Frank C. Sciurba Sanjay A. Patel
Division of Pulmonary and Critical Care Medicine, University of Pittsburgh, Pa., USA
Summary
Lung volume reduction surgery (LVRS) remains a contro-versial intervention for patients with advanced emphysema due to the inconsistent outcome and poorly defined selection crite-ria. In selected patients, LVRS can elicit significant functional improvements and partial reversal of the pathophysiologic cas-cade has been observed. Improvements in lung elastic recoil and more appropriate resizing of the lung relative to the chest wall translate into improved inspiratory and expiratory airflow with less dynamic hyperinflation during exercise. Further im-provements in gas exchange are attributed to improved regional V-Q matching and increases in mixed venous oxygen saturation. Improvements in cardiovascular and peripheral muscle function may complement the pulmonary effects to even further impact on exercise performance. Parameters derived from exercise testing may contribute significantly to outcome and risk stratification since they integrate the func-tional impact of complex changes in many interrelated physio-logic domains. Results from the ongoing NETT should clarify many of these unresolved issues.
Lung Volume Reduction Surgery Background Nearly 8 years after its reintroduction, lung volume reduction surgery (LVRS) remains a highly controversial intervention for patients with advanced emphysema [Cooper et al., 1995; Sciurba, 1997; Utz et al, 1998; Draz-en, 2001]. Various surgical approaches have included uni-lateral stapling and laser techniques; however, a biuni-lateral
stapling approach involving resection of 20–30% of the diseased lung through either a thoracoscopic or median sternotomy incision has resulted in the greatest degree of spirometric improvement [McKenna et al., 1996; Kotloff et al., 1996; Cooper et al., 1996]. While short-term results of this procedure have been promising, yielding improve-ments in FEV1 of 27–96%, its widespread acceptance has been tempered for several reasons:
(a) In most reported series, follow-up rates beyond 3–6 months are low. Thus, results may be overly optimistic, since those who did not return for follow-up may have poorer outcomes than those who did [Health Technology Assessment, 1996].
(b) The mortality rate in general practice appeared to be considerably higher than the 3–10% rate reported in the literature [Keenan et al., 1996; Mckenna et al., 1996;
Cooper et al., 1996; Miller et al., 1996]. A report issued by the Center for Health Care Technology determined the 3-to 12-month pos3-toperative mortality rate using the objec-tive social security death index for all Medicare recipients who were billed for the procedure to be in the 14–23%
range [Health Technology Assessment, 1996].
(c) The mean values of functional improvement re-ported in the literature make it impossible to distinguish a response due to a large proportion of patients with clini-cally significant improvements from one due to a small number of patients with disproportionately large im-provements.
(d) Current selection criteria have failed to consistently distinguish patients with acceptable risk of morbidity and mortality or those with a likelihood of physiologic re-sponse to the intervention.
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(e) Commonly reported simple physiologic outcome parameters such as FEV1 may not reflect true functional improvement following LVRS, which potentially has op-posing effects on pulmonary mechanics and vasculature.
Integrative functional measurements such as exercise test-ing are more likely to reflect true physiologic improve-ments, but have only been reported as short term results in small subsets of patients.
(f) The interpretation of long-term functional and mor-tality data in non-randomized trials is dependent on com-parisons to historical controls. Depending on the center, only 20–40% of patients referred for evaluation are ulti-mately accepted for surgery; such preselection creates a subgroup which is not easily compared to existing popula-tions in the literature.
(g) Randomized controlled trials in the literature only report short term data and were too small to identify base-line characteristics predictive of response [Criner et al., 1999; Geddes et al., 2000; Pompeo et al., 2000].
