Limited research exists regarding nonpharmacologic management of pulmonary arterial hypertension (PAH), except for exercise training. The objective of this study was to investigate the effects of osteopathic manipulative treatment (OMT) alone and combined with respiratory training on fractional exhaled nitric oxide (FeNO), and cardiopulmonary function in patients with PAH. This single-blind, prospective, randomized controlled study included 54 patients with PAH who were randomly allocated to OMT, combined intervention, and control groups. The OMT group (n = 16) and combined intervention group (n = 16) received OMT and yoga respiratory training plus OMT, respectively, twice a week for 8 weeks. The control group (n = 16) received no intervention. All patients undertook an educational lecture. FeNO level, pulmonary function, 6-minute walk distance (6MWD), maximal inspiratory and expiratory pressures, and handgrip strength were assessed at baseline and 8 weeks. Combined intervention and OMT groups significantly improved all outcome measures after 8 weeks of treatment (p <0.01), except mean forced expiratory flow between 25% and 75% of forced vital capacity, which did not change in the OMT group (p >0.05). The control group showed significant deteriorations in 6MWD, inspiratory and peripheral muscle strength, and pulmonary function except peak expiratory flow at 8 weeks (p <0.05). The combined intervention group revealed significantly greater improvements of FeNO, 6MWD, respiratory and peripheral muscle strength, and pulmonary function except mean forced expiratory flow between 25% and 75% of forced vital capacity compared with the OMT group (p <0.05). All outcomes significantly improved in both intervention groups versus the control group (p <0.05). Our study demonstrated that adding respiratory training to OMT provided further benefit to FeNO level and cardiopulmonary function compared with OMT alone and that the OMT might be a useful and safe intervention for patients who cannot attend cardiac rehabilitation programs.
Pulmonary arterial hypertension (PAH), defined by the presence of mean pulmonary arterial pressure at rest >20 mm Hg and pulmonary vascular resistance ≥3 Wood units, is a rare and progressive disorder that leads to right ventricular failure because of pulmonary vasoconstriction, vascular remodeling, and thrombosis. , Fractional exhaled nitric oxide (FeNO) is an indicator of nitric oxide level in the lung tissue. FeNO was reduced in patients with PAH compared with healthy controls. Patients with PAH demonstrate impairments of pulmonary function, respiratory and peripheral muscle strength, and exercise capacity. Because the extensive applicability and reliable sustainability of exercise training remain critical challenges, new therapeutic methods are required for nonpharmacologic treatment of PAH. This study aimed to investigate the effects of adding respiratory training to osteopathic manipulative treatment (OMT), and OMT alone on FeNO level and cardiopulmonary function in patients with PAH.
Methods
This study, a prospective, single-blind randomized controlled trial, was approved by the Clinical Research Ethics Committee of Istanbul Medeniyet University Goztepe Training and Research Hospital (2018/0180) and registered at ClinicalTrials.gov (identification number NCT04076241). The study was carried out at Physiotherapy and Rehabilitation Department of Cardiology Institute, Istanbul University-Cerrahpasa between September 2019 and April 2020 in accordance with the Declaration of Helsinki. The inclusion criteria were diagnosis of clinically and hemodynamically stable PAH, patients aged ≥18 years with the World Health Organization (Geneva, Switzerland) functional class I to III, being under PAH-targeted medical therapy for at least 3 months, and no recent syncope. The exclusion criteria were acute decompensated heart failure, unstable angina pectoris, recent thoracoabdominal surgery, severe neurologic impairments, fractures within the past 6 months, osteoporosis, tumors, pregnancy, using immunosuppressants because of transplants, and severe cognitive impairment.
