure 1: View largeDownload slide Photographs of operative specimen at primary surgery and redo surgery in the same patient. Two patients in this series underwent a concomitant procedure at the time of the redo PEA. Patient 2 required concomitant mitral valve replacement, whereas patient 8 required tricuspid valve repair. Pulmonary haemodynamics Preoperative and immediately postoperative haemodynamic characteristics are listed in Tables 2 and 3. Significant improvements were observed in pulmonary haemodynamics following reoperative PEA. Mean pulmonary arterial pressure decreased from 46.8 ± 2.8 to 29.8 ± 1.8 mmHg (P < 0.0001); mean right atrial pressure decreased from 12.8 ± 2.1 to 7.7 ± 1.1 mmHg (P = 0.04) and pulmonary vascular resistance (PVR) decreased from 662 ± 63.6 to 362 ± 42.1 dyne·s·cm−5 (P = 0.0007). Four patients were discharged, with continued medical therapy for residual PH (3 patients on sildenafil and 1 patient on bosentan). The improvement in haemodynamics persisted following discharge, and repeat right heart catheterization at 6 months postoperatively confirmed an increase in mean PA pressure from 46.8 ± 2.8 to 37.1 ± 3.9 mmHg (P = 0.05) and PVR from 662 ± 63.6 to 472 ± 78.4 dyne·s·cm−5 (P = 0.07). Table 3: Comparison of preoperative and immediate postoperative haemodynamic characteristics on Day 1 in the intensive care unit and at outpatient follow-up 6 months postoperatively Preoperative Immediate postoperative P-value 6 months postoperative P-value Mean PAP (mmHg) 46.8 ± 2.8 29.8 ± 1.8 <0.001 37.1 ± 3.9 0.05 RAP (mmHg) 12.8 ± 2.1 7.7 ± 1.1 0.04 7.6 ± 1.6 0.07 CO (l·min−1) 4.28 ± 0.25 4.56 ± 0.21 0.41 4.78 ± 0.35 0.25 PVR (dyne·s·cm−5) [6] 662 ± 63.6 362 ± 42.1 <0.001 472.7 ± 78.4 0.07 6MWT (m) 327 ± 21.3 460 ± 33.5 0.002 Preoperative Immediate postoperative P-value 6 months postoperative P-value Mean PAP (mmHg) 46.8 ± 2.8 29.8 ± 1.8 <0.001 37.1 ± 3.9 0.05 RAP (mmHg) 12.8 ± 2.1 7.7 ± 1.1 0.04 7.6 ± 1.6 0.07 CO (l·min−1) 4.28 ± 0.25 4.56 ± 0.21 0.41 4.78 ± 0.35 0.25 PVR (dyne·s·cm−5) [6] 662 ± 63.6 362 ± 42.1 <0.001 472.7 ± 78.4 0.07 6MWT (m) 327 ± 21.3 460 ± 33.5 0.002 Values are presented as mean ± standard deviation. Bold values are those that are statistically significant. 6MWT: 6-min walk test (postoperative indicates 6 months following discharge); CO: cardiac output; PAP: pulmonary arterial pressure; PVR: pulmonary vascular resistance; RAP: right atrial pressure. Table 3: Comparison of preoperative and immediate postoperative haemodynamic characteristics on Day 1 in the intensive care unit and at outpatient follow-up 6 months postoperatively Preoperative Immediate postoperative P-value 6 months postoperative P-value Mean PAP (mmHg) 46.8 ± 2.8 29.8 ± 1.8 <0.001 37.1 ± 3.9 0.05 RAP (mmHg) 12.8 ± 2.1 7.7 ± 1.1 0.04 7.6 ± 1.6 0.07 CO (l·min−1) 4.28 ± 0.25 4.56 ± 0.21 0.41 4.78 ± 0.35 0.25 PVR (dyne·s·cm−5) [6] 662 ± 63.6 362 ± 42.1 <0.001 472.7 ± 78.4 0.07 6MWT (m) 327 ± 21.3 460 ± 33.5 0.002 Preoperative Immediate postoperative P-value 6 months postoperative P-value Mean PAP (mmHg) 46.8 ± 2.8 29.8 ± 1.8 <0.001 37.1 ± 3.9 0.05 RAP (mmHg) 12.8 ± 2.1 7.7 ± 1.1 0.04 7.6 ± 1.6 0.07 CO (l·min−1) 4.28 ± 0.25 4.56 ± 0.21 0.41 4.78 ± 0.35 0.25 PVR (dyne·s·cm−5) [6] 662 ± 63.6 362 ± 42.1 <0.001 472.7 ± 78.4 0.07 6MWT (m) 327 ± 21.3 460 ± 33.5 0.002 Values are presented as mean ± standard deviation. Bold values are those that are statistically significant. 6MWT: 6-min walk test (postoperative indicates 6 months following discharge); CO: cardiac output; PAP: pulmonary arterial pressure; PVR: pulmonary vascular resistance; RAP: right atrial pressure. Functional outcomes All patients surviving to 6 months had an improved functional outcome, with an increase in the proportion of patients in NHYA Class I or II from 8.3% preoperatively to 100% postoperatively (Fig. 2). Functional outcome was also assessed by means of the 6-min walk test. A significant increase in mean distance was observed from 327 ± 21.3 m preoperatively to 460 ± 33.5 m at 6 months postoperatively (P = 0.0018). Figure 2: View largeDownload slide Functional improvement in the NYHA class following redo pulmonary endarterectomy. NYHA: New York Heart Association. Figure 2: View largeDownload slide Functional improvement in the NYHA class following redo pulmonary endarterectomy. NYHA: New York Heart Association. Patient outcomes Median length of stay in the intensive care unit following reoperative PEA was 3 (range 1–57) days, and median length of hospital stay was 12 (range 9–57) days. In-hospital mortality was 8.3%, and 1 patient died on postoperative Day 57. Median follow-up of these patients was 6.3 years (Table 4 and Fig. 3). Both the 1- and 5-year survival rates were 83.3%, with 1 death following hospital discharge. Table 4: Summary of postoperative outcome measures ICU length of stay (days), median (range) 3 (1–57) Hospital length of stay (days), median (range) 12 (9–57) In-hospital mortality, n (%) 1 (8.3) 1-year survival (%) 83.3 Median follow-up (years) 6.3 ICU length of stay (days), median (range) 3 (1–57) Hospital length of stay (days), median (range) 12 (9–57) In-hospital mortality, n (%) 1 (8.3) 1-year survival (%) 83.3 Median follow-up (years) 6.3 ICU: intensive care unit. Table 4: Summary of postoperative outcome measures ICU length of stay (days), median (range) 3 (1–57) Hospital length of stay (days), median (range) 12 (9–57) In-hospital mortality, n (%) 1 (8.3) 1-year survival (%) 83.3 Median follow-up (years) 6.3 ICU length of stay (days), median (range) 3 (1–57) Hospital length of stay (days), median (range) 12 (9–57) In-hospital mortality, n (%) 1 (8.3) 1-year survival (%) 83.3 Median follow-up (years) 6.3 ICU: intensive care unit. Figure 3: View largeDownload slide Patient survival following redo pulmonary endarterectomy. Figure 3: View largeDownload slide Patient survival following redo pulmonary endarterectomy. There were 2 perioperative deaths in this series. One patient died in the hospital (patient 12) following a very complicated postoperative course. Before redo surgery, she was dependent on IV prostacyclin infusion and continuous oxygen with a PVR of 897 dyne·s·cm−5 during treatment. She was slow to wake after sedation withdrawal, and a computed tomography brain scan revealed a previously unknown large cystic lesion in the left cerebral hemisphere with significant bleeding around it, creating a mass effect. She was transferred to the hospital for immediate neurosurgical intervention on Day 5, and craniectomy decompression was performed. Subsequently she developed sepsis and renal failure and also had 2 late airway bleeds requiring periods of venovenous extracorporeal membrane oxygenation. She developed a cerebral abscess, and active treatment was withdrawn on Day 57 following further neurological deterioration and the development of multiorgan failure. The second patient underwent a successful surgery, an uneventful initial recovery and was discharged from hospital on postoperative Day 14. Unfortunately, she died on postoperative Day 39 at home due to unexplained circumstances. There have been 2 late deaths in this cohort, both more than 6 years following the redo surgery. DISCUSSION PEA is now established as the guideline-recommended treatment for patients with operable CTEPH and offers excellent symptomatic and prognostic benefits [3]. Our results demonstrate that reoperative PEA is rarely necessary if a good primary operation is performed, but is technically possible, and that good functional and physiological outcomes can be achieved in selected patients. Following PEA, there is an immediate improvement in haemodynamic function with a decrease in pulmonary arterial pressure and PVR. For primary PEA, significant reproducible improvements are reported [16]. A large series from the University of California at San Diego reported a reduction in mean PA pressure from 46.1 ± 11.4 to 28.1 ± 10.1 mmHg and a reduction in PVR from 861.2 ± 446.2 to 294.8 ± 204.2  dyne·s·cm−5 [6]. The haemodynamic improvements observed in our reoperative series are not as significant as with primary surgery but are comparable. The mean cumulative period of deep hypothermic circulatory arrest of 39 min is comparable with the 35 min reported in an international registry for first-time PEA [17]. Despite the magnitude of the intervention, in-hospital mortality rates for first-time PEA range between 2.2% and 4.7% at experienced centres [6, 18]. The in-hospital mortality rate in our series is higher than this, although the number of patients is small and includes 2 patients who had concomitant valve surgery. In general, most reoperative cardiac surgery is associated with a higher perioperative risk [19, 20]. It should be highlighted that patients undergoing reoperative PEA were specially selected and younger than the patients in our overall series (mean age of 40 years compared with 62 years). Therefore, the functional and physiological results achieved in this series will not be generalizable to all patients with residual PH following PEA. Patients undergoing reoperative PEA comprised 2 groups: patients who developed true recurrent CTEPH following a good original surgical clearance and patients in whom it was believed that their presentation was with residual CTEPH following the initial PEA operation. Residual proximal CTEPH is due to a technically incomplete surgical clearance at the primary operation. Three of the 4 patients with residual CTEPH in this series had undergone initial surgery at a low-volume centre. This observation, together with reports confirming improved outcomes, is achieved at high-volume centres and supports the argument that PEA should only be performed by experienced surgeons at high-volume centres [12]. It should be emphasized that the residual PH is relatively common after PEA [9], but this is due to small vessel vasculopathy in