Physical frailty and pulmonary rehabilitation in COPD: a prospective cohort study

Participants and design

Participants were recruited to this prospective cohort study from respiratory outpatient and pulmonary rehabilitation clinics at Harefield Hospital (Middlesex, UK) between November 2011 and January 2015. Eligible patients were aged 35 years or above, with a physician diagnosis of COPD consistent with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria¹⁹ and appropriate for a pulmonary rehabilitation referral. Exclusion criteria were an exacerbation in the previous 4 weeks that required a change in medication, a condition that might make moderate-intensity exercise unsafe, for example, unstable cardiac disease or a predominant neurological disability. Treating clinicians identified potentially eligible patients and offered a written information sheet. Referral criteria for pulmonary rehabilitation were able to walk at least 5 m, any degree of functional impairment secondary to dyspnoea (typically Medical Research Council (MRC) dyspnoea score 2 or more), no previous supervised pulmonary rehabilitation in previous 12 months and without unstable cardiovascular disease, in line with British Thoracic Society Quality Standards.²⁰ Data for some participants (528/816, 64.7%) relating to sarcopenia, but not frailty, have been reported previously.¹⁵ All participants gave written informed consent in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki, and the study was approved by the West London (11/H0707/2) and London Camberwell St Giles (11/LO/1780) Research Ethics Committees.

Frailty assessment

Frailty was defined using the Fried phenotype model,⁹ which is well established and validated in large epidemiological studies.³ This model comprises five characteristics that reduce physiological reserve and precipitate a vulnerable state; shrinking (unintentional weight loss), exhaustion, low physical activity, slowness and weakness.⁹ Characteristics were assessed by weight loss history, two questions from the Center for Epidemiological Studies-Depression (CES-D) questionnaire (exhaustion),²¹ weekly self-reported energy expenditure using the modified Minnesota Leisure-Time Physical Activity Questionnaire (low physical activity),²² 4-m gait speed (4MGS, slowness)²³ and handgrip dynamometry (weakness). Standardised criteria, derived from the original reference cohort,⁹ were used to define each characteristic as either present or absent for each patient (see online supplementary table S1), providing an ordinal score ranging 0–5. Patients with no criteria present were considered not-frail/robust, those meeting 1–2 criteria were considered prefrail and those with ≥3 criteria present were considered frail.

Additional assessments

Bioelectrical impedance analysis (Quadscan 4000, Bodystat, Isle of Man, UK) was used to estimate skeletal muscle mass index (SMI).²⁴ The presence of sarcopenia was defined according to the consensus European Working Group on Sarcopenia in Older People criteria.²⁵ Quadriceps maximum voluntary contraction (QMVC) was measured using a fixed strain gauge,²⁶ with weakness diagnosed according to healthy predicted values²⁷ and sex-specific functionally relevant cut-points.²⁸ Exercise performance was assessed using the incremental shuttle walk test (ISWT).²⁹ Further measurements included evaluation of respiratory disability by MRC dyspnoea score, comorbidity burden using the age-adjusted Charlson Index,³⁰ help with activities of daily care using the Katz Index,³¹ composite disease severity by the age, dyspnoea, and airflow obstruction (ADO) index,³² Hospital Anxiety and Depression Scale (HADS) and health status using the self-reported Chronic Respiratory Questionnaire (CRQ)³³ and COPD Assessment Test (CAT).³⁴

Pulmonary rehabilitation

Pulmonary rehabilitation was an 8-week outpatient exercise and multidisciplinary education programme, comprising two supervised and at least one additional home-based session each week and organised according to the British Thoracic Society Quality Standards for Pulmonary Rehabilitation.²⁰ Supervised sessions comprised 1 hour of exercise and 45 min of education. Exercise training was individualised and progressive. Initial walking speed prescription was at 80% of predicted peak oxygen consumption based on ISWT performance,³⁵ while initial endurance cycling was set at a workload with the aim of patients completing 10 min of continuous training. Lower limb resistance training comprised 2 sets of 10 seated leg press repetitions, performed with an initial training load of 60% one-repetition maximum, as well as sit-to-stand, knee extension, hip flexion and hip abduction exercises with ankle weights. Upper limb resistance training comprised biceps curls, shoulder press and upright row with free weights. Education was delivered by a multidisciplinary team. Topics were chosen to develop patients' understanding and holistic management of their disease and included physical activity and exercise, medication use, diet, smoking cessation, coping strategies, as well as managing infections through early recognition, rescue medication and appropriate general practice/hospital presentation.

Statistical analysis

Our sample size was based on the precision to which the overall prevalence of frailty could be estimated. Assuming it was within the range 10%–60%, prevalence could be estimated to within ±3.5% using 800 participants with a large sample normal approximation (nQuery Advisor V.6.0). Analyses were performed using SPSS (V.22, IBM, New York, USA) and graphs produced using Prism 5 (GraphPad Software, San Diego, California, USA). Data were presented as proportions (95% CIs) or mean (SD).

