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. 2020 Feb 13;17:1479973120904953. doi: 10.1177/1479973120904953

Table 2.

Detailed description of the included RCT studies.

Author and risk of bias Mean age, GOLD stage and BMI Subject Intervention Pulmonary rehabilitation Outcomes measures Result
van de Bool et al.23
Bias: 1/7		 Age: 62 years old.
GOLD: 2.
BMI: 22.7 kg/m2.		 N = 73
(‘low muscle mass’).		 Intervention: 125 mL of 9.4 g protein, 28.1 g carbohydrate and 4.1 g fat, leucine, n-3 PUFA and vitamin D once per day.
Placebo: Flavoured non-caloric aqueous solution.		 Duration: 4 months
Location: outpatient.
Session detail: 40 sessions, two to three times per week.
1. High intensity endurance exercise by cycle ergometry.
2. Treadmill walking.
3. Progressive resistance exercise of upper and lower body.
4. Education session.
 1. Body composition: Body mass, BMC, SMM and FM.
2. Muscle function: Quadriceps muscle strength, MIP.
3. Exercise performance: cycle endurance time (CET) and 6MWT.
4. Anxiety/depression: HADS.
5. Physical activity: 7 days.		 1. Body composition: Significant improvement in body mass (1.5 ± 0.6 kg, p < 0.05) and FM (1.6 ± 0.5 kg, p < 0.01) in the intervention group.
2. Muscle function: No significant differences between the groups.
3. Exercise performance: No significant differences between the groups.
4. Anxiety/depression: No significant differences between the groups.
5. Physical activity: significant benefit in physical activity (929.5 ± 459.2 steps/day, p < 0.05).
Paulin et al.24
Bias: 1/7		 Age: I versus P (56.5 vs. 65.2 years old).
GOLD: 3 and 4.
BMI: I versus P (24.5 vs. 25.1 kg/m2).		 N = 16 Intervention (I): B12 500 mg/day for 8 weeks.
Placebo (P): Maltodextrin.		 Duration: 8 weeks.
Location: outpatient.
Session detail: 3 days/week, 40 minutes of aerobic and resistance exercise.		 1. Cardiopulmonary exercise testing: Incremental or constant-load protocols.
 1. Exercise performance: No significant differences between the groups.
Ahnfeldt et al.25
Bias: 4/7		 Age: I versus P (67 vs. 70 years old).
GOLD: 2 and 3.
BMI: I versus P (24.3 vs. 23.4 kg/m2).		 N = 35 Intervention (I): Protein bar (each 134.8 kcal of energy, 9.3 g protein, 14.6 carbohydrate, 4.2 fat) two times per day for 9 weeks.
Placebo (P): No.		 Duration: 9 weeks.
Location: outpatient
Session detail:
A—1 hour 2 times per week and home-based one time per week of:
1. Endurance.
2. Resistance.
3. Interval training.
4. Educational class.		 1. Muscle function: lower muscle strength.
2. Exercise performance: SWT.
3. Quality of life: SGRQ.		 1. Muscle function: No significant differences between the groups.
2. Exercise performance: No significant differences between the groups.
3. Quality of life: No significant differences between the groups.
Gurgun et al.26
Bias: 2/7		 Age: I versus P (64 vs. 66 years old).
GOLD: 3 and 4.
BMI: I versus P (17.8 vs. 20 kg/m2).		 N = 30 (“wasted”) Intervention (I): 250 mL 83.3% carbohydrate, 30% fat, 16.7% proteins, three times per day.
Placebo (P): No.		 Duration: 8 weeks.
Location: outpatient.
Session detail:
Two times per week 60–80 minutes/day:
A—Education.
