Long-Term Recovery of Exercise Ability After Pulmonary Endarterectomy for Chronic Thromboembolic Pulmonary Hypertension

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1 Long-Term Recovery of Exercise Ability After Pulmonary Endarterectomy for Chronic Thromboembolic Pulmonary Hypertension Hitoshi Matsuda, MD, Hitoshi Ogino, MD, Kenji Minatoya, MD, Hiroaki Sasaki, MD, Norifumi Nakanishi, MD, Shingo Kyotani, MD, Junjiro Kobayashi, MD, Toshikatsu Yagihara, MD, and Soichiro Kitamura, MD Departments of Cardio-Vascular Surgery, and Cardiology and Pulmonary Circulation, National Cardio-Vascular Center, Suita, Japan Background. The exercise capacity of patients with thromboembolic pulmonary hypertension was investigated to clarify the long-term effects of pulmonary endarterectomy. This capacity was assessed by measuring cardiopulmonary factors during cardiopulmonary exercise testing at the maximal level of exercise and a 6-minute walk test at the submaximal level. Their survival rate was also determined. Methods. We conducted a retrospective review of the clinical records of 102 patients who underwent pulmonary endarterectomy (63 women; median age, 53 years). Results. Eight (7.8%) hospital mortalities were encountered. Three late mortalities due to fulminant hepatitis, breast cancer, and pneumonia in a patient under steroid therapy were unrelated to pulmonary endarterectomy. The actual survival rate including hospital mortalities was 90.9% at 3 years and 84.0% at 5 years. All hemodynamic measurements significantly improved and reached a plateau 1-month after endarterectomy. The cardiopulmonary exercise test at the maximal exercise level revealed that peak oxygen uptake (V O2 ) baseline was ml/min/kg, and at 1-month was ml/min/kg (p ) and ventilatory response to carbon dioxide production (V E -V CO2 ) slope baseline was ml/min/kg, and at 1-month was (p ), which gradually and significantly improved during the first year after endarterectomy (peak V O2, ml/min/kg [p < ] and V E -V CO2 slope, ml/min/kg [p <0.0001]). The 6-minute walk test, which reflects the systemic response at the submaximal level of functional capacity, showed that the walking distance gradually and significantly increased for up to 1 year after endarterectomy (baseline, meters [m]; at 1-month, m; and at 1-year, m [p < ]) and then reached a plateau. Conclusions. After pulmonary endarterectomy, the hemodynamic recovery occurred immediately, and the patients exercise capacity improved during the year. The 6-minute walk test was a good indicator to assess the recovery of exercise capacity. (Ann Thorac Surg 2006;82: ) 2006 by The Society of Thoracic Surgeons The incidence of chronic thromboembolic pulmonary hypertension (CTEPH) after acute pulmonary embolism is not as high as it is estimated at approximately 0.5% to 2.0%. [1] However, according to a historical report on the long-term follow-up of patients with pulmonary thromboembolism, pulmonary hypertension further aggravates patients whose initial mean pulmonary artery pressure (mpap) is more than 30 mm Hg and their 5-year survival rate is less than 50% [2]. The primary surgical treatment of CTEPH is pulmonary endarterectomy (PE) with the number of patients subjected to pulmonary transplantation for CTEPH being very limited at present. [3] After the first planned surgery in 1958 by Hurwitt and colleagues [4], PE became the Accepted for publication March 29, Presented at the Forty-second Annual Meeting of The Society of Thoracic Surgeons, Chicago, IL, Jan 30 Feb 1, Address correspondence to Dr Matsuda, Department of Cardiovascular Surgery, National Cardio-Vascular Center, Fujishirodai, Suita, Osaka, Japan; hitmat@hsp.ncvc.go.jp. established procedure to obtain hemodynamic and respiratory improvement, also for prophylactic reasons. More than one half the PEs have been performed at the University of California, San Diego [1, 5 7]. When the lesions in pulmonary arteries can be surgically approached and PE is successfully performed, the hemodynamic measurements improve; a decrease of mpap and pulmonary vascular resistance together with an increase of cardiac output would be immediately achieved. However, the systemic recovery of chronic patients is delayed due to restrictive pulmonary functional impairment after PE performed under extracorporeal circulation (ECC) and profound hypothermia, reperfusion lung injury, pulmonary artery steal phenomenon, pulmonary arteriovenous shunt, or the declining of other systemic functions [8 10]. To clarify the long-term effects of PE for CTEPH, we investigated patients exercise capacity by measuring cardiopulmonary factors during cardiopulmonary exercise testing at the maximal level of exercise and the 2006 by The Society of Thoracic Surgeons /06/$32.