Effect of Maximal Oxygen Pulse on Patients with Chronic Obstructive Pulmonary Disease＊

LI Yun Xiao,WANG Jun,WU Bo,LIN Fang,TAN Chun Ting,YU Gang Gang,NIE Shan,ZHAO Ran Ran ,and XU Bo

Department of Respiratory Medicine,Capital Medical University Affiliated Beijing Friendship Hospital,Beijing 100050,China

Abstract Objective This study evaluated the effect of maximal oxygen pulse (O2Pmax) on patients with chronic obstructive pulmonary disease (COPD) and confirmed the predictive effect on acute exacerbations of COPD (AECOPD).Methods This retrospective study included 91 participants who underwent cardiopulmonary exercise testing (CPET),lung function testing,a dyspnea scale assessment,and a 3-year follow-up.The participants were divided into two groups according to the O2Pmax value.Exercise capacity,ventilatory conditions,gas exchange efficiency,and dyspnea symptoms were compared,and the correlations between O2Pmax and these indices were evaluated.The ability of O2Pmax to predict AECOPD was examined.Results Exercise capacity,ventilatory conditions,and gas exchange efficiency were lower,and dyspnea symptom scores were higher in the impaired O2Pmax group (P ＜ 0.05).O2Pmax was positively correlated with forced vital capacity (FVC)%,forced expiratory volume in 1 sec (FEV1)%,FEV1/FVC%,anaerobic threshold (AT),work rate (WR)%,aximal oxygen uptake (V˙O2max)%,V˙O2/kgmax,V˙O2/kgmax%,WRAT,WRmax,V˙O2AT,V˙O2max,and V˙Emax,and was negatively correlated with EqCO2AT,and EqCO2max (P ＜ 0.05).Most importantly,O2Pmax could be used to predict AECOPD,and the best cut-off value was 89.5% (area under the curve,0.739;95% CI,0.609-0.869).Conclusion O2Pmax reflected exercise capacity,ventilation capacity,gas exchange capacity,and dyspnea symptoms in patients with COPD and may be an independent predictor of AECOPD.

Key words: Oxygen pulse;Chronic obstructive pulmonary disease;Cardiopulmonary exercise test;Acute exacerbation

INTRODUCTION

Chronic obstructive pulmonary disease(COPD) is a common,preventable,and treatable disease characterized by persistent airflow limitation.The chronic airflow limitation progressively traps gas during expiration,resulting in hyperinflation,increased dyspnea,and limitations in exercise capacity.Acute exacerbation of COPD (AECOPD) is defined as an acute worsening of respiratory symptoms necessitating additional therapy.The severity of AECOPD and its increasing frequency is associated with a higher risk of death[1].However,there is a lack of effective indicators to predict AECOPD.A deteriorating airflow limitation is associated with an increasing prevalence of exacerbations[2].Forced expiratory volume in 1 sec(FEV1) is an indicator of airflow limitation,but it lacks sufficient precision to be used clinically as a predictor of exacerbation or mortality in patients with COPD[3].Only a weak correlation is observed between FEV1,symptoms,and impaired health status of patients[4].Thus,it is important to explore other effective indicators for predicting AECOPD.

Exercise capacity is limited in COPD patients and is significantly correlated with overall survival[5].The probable mechanisms include impaired oxygen delivery to skeletal muscle and ventilatory limitations[6].Cardiopulmonary exercise testing (CPET) is used to assess exercise tolerance and evaluate the pathophysiological mechanism(s) of dyspnea and exercise limitation in patients with COPD[7].Oxygen pulse (O2P),an important CPET variable,is a noninvasive and reliable method used to estimate stroke volume and cardiac function[8]with the exclusion of coexisting diseases,but it has rarely been used to evaluate the severity of COPD.O2P is defined as oxygen uptake (V˙O2) divided by heart rate (HR).One study showed that O2P is impaired during exercise in patients with COPD,and this is partly related to lung hyperinflation[9].Miniati et al.[10]reported that peak O2P is significantly lower in patients with moderate to severe emphysema than in those with no or mild emphysema.Thus,O2P may be an important indicator for differentiating COPD severity.O2Pmaxrepresents the O2P at maximal exercise and reflects the maximal aerobic metabolic function.O2Pmaxis extensively used for testing patients with cardiovascular diseases,but it has limited use in those with COPD.Furthermore,increased hyperinflation and gas trapping occur during an exacerbation,with reduced expiratory flow[11].A worsening of gas exchange can also result in hypoxemia[12].O2P is directly related to hyperinflation and reflects gas exchange,so O2P may be a better predictor of AECOPD.Accordingly,we hypothesized that O2Pmaxhas a role in COPD and may be related to AECOPD.