Such gaps in the existing literature are being addressed by the National Emphysema Treatment Trial (NETT) [The National Emphysema Treatment Trial Research Group, 1999]. This multicenter trial is a cooperative effort of the National Institutes of Health and the Agency for Medicare and Medicaid (formerly the Health Care Financing Administration). In this trial, subjects are ran-domized to either maximal medical therapy including for-mal pulmonary rehabilitation or LVRS with pulmonary rehabilitation. The primary outcome parameters are mor-tality and maximal exercise watts measured during symp-tom-limited incremental cycle ergometry. 1,100 patients from 17 centers have been randomized into this trial as of October 2001. A subgroup, representing 14% of subjects randomized, has been identified as having excessive post-operative mortality and will be discussed below [NETT Research Group, 2001]. Ongoing data collection and analysis should identify predictors of long-term function-al exercise responses and mortfunction-ality in the remaining 86%
of subjects. It is anticipated that preoperative parameters identifying a disproportionately low risk group will even-tually also be defined.
Rationale for the Use of Exercise Testing in the Evaluation of LVRS
Various physiologic parameters, including expiratory flow rate, end-expiratory lung volume, pulmonary vascu-lar resistance, gas exchange and peripheral muscle condi-tioning can be affected independently and may even
respond in contradictory directions after LVRS. No single physiologic attribute adequately reflects the clinical re-sponse to LVRS. Thus, the primary outcome parameter following LVRS should be able to represent this com-plexity of physiologic changes in an integrated fashion.
While subjective questionnaires assessing symptoms or health-related quality of life may loosely perform this function, we will restrict the discussion to exercise testing.
Various investigators have used the 6-min walk test (6MWT) or maximal incremental cardiopulmonary exer-cise testing (CPX) as tools to evaluate LVRS response.
Although most studies have used 6MWT for functional assessment, walk distance correlates modestly, at best, with measures of dyspnea, quality of life or other objec-tive functional measures such as CPX [Leyenson et al., 2000; Ferguson et al., 1998]. Keller et al. [1997] reported that of exercise measures, VE/MVV best correlated with reductions in dyspnea and that 6MWT was not a corre-late. Similarly, another study found that improvement in maximum oxygen consumption (VO2), but not 6MWT, correlated with improvement in dyspnea (r2 = 0.59, p ! 0.01) and quality of life measures of physical function (SF-36) (r2 = 0.31) [Ferguson et al., 1998].
The LVRS experience at our institution suggests that improvements in spirometry and lung volumes account for much more of the variability (r2 = 0.42) in exercise watts response, but much less of the variability in 6MWT response (r2 = 0.21), in optimal multiple regression mod-els. Thus, CPX may reflect true physiologic improve-ments better than 6MWT and may be a more meaningful outcome parameter for LVRS.
Physiological Response to Lung Volume Reduction Surgery
Elucidation of the basic physiologic mechanisms of improvement following LVRS not only enhances the scientific validity of the surgery, but may enable us to identify and optimize selection criteria which predict those changes. In this regard, cardiopulmonary exercise performance, in addition to reflecting the integrated ef-fects of changes in multiple underlying mechanisms, can further elucidate the mechanisms of improvement after LVRS.
Lung and Chest Wall Mechanics during Rest and Exertion
The early hypothesis of Brantigan suggested that LVRS, as was reported in the 1960s, results in partial
res-Functional Evaluation in Lung Volume Reduction Surgery
175 Fig. 1. Left panel: Static recoil (Pel)-volume and flow-volume relationships for a 58-year-old man before (open circles) and after (closed circles) bilateral LVRS are shown. Note the higher flows and shift to lower lung volumes in the flow-volume loop. Right panel: Maximal flow-static recoil (MFSR) curve is plotted by matching iso-volume values for flow and Pel from the plots on the left. The MFSR curve suggests the improvement in flow is almost entirely attribut-able to increased lung recoil.
toration of the diminished lung elastic recoil pressure found in advanced emphysema. Experiments at that time documenting improved airway conductance/volume rela-tionship following this procedure also attributed these improvements to renewed tethering of the airways in association with changes in lung recoil [Rogers et al., 1968]. Lung resection, on the other hand, in the form of lobectomy for carcinoma, while reducing lung volume, did not elicit similar changes in conductance because of simultaneous removal of large conducting airways.