B—Exercise training include:
1. Warm-up and bicycle ergometer for 15 minutes.
2. Treadmill (15 minutes).
3. Upper and lower extremity strength (5–10 minutes).
4. Breathing and relaxation therapies (15–20 minutes each).		 1. Body composition: Body weight, BMI, FFMI.
2. Exercise performance: 6MWT, ISWT, and ESWT.
3. Quality of life: SGRQ.
4. Anxiety/depression: HADS.
5. Breathlessness scale: MRC and Borg.
6. Muscle size: QuadCSA.		 1. Body composition: Significant improvement in weight (1.1 ± 0.9 kg, p < 0.05), BMI (0.2 ± 1.4 kg/m2, p < 0.05) and FFMI (0.6 ± 0.5 kg/m2, p < 0.05) in the intervention group.
2. Exercise performance: No significant differences between the groups.
3. Quality of life: No significant differences between the groups.
4. Anxiety/depression: No significant differences between the groups.
5. Breathlessness scale: No significant differences between the groups.
6. Muscle size: Significant increase in QuadCSA (2.5 ± 4.1 cm2, p < 0.05) in the intervention group.
Hornikx et al.27
Bias: 3/7		 Age: I versus P (67 vs. 69 years old).
GOLD: 2, 3 and 4.
BMI: I versus P (25 vs. 24 kg/m2).		 N = 49 Intervention (I): vitamin D monthly dosage (100.000 UI cholecalciferol).
Placebo (P): Arachidis oleum: 4 mL.
 Duration: 3 months.
Location: outpatient.
Session detail: Three times per week 90 minutes training of:
1. Cycling.
2. Walking on treadmill.
3. Stair climbing and arm cranking.
4. Strength exercises for extremities.		 1. Muscle function: quadriceps strength, MIP and MEP.
2. Exercise performance: incremental cycle ergometer and 6MWD.
3. Quality of life: CRDQ.		 1. Muscle function: Significant increase in MIP (11 ± 12 cmH2O, p = 0.004) but no differences between groups in quadriceps strength and MEP.
2. Exercise performance: No significant differences between the groups.
3. Quality of life: No significant differences between the groups.
Sugawara et al.28
Bias: 1/7		 Age: 77 years old.
GOLD: 3.
BMI: not recorded.		 N = 31
 Intervention: Mein (contains 200 kcal 20% protein, 25% lipid, 53.2% sugar, 1.8 fibre, Fisher is 3.7, antioxidant vitamins A, C and E) (two times per day 200 mL) for 12 weeks + provided meal with dietary instruction.
Placebo: No.		 Duration: 12 weeks.
Location: Home-based.
Session detail:
A—Breathing retraining:
1. Pursed-lip breathing.
2. Diaphragmatic breathing.
3. Slow deep breathing.
B—Exercise training:
1. Upper and lower limb exercises.
2. Respiratory muscle stretching calisthenics.
3. Level walking for least 15 minutes.
4. Inspiratory and expiratory muscle exercises.
C—Education program.
D—Physiotherapist supervision every 2 weeks in hospital.
E—Periodic visits at home.		 1. Body composition: Body weight, FFM, FMI, (AC), (AMC), %IBW.
2. Muscle function: MIP and MEP, quadriceps strength.
3. Exercise performance: 6MWD.
4. Quality of life: CRQ.
5. Breathlessness scale: MRC.		 Data reported as change in ratio in interventional group versus placebo group, not as absolute values.
1. Body composition: Significant improvement in body weight (2.6 ± 3 kg vs -0.2 ±1.4 kg, p = 0.0010), FMI (8.6 ± 10.7 kg/m2 versus 0.6 ± 10.6 kg/m2, p = 0.048), %AC (2.4 ± 3.7% vs -0.7 ± 2.4%, p = 0.0134), and %IBW (2.7 ± 3% vs. −0.2 ± 1.3%, p = 0.0017) in the intervention group.
2. Muscle function: MIP (39.2 ± 38.9 cmH2O vs. 0.1 ± 24.1 cmH2O, p = 0.0030) and quadriceps strength (10.0 ± 13.3 kg/kg vs. −1.6 ± 9.5 kg/kg, p = 0.0079) increased significantly in the intervention group.
