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Eur J Cardiothorac Surg 2000;17:666-672
© 2000 Elsevier Science NL

Is long-term functional outcome after lung volume reduction surgery predictable?

Wilfried Wissera, Ömer Senbaklavacia, Cenk Özpekera, Meinhard Plonerb, Theo Wankec, Edda Tschernkod, Ernst Wolnera, Walter Klepetkoa

a Department of Cardio-thoracic Surgery, University of Vienna, Währinger Gürtel 18–20, 1090 Vienna, Austria
b Institute of Medical Computer Science, University of Vienna, Währinger Gürtel 18–20, 1090 Vienna, Austria
c Department of Pulmonology, Lainz Hospital, Vienna, Austria
d Department of Anesthesiology, University of Vienna, Währinger Gürtel 18–20, 1090 Vienna, Austria

Corresponding author. Tel.: +43-1-40400-5620; fax: +43-1-40400-5642
e-mail: wilfried.wisser{at}akh-wien.ac.at


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 Appendix A Conference discussion
 References
 
Objective: The aim of this retrospective study was to analyze which preoperative parameters might predict a persistent improvement in forced expiratory volume in 1 s (FeV1) 1 year after surgery. Methods: Seventy consecutive lung volume reduction surgery (LVRS) patients (age, 56.5±1.2 years) with a follow-up period of at least 1 year were analyzed (from September 1994 to September 1997). The patients were described by lung function tests, blood gas analysis, ventilatory mechanics (intrinsic positive endexpiratory pressure (PEEP)) and morphometric data (degree of heterogeneity, DHG; degree of hyperinflation, DHI; severity of parenchymal destruction, SPD) preoperatively. Based on the postoperative course of FeV1 (percentual increase compared with preoperative values, % increase), patients were divided into four groups: group A, (n=21) no improvement (FeV1<=20% increase); group B, (n=10) FeV1>=20% increase, which declined to preoperative values after 1 year; group C, (n=18) FeV1, 20–40% increase, sustaining at 1 year; group D, (n=21) FeV1>=40% increase, sustaining at 1 year. The statistics comprised of analysis of variance (ANOVA) and chi-square testing, with values presented as means±SEM. Results: No differences were found for lung function parameters (FeV1: 27.7±2.7, 26.0±2.5, 23.9±2.2 and 23.9±1.9% predicted, in groups A, B, C and D, respectively). Arterial blood gas levels preoperatively revealed significant differences between the groups; the arterial pO2 was 66.2±1.2 mmHg in groups A+B compared with 61.8±1.5 mmHg in groups C+D (P=0.030). The arterial pCO2 was 39.2±1.1 mmHg in groups A+B compared with 43.3±1.5 mmHg in groups C+D (P=0.038). The morphometric data had a strong trend towards higher heterogeneity in groups C and D. Marked DHI was found in 59 and 81% of patients in groups A+B versus C+D, respectively (P=0.121). Marked DHG was present in 22 and 54% of patients in groups A+B versus C+D, respectively (P=0.010). Conclusion: Preoperative arterial pO2 and pCO2, and the DHG are predictors for long-term benefit after LVRS with regard to the FeV1, 1 year postoperatively.

Key Words: Lung volume reduction surgery • Diffuse emphysema • Arterial blood gas levels


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 Appendix A Conference discussion
 References
 
Lung volume reduction surgery (LVRS) is an accepted therapeutic option for patients with end stage pulmonary emphysema. During the first years of the rediscovery of this treatment [1,2], the surgical concept was established [3–7]. In recent years, several preoperative parameters were studied, redefining the inclusion criteria for this procedure [8,9]. With a couple of preoperative measurements, it is possible to predict the conceivable initial functional improvement of an individual patient quite accurately. The functional improvement usually peaks around 3–6 months after surgery [10]. However, during long-term follow-up, some patients deteriorate rather rapidly in terms of lung function, whereas others seem to benefit from the operation over a longer period of time. Why some patients deteriorate more rapidly than others is still unclear. It is even more interesting, in which patients, a long-term benefit after LVRS can be expected.

