Pulmonary Endarterectomy Improves Dyspnea by the Relief of Dead Space Ventilation

Transcription

1 ORIGINAL ARTICLES: GENERAL THORACIC GENERAL THORACIC SURGERY: The Annals of Thoracic Surgery CME Program is located online at To take the CME activity related to this article, you must have either an STS member or an individual non-member subscription to the journal. GENERAL THORACIC Pulmonary Endarterectomy Improves Dyspnea by the Relief of Dead Space Ventilation Mart N. van der Plas, MS, Herre J. Reesink, MD, PhD, Carel M. Roos, MD, Reindert P. van Steenwijk, MD, Jaap J. Kloek, MD, and Paul Bresser, MD, PhD Departments of Respiratory Medicine and Cardiothoracic Surgery, Academic Medical Centre, University of Amsterdam; and Department of Respiratory Medicine, Onze Lieve Vrouwe Gasthuis, Amsterdam, the Netherlands Background. In chronic thromboembolic pulmonary hypertension (CTEPH), dyspnea is considered to be related to increased dead space ventilation caused by vascular obstruction. Pulmonary endarterectomy releases the thromboembolic obstruction, thereby improving regional pulmonary blood flow. We hypothesized that pulmonary endarterectomy reduces dead space ventilation and that this reduction contributes to attenuation of dyspnea symptoms. Methods. In this follow-up study we assessed dead space ventilation, hemodynamic severity of disease, and symptomatic dyspnea in 54 consecutive CTEPH patients, before and 1 year after pulmonary endarterectomy. Dead space ventilation was calculated using the Bohr-Enghoff equation. Dyspnea was assessed by Borg scores and the New York Heart Association functional classification. Results. Preoperatively, dead space ventilation was increased ( ) and correlated with severity of disease (mean pulmonary artery pressure: r 0.49, p < 0.001; total pulmonary resistance: r 0.53, p < 0.001), and resting (r 0.35, p < 0.05) and post-exercise Borg dyspnea scores (r 0.44, p < 0.01). Postoperatively, dead space ventilation ( , p < 0.001) and dyspnea symptoms decreased significantly. Changes in symptomatic dyspnea were independently associated with changes in pulmonary hemodynamics and absolute dead space. Conclusions. Dead space ventilation in CTEPH is increased and correlates significantly with hemodynamic severity of disease and dyspnea symptoms. Pulmonary endarterectomy decreases dead space ventilation. The induced change in dead space upon surgical removal of chronic thromboembolism contributes to the postoperative recovery of symptomatic dyspnea. (Ann Thorac Surg 2010;89:347 52) 2010 by The Society of Thoracic Surgeons Accepted for publication Aug 3, Address correspondence to Dr van der Plas, Academic Medical Centre, University of Amsterdam, Department of Respiratory Medicine, F5-260, PO Box 22700, Amsterdam, 1100 DE, the Netherlands; m.n.vanderplas@amc.uva.nl. Chronic thromboembolic pulmonary hypertension (CTEPH) results from incomplete resolution of the vascular obstruction associated with pulmonary embolism [1, 2]. Dyspnea is the common presenting symptom in patients with CTEPH [3, 4] and is associated with decreased exercise performance, functional status, and quality of life [5]. In CTEPH, dyspnea is partly considered related to ventilation-perfusion mismatching caused by the thromboembolic obstruction of the pulmonary vascular bed [6]. Dead space ventilation increases as blood flow fails to perfuse the ventilated lung. To compensate for this increase in dead space ventilation, the patient s ventilatory requirement increases, leading to a sensation of dyspnea. So far, however, evidence that dead space ventilation is indeed related to the sensation of dyspnea in CTEPH patients is lacking. Pulmonary endarterectomy (PEA) represents the therapy of choice for CTEPH patients with surgically accessible thrombi [1, 3, 7]. PEA has been found to improve and often normalizes pulmonary hemodynamics and New York Heart Association (NYHA) functional status [7 15]. PEA was also reported to cause improvement in pulmonary perfusion [16] and ventilation-perfusion relationships [17]. Surprisingly, however, most likely due to the low number of patients studied, a significant decrease in dead space ventilation after PEA has not been demonstrated [17]. We hypothesized that PEA leads to reduced dead space ventilation in CTEPH patients and that a decrease in dead space ventilation is associated with improvement of dyspnea symptoms. Therefore, we studied the effect of PEA on dead space ventilation in a larger cohort of consecutive CTEPH patients, and assessed whether the changes in dead space ventilation after PEA were related to the reported changes in symptomatic dyspnea. Material and Methods The research protocol for this study was approved by the local Institutional Review Board and the study was con by The Society of Thoracic Surgeons /10/$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 GENERAL THORACIC 348 VAN DER PLAS ET AL Ann Thorac Surg DEAD