More recent reports have documented an increase in maximal static recoil pressure (Pel-max) and the coeffi-cient of retraction (Pel-max/TLC) after LVRS, further supporting Brantigan’s hypothesis. In one series of 20 consecutive patients, the coefficient of retraction in-creased from 1.3 B 0.6 to 1.8 B 0.8 cm H2O 3 months following either unilateral or bilateral LVRS [Sciurba, 1996]. This change reflects an improvement in the
effec-tive driving pressure generating expiratory flow, and should result in proportional improvements in air flow at all lung volumes and consequent reductions in lung hy-perinflation. While the change in elastic recoil measure-ments did not significantly correlate with degree of func-tional improvement, there was a significantly greater im-provement in walking distance in the 16 patients with improved Pel (+146 ft) compared to the 4 patients without improvement (–102 ft).
A subsequent study evaluating the bilateral procedure has confirmed improvements in maximal lung recoil pres-sure. Conductance of the upstream airway segment (maxi-mal flow/Pel) was also analyzed and improved significant-ly in this group [Gelb et al., 1996b]. Flow from maximal expiratory maneuvers was compared to the static recoil pressure curves at constant volume (MFSR plot) using the techniques of Black and Hyatt [Black et al., 1972] (fig. 1).
Inspection of the MFSR curves in this paper reveals 9 of
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12 patients with very little shift or change in slope of the MFSR line but, rather, extension of the pre-operative line to higher recoil pressures and thus higher flows. These findings confirm that the increased expiratory flow rates in this series were largely related to improvements in lung elastic recoil. Interestingly, 3 patients, in addition to improving Pel, had significant increases in slope and upward shifts in the MFSR line, suggesting improved air-way conductance independent of global improvements in lung elastic recoil (fig. 1). This small subset of patients demonstrating a marked shift in the MFSR slope follow-ing surgery may represent patients with significant re-expansion of regionally compressed airways.
Thus ‘volume reduction’ is, in part, due to more com-plete expiratory flow attributable to a global increase in lung elastic recoil. On the other hand, regions of lung ‘het-erogeneity’ are often specifically targeted which have such long time constants that they simply act as space, occupy-ing residual volume. Resection of these extremely slow lung units (in contrast to units with more average time constants, as is likely with diffuse emphysema) should reduce lung volume disproportionately to and possibly independently of increases in global lung elastic recoil.
This concept is highlighted in an elegant model by Fessler and Permutt [1998] which, in essence, attributes the improvements following LVRS to a more appropriate resizing of the lung to the chest wall. In this model, the dominant impact of LVRS lies in the relatively greater reduction in RV compared to TLC, and a consequent increase in VC. In their model, this increase in VC is the dominant factor effecting an increase in FEV1. This is in accordance with the minimal change in the FEV1/FVC ratio observed in most patients following LVRS. This model exemplifies the importance of elucidating mecha-nisms, as it predicts that the best responders to LVRS will be those with the highest pre-operative RV/TLC, a find-ing which has been subsequently confirmed [Patel et al., 2001; Ingenito et al., 2001; Flaherty et al., 2001].
While the changes in lung mechanics discussed above represent the primary mechanical effects of LVRS, the consequent ‘volume reduction’ may secondarily elicit considerable improvement in inspiratory muscle function as well. A less hyperinflated chest wall returns to a more compliant region of its pressuvolume curve and re-duces the work of the respiratory muscles [Gelb et al., 1996a]. Partial normalization of the end-expiratory dia-phragmatic curvature and restoration of the normal buck-et handle configuration of the rib cage further contribute to restoration of respiratory muscle efficiency [Lando et al., 1999; Bellemare et al., 2001].