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg MATSUDA ET AL 2006;82: LONG-TERM SURVIVAL AND RECOVERY AFTER PE minute walk test at the submaximal level. Their survival rate was also determined. Patients and Methods Demographics Since May 1993, PE through a median sternotomy under ECC has been adopted in our institution. In this study, the clinical records of 102 patients operated on in the last decade (February 1995 to November 2005) were reviewed. Of them, 63 patients (62%) were women. Their age at surgery ranged from 19 to 79 years (mean standard deviation, years; median, 53 years). Venous thrombosis of the lower extremities was confirmed in 73 patients (72%), and of them 14 patients presented with some kind of coagulation abnormality. In 12 patients, a coagulation abnormality without any sign of venous thrombosis was detected. Also, in 17 patients the cause of CTEPH was not specified. Pulmonary Endarterectomy The operative indications of PE for CTEPH were symptoms within the New York Heart Association class III or class IV, severe pulmonary hypertension defined by mpap 30 mm Hg and pulmonary vascular resistance 300 dynes/sec/cm 5, and intimal lesion of the proximal pulmonary arteries. The location of the intimal lesions was determined by pulmonary arteriography and enhanced computed tomography. The operative procedure was strictly adhered to according to the University of California, San Diego method [11]. Briefly, through a median sternotomy, ECC was established by bi-caval drainage and return through the ascending aorta. The right atrium was routinely opened for the diagnosis and closure of the foramen ovale. The right main pulmonary artery was exposed between the ascending aorta and the superior vena cava. The left main pulmonary artery was exposed by the retraction of the heart in the right-caudal direction. After systemic cooling to 16 C, PE was carried out through a single and longitudinal pulmonary arteriotomy on both main pulmonary arteries. A dissector, which allowed simultaneous suction, was used, and intermittent systemic circulatory arrest for 15 minutes followed by systemic reperfusion for 10 minutes was induced to obtain a bloodless field [7]. When the patient could not be weaned from ECC due to residual pulmonary hypertension or endobronchial bleeding, or both, ECC was replaced with percutaneous extracorporeal membrane oxygenator and the patient was admitted to the intensive care unit. Extracorporeal membrane oxygenator was initiated by femoral venous drainage and femoral arterial return with an artificial lung and a centrifugal pump. Postoperative care was started after the closure of the pulmonary arteriotomy before weaning from ECC. Some modifications that have been adopted in recent years are as follows: (1) to reduce the concentration of vasoconstrictors in the pulmonary artery, such as angiotensin analogues, thromboxane B 2, and 6-keto-prostaglandin F 1 -, dilutional ultrafiltration during the re-warming phase of ECC and modified ultrafiltration after weaning from ECC have been performed in 2004 and 2005, respectively; and (2) in the intensive care unit, a recruitment maneuver (ie, increasing positive end-expiratory pressure to 30 cm H 2 O, followed by high positive endexpiratory pressure [8 to 15 cm H 2 O]), has been used since 2000 to improve oxygenation [12]. Postoperative anticoagulation with oral warfarin was prescribed on a lifelong basis with repeated measures of prothrombin time (international normalized ratio), which was controlled at around 2. Oxygen therapy was suspended when the SaO 2 under room air was confirmed to be more than 90%. Data Collection All data were collected by a retrospective review of the clinical records. Institutional approval for this study was obtained, and each patient in the study consented to the use of the clinical data. Hemodynamic and respiratory measurements: mpap (mm Hg), cardiac index (cardiac index cardiac output [L/min, Fick method]/body surface area [m 2 ]), pulmonary vascular resistance (dynes/sec/cm 5 ), percentage of vital capacity (percentage of vital capacity vital capacity/ predicted forced vital capacity), percentage of forced expiratory volume in 1 second percentage of forced expiratory volume in 1 second/forced vital capacity), diffusing capacity of lung for carbon monoxide (D LCO ) (ml/min/torr), and PaO 2 (mm Hg) were measured or calculated by a standard method. The patients who could tolerate the test were subjected to cardiopulmonary exercise testing at the maximal level of exercise. Briefly, after 1 minute of pedaling without any load, the work rate was increased by 15 Watts/ minute until a symptom-limited maximum. Heart rate, electrocardiography, and blood pressure were monitored. Breath-by-breath gas analysis was performed using an AE280 analyzer (Minato Medical Science, Osaka, Japan). Peak oxygen uptake (V O2 ) was defined as the averaged value during the final 15 seconds