Research ArticleOriginal Research

Continuous Monitoring of Pulse Oximetry During the 6-Minute Walk Test Improves Clinical Outcomes Prediction in COPD

Kellen S Batista, Igor Dossin Cézar, Igor G Benedetto, Ravena M C da Silva, Litiele Evelin Wagner, Danton Pereira da Silva, Paulo R Sanches, Marcelo B Gazzana, Marli M Knorst, Juan P de-Torres, J Alberto Neder and Danilo C Berton
Respiratory Care January 2023, 68 (1) 92-100; DOI: https://doi.org/10.4187/respcare.10091

Abstract

BACKGROUND: Continuous monitoring of SpO2 throughout the 6-min walk test (6MWT) unveiled that some patients with respiratory diseases may present values across the test lower than SpO2 measured at the end of the test. Nevertheless, it remains unclear whether this approach improves the yield of walk-induced desaturation detection in predicting mortality and hospitalizations in patients with COPD.

METHODS: Four hundred twenty-one subjects (51% males) with mild−very severe COPD underwent a 6MWT with continuous measurement of SpO2. Exercise desaturation was defined as a fall in SpO2 ≥ 4%. All-cause mortality was assessed up to 6 y of follow-up and the rate of hospitalizations in the year succeeding the 6MWT.

RESULTS: One hundred forty-nine subjects (35.4%) died during a mean (interquartile) follow-up of 55.5 (30.2−64.1) months. Desaturation was observed in 299/421 (71.0%). SpO2 along the test was < end SpO2 (88 [82−92]% vs 90 [84−93]%, P < .001). Desaturation detected only during (but not at the end of) the test was found in 81/421 (19.2%) participants. Multivariate Cox regression model adjusted for sex, body composition, FEV1, residual volume/total lung capacity ratio, walk distance, O2 supplementation during the test, and comorbidities retained the presence of desaturation either at the end (1.85 [95% CI 1.02−3.36]) or only along the test (2.08 [95% CI 1.09−4.01]) as significant predictors of mortality. The rate of hospitalizations was higher in those presenting with any kind of desaturation compared to those without exercise desaturation. Logistic regression analysis revealed that walking interruption and diffusing capacity of the lung for carbon monoxide predicted desaturation observed only during the test.

CONCLUSIONS: O2 desaturation missed by end-exercise SpO2 but exposed by measurements during the test was independently associated with all-cause mortality and hospitalizations in subjects with COPD.

Introduction

The 6-min walk test (6MWT) is a field walking test developed for the objective evaluation of functional exercise capacity.1 The duration was adapted from the original 12-min walk test to evaluate the level of physical fitness in healthy individuals,2 which was considered too exhausting to assess patients with respiratory diseases.3 The 6-min, in addition, was considered more reflective of activities of daily living than other walk tests.4 Based on its origins, the 6-min walk distance (6MWD) was considered the main outcome, whereas oxygen saturation by SpO2 was optional and, if measured, recorded at rest before and immediately after exercise cessation.1

In the last 2 decades, however, the 6MWT has been increasingly used in the research and clinical setting not only to assess physical fitness but also for prognostic and interventional evaluation. In this context, other measurements beyond 6MWD have shown useful to expose disease severity and response to interventions. Oxygen desaturation, in particular, is commonly observed during 6MWT in different lung diseases and is related to various patient-centered outcomes.5-11 These relationships supported the clinical importance of detecting and quantifying desaturation during 6MWT.5

Interesting, the kinetics of continuous monitoring of SpO2 during 6MWT unveiled that some individuals with COPD12,13 and interstitial lung disease12 presented SpO2 measurements throughout the test lower than the SpO2 measured at the end of the test (end SpO2), particularly in those who needed to rest during the procedure. This finding prompted the recommendation for constant monitoring of SpO2 during 6MWT to obtain an accurate measure of exercise-induced desaturation.5,14 Whereas the main studies that showed walking desaturation to predict mortality in subjects with COPD already used continuous monitoring and the minimum SpO2 level during 6MWT (nadir SpO2),7,8 it remains unclear if this approach indeed improves the yield of 6MWT-induced desaturation in predicting mortality in COPD compared to discrete SpO2 measurements at the beginning and the end of the test. Moreover, considering the association of 6MWT desaturation with more severe lung disease, higher levels of dyspnea, and impaired physical activity,5 we aimed to evaluate the predictive properties of nadir SpO2 and end SpO2 to anticipate hospitalization in the year succeeding the walking test.