In this study,we examined the relationship between O2Pmaxand exercise capacity,ventilatory conditions,gas exchange efficiency,and healthrelated quality of life (HRQL).We also estimated the predictive value of O2Pmaxfor AECOPD and determined the cut-off value.

MATERIALS AND METHODS

Study Design

This retrospective analysis involved patients with COPD who underwent incremental cardiopulmonary exercise in our exercise laboratory at Beijing Friendship Hospital,Capital Medical University(Beijing,China) from 1 January 2017 to 31 December 2020.This study was conducted in compliance with the Declaration of Helsinki.The Institutional Ethics Committee of Beijing Friendship Hospital of Capital Medical University approved this study (no.2021-P2-334-01).

Participants

All participants were men and women aged ≥ 40 years with a body mass index of 18-32 kg/m2and no episodes of AECOPD within the previous 6 weeks.All of the participants had been diagnosed with COPD and a grade I,II,III,or IV airflow limitation according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria and underwent CPET in our clinic.After enrollment,the participants’ smoking history,comorbidities (hypertension,coronary heart disease,type 2 diabetes,and hypercholesterolemia),medications used for COPD,and medications used for cardiovascular disease were recorded.The patients were followed up outside of the hospital by telephone.AECOPD was classified as mild (treated with short-acting bronchodilators only),moderate(treated with short-acting bronchodilators plus antibiotics and/or oral corticosteroids),or severe(required hospitalization or visits to the emergency room)[13].The exclusion criteria were respiratory diseases other than COPD,heart failure,uncontrolled diabetes mellitus,uncontrolled hypertension,orthopedic problems,neurologic problems,and hemopathy.

Pulmonary Function Testing

All participants underwent static spirometry(MasterScreen Body;CareFusion,San Diego,CA,USA),including measurements of FEV1,forced vital capacity (FVC),vital capacity (VC),peak expiratory flow,and maximal mid-expiratory flow rate 75/25.Body plethysmography was performed to measure the residual volume (RV),total lung capacity (TLC),and the transfer factor of the lungs for carbon monoxide/alveolar volume.All pulmonary function tests were performed according to the American Thoracic Society/European Respiratory Society guidelines[14].

CPET

CPET was performed according to the American Thoracic Society/European Respiratory Society guidelines[15].All patients rested for 3 min,performed unloaded pedaling for 3 min,and then underwent an incremental,symptom-limited exercise test using an electronically braked cycle ergometer (ViaSprint,CareFusion,Hoechberg,Germany) at a pedaling rate of 40-70 rpm(approximately 60 rpm).The work rate (WR) was set to 5-20 W/min and was gradually increased by 5-15 W/min (5 W/min if FEV1＜ 1.0 L and 10 W/min if FEV1≥ 1.0 L).The test ended when the cadence fell below 40 rpm and did not return with an exhortation,the patients requested termination,or the technician terminated the test for safety[16].The limiting symptom was defined as the inability to maintain pedaling frequency or the development of intolerable shortness of breath.Chest pain(suggesting myocardial ischemia),ventricular tachycardia,and blood pressure (BP) ≥ 240/130 mmHg also prevented further exercise.The O2Pmaxwas defined as V˙O2max/HR.According to the current guidelines[17],O2Pmaxvalues ≥ 80% of the predicted value were considered normal,whereas O2Pmax＜ 80% of the predicted value was considered pathological.Accordingly,Group 1 was defined as patients with impaired O2Pmax(＜ 80% predicted),and Group N was defined as patients with normal O2Pmax(≥ 80% predicted).V˙O2,carbon dioxide production (V˙CO2),minute ventilation (V˙E),breathing reserve (BR),and 12-lead electrocardiography were measured continuously.BP was measured at the end of every 2 min.Load was reported at maximum exertion.V˙O2/kg,the ventilatory equivalent for carbon dioxide (EqCO2),and HR recovery after 1 min of rest (HRR1) were calculated automatically.The anaerobic threshold(AT) was identified using the modified V-slope method.