Therefore, a retrospective study was conducted, to analyze if there are preoperative parameters which might predict a persistent improvement in the forced expiratory volume in 1 s (FeV1) 1 year after surgery.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 Appendix A Conference discussion
 References
 
2.1. Patient demographics
Seventy consecutive LVRS patients (42 male, 60%) with a follow-up period of at least 1 year, who underwent LVRS between September 1994 and September 1997 at our institution, were included in the study. The mean age was 56.5±1.2 years. Thirteen patients (19%) suffered from alpha-1-antitrypsin deficiency, and 26 patients (37%) had a history of smoking. For other preoperative morphometric and functional data, refer to Table 1.


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  		Table 1. Preoperative functional and morphometric data of all 70 patients

 
2.2. Operative procedure
Nine patients underwent LVRS by sternotomy. In 40 patients, surgery was carried out by videoendoscopic approach, in 15 patients, by thoracotomy. In six patients, a thoracotomy on one side and videoendoscopic approach on the contralateral side was used. Under single-lung ventilation of the contralateral side, multiple extraanatomical wedge resections of the most destroyed areas of the lung were performed, as described previously [6,11]. The site of the resection was chosen according to the preoperative morphological workup and the intraoperative aspect. The side of the most destroyed areas was done first. The goal was to achieve a well-shaped lung surface, thus avoiding major airspaces in the thoracic cavity.

2.3. Assessment and study groups
All patients had a complete clinical, functional and morphometric workup preoperatively, 1, 3 and 6 months postoperatively, and every 6 months thereafter [6]. Pulmonary function tests were performed, measuring the FeV1 and total lung capacity (TLC). In addition, arterial blood gas testing and measurement of the work of breathing and intrinsic PEEP [12–14] were performed. The morphometric assessment was performed by spiral CT scan with density mask imaging. The degree of heterogeneity (DHG), degree of hyperinflation (DHI) and the severity of parenchymal destruction (SPD) were calculated from the images as described previously [15]. In cases of suspected pulmonary hypertension, right heart catheterization was performed.

The influence of these parameters upon the course of FeV1 throughout the whole follow-up period was studied. Based on the postoperative course of FeV1 (percentual increase compared with preoperative values, % increase), patients were divided into four groups:

2.4. Statistics
Differences of preoperative data between the groups A+B and C+D were analyzed using Fisher's exact test for categorical variables and the Student's t-test for continuous variables. Before doing the latter, a Kolmogorov–Smirnov-test assured that the data were not significantly different from the normal distribution.

The analysis of variance (ANOVA) test was used for the analysis of improvements after LVRS.

In stepwise multivariate analyses, variables passing the significance level of 0.20 in the univariate result were included. A logistic regression extracts significant factors for discriminating between the two groups, A+B and C+D.

A P-value of <0.05 was chosen as significant. All values are expressed as means±SEM.


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 Appendix A Conference discussion
 References
 
In all 70 patients, the mean FEV1 significantly increased from 24.7±0.9% predicted preoperatively to 34.7±1.7 and 33.2±1.7% predicted after 3 and 6 months, respectively (P=0.001; Fig. 1). A similar trend was observed for pO2 and pCO2 levels (Table 2). Patients in group A had no improvement in FeV1 (25.2±1.6% predicted preoperatively; 26.6±1.5 and 25.6±1.9% predicted after 3 and 6 months, respectively). Patients in group B initially improved significantly (27.2±2.8% predicted preoperatively, 36.0±4.4% predicted 3 months postoperatively; P=0.009), but deteriorated to preoperative values after 1 year (27.6±3.4% predicted). In contrast, patients in groups C (23.5±2.1, 35.2±2.8 and 32.3±2.6% predicted, preoperatively, 3 and 12 months after surgery, respectively) and D (24.3±1.9, 42.7±3.8 and 41.4±4.0% predicted, preoperatively, 3 and 12 months after surgery, respectively) showed a sustaining improvement throughout the first postoperative year (Fig. 2).



