Effect of a short multicomponent exercise intervention focused on muscle power in frail and pre frail elderly: A pilot trial

Experimental Gerontology 115 (2019) 114–121

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Experimental Gerontology journal homepage: www.elsevier.com/locate/expgero

Effect of a short multicomponent exercise intervention focused on muscle power in frail and pre frail elderly: A pilot trial

T

José Losa-Reynaa,b,c,1, Iván Baltasar-Fernandezc,1, Julian Alcazara,c, Roberto Navarro-Cruzc, ⁎ Francisco José Garcia-Garciaa,b, Luis M. Alegrea,c, Ana Alfaro-Achaa,b, a

CIBER of Frailty and Healthy Aging (CIBERFES), Madrid, Spain Hospital Virgen del Valle, Complejo Hospitalario de Toledo, Toledo, Spain c GENUD Toledo Research Group, Universidad de Castilla-La Mancha, Toledo, Spain b

ARTICLE INFO

ABSTRACT

Section Editor: Christiaan Leeuwenburgh

Objectives: The aim was to establish whether a short supervised facility-based exercise program improved frailty, physical function and performance in comparison with usual care treatment. Methods: This was a quasi-experimental, non-randomized controlled intervention study in frail (2.75 ± 1.25 Frailty Phenotype criteria) older adults (range:77.2–95.8 years). The exercise (EX) group (n = 11) performed concurrent training (power training + high-intensity interval training, HIIT) twice weekly for 6 weeks while the control (CT) group (n = 9) followed usual care. Results: The exercise intervention improved frailty status in 64% of the subjects improving Frailty Phenotype by 1.6 points (95%CI 0.8–2.5, p < 0.05), and increasing SPPB score by 3.2 points (95%CI: 2.4–4.0, Cohen's d = 2.0, p < 0.05), muscle power by 47% (95%CI: 7–87%, Cohen's d = 0.5, p < 0.05), muscle strength by 34%(95%CI: 7–60, Cohen's d = 0.6, p < 0.05) and the aerobic capacity by 19% (6 minute walking test +45 m, 95%CI: 7-83, Cohen's d = 0.7, p = 0.054). The CT did not experience any significant changes in frailty status, physical function or performance. Conclusions: A short concurrent exercise program of muscle power and walking-based HIIT training is a feasible and safe method to increase physical performance and improve function and frailty in elder (pre)frail patients.

Keywords: Frailty Exercise Muscle power Force-velocity profile Aging Public health

1. Introduction Nowadays, it is a sound fact that the population is aging. Nevertheless, living longer does not mean living better. In fact, there is a difference of 8–10 years, approximately, between life expectancy and healthy life expectancy, which translates into years living with disease and/or syndromes, including frailty and disability (Organization WH, 2016). Frailty is an age-associated, biological syndrome characterized by decreased biological reserve, due to dysregulation of several physiological systems. This puts an individual at risk when facing minor stressors, and is associated with poor outcomes (i.e., disability, hospitalization, and death) (Fried et al., 2001). Age-associated (pre)frailty affects 50% of community-dwelling elders over 65 years (Garcia-Garcia et al., 2011) and up to 85% of those living in assisted living facilities (Theou et al., 2016). (Pre) Frailty is important in the clinical setting because it leads to disability as a result of loss of functional status and physiological reserve (Fried et al., 2001;

Fried et al., 2004). There is current consensus that physical frailty is potentially reversible with the appropriate interventions (Morley et al., 2013), specially at early stages (Fiatarone et al., 1994). Thus, interventions should aim at either delaying the onset of frailty or reducing its adverse outcomes. Furthermore, many basic daily activities, such as walking and standing-up from a chair, are dependent on the ability to generate muscle force at high velocities (i.e. muscle power), therefore power training can improve mobility-related outcomes in the elderly (Weston et al., 2014). A recent systematic review in a frail population, concluded that different exercise interventions can improve functional parameters in frail subjects, but multicomponent exercise programs may be more effective, especially when they are undertaken on a regular basis over a prolonged period of time (Cadore et al., 2013). Multicomponent exercise programs are composed of different physical-conditioning activities (i.e., strength, endurance, balance and flexibility). Interestingly, in elders, skeletal muscle power is more strongly associated to

Corresponding author: Hospital Virgen del Valle, Complejo Hospitalario de Toledo, Toledo, Spain. E-mail addresses: [email protected] (J. Losa-Reyna), [email protected] (A. Alfaro-Acha). 1 Both authors contributed equally to the study. ⁎

https://doi.org/10.1016/j.exger.2018.11.022 Received 29 October 2018; Received in revised form 21 November 2018; Accepted 28 November 2018 Available online 04 December 2018 0531-5565/ © 2018 Elsevier Inc. All rights reserved.