QUICK LOOK

Current Knowledge

The lowest O2 saturation measured by SpO2 during the 6-min walk test might be lower than the end-exercise value in patients with chronic respiratory diseases. Accordingly, continuous monitoring of SpO2 is currently recommended throughout the test.

What This Paper Contributes to Our Knowledge

Desaturation detected only by SpO2 measurement during (but not at the end of) the test was found in around 20% of subjects with COPD. O2 desaturation observed either at the end of the test or only exposed by continuous SpO2 monitoring during the test predicted all-cause mortality and future hospitalization risk in these subjects.

Methods

Study Design and Subjects

This study was a retrospective cohort including subjects with COPD that were referred for 6MWT assessment in a tertiary center (Respiratory Physiology Unit, Respiratory Division, Hospital de Clinicas de Porto Alegre, Brazil) during the year 2015 by indication of their physicians. All-cause and respiratory hospitalizations were recorded in the year succeeding the walking test. Vital status was checked until December 2020. The first evaluation was retained for analyses in participants who performed more than one 6MWT in 2015. Anthropometric, demographic, and clinical information was extracted from electronic medical records and 6MWT requests. The COPD-specific comorbidity test (COTE index)15 using 12 comorbidities that influence survival in COPD was calculated from these data.

Inclusion criteria were both sexes, ≥ 40 y old, and confirmed COPD according to Global Initiative for Chronic Obstructive Lung Disease (GOLD).16 Participants were clinically stable for at least 4 weeks before 6MWT and were receiving optimal medical therapy according to current guidelines. The exclusion criteria were those unable to perform the 6MWT and clinical comorbidities with life expectancy < 1 y at the investigators’ discretion. The study was approved by the research ethics of Hospital de Clinicas de Porto Alegre/Universidade Federal do Rio Grande do Sul (number 2020–0207) and, given its retrospective nature, written informed consent was waived.

Resting Lung Function Testing

Pulmonary function tests (PFTs) were requested by the medical assistant team and generally performed on the same day of the 6MWT. Spirometry, static lung volumes, and lung diffusing capacity for carbon monoxide (DLCO) were performed with a computerized system (CPF, Eric Jaeger GmbH; Würzburg, Germany) according to internationally recommended standards. Air trapping was quantified by the ratio of residual volume (RV) to total lung capacity (TLC).17 The presence of air trapping was characterized by measurements above the upper limit of normal (predicted value + 1.645 Z score).18

6-Minute Walk Test

The walking tests were performed in an indoor 25-m corridor according to European Respiratory Society/American Thoracic Society technical standards for field walking tests in chronic respiratory disease.14 The 6MWT was performed with at least a 30-min resting interval after PFTs. Continuous monitoring of oxygen saturation and pulse frequency was assessed using a sensor (PureLight 8000AA, Nonin, Plymouth, Minnesota) connected to an in-house developed oximeter. The accuracy of this apparatus was regularly checked through a commercially available portable oximeter (Onyx 9500, Nonin). Online measurements were transmitted by radio frequency telemetry (2.4 GHz) with in-house developed hardware and software. SpO2 at rest ≤ 85% was considered contraindication for 6MWT.14 Test cessation was requested whether SpO2 fell to < 80% and to resume if recovered to ≥ 85%. Oxygen supplementation was provided for subjects on long-term oxygen therapy (LTOT) aiming to start the test with SpO2 ≥ 90%. Exercise desaturation was defined as a fall in SpO2 ≥ 4%. 6MWD was presented as absolute values and as percentage of predicted.19

Statistical Analysis

Continuous data were presented as mean ± SD or median (interquartile range) according to data distribution and categorical data as number (%). Baseline characteristics were compared by chi-square tests, Kruskal–Wallis test, or one-way analysis of variance test as appropriate. Kaplan-Meier curves were constructed to display differences in survival according to the SpO2 behavior during exercise. Subjects submitted to lung transplantation during the follow-up period were statistically treated as deceased. Multivariate Cox regression model (backward stepwise) adjusted for presumed confounders assessed independent parameters to predict mortality. Poisson regression model was applied to estimate hospitalization risk. Stepwise logistic regression analysis was applied to identify variables related to the presence of desaturation detected only during but not at the end of the test. The SPSS package (v. 18, IBM, Armonk, New York) was used for the statistical analyses. The level of significance was set at P < .05.

