Effects of combined aerobic, resistance and inspiratory training in patients with pulmonary hypertension: A systematic review

Table 1 Main baseline characteristics of patients included in the systematic review

Ref.	Sample size (n)	Sex (Male/Femail)	Mean age (yr)	Type of PH, n (%)	Mean PAP (mmHg)	Mean PVR (dyn × s /cm5)	Cardiac index (L/min/m2)	Peak VO2 (mL/min/kg)	6MWT (m)
Mereles et al[20]	I: 15	5/10	47 ± 12	PAH: 13 (86.6); CT: 2 (13.3)	49.5 ± 17.6	968.7 ± 444.1	2.3 ± 0.5	13.2 ± 3.1	411 ± 86
	C: 15	5/10	53 ± 14	PAH: 11 (73.3); CT: 4 (26.7)	49.6 ± 12.3	901.8 ± 358.0	2.1 ± 0.5	11.9 ± 3.1	439 ± 82
Ley et al[21]	I: 10	2/8	47 ± 8	PAH: 7 (70); CT: 1 (10); Other1: 2 (20)	48 ± 19	731 ± 256	2.78 ± 0.57	NA	449 ± 80
	C: 10	4/6	54 ± 14	PAH: 5 (50); CT: 3 (30); Other1: 2 (20)	50 ± 15	909 ± 374	2.2 ± 0.51	NA	423 ± 101
Ehlken et al[22]	I: 46	20/26	55 + 15	PAH: 35 (76.1); CT: 11 (23.9)	41.0 + 11.7	540 + 267	2.68 + 0.73	13.3 ± 3.6	453 ± 91
	C: 41	20/21	57 + 15	PAH: 26 (63.4); CT: 15 (36.5)	37.6 + 11.8	512 + 338	2.69 + 0.89	12.7 ± 4.0	413 ± 95
González-Saiz et al[23]	I: 20	8/12	46 ± 11	PAH: 7 (35); CT: 2 (10); Other2: 11 (55)	47 ± 15	11 ± 6 (WU)	Cardiac output: 4414 ± 91 (ml/min)	15.7 ± 3.3	500 ± 70
	C: 20	8/12	45 ± 12	PAH: 11 (55); CT: 2 (10); Other2: 7 (35)	47 ± 14	9 ± 5 (WU)	Cardiac output: 4827 ± 135 (ml/min)	19.8 ± 6.5	546 ± 99
Grünig et al[24]	I: 58	18/40	52.3 ± 12.4	PAH: 39 (67.2); CT: 7 (12.1); Other3: 12 (20.7)	46.5 ± 15.5	8.6 ± 5.5 (WU)	2.7 ± 0.7	14.2 ± 5.2	447.2 ± 117.7
	C: 58	13/45	55.0 ± 12.7	PAH: 34 (58.6); CT: 11 (19.0); Other3: 13 (22.4)	46.7 ± 14.9	7.7 ± 4.5 (WU)	2.8 ± 0.7	15.3 ± 4.3	447.4 ± 120.0

¹PAH associated with connective tissue disease and portal hypertension.

²PAH associated with toxic oil syndrome, connective tissue disorders, HIV and congenital cardiopathy.

³PAH associated with connective tissue disorders and congenital cardiopathy.

I: Intervention group; C: Control group; VO₂: Oxygen consumption; 6MWT: 6-min walking test; PAP: Pulmonary artery pressure; PVC: Pulmonary vascular resistance; PH: Pulmonary hypertension; PAH: Pulmonary arterial hypertension; CT: Chronic thromboembolic; WU: Woods units; NA: Not applicable.

Table 2 Intervention characteristics, outcomes and main results of the studies included in the systematic review