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functional performance than skeletal muscle strength (Byrne et al., 2016). Cadore et al. (2014) showed that frail old subjects improved their functional status and physical performance after a multicomponent exercise intervention, with specific emphasis on muscle power output. Hence, a critical component of a multicomponent exercise program seems to be resistance training, with special focus on high speed movement (Pojednic et al., 2012). Improvement in cardiorespiratory fitness is associated with a lower risk of mortality (Lee et al., 2010), and this is also due to a higher mucle power and strength (Cadore et al., 2013). Thus, endurance training should be included in multicomponent exercise programs. However, elders with severe functional impairments may not be able to perform traditional endurance training. An alternative and time efficient solution may be high-intensity interval training (HIIT) exercise, which combines short intense intervals, alternated with longer periods of lower intensity for recovery, providing physiological benefits in less time than traditional exercise regimens (Gillen and Gibala, 2013). Amongst the benefits of this approach are the well-known improvement in aerobic power and overall health through central and peripheral adaptations (Laursen and Jenkins, 2002). A HIIT-based concurrent training program has been shown to be safe and effective in healthy older people (Garcia-Pinillos et al., 2017). Moreover, Seldeen et al. (2018) demonstrated the benefits of endurance-type HIIT in frail mice. However, the safety and feasibility of HIIT as part of an intervention for frail older adults is still unknown. With this in mind, the aim of our study was to establish whether a short supervised facility-based exercise program improves frailty and physical function, in comparison with usual care. It was hypothesized that a short duration exercise intervention, focused on muscle power, would improve frailty, functional status and physical performance. A secondary aim was to verify the safety and feasibility of performing HIIT training in frail and pre-frail elder subjects.

points in the Short Physical Performance Battery (SPPB) (Guralnik et al., 1994); d) being able to walk independently or assisted. Exclusion criteria included severe cognitive impairment (based on subjective evaluation of the geriatrician), severe disability (score < 15 points on the Barthel Scale (Mahoney and Barthel, 1965)), major surgery in the previous 6 months before the beginning of the study, history of stroke within the previous 6 months or any other disorder that precluded participation in an exercise program. Subsequently, the patient was scheduled to perform the initial evaluation where physical function and frailty criteria were evaluated. After the initial evaluation, the patient was assigned to the control or intervention group based on their willingness, availability or ability to travel to the Virgen del Valle Hospital in Toledo. Those subjects in the intervention group (EX) performed two familiarization sessions, in which the subjects were taught the operation of the training machines. On a separate day, their force-velocity (FeV) profile was evaluated. At the end of the 6-week period, all patients were reassessed on their physical function and frailty syndrome. Forty-eight hours after the final evaluation, the exercise group performed the FeV profile test. All the subjects gave their informed consent and the study was performed in accordance with the Helsinki Declaration of 1975, as last modified in 2000, regarding the conduct of clinical research, and was approved by the Ethical Committee of the Toledo Hospital. 2.3. Sociodemographic and clinical data Sociodemographic information was collected, such as age, sex, race, marital status, educational level and medical history. In addition, blood pressure, heart rate and oxygen saturation were measured in a sitting position after 5 min of rest, on 2 occasions separated by a time interval of 2 min, before and after the 6-week training period. 2.4. Physical function and disability

2. Methods

We used the SPPB to evaluate physical function (Guralnik et al., 1994), which consists of the following tests: 1) balance test: time standing in 3 different positions (feet together, semi-tandem and full tandem) a maximum time of 10 s each; 2) usual gait speed (UGS): tested in a distance of four meters; and 3) chair stand test: time necessary to get up and sit on the chair five times with the arms crossed on the chest as fast as possible. The 10-m Walking Test (10MWT) (Rossier and Wade, 2001) measures the time required to walk 10 m at maximum speed. The test was performed in one of the corridors of the Hospital where a distance of 10 m was delimited with cones. The subjects had to start from a static position and walk in a straight line to complete the established distance in the shortest possible time. The time started in the first cone after previous indication of the evaluator and stopped when the participant crossed the second cone. For this, two attempts were allowed and the shortest time was noted. The maximal gait speed (MGS) was calculated dividing the distance by the time taken to complete the test. Functional aerobic exercise capacity was assessed by means of the 6min walking test (6-MWT) and reported as the total distance that the subjects were able to walk in 6 min.