of exercise. The ventilatory response to carbon dioxide production (V E -V CO2 ) slope was determined as the linear regression slope of V E and V CO2 from the start of exercise until the respiratory compensation point (the time until which ventilation is stimulated by CO 2 output and end-tidal CO 2 tension begins to decrease) [13]. To evaluate the global and integrated responses of all the systems involved during exercise at the submaximal level of functional capacity, the 6-minute walk test was carried out according to the American Thoracic Society Statement [14]. The distance in meters that a patient could quickly walk along the flat corridor of the hospital ward in a period of 6 minutes was the 6-minute walking distance. The 6-minute walk test was also carried out for patients who could tolerate the test. All measurements and tests were measured before and 1 month after PE during hospitalization. During the follow-up period, all values were obtained when the

3 1340 MATSUDA ET AL Ann Thorac Surg LONG-TERM SURVIVAL AND RECOVERY AFTER PE 2006;82: Table 1. Hemodynamics and Respiratory Function Before and After Pulmonary Endarterectomy Pulmonary Endarterectomy Before After 1 month p Value a 1-year p Value a n mpap (mm Hg) CI (L/min/m 2 ) PVR (dynes/sec/cm 5 ) n VC (% predict) FEV 1.0 (% predict) D LCO (ml/min/torr) a p Value versus before pulmonary endareterectomy (paired Student t test). CI confidence interval; D LCO diffusing capacity of lung for carbon monoxide; FEV 1.0 forced expiratory volume in 1 second. patients agreed to a short hospitalization for the hemodynamic evaluation or the exercise testing, or both. Survival was confirmed by a hospital visit or a direct telephone interview with the patient or the attending physician. When the patient died, the attending physician was directly consulted about the cause of death. Statistical Analysis All values were expressed as the mean the standard deviation. Actual survival rate and other cumulative rates were estimated using the Kaplan Meier method. Baseline data before PE was compared with the data after PE by the paired Student s ttest. Regarding the clinical course, data were compared using one-way analysis of variance for repeated measures, followed by Scheffe s multiple comparison test. Findings with a p value 0.05 were considered as statistically significant. All analyses were performed using SAS statistical software (version 8.02 [SAS Institute Inc., Cary, NC]). Results Morbidity, Mortality, and Survival Nine patients (8.8%) could not be weaned from ECC and support with extracorporeal membrane oxygenator was initiated. Other major morbidities were as follows: reexploration for bleeding in 5 patients (4.9%), pericardial drainage for cardiac tamponade in 4 patients (3.9%), and tracheostomy in 8 patients (7.8%). Eight (7.8%) hospital mortalities due to residual pulmonary hypertension or endobronchial bleeding were encountered. During the follow-up period (0 to 130 months, months), there were 3 late mortalities due to fulminant hepatitis (10 months), breast cancer (55 months), and pneumonia in a patient who had been treated with steroids for systemic lupus erythematosus (58 months). These deaths were all unrelated to pulmonary endarterectomy. The actual survival rate after PE including hospital death was 90.9% at 3 years (83 patients at risk), and 84.0% at 5 years (31 patients at risk). Hemodynamics and Respiratory Function All hemodynamic measurements (see Table 1) (ie, mpap, cardiac index, pulmonary vascular resistance) showed significant improvement at 1 month and at 1year after PE compared with the values before PE. No significant changes were observed from 1 month to 1 year after PE. Among respiratory measures, percentage of vital capacity, and D LCO worsened 1 month after PE, but improved and showed no difference at 1 year after PE compared with the preoperative measures. Percentage of forced expiratory volume in 1 second was not altered 1 month after PE, but then improved significantly 1 year after PE. Blood gas analysis revealed that PaO 2 improved significantly from preoperative values ( mm Hg) to postoperative values ( mm Hg at 1 month, mm Hg at 1 year, mm Hg at 2 years; p ). The time-course analysis showed a significant rise during the postoperative period (p ). Cardiopulmonary Exercise Test and 6-Minute Walk Test Baseline peak V O2 ( ml/min/kg) and V E -V CO2 slope ( ) were significantly improved 1 month after PE (peak V O2, ml/min/kg, V E -V CO2 slope, ). The values at 1 year (peak V O2, ml/min/kg, V E -V CO2 slope, ) and 2 years (peak V O2, ml/min/kg, V E -V CO2 slope, ) Fig 1. Recovery from cardiopulmonary exercise test after pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension. (pre preoperative; post postoperative; V E -V CO2 ventilatory response to carbon dioxide production; V O2 oxygen uptake.)