Ref.	Intervention by study group	Duration	Outcomes	Main results
Mereles et al[20]	I: First 3 wk: (1) Interval bicycle ergometer training with a lower workload (10-60 W) for 1⁄2 min and a higher workload for 1 min (20 to 35 W) for 10 to 25 min/d, corresponding to 60% to 80% of the heart rate and 60 min of walking was performed 5 d/w (flat-ground and uphill walking); (2) 30 min of dumbbell training of single muscle groups with low weights (500 to 1000 g) 5d/w; and (3) 30 min of respiratory training, including stretching, breathing techniques such as pursed lip breathing, body perception, Yoga, and strengthening of respiratory muscles	15 wk (7 d per week for 3 wk in-hospital training and 5 d per week for 12 wk training at home)	Primary (after 3w and 15w): 6MWT, SF-36. Secondary (after 3w and 15w): WHO functional class, Borg scale, echocardiographic indices, CPET indices (peak VO2, VO2@AT, peak workload, etc.)	Intervention group: ↑ in 6MWT and ↓ in SF-36 after 15 wk. Also, ↑ in max workload, max heart rate, peak VO2, predicted peak VO2, workload and VO2@AT after 15 wk. Control group: ↓ in 6MWT and SF-36 after 15 wk. ↑ in Borg scale after 15 wk. Intervention vs control group: Intervention group improved 6MWT and SF-36, as well as max workload, max heart rate, peak VO2, workload and VO2@AT and PASP at rest compared to controls after 15 wk. Improvements within each group and between groups in the same indices after 3 wk
	12 wk: (1) Bicycle exercise training close to their target heart rate once daily for a total of 15 to 30 min for 5 d/w; (2) respiratory exercise; and (3) dumbbell training for 15 to 30 min every other day, iv. walking 2 d/w
	C: Common rehabilitation program based on healthy nutrition, physical therapy such as massages, inhalation, counseling, and muscular relaxation without exercise and respiratory training. Allowed to perform daily activity as usual
Ley et al[21]	I: Specialized respiratory and exercise training program at home similar to Mereles et al[18]	3 wk	After 3 wk: 6MWD, MR perfusion (time to peak, pulmonary blood flow, pulmonary blood volume and mean transit time) and flow measurements (peak velocity, time to peak velocity, mean velocity and average blood flow per minute)	Intervention group: ↑ in 6MWT, pulmonary blood volume and ↓ in peak velocity after 3 wk. Control group: ↑ in mean transit time after 3 wk. Intervention vs control group: Intervention group improved 6MWT and peak velocity compared to controls after 3 wk
	C: Program without specific exercise training
Ehlken et al[22]	I: Similar to Mereles et al[18]	15 wk (7 d per week for 3 wk in-hospital training and 5 d per week for 12 wk training at home)	Primary (after 15 wk): Peak VO2. Secondary (after 15 wk): Hemodynamics at rest and during CPET (oxygen pulse, heart rate at rest and max, systolic and diastolic BP at rest and max, max workload), RHC indices (mPAP, CO, CI, PAWP, PVR), 6MWT, SF-36, WHO functional class and NT-proBNP	Intervention group: ↑ in peak VO2 and 6MWT after 15 wk. Also, improvement in most hemodynamics measurements and RHC indices at rest and during exercise after 15 wk. Control group: No change in peak VO2 and 6MWT after 15 wk. Also, most hemodynamics measurements and RHC indices at rest and during exercise remained unchanged after 15 wk. Intervention vs control group: Intervention group improved peak VO2, 6MWT, hemodynamics measurements at rest and during exercise compared to controls after 15 wk. Quality of life (improvement in most aspects of SF-36) improved in all patients compared to the general population
	3 wk in-hospital: 1.5 h/d exercise training consisting of: (1) Interval cycle ergometer training at low workloads 7 d/w; (2) walking; (3) dumbbell training of single muscle groups using low weights (500–1000 g); and (4) respiratory training 5 d/w
	12 wk at home: 15 min/d for 5 d/w, mental training
	C: Did not receive any advice on exercise training. Psychological support was offered to all participants
González-Saiz et al[23]	I: Aerobic training→ cycle ergometer training for 20-40 min/session for 5 d/w with a gradually increased duration/intensity in each session, with exercise-rest intervals at a 1:1 ratio and at 50% of the power output eliciting the AT. Resistance training→ 3-time circuit of exercises involving large muscle groups in the following order: Leg and bench press, leg extension, lateral pulldown and abdominal crunches, following aerobic sessions 3 times per week. Inspiratory training→ 30 inspirations through a specific pressure-load device against 40% of PImax, total session duration approximately 5 min, 2 times daily for 6 sessions/w	8 wk [Aerobic: 5 sessions per week from Monday to Friday, 40 sessions in total, 20–40 min each session duration; Resistance: 3 sessions per week (Monday, Wednesday and Friday), 24 sessions in total, following the aerobic sessions; Inspiratory: 6 sessions per week from Monday to Saturday, 2 times daily]	Primary (after 8 wk): Upper/lower body muscle power (leg press, bench press). Secondary (after 8 wk): NT-proBNP, 6MWT, peak VO2, VE/VO2@AT, PETO2@AT, PETCO2@AT, VE/VCO2@AT, SF-36, adverse episodes (syncopal/pre-syncopal episodes, severe dyspnea, arrhythmias, asthma, signs of poor peripheral perfusion, ataxia, tremors), muscle mass	Intervention group: ↑ in leg press and bench press after 8 wk. Also, improvement in peak VO2, VE/VO2@AT, PETO2@AT, PETCO2@AT, VE/VO2@AT, PImax, 6MWT, 5-STS, MVPA and physical component of SF-36 after 8 wk. Control group: No change in upper/lower body muscle power, 6MWT, peak VO2 and SF-36 after 8 wk. Also, improvement in PETCO2 @AT and MVPA after 8 wk. Intervention vs control group: Intervention group improved leg press and bench press, peak VO2, PImax and 5-STS compared to controls after 8 wk. No difference in 6MWT and SF-36
	C: Standard care, regularly scheduled visits with their clinicians
Grünig et al[24]	I: Respiratory therapy, cycle ergometer training, dumbbell training, guided walks, and mental training 5-7 d per week for 10-30 d in-house training and 3-7 d per week for 11-12 wk training at home, similar to Mereles et al[18] and Ehlken et al[20] protocols. Training intensity was 40%–60% of the patients’ achieved max workload during ergometer test	15 wk (5-7 d per week for 10-30 d in-house training and 3-7 d per week for 11-12 wk training at home)	Primary (after 15 wk): 6MWT. Secondary (after 15 wk): Peak VO2, WHO functional class, NT-proBNP, CPET indices (HR at rest, SaO2 at rest, peak HR, peak SaO2, peak VO2, predicted peak VO2, predicted workload, VE/VCO2 slope), echocardiographic indices (sPAP, TAPSE, RA area, RV area), SF-36, adverse events	Intervention group: ↑ 6MWT after 8 wk. Also, improvement in peak VO2, predicted peak VO2, and most aspects of SF-36 after 15 wk. Control group: Slight but not statistically significant ↓ in 6MWT after 15 wk. Also, improvement in sPAP and some aspects of SF-36 after 15 wk. Intervention vs control group: Intervention group improved 6MWT, SF-36, WHO functional class, peak VO2, sPAP, compared to controls after 15 wk. No difference in other parameters were observed
	C: Usual daily activity at home