3. Exercise performance: 6MWD (19.7 ± 24.7 m vs. −7.1 ± 50.8 m, p = 0.0137) improved significantly in the intervention group.
4. Quality of life: total score (6.2 ± 7.5 vs. −2.7 ± 13.1, p = 0.0374) and emotional domain (8.9 ± 14.4 vs. −3.9 ± 12.2, P = 0.0097) increased significantly in the intervention group.
5. Breathlessness scale: MRC 22.6 ± 40.6 vs. −4.4 ± 17.2 (p = 0.0339) improved significantly in the intervention group.
Baldi et al.29
Bias: 3/7		 Age: I versus P (73 vs. 70 years old).
GOLD: 3.
BMI: I versus P (19.9 vs. 21 kg/m2).		 N = 28 depleted Intervention (I): Amino acids 4 g two times per day for 12 weeks.
Placebo (P): No.		 Duration: 4 weeks.
Location: inpatient
Session detail: five days per week.
30 minutes submaximal cycle ergometry.
30 minutes walking and 1 arm exercise session.
Then:
Duration: 8 weeks
Location: Home
Session detail: Twice per day 30 minutes unloaded bicycle training.		 1. Body composition: weight and FFM. Data reported as change in the interventional group versus change in the placebo group.
1. Body composition: Significant increase in weight (3.8 ± 2.6 kg, p versus = 0.0002). (−0.1 ± 1.1 kg, p = 0.81) and FFM (1.5 ± 2.6 kg, p versus = 0.05). (−0.1 ± 2.3 kg, p = 0.94).
Laviolette et al.30
Bias: 2/7		 Age: I versus P (63 vs. 68 years old).
GOLD: 2 and 3.
BMI: I versus P (29.7 vs. 26.7 kg/m2).		 N = 22 Intervention (I): Whey protein 20 g in 120 mL/day for 16 weeks (8 without PR and 8 with PR).
Placebo (P): casein 20 g in 120 mL/day for 16 weeks (8 without PR and 8 with PR).		 Duration: 8 weeks
Location: not specified
Session detail:
Three times per week. 90 minutes of:
1. Endurance.
2. Resistance exercise.
3. Education and self-management strategies.		 Baseline, 8th, and 16th week:
1. Body composition: weight.
2. Muscle function: quadriceps muscle strength and fatigue.
3. Exercise performance: constant work rate cycle endurance.
4. Quality of life: CRQ.
5. Lung function: spirometry and lung volumes.		 1. Body composition: No significant differences between the groups.
2. Muscle function: No significant differences between the groups.
Exercise performance: No significant differences between the groups.
4. Quality of life: No significant differences between the groups.
5. Lung function: No significant difference between groups.
Wetering et al.31
Bias: 3/7		 Age: 64 years old.
GOLD: 2.
BMI: 21.7 kg/m2.		 N = 30 (“wasted”) Intervention: respifor (high-carbohydrate supplement; 125 mL, 188 kcal) three times per day for 4 months.
Placebo: No.		 Duration: 4 months.
Location: outpatient.
Session detail: 1. Two times per week for 30 minutes of intensive exercise.
2. 1, 2 and 3 months dietician counselling for weight losing and muscle-wasted patients.
3. Education program.
4. Smoking cessation.		 1. Body composition: FFMI and BMI.
2. Muscle function:
MIP and quadriceps average power.
3. Exercise performance: Peak exercise capacity (W max), cycle endurance test (CET) and 6MWD.
4. Quality of life:
SGRQ.		 1. Body composition: Significant increase in BMI (mean difference 1 kg/m2, p < 0.05), and FFMI (mean difference 0.9kg/m2, p < 0.05).
2. Muscle function: Significant increase in MIP (mean difference 1.4 kPa, p < 0.05) and QAP (mean difference 13.1 W, p < 0.05).
3. Exercise performance: Significant increase in W max (mean difference 11.7 W, p < 0.05), CET (mean difference 525 second, p < 0.05), and 6MWD (mean difference 27.2 m, p < 0.05).