Dyspnea and Symptom Assessment

The COPD Assessment Test (CAT) and the St.George’s Respiratory Questionnaire (SGRQ) were used to measure the impaired health status of patients with COPD.The SGRQ includes four categories,such as symptoms,physical activities,psychosocial impacts,and the total score.The CAT total score ranges from 0 to 40,and the SGRQ total score ranges from 0 to 100.An SGRQ score ≥ 25 was used as the threshold for breathlessness,and the equivalent cut-off point for the CAT was 10[13].The modified British Medical Research Council Questionnaire (mMRC) was used to assess dyspnea severity.The mMRC score ranges from 0 to 5,and≥ 2 was considered the threshold for separating“l(fā)ess breathlessness” from “more breathlessness.”Because our patients were using mouthpieces and could not conveniently answer the doctors’questions during exercise,the dyspnea level and leg muscle fatigue were scored using Borg’s 10-point category-ratio scale (Borg CR10 scale) after the patients finished exercising.A Borg CR10 scale score of 4-6 indicated moderate to severe symptoms.

AECOPD Follow-up

Fifty-seven patients (63%) completed the 3-year follow-up.AECOPD was tracked during the next 3 years.Telephone calls were made to the patients every 4 months to determine whether they had experienced any exacerbations,had taken any shortacting bronchodilators,antibiotics,or oral corticosteroids,or had been hospitalized.According to the GOLD[13],patients with AECOPD (AE2 group)developed more than one acute exacerbation episode within 1 year.Patients without AECOPD(AE1 group) had developed no or only one acute exacerbation episode within the year.

Statistical Analysis

Continuous data were expressed as mean ±standard deviation,number,and percentage,or median (IQR),while categorical data were expressed as frequencies and percentages.Continuous data were compared using thet-test or Mann-Whitney test,and categorical data were compared using the chi-square test.AP-value ＜ 0.05 was considered significant.

Pearson’s correlation coefficient (r) was used to assess the correlations between the static lung function variables (FEV1/FVC%,FEV1%,FVC%,and VC) and the CPET variables (AT%,WRAT,WRmax,WR%,V˙O2AT,V˙O2max,V˙O2%,V˙O2/kgmax,V˙O2/kg%,V˙Emax,V˙E%,BRAT,BRmax,EqCO2AT,EqCO2max,and HRR1) and O2Pmax.

Univariate logistic regression analysis was performed to assess the efficiency of O2Pmaxfor predicting AECOPD.Static lung function and CPET variables that were significantly different between the AE2 and AE1 groups were assessed to identify risk factors for AECOPD using multivariate logistic regression analysis.Wald’s test was used to obtain the logistic regression parameters.

The discriminative ability of O2Pmaxin predicting AECOPD was evaluated by receiver operating characteristic (ROC) analysis.The area under the ROC curve (AUC) and the 95% confidence interval(CI) were calculated.The best cut-off value was determined.

RESULTS

Patient Demographics and Characteristics

Table 1shows the patient demographics and baseline characteristics.Ninety-one patients with COPD were divided into Group 1 (n=27) and Group N (n=64) according to their O2Pmaxvalue.No significant differences in age,sex,body height,body mass index,smoking history,comorbidities,or medications were observed between the two groups.However,significant differences in body weight and classification of the airflow limitation were detected between the two groups (P＜ 0.05).The airflow limitation was more severe in Group 1 than in Group N.

Differences in Static Lung Function

Table 2shows the static lung function parameters.Patients with a lower O2Pmaxhad lower FVC%,VC%,FEV1%,and FEV1/FVC% values(P＜ 0.05).

Differences in CPET

Table 3shows the CPET variables.AT,WR,V˙O2,V˙O2/kg,HR,systolic BP,diastolic BP,V˙E,BR,and EqCO2were measured at the AT and maximum exercise during CPET.HRR1was calculated after the exercise.Significant differences in AT,WR%,V˙O2%,V˙O2/kg%,V˙E%,EqCO2AT,and EqCO2maxwere observed between the two groups (P＜ 0.05).Among these variables,EqCO2ATand EqCO2maxwere higher in patients with impaired O2Pmax,whereas the other variables were lower.Significant differences were also detected in HRR1(P＜ 0.05),which was regarded as a circulatory parameter.