the majority of cases, and if a good technical clearance of macroscopic disease has been performed, there is no role for attempted repeat surgery. The remaining patients developed recurrent CTEPH following a good surgical clearance at the first operation. It is not clear whether recurrent CTEPH develops following a subsequent pulmonary embolic event or in situ thrombosis within the endarterectomized pulmonary arterial tree. None of the patients reported a clinical episode of pulmonary embolism, although there is the possibility of an occult event [2, 17]. Reviewing the patients in this series, the majority had at least 1 recognized risk factor for the development of thrombosis or embolic disease. Seven of the 12 patients were known to have a coagulation disorder with a thrombophilic tendency and 4 patients had confirmed antiphospholipid syndrome, which is known to predispose to CTEPH development. In 1 additional patient, the history of poor compliance with anticoagulation was reported. This incidence of thrombotic risk factors of 58% in this series is far higher when compared with a CTEPH population undergoing primary PEA surgery. The European registry reported an incidence of thrombotic risk factors of 27.7% [17]. Hence, the presence of thrombotic risk factors, and APLS in particular, may be a risk factor for recurrent disease [10]. The utility of long-term vena caval filtration in CTEPH is controversial. Five of the patients in this series did not have an IVC filter. Previously, IVC filters were routinely placed in patients due to undergo PEA in keeping with the recommendations on the management of pulmonary thromboembolism [13, 21]. However, large randomized controlled trials demonstrating no significant improvement in survival or episodes of recurrent PE in patients with IVC filters have resulted in reduced interest [22, 23], especially with data revealing late complications of IVC filter placement such as IVC erosion, thrombosis and filter displacement or migration [24]. As a result, most centres no longer routinely use IVC filters in patients undergoing PEA [16]. One previous study has reported on outcomes following reoperative PEA in 1999 [11]. This group similarly observed a high proportion of patients having had an initial operation elsewhere. They observed functional and physiological improvements in patients following reoperative PEA and similar mortality. It is worth noting that more than half of their reoperative patients had previously undergone unilateral PEA at another low-volume centre. Bilateral exploration and dissection are always recommended [16]. This is a single-centre experience, although from a national referral centre with one of the highest PEA volumes worldwide. CTEPH is a relatively rare disease, and recurrent CTEPH is even rarer, so the number of patients reported is necessarily low. The patients included in this report of redo PEA were specially selected and noted to have significant symptomatic and prognostic benefits from repeat surgery. The results reported herein may not be generalizable to older patients or less experienced centres. Although this series confirms reoperative PEA to be technically feasible with good outcomes, the future role for reoperative PEA is unclear with emerging therapies that may allow for less invasive management of patients with recurrent CTEPH. The soluble guanylate cyclase stimulator, Riociguat, has been shown to improve exercise capacity and symptoms in patients with persistent or recurrent PH after PEA [25, 26]. However, it is too early to report whether this drug will lead to improved longer term outcomes for patients with recurrent CTEPH. A second therapy, percutaneous transcatheter BPA, may also have a role to play in recurrent CTEPH [27]. BPA uses a similar technology when compared with coronary angioplasty to dilate obstructed pulmonary arteries using selective angiography. To date, BPA has mostly been utilized in patients deemed inoperable for PEA, but encouraging results have been reported [28, 29], and this modality may become an alternative approach to reoperative PEA for some patients presenting with recurrent CTEPH due to segmental and subsegmental web lesions but would not be suitable for true occlusive disease [30]. It is thus important that patients are assessed by an experienced CTEPH team with the availability of all modalities for CTEPH treatment, so the best decision can be made for each individual patient. 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Additional percutaneous transluminal pulmonary angioplasty for residual or recurrent pulmonary hypertension after pulmonary endarterectomy . Int J Cardiol 2015 ; 183 : 138 – 42 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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Interactive CardioVascular and Thoracic SurgeryOxford University Press

Published: Jan 23, 2018

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