4. Quality of life: No statistically significant difference although absolute difference between groups at 6.1 units is greater than the MCID.
Deacon et al.32
Bias: 2/7		 Age: I versus P (68 vs. 68 years old).
GOLD: 3.
BMI: I versus P (28.1 vs. 25.7 kg/m2).		 N = 80 Intervention (I): Creatine
Loading phase: 22 g daily, 4 divided doses for 5 days.
Maintenance phase: (PR) 3.76 g daily.
Placebo (P): lactose.		 Duration: 7 weeks.
Location: outpatient
Session detail: three times per week of:
1. Endurance training.
2. Individually prescribed resistance training using gym equipment and free weights.		 1. Body composition: weight, FFM and FM.
2. Muscle function: quadriceps, triceps and biceps.
3. Exercise performance: ISWT and ESWT.
4. Quality of life: CRQ-SR.		 1. Body composition: No significant differences between the groups.
2. Muscle function: No significant differences between the groups.
3. Exercise performance: No significant differences between the groups.
4. Quality of life: No significant differences between the groups.
Borghi-Silva et al.33
Bias: 1/7		 Age: I versus P (69 vs. 65 years old).
GOLD: 3.
BMI: I versus P (22 vs. 23 kg/m2).		 N = 16 Intervention (I): Oral l-carnitine 2 g, twice per day in 10 mL bottle for 6 weeks.
Placebo (P): Saline solution.		 Duration: 6 weeks.
Location: outpatient.
Session detail: 1 hour three times per week:
30 minutes treadmill, inspiratory muscle training.		 1. Body composition:
Triceps skinfold, mid-arm circumference and BMI.
2. Muscle function:
MIP and MEP.
3. Exercise performance: incremental exercise test (treadmill) and 6MWT.
4. Breathlessness scale: Borg.		 Data reported as change in interventional group vs change in the placebo group.
1. Body composition: No significant differences between the groups.
2. Muscle function: MIP (40 ± 14 cmH2O vs. 14 ± 5 cmH2O, p < 0.05) but not MEP, increased significantly in the intervention group.
3. Exercise performance: No significant differences between the groups.
4. Breathlessness: No significant differences between the groups.
Faager et al.34
Bias: 1/7		 Age: I versus P (67 vs. 64 years old).
GOLD: 3.
BMI: I versus P (25 vs. 22 kg/m2).		 N = 23 Intervention (I): creatine 0.3 g/kg body weight/day, divided in four doses/day for 7 days.
Creatine 0.07 g/kg body weight/day one dose/day for remaining 7 weeks.
Placebo (P): Glucose.		 Duration: 8 weeks.
Location: outpatient.
Session detail:
Two times per week for 60–75 minutes of exercise training and education consisting of:
1. Ergometer cycling.
2. Arm muscle training with dumbbells.
3. Rising and getting up from a stool and getting up onto a low stool.
4. Thera band exercises for shoulder girdle.
5. Thigh muscle training with weight cuffs.
6. Abdominal muscle training.
7. Flexibility exercises for thorax and adjacent joints.		 1. Body composition: weight.
2. Muscle function: Grip strength, maximal right knee strength and fatigue.
3. Exercise performance: ESWT.
4. Quality of life:
SGRQ.
5. Lung function: spirometry.		 1. Body composition: No significant differences between the groups.
2. Muscle function: No significant differences between the groups.
3. Exercise performance: No significant differences between the groups.
4. Quality of life: No significant differences between the groups.
5. Lung function: No significant differences in FEV1 between the groups.
Broekhuizen et al.35
Bias: 3/7		 Age: I versus P (62 vs. 64 years old.
GOLD: 3.
BMI: I versus P (22.5 vs. 22.1 kg/m2).		 N = 80 Intervention (I): PUFA 1 g 9 capsules/day.
Placebo (P): 9 capsules/day of palm and sunflower oil, vitamin E.