Disease-specific Health Status Questionnaires

Table 4shows the CAT,mMRC,Borg CR10 scale,and SGRQ scores.The Borg CR10 scale,SGRQ total,SGRQ symptom,and SGRQ activity scores were significantly higher in Group 1 than those in Group N(P＜ 0.05).

Correlation between O2Pmax and FEV1/FVC%,FEV1%,and FVC%

Figure 1shows the correlation coefficients between O2Pmaxand FEV1/FVC%,FEV1%,and FVC%,which were regarded as lung ventilation function variables.O2Pmaxwas slightly but significantly correlated with FEV1/FVC% (r=0.207,P＜ 0.05),FEV1% (r=0.267,P＜ 0.05),and FVC% (r=0.288,P＜0.01).

CPET Variables

Figure 2shows the correlation coefficients between O2Pmaxand the CPET variables.O2Pmaxwas positively correlated with AT (r=0.623,P＜ 0.001),WR% (r=0.613,P＜ 0.001),V˙O2max% (r=0.681,P＜0.001),V˙O2/kgmax% (r=0.707,P＜ 0.001),and V˙Emax%(r=0.399,P＜ 0.001),but negatively correlated with EqCO2AT(r=-0.302,P＜ 0.01) and EqCO2max(r=-0.214,P＜ 0.05).

Comparison between the AE1 and AE2 Groups

Table 5shows that FVC%,FEV1%,O2Pmax%,WRmax,and V˙O2maxwere significantly lower in the AE2 group than in the AE1 group (P＜ 0.05).

Logistic Regression Analysis

The univariate logistic regression confirmed that O2Pmaxwas an independent predictor of AECOPD[odds ratio (OR),1.068;95%CI,1.023-1.116;P=0.003].Five variables (FVC%,FEV1%,O2Pmax,WRmax,and V˙O2max) were used to build a logistic regression model to predict AECOPD in a multivariate analysis(Tables 6-7).Only O2Pmaxwas a predictor of AECOPD(OR=1.062,95%CI=1.012-1.114,P=0.015).ROC curve analysis was applied to categorize the optimal cut-off value of O2Pmaxfor exacerbation (Figure 3).The AUC was 0.739 (95%CI=0.609-0.869,P=0.002).The cut-off value was 89.5%,with a sensitivity of 63.30% and a specificity of 77.80%.

Figure 3.ROC curve of O2Pmax as an overall predictor of AECOPD.Abbreviations: AUC,area under the ROC curve;CI,confidence interval.

Table 5.Characteristics,pulmonary function,and CPET data of the patients with COPD grouped in acute exacerbation

Table 6.Multivariate logistic regression analysis of lung function and the CPET data in patients with AECOPD

Table 7.Univariate logistic regression analysis of O2Pmax in patients with AECOPD

Figure 1.Correlations between O2Pmax and FEV1/FVC%,FEV1%,and FVC%.Abbreviations: O2P,oxygen pulse;FEV1,forced expiratory volume in 1 sec;FVC,forced vital capacity.

Figure 2.Correlations between O2Pmax and the CPET parameters Abbreviations: O2P,oxygen pulse;AT,anaerobic threshold;WR,work rate;V˙O2,oxygen uptake;V˙O2/kg,oxygen uptake per kilogram;V˙E,minute ventilation;EqCO2,ventilatory equivalent for carbon dioxide.

Table 1.Baseline characteristics of Group 1 (O2Pmax ＜ 80% predicted) and Group N (O2Pmax ≥ 80% predicted)

Table 2.Differences in the static lung function test parameters between Group 1 (O2Pmax ＜ 80% predicted) and Group N (O2Pmax ≥ 80% predicted)

Table 3.Differences in the CPET parameters between Group 1 (O2Pmax ＜ 80% predicted) and Group N(O2Pmax ≥ 80% predicted)

Table 4.Differences in the dyspnea scores between Group 1 (O2Pmax ＜ 80% predicted) and Group N(O2Pmax ≥ 80% predicted)

DISCUSSION

The main finding of the present study was that impaired O2Pmaxin patients with COPD indicated an impaired ventilatory condition,gas exchange efficiency,exercise capacity,and HRQL.The correlation analysis showed that O2Pmaxwas correlated with FEV1/FVC%,FEV1%,FVC%,WR,AT,V˙O2,V˙O2/kg,V˙E,and EqCO2.Moreover,O2Pmaxwas significantly different between the AE2 and AE1 groups,which was a new finding.The univariate and multivariate logistic regression analyses demonstrated for the first time that O2Pmaxpredicted AECOPD (OR1.068,95%CI=1.023-1.116).The optimal O2Pmaxcut-off value was 89.5%.The AUC was 0.739 (0.609-0.869) with a sensitivity of 0.633 and a specificity of 0.778.