After acquiring information about the research, those meeting the criteria and volunteering to participate gave the written informed consent. Random allocation sequence was generated by a computerized list of random numbers. Patients were randomly assigned to OMT, combined intervention, or control groups using a permuted block randomization design with the block sizes of 6. Allocation sequence was concealed using sealed, opaque envelopes from the study leader. The envelope that was allocated to the patient was opened by the main researcher, who was responsible for conducting interventions. The outcome assessor was blinded to group allocation, and the main researcher was blinded to patient outcomes. Primary outcome measures were FeNO level, pulmonary function, and exercise capacity. Secondary outcome measures were respiratory and peripheral muscle strength. Outcome measurements were conducted at baseline and 8 weeks. FeNO level was measured using a portable electrochemical analyzer (NObreath, Bedfont Scientific Ltd., Rochester, United Kingdom). Obtainment of 3 reproducible recordings were aimed with maximum 6 attempts. A period of at least 30 seconds of rest elapsed between tests. FeNO was calculated as the average of 2 acceptable peak values agreed within 10% of each other. Pulmonary function tests were performed using a spirometer (SpiroUSB, CareFusion, San Diego, California). Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV 1 ), FEV 1 /FVC, mean forced expiratory flow between 25% and 75% of FVC (FEF 25-75 ), and peak expiratory flow were measured and expressed as percentage of predicted values. Exercise capacity was assessed with 6-minute walk test (6MWT). Heart rate, peripheral oxygen saturation, and blood pressure were recorded before and after 6MWT. Dyspnea and fatigue were evaluated using modified Borg scale at the beginning and at the end of the test. Respiratory muscle strength was evaluated by measuring maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) with a mouth pressure meter (MicroRPM, Micro Medical-Care Fusion, Chatham, United Kingdom). For MIP and MEP, the largest value of 3 maneuvers that differ by <10% was recorded and expressed as a percentage of predicted values. A total of 30 to 60 seconds of rest was allowed between each measurement. Peripheral muscle strength was determined by measuring handgrip strength with hand dynamometer (TTM Dynamometer, Tokyo, Japan). Patients in standing position, with the arm at the side and slightly away from the body, the forearm in full extension and in midrotation, and the wrist in 0° to 30° degree of extension, were requested to carry out maximal voluntary grip contraction against dynamometer continuously at least 2 seconds. Three attempts were performed for each hand alternately, starting with the dominant hand. Measurements were separated by an interval of approximately 30 seconds of rest and the highest value obtained was recorded in kilograms.
Combined intervention and OMT groups received standardized OMT including rib raising, diaphragm release, suboccipital decompression, first rib mobilization, mediastinum mobilization, and thoracic inlet myofascial release 2 times a week for 8 weeks, with each session lasting for 45 to 60 minutes ( Supplementary Material ). The sessions were conducted by the same physiotherapist. Combined intervention group received a supervised yoga respiratory training session consisting of nadishodhana, ujjayi, and bhramari pranayama after OMT ( Supplementary Material ). The exercises were undertaken once daily for the rest of the week as prescribed home exercises. Control group did not receive any additional intervention. After the initial assessment, patients received an educational lecture about disease pathophysiology, medication use, airway clearance, sleep disorders, nutrition, physical activity, dyspnea management, and diaphragmatic breathing.
Sample size was estimated using G*Power 3.0.10 statistical software based on the means and SDs for FeNO level according to a previous study. A repeated-measures analysis of variance (ANOVA) between-factor interactions was carried out with 2 test repetitions. A sample size of 14 patients per study group was calculated with a 2-sided alpha error probability of 0.05, a power of 0.95, and a correlation among repeated measures of 0.50. Considering a potential dropout risk of 20%, sample size was set at 18 patients for each group. Statistical analyses were performed using SPSS 25.0 statistical software (IBM SPSS Inc., Chicago, Illinois). Descriptive statistics of the data were reported as mean (SD) or percent frequency. The normality of distribution for examined variables was assessed with the Shapiro-Wilk test and also values of skewness and kurtosis and was reviewed through histograms and quantile-quantile plots. The analyses demonstrated that all variables were normally distributed. For between-group comparisons of baseline data, one-way ANOVA was used. The chi-square test was performed for comparison of categorical variables between groups. For between-group comparisons of baseline with 8 weeks, one-way ANOVA with between-subject factor was used. When significant intergroup differences were found, pairwise multiple comparisons were carried out using Bonferroni post hoc tests. Within-group differences were analyzed through the paired samples t test. In each group, the mean change from baseline was presented along with 95% confidence interval. A p <0.05 was identified as statistically significant.