Accordingly, significant increases in maximal inspira-tory pressure and trans-diaphragmatic pressure (Pdi) of 25–50% have been documented following LVRS [Tesch-ler et al., 1996; Sciurba, 1997; Laghi et al., 1998; Criner et al., 1998]. Other reports have provided evidence that intrinsic positive end-expiratory pressure may decrease following LVRS, further decreasing the oxygen cost of breathing [Gelb et al., 1996a, Sciurba et al., 1996a, b;
Lahrmann et al., 1999; Tschernko et al., 1997]. Improved neuro-mechanical coupling of the diaphragm, as indi-cated by increases in twitch Pdi with phrenic nerve stimu-lation, have also been documented following LVRS [Laghi et al., 1998, Criner et al., 1998].
In summary, changes in resting pulmonary mechanics and diaphragmatic function translate into improved air-flow with less hyperinflation during exertion. Figure 2 illustrates the impact of LVRS on minute ventilation and respiratory timing following LVRS during exercise which has been found by many investigators [Sciurba, 1997, Benditt et al., 1997b, Martinez et al., 1997; Tschernko et al., 1997; Keller et al., 1997; Criner et al., 1999; Ferguson et al., 1998; Stammberger et al., 1998]. At iso-workloads patients have a slower respiratory rate with significantly greater tidal volumes and associated improved inspirato-ry flow rates. This results in significantly lower Borg dys-pnea ratings at equivalent workloads. At maximal exer-tion, respiratory rate is similar before and after surgery, but tidal volume and minute ventilation are significantly increased. The improved tidal volumes observed may be due to a reduction in dynamic hyperinflation associated with the significantly greater inspiratory and expiratory flow rates. Furthermore, the changes in diaphragm func-tion described above result in relatively greater contribu-tions of the diaphragm to tidal breathing at rest and dur-ing exertion (fig. 3), and correlate with improvements in exercise performance [Benditt et al., 1997b; Martinez et al., 1997; Laghi et al., 1998].
Impact of LVRS on Resting and Exercise Gas Exchange
While resting and exercise arterial oxygenation has been shown to improve following bilateral LVRS, the improvement is variable [Christensen et al., 1999] and the precise mechanisms of improvement are unclear. Poten-tial mechanisms include global increases in alveolar venti-lation, regional improvements in V/Q matching due to local re-expansion of less diseased but previously poorly ventilated lung, and improved mixed venous saturation secondary to improved right or left heart function.
Functional Evaluation in Lung Volume Reduction Surgery
177 Fig. 2. Effect of LVRS on minute volume (VE), tidal volume (VT), inspiratory-expiratory ratios in 16 patients during incremental cycle ergometry before (solid lines) and 3 months after (dashed lines) LVRS. Left panel: Postoperatively, at iso-workloads, patients demonstrate a slower respiratory rate (longer respiratory cycle duration) with greater tidal volume and greater inspiratory flow rates (VT/TI) in association with lower Borg dyspnea ratings. Right panel: At maximal exercise, respiratory rate is similar after LVRS, but VE and VT are significantly increased, in association with lower Borg dyspnea ratings despite higher levels of work achieved. Adapted from Sciurba [1997].
Fig. 3. Gastric pressure (Pga) vs. esophageal pressure (Pes) at rest and isowatt exercise, before (dashed lines) and after LVRS (solid lines). The pressure changes reflect the dramatic reduction in Pga at end expiration during exertion following LVRS thought to be related to excessive activation of the abdominal muscles of expiration associated with severe COPD. Adapted from Benditt et al. [1997].
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The significant improvement in resting arterial PaCO2 described in most series may be the result of improved alveolar ventilation due to improved pulmonary mechan-ics, but reductions in dead space ventilation from removal of partially ventilated bullae and increases in capillary flow to high V/Q areas are likely mechanisms as well.