V˙O2represents metabolic efficiency,and WR represents exercise capacity.The AT represents a transition point from aerobic to anaerobic metabolism,and a lower AT indicates reduced oxygen delivery to muscle cells.Declines in AT%,WR,and V˙O2contribute to exercise intolerance[18].The present study indicated that AT,WR%,V˙O2%,V˙O2/kg%,and V˙E% were lower in Group 2 than those in Group 1 (impaired O2Pmaxgroup).This findingsuggests that O2Pmaxmight be an effective indicator for estimating exercise capacity.Patients with COPD develop dynamic hyperinflation during exercise.Dynamic hyperinflation can reduce left ventricular stroke volume secondary to the increased intrathoracic pressure,which,in turn,decreases preload by reducing venous return and the volume of the left ventricle.This explains why O2Pmaxis impaired in patients with COPD.Hyperinflation leads to limited cardiac performance,which occurs when there is a mechanical limitation to an increase in V˙E.Therefore,dynamic hyperinflation in patients with COPD may adversely affect exercise tolerance by reducing O2Pmax.Moreover,lung hyperinflation impairs cardiopulmonary interactions and leads to impaired muscle oxygen availability during exercise.Research has also shown that impaired circulation is not usually a limiting factor for exercise intolerance in patients with COPD[6].Thus,O2Pmaxmay be a predictor of exercise capacity independent of cardiovascular function.The present study also demonstrated that O2Pmaxwas highly positively correlated with AT,WR%,V˙O2max%,and V˙O2/kg%.Montes de Oca et al.[16]showed that inspiratory intrathoracic pressure has a direct relationship with O2P at peak exercise in patients with severe COPD.Torres-Castro et al.[19]reported that V˙O2peakand Wmaxdecrease in patients with COPD and pulmonary hypertension,in line with the decrease in O2P.An inadequate increase in stroke volume may contribute to the inability of V˙O2to increase.These results explain why V˙O2was positively correlated with O2Pmax.WR and O2Pmaxrepresent exercise capacity;thus,it is easy to understand why O2Pmaxwas positive correlated with WR.In addition,the circulatory system is responsible for oxygen delivery.When the metabolic demands begin to exceed oxygen delivery to contracting muscles,anaerobic metabolism begins.The AT is the exercise level that reflects the metabolic condition of anaerobic glycolysis[20].A lower AT is observed if a patient’s oxygen consumption efficiency is poor.The AT reflects oxygen consumption efficiency,and circulatory function can be used to determine theAT.This explains why O2Pmaxwas associated with the AT in our study.

The present study also illustrated that O2Pmaxcan be used to assess a ventilation obstruction.FVC%,VC%,FEV1%,FEV1/FVC%,V˙E%,and BRATwere lower,and EqCO2ATand EqCO2maxwere higher in patients with impaired O2Pmaxthan in those without impaired O2Pmax.Additionally,O2Pmaxwas negatively correlated with EqCO2AT,and EqCO2maxwas positively correlated with FEV1/FVC%,FEV1%,FVC%,and V˙Emax%.Our data corroborate the findings of Fraz?o et al.[21],who reported that the ability to increase V˙Eduring aerobic exercise is impaired in patients with COPD because exhalation may not be completed prior to the onset of the next breath,causing an increase in operational lung volume and progressive air retention.EqCO2is a measure of ventilatory efficiency and is calculated as V˙Edivided by V˙CO2.EqCO2symbolizes the capacity to remove carbon dioxide.In patients with COPD who develop impaired O2Pmax,these higher EqCO2values may be explained by disproportional reductions in V˙Eand perfusion.The decrease in ventilation and perfusion are different[21],and perfusion may have a higher degree of reduction in patients with impaired O2Pmax.The correlations between V˙Emax%,EqCO2AT,EqCO2max,and O2Pmaxcan be explained by the fact that airflow limitation impairs cardiac function[21].The increase in inspiratory intrathoracic pressure decreases lung elastic recoil pressure.The combined effects of decreased lung elastic recoil pressure and increased airway resistance result in reduced V˙Eand the development of hyperinflation[21].Improvement in ventilatory mechanics results in improved cardiac function,which manifests as a decrease in HR with improved O2P[22].Lung hyperinflation also causes mechanical constraints on the heart and a reduction in preload[23].These interactions between hyperinflation,ventilation and cardiac function may explain why O2Pmaxwas positively correlated with V˙Emax%.EqCO2was negatively correlated with V˙E,and O2Pmaxwas negatively correlated with EqCO2.