4 Ann Thorac Surg MATSUDA ET AL 2006;82: LONG-TERM SURVIVAL AND RECOVERY AFTER PE 1341 Fig 2. Recovery from 6-minute walk distance (6MWD) after pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension. (pre preoperative; post postoperative.) after PE also showed significant improvement compared with the values before PE. The time-course analysis showed that peak V O2 and V E -V CO2 slope significantly improved from 1 month to 1 year after PE and that no further improvement was observed at 2 years after PE (Fig 1). Similar improvement was revealed in a 6-minute walking distance. Baseline 6-minute walking distance ( m) significantly increased at 1 month ( m), 1 year ( m), and 2 years ( m) after PE. The increase from 1 month to 1 year after PE was significant, but no increase was found from 1 year to 2 years after PE (Fig 2). Oxygen Therapy Among the 94 patients who survived the operation, oxygen therapy was indicated in 88 patients (93.6%) before PE. The rate of patients under oxygen therapy gradually decreased during the postoperative period to 71.3% at 1 year (54 patients at risk), 36.6% at 3 years (22 patients at risk), and 21.4% at 5 years (6 patients at risk) using the Kaplan-Meier method. Comment Previous reports in the last decade have documented an immediate hemodynamic improvement after PE [15 27]. Other reports regarding the long-term results of hemodynamic changes after PE showed no change during the follow-up period, except for the report of Mayer and colleagues [15], which showed further improvement of mpap and pulmonary vascular resistance between 1 month and 13 to 48 months after PE (Table 2) [8, 24, 28 30]. In this study, we again confirmed that the hemodynamic measurements improved significantly and reached a plateau 1 month after PE. Three reports regarding long-term results of pulmonary function revealed no significant change after PE except for transfer factor of lung for carbon monoxide (T LCO ), which remained unchanged until 1 year [31], improved after PE [24], or deteriorated after PE and then improved during follow-up. [8] In this study, we observed deterioration in percentage of vital capacity and D LCO after PE, but an improvement of percentage of forced expiratory volume in 1 second during the 1-year follow-up. The changes of percentage of vital capacity and D LCO were considered a deterioration after major surgery, and the improvement of percentage of forced expiratory volume in 1 second as the result of the improved exercise capacity due to the restoration of respiratory function. However, these findings were not in agreement with those of previous reports and should be further investigated. The long-term recovery of exercise capacity has been rarely reported. Archibald and colleagues [32] reported good functional recovery based on the fact that 22.4% of the patients could walk indefinitely, and the median distance walked was as long as 5,280 feet. This study did Table 2. Previous Reports of Long-Term Follow-up of Hemodynamic Change After Pulmonary Endarterectomy Pulmonary Endarterectomy Reference No. Before After Follow-up Follow-up Period mpap (mm Hg) Zoia and colleagues, 2002 [24] a yrs D Armini and colleagues, 2000 [28] a yrs Kramm and colleagues, 1999 [29] yrs Mayer and colleagues, 1996 [15] a b 13 mos 4 yrs Fedullo and colleagues, 1995 [30] a mos 2 yrs PVR (dynes/sec/cm 5 ) Zoia and colleagues, 2002 [24] a yrs D Armini and colleagues, 2000 [28] a yrs Kramm and colleagues, 1999 [29] yrs Tanabe and colleagues, 1997 [8] a yrs Mayer and colleagues, 1996 [15] a b 13 mos 4 yrs Fedullo and colleagues, 1995 [30] a mos 2 yrs a Significant decrease versus values before pulmonary endarterectomy; b significant decrease versus values after pulmonary endarterectomy.