2.1. Study design This was a quasi-experimental, non-randomized, single-blinded controlled study. The follow up time was 6 weeks, and it was carried out at Virgen del Valle Hospital in Toledo (Spain). Due to ethical issues (Izquierdo et al., 2016), randomization was not possible and the exercise intervention was offered to all the subjects. Those who refused to participate in the intervention exercise program or were unable to attend due to transport problems, were allocated to the control group. The intervention group went on to perform concurrent training (power training + HIIT) while the control group was advised not to change their eating habits or physical activity during the course of the present study (2 sessions of initial evaluation, 2 sessions of familiarization, 12 training sessions and 2 final assessment sessions). Measurement were obtained before and after the 6-week concurrent exercise training program. Evaluations were completed by the same investigators, who were blinded to the group allocation and not involved in training the participants. 2.2. Sample

2.5. Activities of daily living

Subjects were recruited at the Frailty Unit in the Hospital Virgen del Valle that belongs to the Complejo Hospitalario of Toledo, Spain. In the first concerted visit, a geriatrician rated the patient's eligibility and proposed to participate in the study if the subject met criteria. The patients were informed about the potential positive and negative effects of the intervention to which they would be subjected. Those who met the inclusion criteria and agreed to participate, signed the informed consent. The eligibility criteria were: a) men and women aged 75 years or more; b) diagnosed as pre-frail or frail according to the frailty phenotype (Fried et al., 2001); c) a score between 2 and 10

To measure basic and instrumental activities of daily living we used the Barthel index (BI) (Mahoney and Barthel, 1965) and the Lawton and Brody Scale (Graf, 2008). Both are composed of a series of items that provide a different score depending on the ability to perform each of them independently, so the Barthel index is a 10-item questionnaire that provides information about the autonomy to cook food, wash, dress, groom, perform bowel movements and urination, go to the toilet, move from the bed to the chair, walk and climb stairs (Mahoney and Barthel, 1965). 115

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Table 1 Training protocol. Week

Strength Legpress Intensity

Endurance Plantar flexion

Volume

Recovery

Intensity

Volume

Intense Interval Recovery

Intensity

Active Recovery

Volume

Intensity

Duration

(%F0)

(Sets)

(Reps)

(min)

(%BW)

(Sets)

(Reps)

(min)

(% MGS)

(Sets)

(Duration)

1

30

3

15

1

3

6

1

50

1

8 min

–

–

2

40

3

12

1

3

8

1

50

1

10 min

–

–

3

50

4

8

1

3

10

1

90

10

10 s

UGS

50 s

4

50

4

8

1

3

12

1

90

6

20 s

UGS

100 s

5

50

4

8

1

3

6

1

90

6

20 s

UGS

100 s

6

60

4

8

1

100% 2 legs 100% 2 legs 100% 2 legs 100% 2 legs 100% 1 leg 100% 1 leg

3

8

1

90

6

30 s

UGS

90 s

BW: body weight; F0: theoretical maximum force; MGS: maximal gait speed; UGS: usual gait speed.

g = 9.81 m·s−2, height and chair height are measured in metres and Five STS time was calculated in seconds.

The Lawton scale assesses the ability to use the telephone, shopping, cooking, household duties, laundry, use of transportation, responsibility for their medication and handling of economic matters. Each item is assigned a numerical value (1 = independent, 0 = dependent), therefore, the maximum dependence would be marked by obtaining 0 points and total independence by obtaining 8 points (Graf, 2008).

2.7. Frailty To assess frailty, Linda Fried's frailty criteria (Fried et al., 2001) were used, which take into account the usual speed of walking in 4.5 m, the hand grip strength (kg) (Jamar Preston, Jackson, MI, USA), involuntary weight loss, exhaustion or low resistance and low level of physical activity, measured through the “Physical Activity Scale for the Elderly” (PASE) (Washburn et al., 1993). The subjects were considered frail when they presented 3 or more criteria, pre-frail if they presented 1–2 criteria, and robust when no criteria was present.