The positive correlations between FEV1/FVC%,FEV1%,FVC%,and O2Pmaxcan be explained by the fact that the decreases in FEV1/FVC%,FEV1%,and FVC% contribute to lung hyperinflation,which,in turn,reduces left ventricular stroke volume.Furthermore,O2P is negatively correlated with lung hyperinflation[24],and lung hyperinflation is negatively correlated with FEV1[25].In addition,Silvestre et al.[26]suggested that the association between lung function and exercise capacity may be related to specific abnormalities in cardiopulmonary performance.All of these findings support the relationships between FEV1/FVC%,FEV1%,FVC%,and O2Pmax.BR reflects the respiratory reserve capacity during extreme exercise,and a lower BR is the main feature of ventilation limitation in patients with pulmonary disease.It is calculated as the maximum ventilatory volume minus V˙E.BRdecreases in patients with COPD but increases in those with cardiovascular disease.The present study showed that BR decreased in patients with impaired O2Pmax,whereas no correlation was detected between BR and O2Pmax.This finding could indicate that the decreased O2Pmaxin patients with COPD is not only caused by reduced filling of the ventricles but may also be attributable to other mechanisms.

HRR is a marker of cardiac autonomic function independent of the workload and the change in HR during exercise.A low HRR is a common finding in patients with impaired lung function and is associated with decreased survival in patients with COPD[27].In these patients,autonomic nervous dysfunction contributes to the increased work of breathing,which promotes a wider airway caliber[27].HRR1is defined as the decrease from peak HR to 1 min of recovery and is an independent predictor of morbidity and all-cause mortality[28].To our knowledge,no study has explored the correlation between HRR1and O2P in patients with COPD until now.Our present results indicate that HRR1decreased significantly in patients with impaired O2Pmax.This may be attributed to the fact that both parameters are regulated by the autonomic nervous system,and an increase in sympathetic tone and/or a decrease in parasympathetic tone may reduce HRR1and contribute to tachyarrhythmia.

COPD is largely characterized by breathlessness.The mMRC is considered adequate for assessing breathlessness symptoms.However,COPD affects patients beyond dyspnea.The SGRQ is the most comprehensive disease-specific health status questionnaire.The CAT is simpler.The Borg CR10 scale is mainly used to evaluate dyspnea and leg muscle fatigue during maximum exercise[29].Because our patients had instruments in their mouths and could not conveniently answer questions during exercise,we evaluated the patients using the Borg CR10 scale at the end of the exercise.As a result,the Borg CR10 scale score and the SGRQ symptom,activity,and total scores were higher in the O2Pmaximpaired group than those in the other groups.Souza et al.[30]showed that patients with COPD who had lower activities of daily living exhibit lower O2P,which may reflect the presence of a limiting cardiac component.Lan et al.[31]indicated that the increased O2Pmaxis accompanied by improvements in the SGRQ.Therefore,O2Pmaxis a valid indicator of HRQL and should be measured in patients with COPD.This may be attributed to the increase in right ventricular afterload during exercise,impairing stroke volume,which was augmented by increased intrathoracic pressure swings and is related to O2Pmax[32].

