| | The 12-min walk test as an assessment criterion for lung transplantation in subjects with cystic fibrosis☆Abstract Timing for the evaluation and listing of patients with cystic fibrosis who are candidates for lung transplantation is still uncertain. Our study goal was to determine the value of the 12-min walk test as a simple and easy-to-use adjunctive assessment tool for pre-transplant evaluation. A total of 34 cystic fibrosis patients (17 male, mean age 22 years) with end-stage lung disease were evaluated in this retrospective analysis. The 12-min walk test was carried out according to an established protocol. Before walking, body plethysmography was performed and a capillary sample was taken for blood gas analysis. Walking distance and SaO2 via continuous pulse oximetry were recorded online. There was a strong correlation between survival time and walking distance (r=0.7, P=0.003). No other single parameter, such as FEV1, SaO2, pCO2 or BMI, showed a statistically significant correlation with survival time. Subjects who walked ≤700 m had a lower cumulative survival (P=0.02). There was a statistically significant positive correlation between walking distance and SaO2 at rest and after 12 min of walking (r=0.5, P=0.001; and r=0.5, P=0.04, respectively). There was no correlation between walking distance and pCO2 at rest, BMI, FEV1, or degree of change in SaO2 during the walk test. This study demonstrates that in CF patients with end-stage lung disease, walking distance during a 12-min walk test is more informative with respect to survival than single parameters such as SaO2, pCO2, FEV1 or BMI.
1. Introduction  Currently, lung transplantation (LTX) provides the only opportunity to prolong survival for cystic fibrosis (CF) patients with end-stage lung disease [1]. This procedure often leads to an improved quality of life, but also carries a primary risk of acute lung failure, hemorrhage, rejection or infection [2]. Due to the limited supply of donor organs, the annual number of transplantations has leveled off and waiting times for adults have increased [3], [4]. Consequently, it is important to be placed on the waiting list at an appropriate time. There are guidelines for the selection of LTX candidates [5], [6], but the clinical course of the patients is extremely variable and the decision has to be individualized. Furthermore, there is a need to regularly re-evaluate the criteria. In 1976, McGavin et al. introduced the 12-min walking test as a measure of exercise capacity for subjects with chronic lung disease [7]. The majority of subsequent publications have analyzed walk tests in subjects with chronic obstructive pulmonary disease (COPD) [8], [9], [10]. As little information is available on the predictive value of walk tests in subjects with end-stage cystic fibrosis [11], we studied performance in a standardized 12-min walk test as a parameter for evaluating CF patients for LTX by addressing the following questions:
1.Is there a correlation between survival time and walking distance, pCO2, oxyhemoglobin saturation (SaO2) at rest or after 12 min of walking, decrease in SaO2, forced expiratory volume in 1 s (FEV1), or body mass index (BMI)?
2.Is the walking distance predictive with respect to probability of survival?
3.Is there a correlation between walking distance and SaO2 at rest, SaO2 after exercise, the decrease in SaO2 during the 12-min walk, pCO2, FEV1 or BMI? 2. Materials and methods 2.1. Subjects Between January 1995 and December 1999, the 12-min walk test was performed in 34 cystic fibrosis patients (17 male, 17 female) at the time of assessment for lung transplantation. Subjects with an acute pulmonary exacerbation were excluded. Ages ranged from 12 to 40 years (mean 22). A total of 15 subjects (8 male, 7 female) died during the following months or years prior to transplantation. Ages ranged from 17 to 40 years (mean 24). We analyzed results obtained for all subjects (total group) and for subjects who died (subgroup), as well as according to gender. 2.2. Functional data All spirometric data (body plethysmograph, Jäger, Würzburg, Germany) were expressed as percentage predicted. Subjects were breathing ambient air. An arterialized blood sample was taken from a hyperemic (by topical Nonivamid and Nicoboxil, Boehringer, Ingelheim) lobe of the ear and analyzed using a blood gas analyzer (AVL 990, Medizintechnik GmbH, Germany). The walk test was carried out along a level, enclosed hospital corridor according to the method described by McGavin et al. [7]. Two tests were performed whenever possible on two consecutive days at approximately the same time of day. The test with the greater distance was used for analysis. The performance of more tests was difficult because of time constraints and the clinical condition of our patients [12], [13]. Each subject was instructed to walk as far as possible in 12 min, resting only when necessary. All tests were supervised by the same investigator, who accompanied each subject, acting as a timekeeper and giving encouragement [14]. As is common practice in exercise testing, pulse oximetry was used to measure SaO2 during the walk, because it is simple and non-invasive. SaO2 measurements were recorded at 60-s intervals with a hand-held oximeter (Nellcor, NPB-40, Idstein, Germany). The oximeter was held by the investigator at a comfortable distance from the patient throughout the test. The subject's arm was placed in a sling to hold the hand and finger probe in a horizontal position and to provide stable measurements. The distance covered in 12 min was recorded. 