Considering a walking-induced desaturation prevalence of 40% in COPD, a relative risk of death of 2.63 in relation to non-desaturators, the median survival of 15 y in the subgroup without desaturation,8 a mean follow-up of 3 y, a censor rate of 20% (censored/unit of follow-up time), and α and β error of 5% and 20%, respectively, we estimated a minimum sample of 230 subjects to assess the relationship between walking desaturation and mortality.20

Results

Four hundred twenty-one subjects (51% males) with mild to very severe COPD were included with a mean follow-up of 55.5 (30.2−64.1) months. During this period, 149 subjects (35.4%) died and 7 (1.7%) were submitted for lung transplantation. As could be expected, average participants presented with lung hyperinflation, air trapping, and reduced DLCO. Demographic, anthropometric, resting lung function, and walking performance stratified according to desaturation behavior during the 6MWT are presented in Table 1. In those with lung volume measurements (n = 340), the proportion of subjects with air trapping was similar in the 3 groups (non-desaturation [97%], desaturation at end exercise [98%], and desaturation only during exercise [96%], [P = .40]) despite the higher RV/TLC ratio in those presenting with exercise desaturation at end exercise. The prevalence of some comorbidities was higher in subjects presenting exercise desaturation (Table 2). Smoking history, spirometric GOLD stage, and daily-life dyspnea are described in Table 3.

View this table:
Table 1.

Demographic and Functional Characteristics Comparing Subjects According to Their Pulse Oximetry Behavior During 6-Min Walk Test

View this table:
Table 2.

Prevalence of Comorbidities in Each Group

View this table:
Table 3.

Smoking History, Spirometric COPD Severity, Dyspnea, and Comorbidities Burden in Each Group

Detection of desaturation only during but not at the end of the test allowed the identification of desaturation in an additional 81 subjects (19.2%) beyond the 218 subjects (51.8%) with end-exercise criterion. These groups presented similar mortality rates (37/81 = 46% vs 96/218 = 44%) that were significantly higher compared to subjects without exercise desaturation (23/122 = 19%, P < .001). Of note, the former group presented a higher proportion of walking interruptions compared to the other 2 groups (Table 1). Multivariate Cox regression model adjusted for sex, body mass index, FEV1 (% of predicted), RV/TLC, 6MWD, O2 supplementation during the test, and COTE index retained the presence of desaturation detected either at the end or only during exercise as significant predictors of mortality (Fig. 1). The risk ratios (Exp [β]) for mortality in the desaturation groups compared to the non-desaturation group adjusted for confounders are provided in Table 4.

Fig. 1.
Fig. 1.

All-cause mortality according to the presence and kinetics of oxygen desaturation during 6-min walk test.

View this table:
Table 4.

Multivariate Cox Regression Model to Predict Mortality (Backward Stepwise Method)

The proportion of subjects with ≥ 1 as well as ≥ 2 general hospitalizations and hospitalizations due to respiratory causes in the year succeeding the 6MWT was higher in both desaturation groups compared to the non-desaturation group (Table 5). Accordingly, the rate of hospitalizations was higher in those presenting any kind of desaturation compared to those without exercise desaturation (Fig. 2). The risk ratio for overall hospitalization was 2.82 (95% CI 1.70–4.66) in the group presenting desaturation at the end of exercise and 2.53 (95% CI 1.38–4.62) in the group presenting desaturation only during exercise.

Fig. 2.
Fig. 2.

Rate of overall (A) and respiratory (B) hospitalizations in the year following the 6-min walk test. * P < .001 versus non-desaturation group; † P = .003 versus non-desaturation group; 6MWT = 6-min walk test.