SPACE AND DYSPNEA AFTER PEA 2010;89: ducted in accordance with the principles of the Declaration of Helsinki. Patients Patients with operable CTEPH, referred to the Academic Medical Centre of the University of Amsterdam, were considered eligible for this study. Diagnosis of CTEPH was established on the basis of previously reported procedures [18]. Diagnosis and cardiopulmonary hemodynamics were determined by pulmonary angiography and right heart catheterization. Pulmonary hypertension was defined as mean pulmonary artery pressure (mpap) exceeding 25 mm Hg at rest or exceeding 30 mm Hg during a standardized exercise test on a cycle ergometer [19]. All patients received oral anticoagulation therapy for at least 3 months before referral to our hospital. Study Design The follow-up design included assessments performed before and after intervention. Measurement of dead space ventilation and assessment of dyspnea was routine in all patients during the preoperative workup. Postoperative hemodynamics were determined on the first or second day after PEA, before removal of the Swan-Ganz catheter. Dead space ventilation and dyspnea scores were reassessed 1 year after PEA. Dead Space Ventilation Bohr s dead space ventilation (V D /V T ) was measured with the patient supine. Exhaled air was collected using a two-way valve and Douglas bag during 5 minutes of tidal breathing. After 2 minutes, a blood sample was taken from the radial artery. The arterial blood samples and expiratory gases were analyzed (ABL 700, Radiometer, Copenhagen, Denmark), and expiratory volume was measured via a dry gas meter (Mijnhardt, the Netherlands). Absolute dead space (V D ) in milliliters and dead space ventilation (V D /V T ) were calculated using the Bohr-Enghoff equation [20]. AV D /V T of 0.30 or less is considered normal [21]. Because Bohr dead space ventilation is known to be sensitive to shunting, the effect of shunting on the calculated Bohr-Enghoff V D /V T was assessed using the equation for shunt independent V D /V T according to Kuwabara and Duncalf [22]. Dyspnea Assessment Dyspnea was assessed using two different methods: the NYHA functional classification and the Borg score. NYHA functional class is a doctor-reported dyspnea scoring system that quantifies a patient s level of exercise intolerance, expressing the patients (dis)ability to perform everyday activities [23]. Each patient was classified by an independent physician according to the NYHA classification of the World Health Organization before enrolment in the study and at 1 year after PEA. The Borg score is a patient-reported quantitative scaling method of the symptomatic dyspnea [24]. Patients rate their own dyspnea on a scale from 0 (no dyspnea) to 10 (absolutely breathlessness). The Borg score is a momentary measurement, which can change rapidly over time and with activities, allowing the assessment of the effect of exercise on the dyspnea. We assessed the Borg score before and immediately after a 6-minute walk test (6-MWT) that was performed according to the guidelines of the American Thoracic Society (ATS), as previously described [14, 25]. The 6-MWT was introduced in a later stage of the program, so it was performed in 38 consecutive patients only. Surgical Procedure PEA was performed according to the protocol of the University of California, San Diego [3, 26]. PEA is performed through a median sternotomy. After initiation of cardiopulmonary bypass, during deep hypothermia (20 C), the right pulmonary artery is incised where it passes the aorta to the division of the lower lobe arteries. On the left, the incision extends from the main pulmonary artery to the origin of the left upper lobe branch. The organized thromboembolic material is fibrotic and adherent to the vessel wall. An endarterectomy plane is established between the intima and the fibrotic thromboembolic material. The obstructing material is then grasped with a forceps, and distal, circumferential dissection is performed with an aspirating dissector. Circulatory arrest is mandatory to ensure optimal visibility in the presence of usually copious retrograde blood flow from a hypertrophied bronchial circulation. The circulatory arrest period is limited to 20 minutes, with restoration of flow between each arrest. Statistical Analysis Results are expressed as mean standard deviation. All analyses were performed with the SPSS 13.0 software (SPSS, Chicago, IL). Borg score and NYHA functional class were considered as numeric outcome values in a stepwise multivariate linear regression analysis. The Pearson correlation test was used to assess correlations between dead space ventilation, Borg score, NYHA, and the hemodynamic and ventilatory variables and was tested for two-sided significance. Multivariate linear regression analysis of all individual parameters that correlated significantly with the Borg score or the NYHA functional class was performed to calculate the predictive value of different parameters in relation to the Borg score and the NYHA. A paired t test was used to analyze the effect of PEA. A value of p 0.05 was considered statistically significant. Results Patient Characteristics The study included 54 consecutive patients (21 men, 33 women) who were a mean age of (range, years). Most of the 48 patients with pulmonary arterial hypertension at rest had moderate to severe pulmonary hypertension, with a median mpap of 48 mm Hg (range, mm Hg) and a median total pulmonary resistance (TPR) of 800 (dynes s cm 5 (range, 346 to 1875 dynes s cm 5 ). Six additional patients with exercise-