2.3. Statistical analyses For statistical analysis, we used spss for Windows version 8.0 (SPSS Inc, Chicago, IL, USA). Spearman's non-parametric correlation was used to examine correlations between the walking distance in a walk test and FEV1, BMI, pCO2 or pO2 at rest, SaO2 at rest, after 6 and after 12 min of walking, or drop in SaO2. The same test was used to check whether there was an association between survival time and the above-mentioned parameters. Kaplan–Meier survival analysis was used for the probability of survival. P<0.05 was taken as the critical significance level. For technical reasons, complete sets of data were not available for every patient. The number of subjects included in the calculations is indicated in Section 3 and in the tables and figures. 3. Results Characteristics of all subjects assessed (n=34) are indicated in Table 1. At rest all subjects were hypoxic and 40% were hypercapnic. The mean walking distance was below 800 m. During the 12-min walk, SaO2 decreased by a mean of 10%. | | |  | | Mean | Median | S.D. | Range | |
|---|
| SaO2 at rest (%) (n=33) | 89 | 89 | 4.6 |  81–97 | |
| SaO2 at 6 min (%) (n=25) | 81 | 78 | 7.7 | 68–94 | |
| SaO2 at 12 min (%) (n=30) | 79 | 78 | 8.5 | 63–95 | |
| Walking distance (m) (n=34) | 779 | 750 | 257 | 120–1300 | |
| FEV1 predicted (%) (n=34) | 26 | 24 | 9.4 | 14–52 | |
| VC predicted (%) (n=33) | 40 | 39 | 10.9 | 24–69 | |
| pCO2 (mmHg) (n=32) | 47 | 44 | 9.3 | 32–71 | |
| pO2 (mmHg) (n=32) | 59 | 57 | 10.3 | 41–89 | |
| BMI (n=33) | 16.6 | 16.9 | 2.1 | 13–21 | | | | |
During the following months or years, 15 patients died prior to transplantation with a median time to death of 11 (3–28) months. Seven patients were transplanted and 12 were still on the waiting list when analysis was performed. 3.1. Correlation between survival time and different parameters In the subgroup of subjects who died over the following months or years (n=15), we studied whether there was a correlation between survival time and FEV1, BMI, pCO2 at rest, SaO2 before or after 12 min of walking, decrease in SaO2 or the walking distance. Survival time was defined as the time interval from performance of the walk test until death in months. There was good correlation between survival time and walking distance (r=0.7, P=0.003) (Fig. 1), but there was no correlation between survival time and SaO2 at rest (r=0.3, P=0.2), SaO2 after 12 min of walking (r=−0.1, P=0.7), decrease in SaO2 (r=0.2, P=0.6), pCO2 (r=−0.5, P=0.07), FEV1 (r=0.2, P=0.5) or BMI (r=0.02, P=0.9). No subject who walked less than 650 m survived more than 10 months. 3.2. Walking distance and probability of survival We examined if subjects who walked ≤700 m had a lower cumulative probability of survival than subjects who walked >700 m if they were not transplanted (n=27). Within the patients that died on the list (n=15; 7 m, 8 f) females were slightly more frequent in the group that walked ≤700 m (n=8; 3 m, 5 f) compared to the group that walked >700 m (n=7; 4 m, 3 f). The Kaplan–Meier survival curve indicates a significantly lower survival time in subjects who walked ≤700 m than in subjects who walked >700 m (P=0.02; Fig. 2). Results were similar when transplanted patients were included (n=34, P=0.01). 3.3. Correlation between walking distance and different parameters SaO2 at rest (r=0.5, P=0.001) and after 12 min of walking (r=0.5, P=0.004) were positively correlated with the walking distance. There was no correlation between the walking distance after 12 min and BMI (r=0.08, P=0.7), pCO2 at rest (r=−0.01, P=0.9), FEV1 (r=0.3, P=0.08), SaO2 after 6 min of walking (r=0.4, P=0.07) or fall in SaO2 during the walk test (r=−0.3, P=0.1). 4. Discussion This retrospective analysis evaluates the utility of the 12-min walk test as a simple and easy-to-use assessment tool for LTX in CF patients. We determined the exercise tolerance of CF subjects with advanced disease in relation to their subsequent survival. Many of our patients were referred for LTX assessment in the end stage of their disease (Table 1). This is, however, the group which profits most from LTX [15]. The first question addressed is whether there is a correlation between survival time and walking distance, pCO2, pO2, SaO2 at rest or after 12 min of walking, decrease in SaO2, FEV1 or BMI. Our results indicate a significant correlation between walking distance and survival time in the subgroup of subjects who died. A walking distance of <650 m appears to be a marker that the subject is at high risk. No other single parameter, such as BMI, FEV1, pO2 and pCO2 at rest, SaO2 at rest, SaO2 after 12 min of walking or decrease in SaO2 was significantly correlated with survival