View this table:
Table 5.

Proportions of Hospitalizations in the Year Succeeding the 6-Min Walk Test According to Pulse Oximetry Kinetics During the 6-Min Walk Test

Stepwise logistic regression analysis revealed that walking interruption (odds ratio 3.57 [95% CI 1.63–7.85]) and DLCO (odds ratio 1.02 [95% CI 1.01–1.04]) predicted desaturation detected only by SpO2 measured during the test. This group presented with progressive SpO2 decline during the first 2 min of the test, with nadir SpO2 generally occurring between the second and third minute of the test and gradual recovery of the SpO2 in the last half of the walking (Fig. 3).

Fig. 3.
Fig. 3.

SpO2 behavior comparing group without exercise desaturation versus those with exercise desaturation at the end of the test or presenting with desaturation only during exercise. * P < .05 no desaturation versus end-exercise desaturation; † P < .05 no desaturation versus only during exercise desaturation; ‡ P < .05 end-exercise desaturation versus only during exercise desaturation; 6MWT = 6-min walk test.

Discussion

This study expands the previous findings that nadir SpO2 obtained during the walking test was slightly lower than end-exercise SpO212,13 by linking the presence of both kinds of exercise desaturation kinetics to negative patient-centered outcomes. The occurrence of exercise desaturation detected either at the end of the test or only during exercise was independently related to mortality to a similar extent and was a marker of future hospitalization risk due to overall and respiratory causes. Of special clinical relevance, detection of desaturation by continuous monitoring of pulse oximetry allowed extra identification of almost one fifth of the sample as presenting with exercise desaturation. This finding would have passed unnoticed if oximetry was assessed only at the beginning and end of the test. Desaturation detected by continuous SpO2 monitoring confirmed worse clinical end points.

The 6MWT is a simple field test of functional performance that is widely used for cardiorespiratory assessment. The traditional primary outcome (distance) predicts survival in COPD,8,21-23 heart failure,24 idiopathic pulmonary fibrosis,25 and pulmonary hypertension.26,27 Impaired gas exchange that worsens during exercise is an important pathophysiological feature of respiratory diseases. A common thread through different respiratory diseases is that the level of hypoxemia depends critically on the interplay between mixed venous O2 pressure (reflecting cardiocirculatory performance) and the degree of ventilation-perfusion mismatching.28 Detection of exercise-induced desaturation represents, therefore, a simple and noninvasive measure reflecting the cardiopulmonary derangements in these patients. Moreover, walking is more sensitive than cycling to detect exercise-induced O2 desaturation.13,29 Accordingly, it would be a waste of opportunity not to observe the SpO2 behavior along the 6MWT to improve the functional and prognostic stratification of patients with respiratory diseases.14 In fact, the presence of 6MWT desaturation has increased the predictive power of the distance walked in subjects with COPD,7,8 interstitial lung disease,9,10 and pulmonary hypertension.11 Although the continuous monitoring of SpO2 during 6MWT was only formally recommended by the European Respiratory Society/American Thoracic Society in 2014,14 all these previous studies published between 2001 and 2008 had already used the lowest SpO2 measured continuously during the test to define walking desaturation. Notwithstanding, none explored the prevalence of subjects presenting desaturation only during exercise nor if the lack of significant desaturation at the end of exercise would indeed translate into worse clinical outcomes. The proportion of subjects with COPD presenting desaturation only during but not at the end of the exercise was later reported by Fiore et al12 in 2011 (23%) and by Chuang et al13 in 2014 (46%) without following up longitudinal clinical outcomes.

Our data showed a prevalence of 19% of desaturation detected only during (but not at the end of) the exercise. These subjects presented a worse prognosis. Exercise desaturation is usually associated with more severe disease.5,7,8,23,30,31 Thus, adjustment for important survival confounders such as sex, the severity of ventilatory constraint, resting severe hypoxemia (as indicated by LTOT prescription), body composition, 6MWD, and comorbidities burden (COTE index) was important in assessing the independent effect of 6MWT desaturation.