3 Ann Thorac Surg VAN DER PLAS ET AL 2010;89: DEAD SPACE AND DYSPNEA AFTER PEA Table 1. Effect of Pulmonary Endarterectomy (n 47) Variable Before PEA Mean SD After PEA Mean SD p Value mpap, mmhg TPR, dynes s cm V D /V T V D, L V D,alv /V T V D,anat /V T V E, L/min V T, L F R, breaths/min Paco 2, mm Hg Pao 2, mm Hg Petco 2, mm Hg Paetco 2,mmHg Alveolar slope, %CO 2 /L MWD, m (n 38) Borg at rest (n 38) Borg after 6-MWT (n 38) MWD 6-minute walk distance; F R breathing frequency; mpap mean pulmonary artery pressure; Paco 2 arterial pressure of carbon dioxide; Pao 2 arterial oxygen pressure; Petco 2 end tidal pressure of carbon doixide; Paetco 2 arterial-end tidal pressure of carbon dioxide difference; PEA pulmonary endarterectomy; TPR total pulmonary resistance; V D absolute dead space; V D /V T dead space ventilation; V D,alv /V T alveolar dead space ventilation; V D,anat /V T anatomical dead space ventilation; V E expired ventilation; V T tidal volume. induced pulmonary hypertension presented disabling impairment of exercise tolerance and had angiographic evidence for proximal chronic thromboembolic occlusion of at least 2 lobes. Asymptomatic coronary artery disease was present in 2 patients, who had a significant stenosis in the left anterior descending coronary artery and the right coronary artery, respectively. Dead Space Ventilation Preoperatively, V D /V T was elevated and correlated significantly with the hemodynamic severity of disease (mpap: r 0.49; TPR: r 0.53, both p 0.001); in line, in the 6 patients with exercise-induced pulmonary hypertension, V D /V T was compared with in the other patients, which was significantly lower (p 0.005). The shunt independent V D /V T, that was calculated in a subgroup of 22 consecutive patients only did not differ from the Bohr-Enghoff V D /V T, at vs (r 0.93, p 0.001). In line with this observation, the average shunt (Q S /Q T ) remained below the reported critical value of 0.20 ( ) [22]. Preoperative Dyspnea Preoperatively, the mean Borg score at rest in 38 patients (Table 1) was 1.1, ranging from no dyspnea (Borg score 0) to mild dyspnea (Borg score 3). The reported Borg score after exercise (6-MWT) increased to a mean of 4.6 (range 2 to 8), which was significant (p 0.001). Both resting and postexercise Borg scores correlated significantly with V D /V T (r 0.35, p 0.05 and r 0.44, p 0.01, respectively). In contrast, neither resting nor postexercise Borg score correlated with any of the variables reflecting the hemodynamic severity of disease; the best correlation reached r and p for the preexercise Borg score and PVR. The NYHA functional class correlated with dead space ventilation (V D /V T : r 0.34, p 0.05; Fig 1). In contrast to both Borg scores, the NYHA functional class also correlated significantly with the hemodynamic severity of disease (mpap: r 0.55; TPR: r 0.50; both p 0.001). By multivariate linear regression analysis, however, mpap only was shown to be independently associated with the reported NYHA functional class. (model: r , p 0.001; 0.51, p 0.001). Effect of PEA on Dead Space and Dyspnea The effects of PEA are summarized in Table 1. Four patients died postoperatively, 2 because of progressive right heart failure caused by persistent pulmonary hypertension and 2 due to postoperative massive alveolar hemorrhage. In the other 50 patients, mpap and TPR decreased significantly after PEA. However, residual pulmonary hypertension directly after PEA (by definition, mpap 25 mm Hg) was observed in 17 patients, 7 of whom had mpap 30 mm Hg. Follow-up dead space data, 1 year after PEA, were available in 47 of the 50 survivors. Follow-up was too exhaustive for 3 patients who had severe residual pulmonary hypertension. After PEA, dead space ventilation decreased and normalized in 29 patients (62%). Changes ( ) inv D /V T did not correlate with the observed changes in pulmonary hemodynamics ( mpap: r 0.22; TPR: r 0.18). Individual changes in resting Borg score were significantly correlated to changes in dead space ventilation (r 0.39, p 0.05) and absolute dead space (r 0.54, p GENERAL THORACIC Fig 1. Preoperative dead space ventilation (V D /V T ) and mean pulmonary arterial pressure (mpap) against New York Heart Association (NYHA functional class). Error bars show the standard deviation.