Depleted patients n = 48 respifor (see above) 3times per day.		 Duration: 8 weeks.
Location: inpatient.
Session detail:
A—General physical training of:
1. Exercise in relation to daily activities.
2. Cycle ergometry.
3. Treadmill walking.
4. Swimming.
B—Sports and games.
C—Educational program.
D—Regular meals.		 1. Body composition: BMI, weight, FFM, FM and FFMI.
2. Muscle function: quadriceps strength, handgrip and MIP.
3. Exercise performance: endurance time incremental bicycle ergometry and submaximal bicycle ergometry.
4. Lung function: spirometry.		 1. Body composition: No significant differences between the groups.
2. Muscle function: No significant differences between the groups.
3. Exercise performance: Maximal exercise capacity (peak workload (9.7 W difference, P = 0.009) and bicycle ergometry duration (4.3 minutes difference, p = 0.023) improved significantly in the intervention group.
4. Lung function: No significant differences between the groups.
Fuld et al.36
Bias: 3/7		 Age: I versus P (64 vs. 62 years old).
GOLD: 3.
BMI: I versus P (23.2 vs. 24.3 kg/m2).		 N = 25 Intervention (I): Creatine + glucose polymer (5 g creatine and 35 g glucose/dose).
A—Loading phase: three times daily for 14 days.
B—Maintenance phase: one time daily for 10 weeks (PR).
Placebo (P): Glucose polymer (40.7 g/dose).		 Duration: 8 weeks
Location: outpatient
Session detail:
Two times per week each 1 hour consisting of:
1. A warm-up.
2. Mobility training.
3. Dynamic strength training of all extremities.
4. Whole body endurance training.
5. Education and behavioural interventions.		 1. Body composition: Body mass, FFM and FM.
2. Muscle function: MIP, lower limb muscle performance, handgrip.
3. Exercise performance: ISWT, ESWT, cycle ergometry.
4. Quality of life: SGRQ.
5. Lung function: Spirometry.		 Data reported as change in interventional group versus change in the placebo group.
1. Body composition: FFM increased significantly by (2 kg vs. 0.4 kg, p < 0.05) in the creatine group.
FM and BM: No significant differences between the groups.
2. Muscle function: Significant increase in lower limb strength (19.5 N.m vs. 12.2 N.m, p < 0.05), endurance (1216 J vs. 362 J, p < 0.05), handgrip strength (2.9 N vs. 0.6 N, p < 0.05) and endurance (15.6 repetitions vs. 8.4 repetitions, p < 0.05) in the creatine group.
No significant change in MIP.
3. Exercise performance: No significant differences between the groups.
4. Quality of life: Total score decreased (5.9, p < 0.05) and activity domain deceased (5.3, p < 0.01) in the creatine group.
5. Lung function: No significant improvement in FEV1.
Steiner et al.37
Bias: 3/7		 Age: I versus P (66 vs. 68 years old).
GOLD: 3.
BMI: I vs. P (23.9 vs. 23.5 kg/m2).		 N = 60. Intervention (I): respifor (high-carbohydrate supplement; 125 mL, 188 kcal) three times per day for 7 weeks
Placebo (P): non-nutritive.		 Duration: 7 weeks.
Location: outpatient.
Session detail: two times per week of:
1. Endurance training (walking exercise + home walking program).
2. Circuit of low impact conditioning exercise.
3. Educational sessions.		 1. Body composition: weight, BMI, BM, lean mass, fat mass.
2. Muscle function: quadriceps and handgrip strength.
3. Exercise performance: ISWT and ESWT.
4. Quality of life: CRQ-SR.		 1. Body composition: Significant improvement in weight (0.63 kg, p = 0.004), BMI (0.24 kg/m2, p = 0.002), and fat mass (0.67 kg, p = 0.001) in the intervention group.
2. Muscle intervention: No significant differences between the groups.
3. Exercise performance: No significant differences between the groups.
4. Quality of life: No significant differences between the groups.
Vermeeren et al.38
Bias: 3/7		 Age: part I 65 versus part II 62 years old.