2.6. Force-velocity profile and muscle power The force-velocity and muscle power testing was performed according to Alcazar et al. (2017). Briefly, subjects performed a 5 min cycling warm-up (Ergoline, 800S, Bitz, Germany) at a self-reported light intensity (10–40 W), plus a specific warm-up in which the subjects performed 3 sets of 10 repetitions on the leg press equipment (Element + Inclusive, Technogym, Barcelona, Spain) at an intensity equivalent to 40% of their body mass with 1-min resting period between sets. The last 3 repetitions of each set were performed explosively. During the FeV and muscle power testing procedure, the subjects performed 2–3 sets of 1 repetition with increasing load until they perceived exertion of 8 in a scale of 0–10.A recovery time of 1–2 min was used, according to the mean velocity of the repetition. Force and velocity data during the concentric phase of each repetition were recorded by a linear position transducer device (T-Force System, Ergotech, Murcia, Spain). The subjects were continually encouraged to perform each repetition as fast and strong as possible. Force and the highest mean velocity data for each load from each repetition were computed and plotted in a Microsoft Excel® template (Alcazar et al., 2017) (freely available online). Any load not performed at maximal speed was discarded and the FeV relationship was computed considering the remaining loads. Several variables were extracted from the FeV regression equation as previously reported (Alcazar et al., 2017) (force-intercept or maximal force (F0), velocity-intercept, maximal velocity (V0), slope of the FeV relationship, maximal muscle power (Pmax), the load that elicited Pmax and optimal force (force at which Pmax is produced)), and Pmax was also relativized to body mass. Graphically, F0 and V0 correspond to the force axis and velocity axis intercepts of the linear F–v relationship, respectively, and Pmax corresponds to the apex of the parabolic Power–velocity relationship. As the FeV profile was only measured in the exercise group, muscle power was assessed additionally through a novel and easy method recently validated (Alcazar et al., 2018), the sit-to-stand test (STS), with the following equation: STS power (W) = [body mass * 0.9 * g × (Height * 0.5- Chair height)]/ Five STS time * 0.1; where body mass is measured in kg,

2.8. Concurrent exercise program The training program was applied for 6 weeks, with a total of 12 training sessions distributed in 2 weekly sessions. Each session had an approximate duration of 45 min, and a resting period of at least 48 h was allowed between training sessions. The sessions began with a 5-min warm-up that consisted in walking at the usual gait speed (UGS) (measured through the 4 m test on the SPPB battery) with 1% inclination on a treadmill (Lode BV, Valiant 2 Rehab, Groningen, Netherlands). Then, the participants performed the following resistance exercises to improve lower-limb muscle power: leg press (Element + Inclusive, Technogym, Barcelona, Spain) and plantar flexion (using steps) followed by a HIIT-type cardiovascular exercise consisting in walking on a treadmill (Table 1). Briefly, for the leg press, 3–4 sets of 8–15 repetitions at an intensity of 30–60% of F0 with 1 min of recovery between sets, and for the plantar flexion, subjects performed 3 sets of 4–12 repetitions at their bodyweight (BW) using1 or 2 legs with 1 min of recovery between sets. The first two weeks were used for conditioning (3 sets of 12–15 reps at 30–40% of F0for leg press and 3 sets of 6–8 reps at 1BW using two legs for the plantar flexion, both with 1 min of recovery between sets). The following weeks were focused on muscle power improvement (4 sets of 8 reps at the intensity eliciting maximal power in the FeV test for the leg press and 3 sets of 6–12 reps using 1 or 2 legs for the plantar flexion, both with a 1-min recovery period between sets). Special emphasis was placed on the subjects performing all the repetitions with the maximum speed of execution during the concentric phase, and performed slowly (2–3 s) the eccentric phase of the exercise. Regarding the cardiovascular exercise, the first two weeks also served as conditioning and consisted of 8–10 min of continuous exercise at 50% of MGS. The following weeks, the HIIT protocol consisted in 116

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6–10 intervals with a work:rest ratio of 1:5 (10–20s at 90% of MGS and 50–100 s at 50% UGS) increasing to a 1:3 ratio (30s at 90% MGS and 90 s at 50% UGS) at the end of the program. Each session ended with a cool-down consisting of 5 min of stretching of the main muscles involved in the session.

as pre-frail. The frailty item that EX patients improved the most was exhaustion (n = 5), followed by low physical activity, slow walking speed and grip strength (n = 3 for each item). None of the later items was improved in the CT group. According to the number of frailty criteria met, the EX group significantly improved by 1.6 points (95%CI 0.8–2.5, p < 0.05) its frailty phenotype, while the CT group exhibited a non-significant decrement of 0.4 points (95%CI -0.8; 0.1) (p = 0.08) (Table 3).