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  		Fig. 1. Course of FeV1 in all 70 patients.

 

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  		Table 2. Course of FeV1 and arterial pO2 within the first postoperative year

 


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  		Fig. 2. Course of FeV1 split by subgroups.

 
The surgical approaches in the four groups were similar, as shown in Table 3.


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  		Table 3. Type of surgical approach split by groupsa

 
During the late follow-up period (after the first 12 months postoperatively), nine patients died (one, two, three and three patients in the groups A, B, C and D, respectively). In addition, four patients were lost to follow-up between 18 and 36 months postoperatively (three patients in group A and one patient in group D). Eighteen patients underwent lung transplantation between 13 and 38 months postoperatively (eight, three, four and three patients in groups A, B, C and D, respectively).

3.1. Analysis of preoperative parameters (Table 4)
3.1.1. Demographic data
No difference was detected for any demographic parameter.


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  		Table 4. Preoperative parameters of all patients split by the functional coursea

 
3.1.2. Lung function parameters
No difference was detected for FeV1, vital capacity (VC), residual volume (RV) and TLC between the four groups. Nevertheless, a tendency towards more compromised lung function in groups C and D was detected. The TLC was 142.3±4.3% predicted in groups C+D compared with 135.2±2.8% predicted in groups A+B. The vital capacity was 54.7±2.7% predicted in groups C+D compared with 57.7±2.8% predicted in groups A+B.

3.1.3. Arterial blood gas
In contrast, blood gas levels showed a strong significant difference favouring the patients with more compromised gas exchange. Patients in groups C+D had a pO2 of 61.8±1.5 mmHg preoperatively, compared with 66.2±1.2 mmHg in groups A+B (P=0.030). The preoperative pCO2 level of patients in groups C+D was 43.3±1.5 mmHg compared with 39.2±1.1 mmHg in groups A+B (P=0.038).

3.1.4. Ventilatory mechanics
The ventilatory mechanics in terms of intrinsic PEEP and work of breathing were similar between the groups. The intrinsic PEEP was 5.0±0.6 cmH2O in groups C+D, compared with 4.5±0.5 cmH2O in groups A+B. The work of breathing was 1.6±0.1 J/l in groups C+D compared with 1.5±0.1 J/l in groups A+B.

3.1.5. Morphometric data
No significant difference was found for the SPD and the degree of impairment in diaphragmatic movement (DIDM), respectively. Although the DHI showed no significance between the groups, a tendency was detectable. Fifty-nine percent of patients in groups A+B and 81% of patients in groups C+D presented with marked DHI (DHI 3 and 4; P=0.121). A significant difference between the groups A+B and C+D was found for the DHG. Of the patients in the groups A+B and C+D, 25 and 55% presented with marked DHG, respectively (DHG 3 and 4; P=0.010). Only 12% of patients in group D had a complete homogeneous type of emphysema DHG grade 1. In contrast, 25% of patients had marked DHG in groups A and B, but 44 and 33% of patients presented with a homogeneous type of emphysema (DHG grade 1) in groups A and B, respectively.

The topographic distribution of emphysema was different between the groups as well. In groups A+B, 55% of patients had a homogeneous or indifferent type of distribution, but only 45% of these patients presented with the surgically favourable upper, lower or anterior type of distribution. In contrast, 67% of patients in groups C+D had an upper, lower or anterior type of distribution, whereas only 33% of patients presented with a homogeneous or indifferent type of distribution (P=0.091).

3.1.6. Regression analyses
The logistic regression extracted the variables marked DHG and arterial pO2 for discrimination between the groups A–B and C–D (marked DHG: P=0.018, odds ratio, 0.176; pO2: P=0.091, odds ratio, 1.069).