4 GENERAL THORACIC 350 VAN DER PLAS ET AL Ann Thorac Surg DEAD SPACE AND DYSPNEA AFTER PEA 2010;89: Fig 2. Change in absolute dead space (Delta V D ) and change in mean pulmonary arterial pressure (Delta mpap) against changes in Borg score at rest (Delta Borg) ) as well as mpap (r 0.41, p 0.02). In a multivariate analysis, V D and mpap were independently associated with patient-reported changes in resting Borg score (Fig 2). The Borg score after exercise decreased significantly, but the observed changes did not correlate with changes in V D /V T,V D, or the hemodynamic severity of disease. Possible relations, however, might have been obscured because the distance walked in the 6-MWT increased significantly in these patients. NYHA functional class improved in 46 of the 50 surviving patients. NYHA remained constant in 4 patients, 2 of whom had residual pulmonary hypertension. All other patients with residual pulmonary hypertension, however, did improve in NYHA functional class. The change in NYHA functional class ( NYHA) 1 year after PEA correlated significantly with the changes in dead space ventilation (r 0.34, p 0.05) and absolute dead space (r 0.64, p 0.001), as well as the hemodynamic improvement noted by mpap (r 0.54, p 0.001), and TPR (r 0.33, p 0.05). By multivariate linear regression analysis V D and mpap were significantly associated with the reported change in NYHA functional class (Model: r , p 0.001; V D : 0.51, p 0.001; mpap: 0.42, p 0.001; Fig 3). Comment In the present study, we demonstrated increased dead space ventilation in patients with CTEPH, which correlated significantly with hemodynamic severity of disease and patient-reported sensations of dyspnea. After PEA, dead space ventilation decreased and normalized in most patients. Moreover, the observed change in absolute dead space after PEA was independently associated with the reported changes in resting Borg score and NYHA functional class. Hence, although the primary objective of PEA is to lower right ventricular afterload, normalization of dead space by surgical removal of chronic thromboembolism contributed to the postoperative recovery of the symptomatic dyspnea. CTEPH results from incomplete resolution of the thromboembolic obstruction of the pulmonary vascular bed. Dead space ventilation increases as blood flow fails to perfuse ventilated lung. As a consequence, expired CO 2 pressure will decrease because air from nonperfused parts of the lung will mix with air from parts with a normal ventilation/perfusion ratio. The Bohr-Enghoff equation uses the difference between arterial and expired Pco 2 to quantify dead space ventilation. A V D /V T of 0.30 or less is considered normal [21], indicating that 30% of the expired air comes from parts of the respiratory system that do not contribute to gas exchange. The higher-than-normal V D /V T found in our study is consistent with a small previous study that reported increased Bohr dead space ventilation in patients with CTEPH [17] but is in contrast with studies that used the inert gas method to quantify dead space [27 30]. The applicability of the inert gas elimination technique in patients with CTEPH can be questioned. Petrini and colleagues [31] showed that the inert gas elimination technique will underestimate dead space when, as in CTEPH, both serial and parallel dead space coexist, because the analysis does not account for reinspiration of gas from the common dead space [31]. A comprehensive cardiorespiratory system model found the Bohr-Enghoff equation, on the other hand, was a reliable tool to estimate dead space ventilation, even when alveolar dead space and ventilation perfusion ratio distribution vary [32]. After PEA, dead space ventilation decreased. Because PEA does not affect the anatomic dead space, the observed decrease in dead space ventilation must be the consequence of a decrease in alveolar dead space. PEA relieves the thromboembolic obstruction of the pulmo- Fig 3. Change in absolute dead space (Delta V D ) and change in mean pulmonary arterial pressure (Delta mpap) against changes in NYHA functional class (Delta NYHA).