GOLD: 3.
BMI: part I 20.6 versus part II 22.6 kg/m2.		 Part 1: N = 14
Part II: N = 11		 Part I: Intervention 1: 1046 kJ, 21% protein, 34% fat, 45% carbohydrate.
Intervention 2: 2092 kJ, 21% protein, 36% fat, 43% carbohydrate.
Placebo: 209 kJ coffee creamer and lemon syrup.
Part II: respifor (see above) versus pulmocare (high fat supplement) 200 mL.		 Duration: not specified.
Location: inpatient.
Session detail: Not specified.		 1. Exercise performance: cycle ergometer.
2. Lung function: spirometry.
3. Self-reported:
A—Change in breathlessness during meals.
B—Leg pain.		 1. Exercise performance: Part I: No significant differences between the groups.
2. Lung function: Part I: No significant differences between the groups.
Part II: PEF (pre 3.1 L/second ± 1.0, post 3.3 L/second ± 1.2) increased significantly after the respifor supplement versus pulmocare (pre 3.1 L/second ± 0.9, post 3.1 L/second ± 0.9) (p < 0.05).
3. Self-reported symptoms: Part I: Satiety changed significantly after the supplements for the 2092-kJ supplement (p < 0.05).
Part II: Significant increase in breathlessness at 30 and 60 minutes following a meal with pulmocare versus respifor (raw data not provided, p < 0.05).
Schols et al.39
Bias: 4/7
 Age: not recorded.
GOLD: 3.
BMI: not recorded.		 N = 71 per protocol group. Complex, three group study:
p group: placebo steroid.
N group: placebo steroid + nutritional supplement.
N + A: 4 IM injections of nandrolone + nutritional supplement (not considered further).
Nutrition: one time per day 200 mL for 57 days mixture of nutridrink (high energy), protifar (high protein) and fantomalt (high energy carbohydrate and oil).
 Duration: 57 days.
Location: inpatient.
Session detail:
1. General physical training related to daily activates.
2. Cycle ergometry.
3. Treadmill walking.
4. Walking circuits.
5. Swimming.		 Measurements were made at entry, 29 and 57 days:
1. Body composition: weight, arm circumference, skinfolds, FFM.
2. Muscle function: MIP.
3. Exercise performance: 12MWT.		 Comparing group p with group N. Patients were stratified to depleted group versus non-depleted group:
Depleted group:
1. Body composition: No significant difference in FFM or arm circumference between N and P but significant increase in skinfold and weight in the N groups (raw data not provided, p < 0.03).
Non-depleted group: Only reported in per protocol analysis
2. Muscle function: No significant differences between the groups.
3. Exercise performance: No significant differences between the groups.

I: intervention group; P: placebo or control group; 12MWT: 12-minute walk Test; 6MWD: 6-minute walk distance; BM: body mass; BMC: bone mineral content; BMI: body mass index; CRQ, Chronic Respiratory Disease Questionnaire; CWT: constant work rate test; ESWT: endurance shuttle walk test; FEV1: forced expiratory volume in 1 second; FFM: fat-free mass; FM: fat mass; FMI: fat mass index; IBW: ideal body weight; ISWT: incremental shuttle walking test; MEP: maximum expiratory pressure; FFMI: fat-free mass index; MIP: maximum inspiratory pressure; MMC: mid-arm muscle circumference; PEF: peak expiratory flow; QAP: quadriceps average power; QuadCSA: quadriceps cross-sectional area; SGRQ: St. George’s Respiratory Questionnaire; SMM: skeletal muscle mass; UI: International unit; LBM: lean body mass; LBMI: lean body mass index; SMI: skeletal muscle mass index; BCM: body cell mass; BMC: bone mineral content; ASM: appendicular skeletal muscle mass; EQ-5D-3 L: EuroQoL five-dimensions Questionnaire; W, Watt.