AECOPD is associated with an increased risk of death[33].It is defined as an acute worsening of respiratory symptoms that results in additional therapy[34].AECOPD is classified as mild (treated with short-acting bronchodilators only),moderate(treated with short-acting bronchodilators plus antibiotics and/or oral corticosteroids),or severe(requires hospitalization or an emergency room visit).No effective indicator has been established to predict AECOPD.History of earlier AECOPD may be a predictor of frequent exacerbations[35].Deteriorating airflow limitation is associated with an increasing prevalence of exacerbations[2],but FEV1lacks sufficient precision to be used clinically as a predictor of exacerbations or mortality in patients with COPD[36].A novelty of our study is that O2Pmaxwas an effective predictor of AECOPD,and,to the best of our knowledge,this is the first study to identify the O2Pmaxcut-off value for predicting AECOPD.Wu et al.[37]reported that patients with impaired peak O2P were hospitalized more frequently during a 1-year follow-up.In the present study,the O2Pmaxdecreased in the AE2 group.Multivariate and univariate logistic regression analyses showed that O2Pmaxpredicted AECOPD.We used a ROC curve to determine the best cut-off value of O2Pmaxfor AECOPD (89.5%).The AUC was 0.739(0.609-0.869) with a sensitivity of 0.633 and a specificity of 0.778.Our findings indicate moderate accuracy of O2Pmaxfor predicting AECOPD.Further research is needed to validate whether O2Pmax,in combination with other parameters,would increase the accuracy of prediction.Nevertheless,it is important to inform patients of the high risk of acute exacerbations once the CPET reveals an impaired O2Pmaxvalue (＜ 89.5%).Doctors should choose higher-level treatment strategies for these patients.

Why lower O2Pmaxis associated with more frequent AECOPD is not entirely clear.To our knowledge,progressive respiratory failure,cardiovascular disease,and other diseases are the primary cause of death in patients with COPD hospitalized for an exacerbation[36].In addition,deteriorating airflow limitation is associated with an increasing prevalence of exacerbations[2].Hyperinflation and gas trapping increase with the reduced expiratory flow during exacerbations[11].Therefore,the association between impaired O2Pmaxand AECOPD may be related to hyperinflation,which can be caused by airflow limitation and is associated with poor cardiac function.A larger scale study is needed to validate the role of O2Pmaxin the risk of AECOPD.

This study had several limitations.First,this was a retrospective study,and not all of the patients finished the 3-year follow-up for AECOPD.Additionally,the sample size was small.Second,O2Pmaxis an effective indicator of cardiac function and muscle function,but the echocardiographic parameters and stroke volume were not tested.Third,we did not measure dynamic lung hyperinflation parameters,such as the endexpiratory lung volume,inspiratory capacity,or RV using CPET.Thus,the evidence indicating that O2Pmaxis related to dynamic lung hyperinflation is insufficient.Fourth,because not all of the enrolled patients underwent hemoglobin concentration and blood gas analyses,we did not consider these factors in the analysis.Hemoglobin is very important for oxygen carrying capacity,and blood gas values reflect disease severity to some extent.Nevertheless,our current study found that an indicator can play a role in the assessment of COPD severity and prognosis.

CONCLUSION

This present study illustrated that impaired O2Pmaxindicates impairments in exercise capacity,ventilatory condition,gas exchange efficiency,and HRQL.The most important finding was that O2Pmaxwas an independent predictor of AECOPD.This is the first study to identify the O2Pmaxcut-off value.

ACKNOWLEDGMENTS

We thank Professor Zhengyuan Xia from the State Key Laboratory of Pharmaceutical Biotechnology,Department of Medicine,The University of Hong Kong,and Department of Anesthesiology,Affiliated Hospital of Guangdong Medical University,for revising the content of the article;and thank Angela Morben,DVM,ELS,from Liwen Bianji (Edanz) (www.liwenbianji.cn/),for editing the English text of a draft of this manuscript.We also thank Hao Wang,from Beijing Friendship Hospital,for guiding the statistical methods.

AUTHORS’ CONTRIBUTIONS

ZHAO Ran Ran and XU Bo designed the study together.LI Yun Xiao drafted the whole manuscript.WANG Jun,WU Bo,and LIN Fang performed the data analyses.TAN Chun Ting,YU Gang Gang,and NIE Shan followed up the patients.ZHAO Ran Ran and XU Bo contributed equally to this work.All authors read and approved the final manuscript.

COMPETING INTERESTS

The authors declare that they have no competing interests.

Received:May 8,2022;

Accepted:August 3,2022