5 Ann Thorac Surg VAN DER PLAS ET AL 2010;89: DEAD SPACE AND DYSPNEA AFTER PEA nary vascular bed, thereby reestablishing pulmonary perfusion. In line, earlier studies demonstrated improvements in lung perfusion, ventilation/perfusion relationships, and gas exchange after PEA [16, 17]. In view of our findings, the failure of Kapitan and coworkers [17] to show a significant decrease in dead space ventilation is most likely the consequence of the small number of patients (n 9) studied. Surprisingly, the observed changes in dead space ventilation in our current study were not related to changes in hemodynamic severity of disease. It might be argued that the changes in hemodynamics and dead space ventilation are likely to be interdependent; after all, it is the improved pulmonary perfusion that causes the decrease in dead space ventilation. However, Tanabe and coworkers [16] showed an independent development of hemodynamic improvement and improvements in gas exchange over time after the operation. Where significant hemodynamic improvements were observed shortly after PEA, improvements in gas exchange were obtained over a longer period of 6 to 24 months. This might explain why both hemodynamic changes and changes in dead space ventilation were independently associated with changes in dyspnea in a multivariate analysis. Preoperatively, dyspnea at rest and after submaximal exercise (6-MWT), as assessed by the patient-reported Borg score, correlated with dead space ventilation but not with the hemodynamic severity of disease. Dyspnea includes several qualitatively distinct sensations that can arise from different pathophysiologic mechanisms [33, 34]. Increased dead space ventilation, through failure to perfuse areas of ventilated lung, may give rise to an increased ventilatory demand. This will contribute to an increase in respiratory motor output with a corresponding increase in the sense of effort, that is, the work of breathing. Respiratory-related sensation of dyspnea should, however, always be considered in its context. Symptoms of respiration-related dyspnea are more likely to be reported when hyperpnea occurs at rest, and as such cannot be accounted for by an increase in physical activity [34]. This seems to be consonant with our finding that dead space ventilation is in particular related to resting dyspnea sensation, assessed by the resting Borg score. Although the distance walked in the 6-MWT was previously shown to be significantly correlated to the hemodynamic severity of disease [14], our findings indicate that symptomatic dyspnea after submaximal exercise (6-MWT) appears mostly to be determined by an increased ventilatory demand due to increased dead space ventilation. Preoperatively, NYHA functional class was independently associated with the hemodynamic severity of disease only. In contrast to the Borg score, NYHA functional class classifies dyspnea at distinct levels of exercise and takes into account impaired (maximal) exercise tolerance. As a functional classification, it classifies dyspnea at the level of exercise limitation; as such, it represents the ability of patients to perform exercise. In CTEPH, exercise tolerance appears largely determined by circulatory limitations [14]. Exercise limitation, however, was not the subject of the present study. Previous studies in patients with idiopathic pulmonary arterial hypertension, however, appear to support this hypothesis [6, 35]. Postoperatively, changes in both Borg score at rest and NYHA functional class were related to changes in absolute dead space, but not to changes in dead space ventilation. Interestingly, we observed a decrease in ventilation after PEA, which was shown to be primarily the consequence of a decrease in tidal volume rather than breathing frequency. Dead space ventilation represents absolute dead space expressed as percentage of tidal volume ( V D /V T ); as a consequence of an absolute decrease in tidal volume, the improvement in dead space ventilation induced by PEA will be underestimated. As such, changes in absolute dead space may more closely reflect the increased blood flow through the pulmonary vascular bed after PEA than dead space ventilation. Some methodologic aspects of our study need comment. The lack of hemodynamic data at 1 year after PEA may be considered a limitation. As a result, it is difficult to distinguish the contribution of improved hemodynamics or cardiac function vs improvement in dead space ventilation to symptomatic patient improvement. As mentioned earlier, however, hemodynamic improvement and improvements in gas exchange develop independently over time after PEA. Hemodynamic improvements were observed shortly after PEA, and improvements in gas exchange were obtained over a longer period of 6 to 24 months. The delay in measurements of hemodynamic variables directly after PEA and the assessment of dyspnea and dead space ventilation 1 year later might therefore not have been of major influence. In conclusion, dead space ventilation was increased in CTEPH and decreased significantly after PEA. Preoperatively, sensations of dyspnea as assessed by the patientreported Borg score were primarily associated with increases in dead space ventilation. On the other hand, NYHA functional class, which classifies dyspnea at different levels of exercise and takes impaired exercise tolerance into account, appeared mainly determined by the hemodynamic severity of disease. 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