The Six-Minute Walk Test – a Reliable Test for Detection of Exercise-Related Desaturation in Patients with Chronic Obstructive Pulmonary Disease

The six-minute walk test – а reliable test for detection of exercise-related desaturation in patients with chronic obstructive pulmonary disease


INTRODUCTION
Chronic obstructive pulmonary disease (COPD) is a major healthcare problem worldwide, closely related to tobacco smoking and environmental pollution. COPD is now one of the top three causes of death worldwide. [1] It has been estimated that the condition affects 329 million people worldwide, or about 5% of the world's population. [2] In 2013, the disease caused 2.9 million deaths as compared to 2.4 million in 1990. [3] In the European Union, the total direct costs of respiratory diseases are estimated to be about 6% of the total annual healthcare budget, with COPD accounting for 56% (38.6 billion euros) of the cost of respiratory diseases. [4] Evaluation of the physical capacity of COPD patients is essential for defining the characteristic features of the disease, which is notorious for its complexity in terms of both pathophysiological mechanisms and clinical presentation. It facilitates the overall assessment of the severity and prognosis of the disease as well as the choice of therapeutic approach for the different groups. [5] The physical capacity evaluated via exercise tests provides information about the joint response of the respiratory and cardiovascular systems, the blood, and the striated muscles under conditions of increased physical requirements. Wasserman et al. introduced the term cardio-pulmonary exercise test (CPET) to stress the importance of the evaluation of gas exchange. [6,7] The most important metabolic parameter of CPET is the maximal oxygen consumption (VO 2 max). It is defined as the maximal level at which the oxygen consumption remains stable despite the incrementing intensity of the exercise. Thus, it determines the functional aerobic capacity of the individual. This parameter is considered the 'gold standard' for assessment of the cardio-pulmonary system and is the most important measurement during CPET. [8,9] According to the 2003 recommendations of the ATS/ACCP, cycle ergometry is the preferred modality to perform exercise, but, depending on the circumstances, a treadmill could be an acceptable alternative. It is known that the VO 2 max on a treadmill exceeds the values reached on a cycle ergometer due to the involvement of large muscular groups in walking and running. [8] Performing a CPET requires a controlled laboratory environment, sophisticated and expensive equipment, and experienced personnel. For that reason, so-called field tests for the assessment of physical capacity have been developed. Their advantage is that they could be performed in the field without the need of special equipment and personal. In recent years, the most popular and widely used field test has been the six-minute walk test (6MWT). It is a well-standardized and validated tool allowing easy and inexpensive performance of submaximal exercise. [9,10] These characteristics have made 6MWT the method of choice for evaluation of COPD patients as well as for ones with interstitial lung diseases, or with cardiac pathology, or with peripheral vascular diseases, etc. Saturation monitoring via pulse oximetry during exertion tests (6MWT and CPET) allows easy detection of the patients with physical exercise desaturation. [5] The phenomenon of desaturation is a common finding in the advanced stages of COPD and has a complex pathophysiology. It is related to the restricted airflow, reduced diffusion capacity, systemic inflammation, and oxidative stress, affecting multiple organs and systems and causing imbalance between requirement and supply of oxygen. [11] Tojo et al. claim that repeated hypoxemic episodes during submaximal exercise, i.e. daily physical routine of patients, causes vasoconstriction in the pulmonary arteries basin, which is responsible for the development of irreversible pulmonary hypertension as well as for the worse prognosis for the patients. [12] The level of desaturation on exertion in COPD patients is an important marker for the disturbed daily physical routine, faster deterioration of lung function (FEV 1 decrease), and increased mortality risk. [11,13,14]

AIM
The study aimed to compare the six-minute walk test (6MWT) and the cardio-pulmonary exercise test (CPET) as methods of detecting desaturation in COPD patients, as well as their relationships with symptom scores (mMRC, CAT, and SGRQ), lung function, and blood-gas parameters.