3. Data analysis Summary statistics, including mean and standard deviation, were provided for continuous variables and frequencies. Proportions were used to summarize discrete variables. The linear mixed models (GLMM) were used to compare the between-group changes, with adjustments for treatment, time, and treatment-by-time interactions for continuous variables, while the generalized estimating equations (GEE) model was used for categorical variables. The intervention effect can be reasonably estimated by using GEE even if the covariance structure is not specified correctly. When significant interactions were found, individual comparison paired t-tests or Wilcoxon tests were performed adjusting with Bonferroni-Holm procedure (Holm, 1979). To determine the magnitude and meaningfulness of the findings, effect size statistics were calculated using Cohen's d, with cut-offs as small (from 0.2 to 0.5), medium (from 0.5 to 0.8), or large (over 0.8). All the analysis of the data were carried out with SPSS Statistics 22.0 (SPSS Inc., Chicago, IL, USA) for Windows. The level of significance was established at the level of p < 0.05.

4.3. Exercise effect on physical function The effects of the exercise intervention on physical function are shown in Table 3. Overall, there was a significant time x group interaction in physical function measures. Total SPPB score was significantly improved by 48% (3.2 points,95%CI: 2.4–4.0, Cohen's d = 2.0, p < 0.05) in the EX group compared with the non-significant reduction observed in the CT group. Additionally, the chair stand test improved by 30% (−4.8 s, 95% CI -3.4,-6.1, Cohen's d = −1.8, p < 0.05) and UGS by 23% (0.16 m/s, 95% CI 0.09–0.23, Cohen's d = 1.1, p < 0.05) in EX but not in CT. However, SPPB balance score did not change significantly in none of the groups. Handgrip strength was also significantly improved in the EX group by 14% (2.0 kg, 95%CI 0.5–3.5, Cohen's d = 0.6, p < 0.05). In contrast, CT subjects did not experience any significant changes in handgrip strength. Aerobic capacity measured with the 6-MWT improved by 19% in the EX group (+45 m, 95%CI: 7–83, Cohen's d = 0.7, p = 0.054).Regarding functional status, no significant effects were observed in Lawton or Barthel scores (data not shown).

4. Results We screened a total of 49 participants; of which 19 were excluded for two reasons:1) subjects refused to participate in this exercise program because they considered it was too intense but wanted to exercise, so they were reoriented to other light exercise programs (n = 15), and 2) medical reasons that did not make possible their participation (n = 4). Finally, 30 agreed to participate in the study of which 16 were allocated to exercise intervention and 14 to the control group (see study design). One subject abandoned before the start of the intervention, 4 patients were forced to abandon their participation due to reasons not related with the exercise intervention, while 5 of them did so voluntarily during the course of the study. Finally, 20 patients took part in the study, 11 in the intervention group and 9 in the control group (Fig. 1).

4.4. Exercise on muscle power and strength The effects derived from the exercise intervention in the EX group are shown in Table 3.Pmax was significantly improved in the EX group in both absolute (+47%, 95%CI: 7–87%, Cohen's d = 0.5, p < 0.05) and relative values (+46%,95%CI: 11–81%, Cohen's d = 0.6, p < 0.05). Moreover, load attained at Pmax increased by 23% (95%CI:7–38%, Cohen's d = 0.3, p < 0.05). Fig. 2 depicts the different components of the FeV profile. It is clearly shown that velocity improved in the low-moderate intensity range from 5 to 70% 1 Repetition Maximum (RM) (p < 0.05, Fig. 2A) while force improved in the whole 1RM continuum (p < 0.05, Fig. 2B). Thus, peak power was increased too in the whole range of intensities (p < 0.05, Fig. 2C). Finally, muscle strength improved (+34%, 95%CI: 7–60, Cohen's d = 0.6, p < 0.05).