After LVRS, arterial PaO2 is higher during isowatt exertion, but there may be no significant differences at maximal exertion. Similarly, resting and exercise PaCO2 decreases due to both an increase in alveolar ventilation and reduction in proportion of dead space ventilation [Sciurba et al., 1996a; Ferguson et al., 1998; Keller et al., 1997].
Pulmonary Vascular Function at Rest and with Exertion
The great majority of research on LVRS has been directed at the pulmonary mechanical effects of the sur-gery. But very little attention has been directed at its potential impact on pulmonary vascular function, which may independently influence exercise tolerance and sur-vival. On the one hand, resection of perfused lung could further decrease vascular reserve. On the other hand, a decrease in vascular resistance may occur through recruit-ment of vessels in re-expanding lung tissue or through improved elastic recoil, which may increase radial trac-tion on extraalveolar vessels.
Significant increases in right-ventricular fractional area of contraction have been reported following LVRS using echocardiographic techniques, suggesting improve-ments in pulmonary vascular function [Sciurba et al., 1996b]. Furthermore, reduced end-expiratory esophageal pressure, and hence pericardial pressure, may improve right- and left-ventricular filling and cardiac output.
LVRS-mediated reductions in exercise-induced dynamic hyperinflation [Martinez et al., 1997; O’Donnell et al., 1996] may diminish rises in intrathoracic pressure and, therefore, pulmonary vascular resistance elevations dur-ing exertion.
However, hemodynamic studies on patients before and after LVRS show mixed results. This is not surprising given the potentially opposing effects described. Some reports, including one study evaluating patients with more diffuse disease, raise concern about postoperative increases in pulmonary vascular resistance both at rest and with exertion [Weg et al., 1999; Haniuda et al., 2000].
Conversely, another study revealed a reduction in heart rate at iso-workloads following LVRS and thus increased oxygen pulse [Benditt et al., 1997a], suggesting that car-diovascular function improves on average following
LVRS. However, two studies found no effect on pulmo-nary artery pressure after LVRS [Thurnheer et al., 1998;
Oswald-Mammosser et al., 1998].
It is clear, however, from the above studies that indi-vidual patients may demonstrate deterioration in pulmo-nary vascular function. Unfortunately, at present, preop-erative identification of these individuals is not possible.
Furthermore, it is likely that such effects would impact negatively on exercise performance independently of ob-served pulmonary mechanical improvements. Further re-search including results of the NETT should clarify these issues.
Peripheral Muscle Conditioning
Another potentially important mechanism of improve-ment is facilitation of cardiovascular and peripheral mus-cle training, enabled by improvements in pulmonary me-chanical factors. Significant increases in thigh muscle cross-sectional area and patient weight occur following LVRS, and these changes correlate with improvements in 6MWT and DLCO [Donahoe et al., 1996; Christensen et al., 1999].
Following LVRS, patients may have profound residual deconditioning from chronic inactivity. With a successful surgical outcome, this deconditioning may become the limiting factor to exertion if ventilatory mechanical limi-tation no longer exists (fig. 4). The extent to which these severely deconditioned and potentially myopathic pa-tients can recover following aggressive rehabilitation is uncertain. It is likely, however, that the magnitude of improvements in functional exercise tolerance lags be-hind the improvements in pulmonary mechanics follow-ing LVRS, as the elimination of the mechanical ventilato-ry limitation re-enables peripheral muscle training poten-tial. Furthermore, if this occurs, exercise function may be maintained above pre-operative levels, even while pulmo-nary function parameters decline [Flaherty et al., 2001].
Clinical Utility of Exercise Testing Assessing the Response to LVRS
LVRS has improved pulmonary function [Cooper et al., 1996], exercise capacity [Keller et al., 1997; Martinez et al., 1997; Benditt et al., 1997a; Ferguson et al., 1998;
LVRS has improved pulmonary function [Cooper et al., 1996], exercise capacity [Keller et al., 1997; Martinez et al., 1997; Benditt et al., 1997a; Ferguson et al., 1998;