Based on the abovementioned pathophysiological substrate, it is plausible that exercise desaturation may also signal other adverse clinical outcomes in COPD. Surprisingly, there is a paucity of data on the clinical consequences of exertional desaturation in subjects with this disorder. A Korean study did not observe any significant difference between subjects with and without desaturation regarding the proportion of subjects with a COPD exacerbation or requiring hospitalization due to exacerbation in the first year of follow-up.32 Another cohort from Norway, on the other hand, observed that subjects with oxygen desaturation during the 6MWT had an adjusted risk ratio for moderate/severe exacerbations of 1.6 (95% CI 1.1–2.2) compared with subjects with COPD who did not desaturate.30 In accordance, our data revealed a higher risk for hospitalization in those presenting exercise desaturation. Moreover, the proportion of subjects with one or more hospitalizations in the year following the 6MWT was higher among desaturators regardless of the criteria used. Walking desaturation, therefore, could signal future hospitalization risk in COPD.

The mechanism behind SpO2 recovery in some subjects presenting with significant desaturation during the test was not fully clarified. Resting during the test emerges as an obvious cause that indeed predicted the presence of desaturation only across the test. Although the prevalence of walking interruption proved higher in this group, 72% in the current study and 84% in a previous study12 did not rest during the test, raising the need for additional explanations. Replicating the findings from Chuang et al,13 our participants who “resaturated” at the end of the test had better FEV1, FEV1/FVC, and DLCO as well as lower resting lung volumes than those presenting desaturation at the end of the test (Table 1). We hypothesized that some subjects may have volitionally slowed down their pace close to the self-selected walking speed during daily activities where dyspnea perception is significantly lower than the speed requested to cover the highest possible distance during the 6 min of the test.33 Subjects presenting with exercise desaturation who reduced their walking pace in the context of a more preserved lung function may have allowed SpO2 recovery without walking interruption. Unfortunately, the lack of walking speed monitoring during the test is a limitation that is worthy to be explored in future research.

This study has other limitations. Exacerbations in the preceding year are known to be the primary predictor of subsequent exacerbations in COPD.34 Since we did not register exacerbations before our follow-up window, we were not able to adjust the statistical model for this potential confounder. It was also not registered the number of tests performed before the index 6MWT. However, whereas walking distance increases when a second test is performed,5,14 previous studies have not investigated whether a second test would have influenced the presence and reproducibility of desaturation. The prevalence of relevant cardiovascular comorbidities and severe resting hypoxemia (at least as inferred by the prescription of LTOT) was higher in groups presenting with exercise desaturation. Notwithstanding, the burden of comorbidities (COTE index) and the use of O2 during 6MWT were controlled in the Cox regression model, which continued to show the presence of exercise desaturation detected by either method significantly related to mortality. As a final methodological consideration, we should mention that a fall of 4% SpO2 during exercise was considered clinically meaningful: 1–2% accounting for the accuracy of pulse oximeters (motion artifacts, low perfusion in extremities) and 1–2% accounting for the potential shift to the right of the oxyhemoglobin dissociation curve due to exertional acidosis.35

Conclusions

O2 desaturation missed by end-6MWT SpO2 but exposed by nadir SpO2 measured during the test was found in 19% of the sample, predicting all-cause mortality as well as higher general and respiratory hospitalization risk in subjects with COPD.

Footnotes

  • Correspondence: Danilo C Berton MD PhD, Programa de Pós-Graduação em Ciências Pneumológicas, Universidade Federal do Rio Grande do Sul, Unidade de Fisiologia Pulmonar, Serviço de Pneumologia, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, 2350, Sala 2050, CEP 90035–003, Porto Alegre, RS, Brasil. E-mail: dberton{at}hcpa.edu.br

  • The authors have disclosed no conflicts of interest.

  • Dr Berton presented a version of this manuscript at the European Respiratory Society International Congress 2021, held virtually September 5−8, 2021.

  • The study was supported by Incentive Fund of Research of Hospital de Clinicas de Porto Alegre (grant number: 20200207); Dr Berton receives a research fellowship from the Brazilian National Council for Scientific and Technological Development (grant number: 304061/2019-0).

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