4.1. Baseline characteristics For the entire sample (N = 20), mean age was 84.2 ± 4.5 (range: 77.2–95.8 years) and 75% (n = 15) were female. At baseline, 35% of the participants (n = 7) were classified as pre-frail and 65% (n = 13) as frail. Even though all the subjects were considered frail, the subjects enrolled in the trial were relatively healthy with few comorbidities (3.5 ± 2.2), preserved BI (mean 88.0 ± 12.7) and Lawton scores (5.2 ± 2.7). Even more, the usual gait speed was 0.59 ± 0.16 m·s−1 (range: 0.32–0.90), the time spent in the chair stand test was 15.3 ± 2.8 s (range: 11.1–20.8 s, one subject was unable to perform the test) and handgrip strength was 17.8 ± 5.3 kg (range: 10–30). Most baseline characteristics were similar between EX and CT group (Tables 2 and 3). Additionally, 72.7% (n = 8) in EX and 55.6% (n = 5) in CT were frail, which is reflected in the high number of criteria met (Table 3), while none of the patients in either group was classified as robust.

5. Discussion The major findings of this study were that a short intervention of just 6 weeks, implementing a multicomponent exercise program focused on lower body muscle power, enhanced performance in functional outcomes (i.e., HGS, rise from chair, handgrip strength), which led to a reduction in frailty in community-dwelling frail older adults. This study included two novelties: 1) the exercise prescription based on the FeV profile for power-oriented resistance exercise and the use of a simple tool (i.e., the 10MWT) for prescribing endurance exercise; and 2) this is the first study to date performing treadmill-based HIIT training in frail. Exercise interventions are well established to improve physical function capacity and performance measures in frail elderly individuals (Gine-Garriga et al., 2014). There have been multiple trials investigating the effects of exercise on different aspects of frailty, but few have successfully reversed frailty status in older adults by means of an exercise intervention. (Cameron et al., 2013; Ng et al., 2015; TarazonaSantabalbina et al., 2016; Kim et al., 2015; Chan et al., 2012). In comparison with the 31–48% reduction in the prevalence of frailty observed in the literature, our exercise training program was able to

4.2. Effect of exercise on frailty and frailty status transition The rate of patients that improved their frailty status was 7 out of 11 in the EX group, while none of CT subjects improved their frailty status (p < 0.05). Thus, none of the participants were frail in EX at the end of the intervention, while 1 subject ended the intervention as robust and 7 117

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RECRUITMENT

49 paents assessed for elegilibility 19 Excluded - 4 for medical reasons - 15 refused to parcipate (reoriented to other exercise programs)

ALLOCATION

30 Allocated 16 Exercise group 1 abandoned before start

INTERVENTION ANALYSIS

14 Control group

11 Finished 4 Withdrew

9 Finished 5 Withdrew

- 1 died - 2 discharged - 1 Other reasons

10 Analyzed 1 excluded from analysis (missing data)

9 Analyzed 0 excluded from analysis

Fig. 1. Consort diagram with participant flow.

after a training period (Gine-Garriga et al., 2014). Although improvements were found in most of the physical performance tests, balance did not improve with our exercise intervention. However, exercise interventions have not been proven to have consistent effects on balance measures in older subjects (Gine-Garriga et al., 2014; Chou et al., 2012). It is important to mention that our program did not involve specific balance training which could be required to attain significant changes (Cadore et al., 2013). Moreover, this could be possibly due to a ‘ceiling effect’ of the balance test as 45% of our subjects had no chance to improve their balance time (they scored the maximum in the pretest). Muscle power is more closely related to functional ability in older people than any other physical capacity (Byrne et al., 2016). The seminal study in frail nonagenarians performed by Cadore et al. (2014), showed an improvement of 96–116% (4–4.8%/session) in power output after a 12-week multicomponent training, with emphasis on high speed resistance training. Interestingly, these changes were followed by improvements on functional capacity. Our results are in accordance to the previous study, as our subjects improved 4.8–5.6% per session. In contrast, a study developed in pre-frail community-dwelling older adults did not show changes in muscle power of the lower limbs after 3 months of power training (Drey et al., 2012). However, as discussed by the authors, the methodology used to evaluate power may have not been sensitive enough to detect these changes. It could be hypothesized that exercise seems to be more effective in the earlier stages of frailty (Theou et al., 2011), and thus, reversing frailty is more difficult in advanced frail people. However, the studies conducted on frail subjects indicate that frailty can also be reversed in advanced frail older adults (Cameron et al., 2013; TarazonaSantabalbina et al., 2016; Kim et al., 2015; Fairhall et al., 2012). In

Table 2 Baseline characteristics of the participants. Exercise

Control

(n = 11)

(n = 9)

Demographics Age (years) Sex (female), % (n) Height (cm) Weight (kg) BMI (kg·m−2)