5 1342 MATSUDA ET AL Ann Thorac Surg LONG-TERM SURVIVAL AND RECOVERY AFTER PE 2006;82: not show the preoperative values. However, Zoia and colleagues [24] showed a significant increase of the total distance covered until exercise interruption at 2 years after PE. The exercise capacity (peak V O2 ) and the ventilation efficiency (V E -V CO2 slope) at the maximal level of exercise continued to recover until 1 year after PE. The 6-minute walk test also revealed the 6-minute walking distance increased during the year after PE. The correspondence between these 2 exercise tests at different exercise levels still remains to be discussed [13, 33, 34]. However, 6-minute walking distance should be a good indicator of recovery, because it reflects a systemic response, including the pulmonary and cardiovascular systems, systemic circulation, peripheral circulation, blood, neuromuscular units, and muscle metabolism at the submaximal level of functional capacity [14]. The discrepancy in the time course of recovery between hemodynamic data and exercise data led us to speculate that the recovery of exercise capacity was not an immediate result of only hemodynamic recovery. The hypoxemia associated with CTEPH is the consequence of a ventilation and perfusion abnormality, with the hypoxic effect being considerably amplified by a lowered PvO 2, and PE improves gas exchange both by improving the ventilation and perfusion relationship and increasing cardiac output [8, 31, 35]. However, several postoperative adverse effects on the ventilation and perfusion relationship have been reported: (1) preoperative disuse syndrome; (2) restrictive pulmonary functional impairment due to major surgery; (3) diffusion limitation due to reperfusion lung injury (pulmonary edema); (4) pulmonary steal phenomenon, which is defined as the heterogeneous perfusion consisting of hyperperfused areas, which had been endarterectomized, as well as new hypoperfused areas that had not been surgically approached; and (5) a pulmonary arteriovenous shunt due to pulmonary infarction, atelectasis, opening of pre-existing pulmonary arterial venous anastomoses with PH, and patent foramen ovale [8 10, 31, 36]. Among these effects, the recovery from the systemic disuse syndrome and the elimination of the pulmonary steal phenomenon or the pulmonary arteriovenous shunt, or both might delay or need a long time to be restored through rehabilitation with daily exercises. This study has several limitations that should be taken into account in future investigations. The study design was a retrospective review of clinical records and the selection of patients for the long-term follow-up depended on various social reasons, such as geographically and the patient s willingness to undergo a re-evaluation. The number of patients was mid-size and was probably insufficient to consider the intraoperative classification of pulmonary thromboembolism [26, 37]. A previous report from the same institution showed that peak V O2 and V E -V CO2 slope in 20 patients of the same study population improved 4 months after PE [38]. As most data of other patients were not obtained at 4 months after PE, the data obtained at 1 year after PE were adopted in the current study. The possibility that the values were found to have reached a plateau at 1 year after PE might have reached it before that time point should be re-evaluated after accumulating sufficient data at 4 months after PE. In conclusion, after pulmonary endarterectomy, hemodynamic recovery was immediately obtained, and exercise capacity improved within 1 year. The 6-minute walk test was a good indicator of the recovery of exercise capacity. In addition to the three major aims of PE, namely, hemodynamic goal, restoration of respiratory function, and prophylaxis [1], long-term recovery of exercise capacity and a high survival rate can be expected based on the attainments of these goals. References 1. Thistlethwaite PA, Madani M, Jamieson SW. Pulmonary thromboendarterectomy surgery. Cardiol Clin 2004;22: 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. 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