I: Intervention group; C: Control group; WHO: World Health Organization; VO₂: Oxygen consumption; AT: Anaerobic threshold; CPET: Cardiopulmonary exercise testing; PASP: Pulmonary arterial systolic pressure; BP: Blood pressure; RHC: Right heart catheterization; CO: Cardiac output; CI: Cardiac index; mPAP: Mean pulmonary arterial pressure; PAWP: Pulmonary arterial wedge pressure; PVR: Pulmonary vascular resistance; NT-proBNP: N-terminal prohormone brain natriuretic peptide; VE/VO₂: Ventilatory equivalent for oxygen uptake; PETO₂: End-tidal partial pressure of oxygen; VE/VCO₂: Ventilatory equivalent for carbon dioxide output; MVPA: Moderate-vigorous physical activity; PETCO2@AT: End-tidal partial pressure of carbon dioxide at the anaerobic threshold; PImax: Maximal inspiratory pressure; HR: Heart rate; sPAP: Systolic pulmonary arterial pressure; TAPSE: Tricuspid annular plane systolic excursion; RA: Right atrial; RV: Right ventricular; SaO₂: Arterial oxygen saturation.

Table 3 Quality assessment of the included studies using the physiotherapy evidence database

	Mereles et al[20], 2006	Ley et al[21], 2013	Ehlken et al[22], 2016	González-Saiz et al[23], 2017	Grünig et al[24], 2021
Eligibility Criteria		√		√	√
Random allocation	√	√	√	√	√
Concealed allocation					√
Baseline comparability	√	√	√	√	√
Blinded subjects
Blinded therapists
Blinded assessors	√	√	√	√
Adequate follow-up	√		√	√	√
Intention-to-treat				√
Between-group-analysis	√	√	√	√	√
Point estimates and variability	√	√	√	√	√
Total score	6/10	5/10	6/10	7/10	6/10