The prevalence of frailty was determined overall and then compared across groups according to age, GOLD spirometry stage, MRC dyspnoea score and age-adjusted Charlson comorbidity score using χ² for trend. Baseline characteristics as well as pulmonary rehabilitation uptake, attendance and completion rates were compared across groups (not frail/robust, pre-frail, frail) using one-way analysis of variance or χ² for trend with a Bonferroni correction applied to post hoc pairwise comparisons. Uptake was defined as the proportion of assessed patients who attended the first supervised session, adherence was assessed using the number of supervised sessions attended and completion was defined as the proportion of patients who had documented attendance at a minimum of eight supervised sessions, representing 50% attendance.³⁶

Univariate logistic regression was used to assess the relationships between non-completion, frailty status (not or prefrail/frail) and candidate explanatory variables informed from existing literature and clinical judgement.^{17 18} Variables associated with non-completion (p<0.15) were considered in a multivariate model. After checking for collinearity (r<0.75), we used a backwards conditional approach to retain variables in the model (p<0.10). Outcomes of rehabilitation were summarised as change pre-to-post rehabilitation for patients who completed as per the above definition. Outcomes were then compared across groups using analysis of covariance adjusting for age and sex. To control for Type I errors in view of multiple testing, we applied a Bonferroni correction to a significance level of 0.05 when comparing baseline patient characteristics and rehabilitation outcomes.

Prevalence of frailty

Eight-hundred and sixteen patients took part (484 men, mean (SD) age 70 (10) years, FEV₁ 48.9 (21.0) % predicted, MRC score 3.3 (1.0)) (table 1). The overall prevalence of frailty was 25.6% (95% CI 22.7% to 28.7%), while 10.0% (95% CI 8.2% to 12.3%) of patients did not meet any of the frailty criteria and were considered robust (figure 1). Of the frailty characteristics, the exhaustion criterion was met by the largest proportion of patients (65.3%) followed by weakness, low physical activity and slowness. The unintentional weight loss criterion was met by fewest patients (14.2%) (table 1). Frailty tended to be more common among women than men (29.7% vs 22.8%, p=0.08). Prevalence increased statistically with increasing age (p<0.001), GOLD stage (p=0.01), MRC score (p<0.001) and comorbidity burden (p=0.004). There was a twofold increase in frailty prevalence among patients with GOLD stage IV as compared with stage I disease (34.7% vs 17.9%, p<0.001) and a threefold increase among patients with an MRC score of 5 as compared with a score of 3 (62.1% vs 21.0%, p<0.001; figure 2).

The COPD frailty phenotype

Patients who were frail with COPD had significantly reduced SMI but not body mass index as compared with prefrail or robust patients (table 1). Reduced physical function was evident beyond the characteristics used to define frailty, with reduced QMVC and ISWT performance, and a greater prevalence of sarcopenia (23.9% vs 9.5% in the prefrail group and 1.2% in the robust group, p<0.001). Patients who were frail reported a worse health status across all instruments and domains, and higher levels of anxiety and depression as compared with patients who were not-frail and prefrail (table 1). Among patients with QMVC measurements (n=707), almost three-quarters (73.1%) of patients who were frail had concurrent quadriceps weakness,²⁰ while only 25.0% had concurrent sarcopenia. Similar proportions of patients who were frail had both (14.4%) or neither (16.3%) of these phenotypes.

Engagement in pulmonary rehabilitation

Overall rates of programme uptake and completion for the cohort were 84.7% (95% CI 82.0% to 87.0%) and 70.3% (95% CI 67.1% to 73.4%), respectively, and mean (SD) attendance was 11.4 (4.2) of 16 supervised sessions (table 1). Rates were lowest in the frail group such that 55.0% of candidates completed rehabilitation, as compared with 74.5% of prefrail and 84.1% of not frail/robust candidates (p<0.001). In the univariate regression age, MRC score, FEV₁% predicted, Charlson Index, ISWT, QMVC, ADO, CAT score, HADS anxiety and depression, and frailty status were associated with non-completion. Each of the frailty characteristics was individually associated with non-completion though the relationship was strongest when frailty status was considered overall (table 2). In the multivariate regression, frailty status, age, ISWT and CAT score were retained in the final model. Frailty was a strong independent predictor and being frail was associated with double the odds of non-completion; adjusted OR 2.20 (95% CI 1.39% to 3.46%), p=0.001 (table 2). When examining reasons for not taking up or completing a programme, proportionally more frail patients experienced deterioration in their condition or were admitted to hospital (figure 1). Among patients who were frail, baseline MRC score was higher in non-completers as compared with completers (4.3 vs 3.9, p=0.001) and there was weak evidence of additional functional impairment in non-completers (see online supplementary table S2).

Outcomes of pulmonary rehabilitation

Following completion of rehabilitation, significant improvements were observed across all groups for SMI, QMVC, CRQ dyspnoea, fatigue, emotional and mastery domains, and physical activity (table 3) and in prefrail and frail groups for MRC score, handgrip strength, ISWT, CAT score and HADS domains (table 3). Adjusting for age and sex, a gradient of treatment response in favour of patients who were frail was evident for MRC score, handgrip strength, ISWT, CRQ fatigue, emotional and mastery domains, CAT score and HADS scores (table 3). Outcomes related to frailty characteristics (handgrip strength, 4MGS and physical activity) and responses to CES-D exhaustion questions also improved, such that postrehabilitation, fewer patients met case criteria for frailty (figure 3). Among the 115 completers who were frail prior to pulmonary rehabilitation, 71 (61.7%) were prefrail (64, 55.6%) or robust (7, 6.1%) following it. A small minority of completers, 13/390 (3.3%), had moved from a prefrail to a frail state (figure 3).