It is discussed controversially whether patients with alpha-1-antitrypsin deficiency emphysema should be operated on, since they tend to deteriorate much faster after surgery. Although this subgroup of patients was equally distributed between the groups, we excluded 13 patients suffering from alpha-1-antitrypsin deficiency, and conducted the same analyses with the remaining 57 patients. The preoperative parameters for which significant differences were calculated, are shown in Table 5. In all other parameters, no significant difference was calculated between groups A+B and C+D. The results are similar to the analyses of the whole patient cohort.


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  		Table 5. Preoperative parameters split by functional course in the groups A+B and C+D, excluding all patients with alpha-1-antitrypsin deficiencya

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
Appendix A Conference discussion
 References
 
LVRS has found its role as a therapeutic option for patients with end stage pulmonary emphysema. Many studies have proven its impact upon functional improvement [3,7,16]. In the early period of the rediscovery of LVRS, the inclusion criteria were restricted to ‘ideal’ patients with gross hyperinflation of the lungs and an upper type of distribution of their emphysema solely [8]. On understanding the responsible pathophysiological principles more precisely, the selection criteria were widened [12,17,18]. More and more importance was put on the ventilatory mechanics as additional tools for patient selection.

In our own experience, we were very liberal from the very beginning in accepting patients for LVRS. The inclusion criteria were pushed to complete homogeneous types of emphysema, patients with marked hypercapnia or alpha-1-antitrypsin deficiency emphysema. Just recently, we reported a subgroup of patients with hypercarbia preoperatively [19], demonstrating significant functional improvement in these patients as well.

As reported in the literature [10], the maximum functional benefit, in terms of FeV1, peaks at around 3–6 months after LVRS. Most patients respond to LVRS within this time frame, and are usually defined as responders to the procedure. Only 5–10% of patients seem to lack improvement after LVRS. However, the faith of patients in the long run, who initially improve after surgery, is also still unclear. Since LVRS is a palliative treatment and the underlying disease of the lung will keep on progressing, a further ongoing decrease of the lung function parameters over time can be expected [10]. The possible duration of improved lung function and increase in life quality is unclear by now and changes individually. The lung function of some patients seems to deteriorate more rapidly after surgery than others.

Therefore, a retrospective analysis was conducted to investigate if there are preoperative predictors which patients will show a persistent functional improvement over a longer period of time.

For that purpose, the functional course, in terms of FeV1, of 70 patients was analyzed retrospectively. According to their individual trend, patients were divided into four groups.

Group A consisted of patients who did not benefit from LVRS at all. Despite the clear selection criteria, about 5–10% of all patients usually fail to improve their lung function at all. The reason for this phenomenon remains unclear. Since the amount of resection is still a matter of experience and the choice of the surgeon, it has to be speculated whether technical or surgical facts may contribute to this phenomenon. Too small a resection area will not resolve overinflation and autocompression of the lungs, thus failing to improve FeV1. On the other hand, resections which are too aggressive will be disadvantageous by leaving too few parenchyma. In our reported series, the amount of patients who failed to improve is rather high compared with personal reports of other groups. The explanation can be two-fold. On one hand, we tried to expand the indication criteria even to unfavourable combinations of indifferent or homogeneous types of emphysema with only moderately elevated PEEP. On the other hand, we had a high proportion of patients with alpha-1-antitrypsin deficiency emphysema. Although reaching no significance, 27% of patients in group A suffered from alpha-1-antitrypsin deficiency, which was higher than in the other groups. It is known that these patients tend to deteriorate more quickly and often have a dissatisfying functional outcome. That is why many centres reject patients with alpha-1-antitrypsin deficiency completely. We therefore performed an additional analysis which will be discussed later.

The improvement in arterial pO2 levels after surgery was interesting, despite the lack of improvement in FeV1. Arterial pO2 peaked around 3–6 months compared with preoperative and 12 month levels (P=0.040; Table 2). In addition, the intrinsic PEEP showed a similar trend with a significant decrease to 2.9±0.4 cmH20, 3 months after surgery (P=0.047). This may be the reason why, even in this group of patients, some relate an improvement in life quality. In this context, it has to be questioned, if FeV1 is really the most important parameter defining the success or failure of LVRS.