time. In addition, Kaplan–Meier survival analyses indicated a significantly lower time of survival in subjects who walked ≤700 m than in subjects with a walking distance >700 m. The fact that females were more frequent in the group who walked <700 m suggests that they were referred late due to a rapid decline in their overall condition. The correlation between walking distance and survival time was confirmed by results from transplanted patients who were analyzed separately because of a potential bias generated by supposedly greater physical fitness enabling them to survive until their transplantation. Few results from walk tests have been related to survival of different patient groups with pulmonary diseases in the literature. Kadikar et al. [11] demonstrated that walking distances differed significantly between CF recipients who died and those who did not die while on the waiting list (mean 367±112 vs. 505±94 m in a 6-min walk test). Their results cannot be directly compared to ours, however, as they included subjects with oxygen supplementation while walking. FEV1 has been described as the gold standard for predicting survival in CF patients. In 1992, Kerem et al. reported that the best predictor of 2-year mortality in the Toronto CF patient population was FEV1 <30% of the predicted value for height and sex in children and adolescents of both genders, as well as adult women. Subjects with FEV1 <30% of predicted had a 2-year mortality of more than 50% [16]. For men, the threshold was a FEV1 <20% predicted. However, assessment criteria are becoming more individualized [15]. Recent studies have demonstrated that FEV1 <30% may no longer be considered as an accurate predictor of 50% mortality after 2 years in cystic fibrosis lung transplant candidates [17]. Milla et al. showed that with FEV1 <30% predicted the median survival (50%) is 3.9 years. In addition, they demonstrated that the individual annual rate of decline of FEV1 was a more useful parameter to predict the risk of death [17]. Other authors have described a significant correlation between FEV1 and walking distance in subjects with obstructive airway disease [12], [18]. In our patient group there was a lack of correlation between FEV1 and walking distance. Walking distance is probably influenced by a combination of factors, including cardiorespiratory adaptation, pulmonary hypertension, hypoxemia and muscular fitness, the functional status of the respiratory and cardiovascular systems, and neuromuscular function, as well as motivation and endurance [11], [14]. One could speculate that airway obstruction affects exercise tolerance in the earlier stages of the disease, whereas in our patient group, where FEV1 was approximately predicted as 25%, walking capacity is influenced to a greater degree by reduced diffusion and increased oxygen consumption, as well as physical conditioning. It may also be reasonable to assume that exercise is associated with worsening in V/Q mismatching due to increased perfusion to poorly ventilated areas as cardiac output increases with exercise. An important question is whether the test provides information that could not be obtained by procedures performed at rest. Our study demonstrates that SaO2 before as well as after 12 min of walking was positively correlated with walking distance, whereas pCO2 was not. One possible explanation might be that diffusion capacity and oxygen consumption [11] play an important role. As long as there is no critical obstruction and hyperinflation, pCO2, which is a marker of hypoventilation, does not seem to be critical for the exercise limitation. For the individual patient, a follow-up of the performance in exercise tests may be critical. Intraindividual changes or trends of exercise tolerance over months or years might be especially informative and will hopefully be addressed in future studies. 5. Conclusion Our results indicate that walking distance during a 12-min walk test is more informative with respect to survival than single parameters such as SaO2, pCO2, pO2, FEV1 or BMI. We conclude that walk tests are simple investigations and suitable assessment criteria for LTX in CF patients, which should be investigated in comparison to new screening systems. [15] Acknowledgements We thank Irene Kleinau and Jörg Moldenhauer for their assistance with the acquisition and management of data essential to this project. References [1].
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a Department of Pediatric Pneumology and Immunology, Charité, Humboldt University of Berlin, Augustenburger Platz 1, 13353 Berlin, Germany b Institute for Statistics and Epidemiology, Benjamin Franklin Hospital, Free University of Berlin, Berlin, Germany c Fachklinkik Sattledüne, Amrun, Germany  Corresponding author. Tel.: +49-4682-34300; fax: +49-4682-34708
☆ Parts of this project were presented at the 23rd European Cystic Fibrosis Conference in The Hague, June 1999. PII: S1569-1993(02)00145-5 doi:10.1016/S1569-1993(02)00145-5 © 2002 European Cystic Fibrosis Society. Published by Elsevier Inc. All rights reserved. | |
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