Results
A total of 102 patients with PAH were screened for eligibility. Among them, 54 patients who met inclusion criteria were allocated to 3 groups. Because 6 patients withdrew during the 8-week follow-up, 48 patients aged between 20 and 74 years (mean [SD] age 48.4 [12.1] years) completed the study, with 16 patients in each group ( Figure 1 ). Throughout the treatment period, no side effects or serious complications were reported by the patients. Demographics and baseline characteristics of patients are listed in Table 1 . There were no significant differences between groups (p >0.05). At baseline assessment, values of outcome measures among the groups were also similar (p >0.05).
| Characteristics | OMT (n = 16) | Combined (n = 16) | Control (n = 16) | p Value |
|---|---|---|---|---|
| Age (years), mean (SD) | 47.06 (14.53) | 50.38 (9.02) | 47.81 (12.67) | 0.728 * |
| BMI (kg/m 2 ;), mean (SD) | 29.76 (6.64) | 28.02 (3.88) | 27.98 (4.98) | 0.556 * |
| Female | 15 (94%) | 14 (88%) | 12 (75%) | 0.467 † |
| Male | 1 (6%) | 2 (13%) | 4 (25%) | |
| WHO functional class | ||||
| Class I | 1 (6%) | 1 (6%) | 1 (6%) | 0.983 † |
| Class II | 7 (44%) | 6 (38%) | 8 (50%) | |
| Class III | 8 (50%) | 9 (56%) | 7 (44%) | |
| PAH etiology | ||||
| Idiopathic | 7 (44%) | 8 (50%) | 7 (44%) | 0.999 † |
| Congenital heart disease | 9 (56%) | 8 (50%) | 9 (56%) | |
| Right heart catheterization, mean (SD) | ||||
| mPAP (mm Hg) | 50.44 (22.05) | 65.56 (20.39) | 59.69 (29.30) | 0.216 * |
| PVR (Wood units) | 8.13 (5.02) | 10.15 (4.71) | 7.61 (4.06) | 0.268 * |
| PAWP (mm Hg) | 11.28 (2.75) | 13.97 (5.14) | 12.22 (2.92) | 0.134 * |
| Right atrial pressure (mm Hg) | 12.89 (8.25) | 15.67 (7.46) | 13.70 (3.95) | 0.500 * |
| Cardiac output (L/min) | 4.90 (1.55) | 4.36 (0.84) | 4.37 (1.45) | 0.431 * |
| NT-proBNP (pg/mL), mean (SD) | 447.7 (343.7) | 732.8 (938.7) | 1086.2 (1364.3) | 0.191 * |
| Medications | ||||
| Bosentan | 6 (38%) | 7 (44%) | 5 (31%) | 0.766 † |
| Sildenafil | 4 (25%) | 8 (50%) | 3 (19%) | 0.131 † |
| Iloprost | 0 (0%) | 3 (19%) | 1 (6%) | 0.304 † |
| Calcium channel blockers | 2 (13%) | 0 (0%) | 1 (6%) | 0.763 † |
| Anticoagulants | 3 (19%) | 6 (38%) | 3 (19%) | 0.530 † |
| Diuretics | 8 (50%) | 5 (31%) | 8 (50%) | 0.467 † |
| Drug combination therapy | ||||
| Monotherapy | 10 (63%) | 4 (25%) | 7 (44%) | 0.102 † |
| Dual therapy | 6 (38%) | 9 (56%) | 8 (50%) | 0.557 † |
| Triple therapy | 0 (0%) | 3 (9%) | 1 (6%) | 0.304 † |
| Risk factors | ||||
| Hypertension | 11 (69%) | 9 (56%) | 11 (69%) | 0.695 † |
| Atrial fibrillation | 3 (19%) | 5 (31%) | 3 (19%) | 0.624 † |
| Diabetes | 5 (31%) | 4 (25%) | 5 (31%) | 0.999 † |
| Hyperlipidemia | 1 (6%) | 3 (19%) | 4 (25%) | 0.492 † |
| Anemia | 6 (38%) | 5 (31%) | 6 (38%) | 0.913 † |
| Thyroid disease | 1 (6%) | 4 (25%) | 3 (19%) | 0.492 † |
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