Group B consisted of patients whose FeV1 initially increased by more than 20%, but declined after 1 year to preoperative values. In fact, the mean improvement in FeV1 was 35%. It was astonishing how rapidly the FeV1 deteriorated in some cases. This was paralleled by the intrinsic PEEP, which was 6.6±1.5 cmH2O preoperatively, improved to 1.9±0.4 cmH2O after 3 months (P=0.039), and deteriorated until 1 year to 4.2±1.5 cmH2O. Despite the functional deterioration, arterial pO2 levels remained improved throughout 1 year (P=0.037; see Table 2). This interesting observation matches the findings of group A, probably reflecting the persistent improvement of subjective life quality.

Groups C and D consisted of patients whose FeV1 initially increased by more than 20 and 40%, respectively, and sustained until 1 year. In these groups of patients, the lung function, as well as blood gases and ventilatory mechanics, improved initially and stayed stable during the first postoperative year.

In the next step, we analyzed the predictive value of all preoperative parameters. Preoperative FeV1 and all other spirometric data showed no significant difference between the four groups. Nevertheless, patients in groups C and D had a tendency for more compromised lung function. Patients with a mean FeV1 of 23.9% predicted belonged to group D, compared with 27.7% predicted belonging to group A. A similar trend was observed for vital capacity and TLC (see Table 4). A significant impact upon functional state after 1 year was calculated for the arterial blood gases. Arterial pO2 levels were significantly more deteriorated in patients belonging to group D (59.7±1.9 mmHg). This was paralleled by the pCO2 levels, which were 45.6±2.2 mmHg in group D compared with 40.2 and 37.1 mmHg in groups A and B, respectively. Perhaps this higher compromise in gas exchange reflects a marked intrapulmonary shunt, indicating a more heterogeneous type of distribution, which may be favourable in the long-term outcome. The explanation for these significant differences in blood gases preoperatively must remain speculative. Anyhow, the DHG strongly supports these findings. In groups A and B, 75% of patients presented with a DHG of 1 or 2, whereas only 36% of patients in group D presented with DHG 1 or 2. In contrast, almost 30% of patients in group D had marked heterogeneity (DHG 4), but no patient in groups A and B, respectively.

A strong predictive value was found for the type of distribution. In the very beginning of the LVRS procedures, it was proven that patients with an upper type distribution of their emphysema improve best initially. It was interesting that the favourable upper, lower and anterior types of emphysema, which represent clear surgical target areas for resection, also count for long-term improvement (see Table 4). In contrast, 63 and 43% in groups A and B, respectively, had a homogeneous or indifferent type of distribution, but only 33% of patients in each of groups C and D.

These findings were supported by regression analysis. The DHG and arterial pO2 preoperatively could discriminate between the groups A+B and C+D.

Although reaching no level of significance, alpha-1-antitrypsin deficiency may serve as an additional parameter for estimating which patient will show a long-term benefit after surgery. The percentage of patients with alpha-1-antitrypsin deficiency was higher in groups A and B, probably being responsible for a faster deterioration in this disease.

That is why we conducted an additional analysis, excluding all patients suffering from alpha-1-antitrypsin deficiency. In the remaining 57 patients, the same analyses were carried out as before. Surprisingly, no change in the results was found. A significant impact upon the functional outcome in the long run was calculated for the same parameters (see Tables 4 and 5).

Deriving from our investigations, it seems to be apparent, that patients with unfavourable parameters (e.g. homogeneity, alpha-1-antitrypsin deficiency, etc.) during the evaluation process should not undergo surgery, since a long-term benefit is unlikely. However, a LVRS procedure can be offered even to these patients, if a bridge to transplantation is desired. Some studies [20,21] recently reported the value of LVRS as a bridging therapy towards lung transplantation (LTX). In this setting, the long-term improvement of the patients is not the primary aim, but the chance to bring a patient in stable or even better shape over the next 6–12 months, until an organ for the subsequent transplant procedure is available.