PATIENTS AND METHODS
The study enrolled 40 male patients at different COPD stages according to GOLD 2011: one patient in stage 2A, eleven patients in stage 2B, one -in 3C, twenty -in 3D, and seven in stage 4D ( Table 1). The current study was conducted in the Departments of Pulmonology, Cardiology, and Pathophysiology in the Medical University of Plovdiv in Bulgaria. The Ethics Committee of the Medical University of Plovdiv approved the design of the study. Each patient who met the selection criteria signed an informed consent form prior to undertaking any actions related to the study.
The following exclusion criteria were used: -Left heart insufficiency (EF ≤50%, BNP ≥150 pg/mL), uncontrolled arrhythmias, unstable coronary artery disease (CAD), recent myocardial infarction (MI), and conditions following pulmonary thromboembolism (PTE). All the patients had baseline echocardiography and ECG in order to exclude systolic left ventricular dysfunction of myocardial or valvular origin. -Bronchial asthma -Lung cancer -Musculoskeletal and other morbidity, precluding 6MWT and CPET -Active lung tuberculosis (TB). For each patient, a detailed history was taken of any current, concomitant, and previous diseases, smoking status, and number of exacerbations within the last year. The following diagnostic tests were performed: -Bronchodilator spirometry. The test was performed at a room temperature (22-24°C) by a computer-based spirometer Master Screen Diffusion™ (Jaeger, Würzburg, Germany) with real time curve display and automatic correction (BTPS -body temperature pressure saturated); -Body plethysmography (Master Screen Diffusion/ Body, E. Jaeger); -Evaluation of diffusion capacity (Master Screen Diffusion/Body, E. Jaeger); the diffusion was measured by the single breath method; blood-gas analysis of arterialized capillary blood (Flex 830, Radiometer); -Six-minute walk test (6MWT): conducted in a 35-meter-long closed corridor, in which patients had to walk for 6 minutes with the aim of covering as much distance as they could. Patients were instructed to walk from end to end as fast as they could for 6 minutes. Rest stops were allowed. During walking, ; O -Obstruction, D -Dyspnea, E -Exercise, DOREMIBOX -the first index in which exacerbations are included as an important criterion for disease severity and progression [15] ; mPAP: mean pressure in the pulmonary artery; EF: ejection fraction; BNP: natriuretic peptide type B. N exacerbations* -According to GOLD definition: moderatethe symptoms require application of corticosteroids and/or antibiotics, severe -the symptoms require evaluation in an emergency center or hospital admission. the patients were encouraged by standardized phrases. Covered distance was measured in meters. At the start and at the end of the test, the dyspnea was assessed via the Borg scale. Each patient performed the test minimum twice in 2 days. -Cardio-pulmonary exercise test (CPET) was conducted on a treadmill TrackMaster™ and a CPET system MedGraphics CardiO 2 TM (Medical Graphics, St Paul, Minnesota, USA) according to the Bruce protocol, characterized by a simultaneous increase in speed and slope. The tests were performed in the morning, 2 hours after a meal, at a standardized room temperature, humidity, and atmospheric pressure. Prior to each test, the gas analyzer and the pneumotach had been calibrated precisely.
-CPET and 6MWT were performed without O 2 supplementation. Patients had been informed and instructed about the procedure and its parameters in advance and their consent was taken prior to conduction. Echocardiography was performed on a Hewlett Packard Sonos 2500 System. Left ventricular ejection fraction was assessed by Simpson's method. Mean arterial pressure of the pulmonary artery (mPAP) was measured via the built-in software of the device. Oxygen saturation was monitored during exercise (6MWT and CPET) by a Palm Sat 2500+ (Nonin Medical, Plymouth, MN, USA). A decrease in SpO 2 ≥4% and a drop ≤88% for at least 3 minutes was considered a desaturation. Desaturation was defined as a drop in SpO 2 of at least 4% and/or a level less than 88%. Questionnaires for symptoms and health status (mMRC, SGRQ, and CAT), standardized tests to assess patient's quality of life, feeling of dyspnea, and the reduction of the physical capacity related to it were used. [16][17][18][19][20][21]