84.0 ± 4.7 81.8 (9) 154.8 ± 8.8 64.0 ± 11.6 26.5 ± 3.3

84.4 ± 4.6 66.7 (6) 156.0 ± 8.6 67.4 ± 12.4 27.8 ± 5.9

Health Systolic pressure (mmHg) Diastolic pressure (mmHg) Heart rate (bpm) SpO2 (%) Barthel Index Lawton Index

138.3 ± 22.7 77.4 ± 7.7 73.4 ± 12.2 95.0 ± 2.2 91.4 ± 8.1 6.0 ± 2.3

134.6 ± 18.4 66.3 ± 16.8⁎ 77.8 ± 11.2 94.3 ± 1.9 83.9 ± 16.4 4.1 ± 2.9

⁎

p = 0.066. All data are expressed as mean ± SD unless otherwise stated.

reverse the frailty status in 67% (95% CI 36–114%) of the patients, whereas, as expected, none of the subjects in the control group improved their frailty status after the 6-week control period. Importantly, these changes in frailty status were also mirrored by changes in physical function and performance. Our patients improved greatly their SPPB (+3.2 points, 95%CI: 2.4–4.0) mainly due to the improvement in the Chair Stand Test (53%) but also to the gait speed test (25%). These improvements represent clear clinical substantial meaningful changes (Perera et al., 2006), and are in accordance with a meta-analysis that points out the significant improvement in SPPB score (+1.87 units 95%:CI, 1.17–2.57) and gait speed (+0.06 m·s−1 95%CI: 0.06–0.08) 118

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Table 3 Frailty, functional status and muscle power profile parameters. Exercise

SPPB total score Gaitspeed Balance Chair-stand test UGS (m·s−1) Balance time (s) Chair-stand (s) PASE Handgrip (kg) Frailty (criteria) STS power (W) Absolute Pmax (W) Relative Pmax (W·kg−1) Load at Pmax (kg) 1 RM (kg) Optimal Force (N) 6 MWT (m)

p-Value

Pre

Post

6.8 ± 1.5 2.1 ± 1.0 2.9 ± 1.0 1.8 ± 1.1 0.56 ± 0.17 24.6 ± 5.2 15.6 ± 2.7 36.1 ± 26.9 16.3 ± 3.6 3.1 ± 1.1 104 ± 32 112.7 ± 62.1 1.6 ± 0.7 36.3 ± 18.1 49.2 ± 19.0 448.4 ± 236.6 257.4 ± 61.7

9.8 ± 1.5 2.8 ± 0.8 3.6 ± 0.8 3.5 ± 0.8 0.72 ± 0.12 27.8 ± 1.5 10.8 ± 2.5 57.1 ± 23.7 18.3 ± 2.3 1.5 ± 0.8 156 ± 50 152.6 ± 96.1 2.2 1.1 42.3 ± 17.4 62.4 ± 23.2 507.3 ± 234.5 302.1 ± 71.8

Control

< 0.001 0.01 – < 0.001 < 0.001 0.054 < 0.001 0.06 0.02 < 0.001 < 0.001 0.03 0.01 0.03 0.04 0.03 0.06

Pre

Post

7.4 ± 2.0 2.5 ± 0.9 2.9 ± 1.1 2.0 ± 0.8 0.64 ± 0.16 24.4 ± 5.5 15.7 ± 3.0 43.3 ± 38.4 20.8 ± 6.0 2.3 ± 1.4 123 ± 23 – – – – – –

6.9 ± 2.7 2.3 ± 1.0 2.6 ± 1.1 2.0 ± 1.3 0.58 ± 0.21 22.3 ± 6.5 14.8 ± 4.0 35.9 ± 24.7 20.1 ± 5.7 2.6 ± 1.3 134 ± 35 – – – – – –

p-Value

p-Value Time*group

0.23 0.52 – 1.00 0.35 0.50 0.25 0.04 0.50 0.30 0.13 n.a. n.a. n.a. n.a. n.a. n.a.

< 0.001 0.03 0.08 < 0.001 < 0.001 0.02 < 0.001 0.06 0.02 < 0.001 < 0.001 n.a. n.a. n.a. n.a. n.a. n.a.

1RM: 1 repetition maximum, 6MWT: 6 min walking test, Pmax: maximal muscle power;UGS: usual gait speed.

0.8 5

*

4

Frailty Criteria

Velocity (m/s)

0.6

0.4

3

2

0.2 1

0.0 0

20

40

Power (W)

200

60

80

0

100

Pre

Fig. 3. Frailty status before (pre) and after (Post) the exercise intervention in the training group (EX). Note: Columns represent mean data. Some points, which represent individual data, are overlapped.