In conclusion, arterial pO2, in combination with the DHG, are predictive factors for a long-term benefit after LVRS. Arterial pCO2 and other morphometric data, such as the DHI and type of distribution, can serve as additional tools in estimating functional improvement 1 year after surgery. In addition, patients with alpha-1-antitrypsin deficiency seem to deteriorate after LVRS quicker, and have to be considered as poor long-term improvers. Further analyses of 2 or 3 years follow-up may bring more clarification in the future.


   Footnotes
 
Presented at the 13th Annual Meeting of the European Association for Cardio-thoracic Surgery, Glasgow, Scotland, UK, September 5–8,1999.


   Appendix A Conference discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 Appendix A Conference discussion
References
 
Dr W. Weder (Zurich, Switzerland): I have great difficulties in understanding the rationale of your main conclusion that hypoxia and hypercarbia are good predictors of outcome. The ultimate patient at risk for hypoxia and hypercarbia is a patient with a vanished lung, which we know is a terrible candidate for this type of surgery. In our data, the only predictor of outcome is heterogeneity. So my first question is, what is your physiologic explanation for this main conclusion?

The second is regarding the loss of follow-up. How many of the 70 patients were available at 1 year for the analysis, and what was the size of the smallest group, group B, at 1 year?

Dr Wisser: We are continuing our discussion once again. Just to start off with the last question, the smallest group was group B, with nine 9 patients. We took 70 patients, of whom a follow-up of 1 year was available, so we had 70 patients at 1 year.

With regard to the first question, which I think is a very important one. Of course, you are right, that patients with marked hypercarbia usually present with vanished lung. But I think you have to keep in mind that all these patients underwent a normal selection process, and therefore, none of these patients had a vanished lung, we wouldn't have accepted them. So, besides the good distribution of emphysema, some of them had marked hypercarbia.

If you remember, I presented 2 years ago at this society's meeting in Copenhagen our data of pCO2 levels. We could demonstrate that patients with hypercarbia had a much higher functional improvement initially within the first 3 months than others. It was interesting that this is true to the long-term benefit as well. Perhaps the reason is some sort of distribution pattern. If we have an upper type distribution with pretty much no lung structure in there, patients benefit better than others. And if there is hypercarbia as well, they have more of a chance to benefit throughout 1 year. The exact reason must remain speculative, so far.

Dr J. Hasse (Freiburg, Germany): To which extent do you or don't you any longer include patients with alpha1 antitrypsin deficiency as candidates for lung volume reduction?

Dr Wisser: Well, we have been very aggressive in our inclusion criteria from the very beginning. You saw that we had a fairly high amount of alpha1s, and we have a really high amount of very, very homogeneous emphysema, because we tried to push the limits in the inclusion criteria. Of course, deriving from these data, we know that such patients won't be good long-term improvers. But, I think that we have to approach the lung volume reduction procedure with a new attitude. On one hand, we treat patients in whom we want to achieve long-term benefit. On the other hand, we can offer the LVRS to patients as a bridge towards transplantation.

Dr J. Pepper (London, England): Can you tell us about your rehabilitation program preoperatively, and what threshold of exercise, for example, how far on a 6-min walk test do you require the patient to perform, if at all, before undergoing lung volume reduction?

Dr Wisser: We have no routine rehab program like in the US. We have only data on bicycle ergometry, not on 6-min walk tests.

Dr Pepper: But these were all walking patients, none of them were on ventilators in intensive care, for example?

Dr Wisser: They are not ventilated in intensive care, but they are not walking patients.

Dr Pepper: But there is no correlation between their preoperative exercise and your groups?

Dr Wisser: No.


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 Appendix A Conference discussion
 References
 

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Received September 6, 1999; received in revised form March 6, 2000; accepted March 29, 2000.




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