Statistical analysis
Statistical analyses were performed using SPSS software (IBM SPSS Statistics for Windows, Version 22.0. Armonk, NY, USA& IBM Corp. Released 2013). The results are displayed as a mean value ± standard deviation (mean ± SD), unless otherwise stated. The non-parametric test of Kolmogorov-Smirnov was used to check normal distribution. The Student's t-test for independent variables (independent samples t-test) and for paired variables (paired samples t-test) was applied for comparison of mean values. Correlations between normally distributed quantitative variables were analyzed with the help of Pearson correlation; p<0.05 was a cut-off for significance.
The patients were categorized into two groups -with desaturation (A) and without desaturation (B) based on the SpO 2 decrease during the test ( Table 2).
The walking distance [m] covered during 6MWT was 498±82 vs. 510±81 (p>0.05) for the patients with and without desaturation, respectively -no significant difference was found for this parameter.
The desaturation on exertion during 6MWT correlates strongly with that during CPET (r=0.77, p<0.001) (Fig. 4). N exacerbations* -According to GOLD definitions: Moderate -symptoms require administration of corticosteroids and/or antibiotics; Severe -symptoms require evaluation in an emergency center and/or hospital admission.   A significant correlation was also found between the maximal oxygen consumption VO 2 % pred. max. reached during CPET and the distance covered during 6MWT (r=0.55, p<0.001).