*

addition, we observed that all the frail patients included in our investigation improved their frailty status (Fig. 3). Therefore, it is evident that frailty can be reversed even in subjects presenting 4–5 frailty criteria. Age might be also hypothesized to have an impact on the effect of exercise on the management of frailty. A previous study observed that the benefits derived from exercise training may be greater in frail people aged 80–90 years compared with younger frail participants (71–79 y) (Theou et al., 2011). Our patients were 84.1 years old on average, which matched with the responder group of older adults above-mentioned. Nonetheless, Cho et al. (2017) studied the effect of a 6-month exercise program in three age groups (young-old, 65–74; oldold, 75–84; oldest-old, ≥85 years), and found that all the age groups showed similar improvements in physical function. Thus, it is more likely that biological age (i.e. frailty status) rather than chronological age has a relevant influence on the adaptations achieved by exercise training in (pre-)frail individuals. Another relevant factor that must have a major influence on exercise-induced adaptations in frail individuals is the type and characteristics of the exercise training program. Frail older adults may need long-term exercise programs with short-duration sessions compared

150

100

50

Pre Post

0 0

20

40

60

Post

80

100

1 RM (%) Fig. 2. Velocity (A) and power (B) in the exercise group before (Pre) and after (Post) the intervention.*p < 0.05 vs. pre.

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with healthy older adults (Chodzko-Zajko et al., 2009). Theou et al. (2011) indicated in a qualitative analysis that exercise programs lasting over 5 months may have better outcomes than short-term interventions. Most exercise interventions targeting frailty have reported a minimum duration of 12 weeks, and a maximum duration of 12 months (GineGarriga et al., 2014). However, in a recent study, frail COPD patients experienced significant improvements in muscle power, physical function and frailty status after an 8-week exercise program (data not published). Furthermore, Izquierdo et al. (2004) also showed improvements in strength after only 8 weeks of combined endurance and resistance training (once weekly each, i.e. 16 sessions). Our 6-week exercise program, including 12 exercise sessions combining HIIT and power training, demonstrated significant improvements in physical function and frailty. Therefore, not only exercise program duration, but the type, intensity and volume of exercise are likely to be relevant factors to consider when prescribing exercise in frail populations. Regarding the type of intervention, to our knowledge, this is the first multicomponent trial to include walking HIIT endurance training in frail elders. In this sense, walking-based endurance training programs have been reported to be superior to other forms of exercise when the main goal is to achieve improvements in walking ability (Leung et al., 2010). In addition, HIIT can also induce early adaptations in skeletal muscle function (Martinez-Valdes et al., 2017) along with well-known cardiovascular adaptations (Laursen and Jenkins, 2002). Thus, the combined effect of both types of exercise could have added up to promote the changes we observed in our sample with our short intervention. An important issue for clinicians and researchers is that an improved physical performance translates into better functional status. However, our subjects did not improve their BADL or IADL. Strength training studies with a duration > 16 weeks showed strength gains but marginal or no improvement in various functional performances (Liu and Latham, 2009). The lack of improvement could have been due to the high-functioning in ADLs of our sample at baseline, poor sensitivity of questionnaires and/or the short program duration. There are some limitations to this trial. We offered every subject to participate in the exercise intervention. Despite random allocation was not possible, baseline characteristics were similar between groups, except for the frailty status, thus selection bias cannot be ruled out. Nonetheless, currently, not prescribing exercise to frail elders may be considered unethical (Izquierdo et al., 2016). Strengths include: 1) the use of a safe and low time-consuming evaluation which can be applied in a clinical environment with little resources, 2) the short duration of the intervention program which is still effective in reversing frailty; and 3) the use of HIIT walking-based training in frail elders.

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6. Conclusions In conclusion, a short training program of only 6 weeks of muscle power and walking-based HIIT training is an effective intervention to induce gains in physical performance and reverse frailty in elder patients, independently of the initial level of frailty. Conflict of interest None to declare. Funding source This work was supported by the Biomedical Research Networking Center on Frailty and Healthy Aging (CIBERFES) funds from the European Union (CB16/10/00477 and CB16/10/00456). Julián Alcázar received a PhD grant from the “Ministerio de Educación, Cultura y Deporte” of the Government of Spain (FPU014/05106). 120

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