DISCUSSION
The main finding of the present study is that exercise-related desaturation was established in 19 (48%) out of 40 patients during 6MWT desaturated compared to 21 (53%) during CPET. Saturation monitoring during 6MWT via constant pulse oximetry is a reliable tool for detection of desaturation. It is comparable to the gold standard (CPET) test and does not require expensive equipment and special skills from the personnel. The choice of criteria of desaturation on exertion is based on trials with professional athletes. These 4% are a combination of 2% decrease due to probable inaccuracies in pulse-oximetry and 2% to reflect the right shift of the saturation curve, taking into account the metabolic acidosis caused by the exercise. [22] In order to avoid errors, the decrease in saturation by minimum 4% had to last for at least 3 minutes during exercise.
The comparison between CPET and 6MWT reveals close results in terms of peak VO 2 and heart rate. Along with that, 6MWT has considerably lower ventilatory requirements (peak CO 2 production, peak ventilation, and respiratory coefficient RER), which makes the test appropriate for elderly people with chronic respiratory pathology. [13] The 6MWT distance is the most important test result -it has been shown to be associated with clinically significant consequences in patients with chronic lung disease. There is an inverse association between the length of the distance and mortality risk. For this reason, it is one of the four prognostic criteria of the renowned BODE index. [23] According to ATS 2002 guidelines, pulse-oximetry during 6MWT is optional. [10] Taking into consideration the recently accumulated evidence that desaturation upon exertion corresponds to a much worse prognosis (faster lung function deterioration -a decrease in FEV 1 , impaired daily physical activity, more frequent exacerbations -after some authors, higher mortality risk), the European Respiratory Society (ERS) and ATS published in 2014 technical standards for field test conduction in which continuous pulse-oximetry during 6MWT is recommended for detection of this important and not infrequent phenomenon with significant negative sequelae for the patients. [24] According to the analysis of the data obtained with 6MWT and CPET (n=40), the two tests show similar results in identifying desaturating patients. The advantage of 6MWT is that it is easier and cheaper to perform. The de-saturation ΔSpO 2 during CPET was 6.6±4.9% and during 6MWТ -6.0±4.9% (p<0.001). Studying the potential impact of exercise tests in assessing the physical capacity of patients with COPD, many researchers come to the conclusion that CPET on a treadmill is more suitable and sensitive for detecting desaturation in COPD patients than the ergometer modality. [25][26][27] Poulain et al. [25] examined the previously established fact that patients with respiratory disorders desaturate during walking tests, but not during CPET, and compared 6MWT and CPET on an ergometer. Eighty patients had had a CPET on an ergometer as well as 6MWT twice with a constant SpO 2 record during all tests. Desaturation during 6MWT, which is not present in CPET, was detected in 23 (28%) patients (verified also by another CPET in those patients). Based on this data, the authors concluded that 6MWT was much more sensitive than CPET on an ergometer for detection of desaturation upon exertion. Valerio et al. [27] measured the metabolic requirements during 6MWT and CPET of patients in different COPD stages, compared them to the results of healthy volunteers and found out that VO 2 reached during 6MWT remains constant after the third minute both in COPD patients (3-4 stage) and the control group. The 6-minute walk distance is significantly related to VO 2 max from CPET. VO 2 at the end of 6MWT is very similar to the one measured at the anaerobic threshold (AT) and at the threshold of decompensated metabolic acidosis (TDMA) both in COPD patients (1-3 stage) and healthy controls. In stage 4 COPD patients, the difference between VO 2 max during CPET and during 6MWT is reduced. 6MWT is found to be more appropriate for detection of desaturation upon exertion. The team concludes that from a physiological point of view 6MWT and CPET are, to a large extent, similar but not altogether replaceable. CPET allows detection of the underlying cause of the decreased physical tolerance, while the informative value of 6MWT result is improved by the multiparametric O 2 indexes, desaturation data, degree of dyspnea, exacerbations, etc. A similar conclusion was drawn by Troosters et al. [28] and other authors based on earlier experiments and a comparison of 6MWT and CPET on a treadmill and an ergometer [29] .
Bearing in mind the above evidence and the main objective of our study -to find out an easy and affordable daily practice test that is able to detect reliably desaturation upon exertion, we have compared 6MWT to CPET and have found that 6MWT is a trustworthy alternative to the gold standard CPET with an excellent potential for everyday practice.
Desaturation upon exertion is not an uncommon phenomenon. Jenkins and Cecins [30] studied a large group of patients (n=741) with chronic respiratory diseases, 572 of whom had COPD, and reported 47% (n=345) desaturators during 6MWT.
Van Gestel et al. [31] also found a considerable frequency of desaturation upon exertion (6MWT) in COPD patients -61.7% out of a group of 154 tested patients and reckoned that FEV 1 % <50% could be a reliable predictor for this phenomenon.
We divided the tested patients into two groups -with desaturation (A) and without desaturation (B), and found that the desaturators with COPD differed significantly from the non-desaturators during 6MWT with regard to the spirometry results (FEV1%; IC%), blood-gas analysis (PaCO 2 ), baseline SpO 2 , diffusion parameters (KCO%), and VO 2 /kg, but there were no significant differences in the symptom score scales (mMRC, САТ, and SGRQ), EF, mPAP, 6MWT and the number of exacerbations in the last year.
Dogra et al. examined 60 COPD patients divided into desaturators and non-desaturators and compared their functional and clinical characteristics and found that the desaturators had significantly lower spirometric parameters FEV 1 %, FVC%, baseline SpO 2 , as well as a higher degree of dyspnea rated on the Borg scale and covered shorter distance during 6MWT. The authors determined an inverse relationship between desaturation on the one hand and baseline SpO2, distance covered in 6MWT, and FEV1% on the other, and concluded that lower baseline SpO2 is a good predictor of desaturation during 6MWT. [32] In our study group as well, a significant correlation with FEV 1 % was found, but also with the diffusion parameters -КСО% (r=−0.55; p<0.001), with the bloodgas analysis values: PaO 2 (r=0.400; p=0.009) and VO 2 % pred. max. (r=0.36; p=0.02). In the group, no remarkable difference was found in the distance [m] covered during 6MWT 498±82 vs. 510±81 (p>0.05) between the desaturators and non-desaturators, respectively. It is consistent with previous studies [13,25] that report no correlation between 6MWT and desaturation, but a significant association between VO 2 % pred. max in CPET and the covered distance in 6MWT (r=0.55, p<0.001). The lower VO 2 % and the shorter 6WMT of patients in more advanced stages of COPD are important markers for poorer survival prognosis. [14,[33][34][35][36] As long as our objective was to compare 6MWT and CPET as methods for detection of desaturation among COPD patients, a possible limitation of our study could be the relatively small number of subjects, wherefore the trends in the statistical differences and correlations between the parameters of the two groups, desaturators and non-desaturators, could be further enriched and specified by increasing the sample size.

CONCLUSIONS
In patients with moderate and severe COPD, desaturation upon exertion is a common finding with important negative predictive value and could be easily and reliably detected via 6MWT. In this respect, the 6MWT is a credible alternative to the gold standard CPET and has a high potential for wide application in daily practice.