Medicinal clays improve the endurance of loaded inspiratory muscles in COPD: a randomized clinical trial of nonpharmacological treatment

Figures & data

Figure 1 Flow diagram of patients’ allocation to the thermal interventions.

Abbreviations: LTA, leisure thermal activity; MBT, mud bath therapy.

Table 1 Anthropometrics, smoking habit, and pulmonary function data in 42 COPD patients according to treatment/comparator allocation

Intervention	MBT group, n=22		LTA group, n=20		P-valuea
Patients	Mean	95% CI	Mean	95% CI
Age, years	64.8	61.2–68.5	64.4	60.2–67.8	0.75
Sex, male:female	[18:4]b	–	[15:5]b	–	0.71
Smoking habit, C:F:NS	{8:12:0}c	–	{9:11:0}c	–	0.36
BMI, kg/m^2	31.0	27.6–34.5	30.8	27.1–34.4	0.92
FEV1, % pred	70.7	65.4–76.0	65.8	60.2–71.3	0.20
VC, % pred	98.4	90.7–106.1	97.5	89.5–105.6	0.88
FEV1/VC, %	56.0	51.7–60.4	55.7	50.2–59.4	0.69
TLC, % pred	102.3	95.5–109.1	103.4	96.3–110.6	0.82
FRC, % pred	113.1	100.2–125.9	120.9	107.4–134.4	0.41
RV, % pred	113.4	97.5–129.3	122.5	105.8–139.2	0.43
DLCO/VA, % pred	67.3	57.8–77.1	56.9	46.4–67.5	0.16
MIP, cm H2O	88.8	80.8–96.8	79.2	70.4–87.6	0.10
PaO2, kPa	10.2	9.8–10.6	9.6	9.2–10.0	0.06
PaCO2, kPa	4.8	4.5–5.0	5.0	4.8–5.2	0.14

Notes:

a P-value.

b Counts in square brackets are compared by Fisher’s exact test.

c Counts in curly brackets are compared by χ².

Abbreviations: BMI, body mass index; C, current smoker; CI, confidence interval; COPD, chronic obstructive pulmonary disease; DLCO/VA, CO-diffusing capacity to alveolar volume ratio; F, former smoker; FEV₁, forced expiratory volume in one second; FEV₁/VC, Tiffeneau index; FRC, functional residual capacity measured by body box; LTA, leisure thermal activity; MBT, mud bath therapy; MIP, maximum inspiratory pressure, pressure can be generated against an occluded airway beginning at functional residual capacity; NS, non smoker; RV, residual volume; TLC, total lung capacity; VC, slow vital capacity.

Table 2 Between-groups comparison in endpoint and exploratory variables, at baseline

Intervention	MBT group, n=22		LTA group, n=20		P-valuea
Endpoint	Mean	95% CI	Mean	95% CI
IL-6, Lnb	0.95	0.56–1.34	1.30	0.928–1.666	0.25
ET, minutes	26.95	19.94–27.95	23.95	19.94–27.95	0.24
Exploratory
CRP, Lnb	1.47	1.09–1.84	1.56	1.10–2.02	0.76
ACTH, Lnb	3.09	2.85–3.34	3.31	3.04–3.58	0.28
IL-1β, [IR:OOR<]c	[B: 2:20]	[A: 2:20]	[B: 1:19]	[A: 1:18]	{3.1–43.3 pg/mL}d
TNF-α, [IR:OOR<]c	[B: 3:19]	[A: 4:18]	[B: 2:18]	[A: 2:17]	{15.8–379.9 pg/mL}d
Lactatebefore_IRB	1.58	1.21–1.94	1.31	1.01–1.61	0.24
Lactateafter_IRB	1.37	1.18–1.56	1.22	0.96–1.47	0.32
MIP, cm H2O	88.8	80.78–96.82	79.2	70.74–87.57	0.10
SIP, cm H2O	35.53	31.89–39.17	32.25	27.96–35.61	0.16
SIP/MIP, %	41.58	37.95–45.22	41.26	41.03–44.84	0.88

Notes:

a P-value.

b Natural logarithm units.

c IR indicates in range of the titration curve and OOR< indicates out of range, and below the lower limits of the titration curve. The numbers in square brackets are IR:OOR< ratios, as both cytokines were undetectable in the majority of patients either before [B] or after [A] thermal interventions.

d Standard reference range in curly brackets is reported as pg/mL.

Abbreviations: ACTH, adrenocorticotrophin hormone; CI, confidence interval; CRP, C-reactive protein; ET, endurance time; IL-6, interleukin 6; IL-1β, interleukin 1-beta; LTA, leisure thermal activity; MBT, mud bath therapy; MIP, maximum inspiratory pressure; SIP, sustainable inspiratory mouth pressure, in cm H₂O, and as SIP/P_imax%; TNF-α, interleukin tumor necrosis factor alfa.

Table 3 Baseline characteristics, accountability of adverse events, and adherence to thermal spa therapy and mud packs interventions

Intervention	MBT group, n=22	LTA group, n=20	P-valuea
Patients
N started (completed)	22 (22)	20 (19)	–
Sex, male/female	18/4	15/5	–
Age (standard deviation)	63.7 (6.7)	65.0 (9.6)	0.643
SAE	No	No
NSAEb	2/22	No
PTPA, R:NR	18:2	15:4
Adherence to balneotherapya, %	58.9 (30.5)	74.3 (24.8)	0.083
Adherence to mud packsb, %	97.4 (7.9)	NA	–
SpO2% before treat./comp.	95.8 (1.4)	94.6 (1.8)	0.034
SpO2% after treat./comp.	95.4 (1.4)	94.6 (2.3)	0.203

Notes: No SAE reported; NSAE, one herpes virus recurrence, and 1 chronic obstructive pulmonary disease exacerbation in MBT group.

a Number of balneotherapy sessions attended over the total scheduled sessions.

b Number of mud pack sessions attended over the total scheduled sessions.

Abbreviations: MBT, mud bath therapy; NR, number of the patients not attending on a regular basis; NSAE, nonserious adverse event; PTPA, patients’ attendance to thermal pool; R, number of the patients attending on a regular basis; SAE, serious adverse event; NA, not applicable.

Table 4 Ventilatory and mechanical parameters during IRB challenge: comparisons within and between groups, before and after thermal interventions

Notes: Data are given as mean (95% confidence interval). ^aStatistically significant effect of IRB on T_I before and after thermal interventions (P<0.0001 for both). ^bStatistically significant effect of IRB on VE before and after thermal interventions (P<0.005 or less for both). ^cStatistically significant treatments-by-trials interaction effect in ET (P<0.003).

Abbreviations: ET, endurance time; LTA, leisure thermal activity; MBT, mud bath therapy; T_{I_rest}, inspiratory time at rest; T_{I_IRB}, inspiratory time during IRB challenge; V_T/T_{I_rest}, inspiratory flow rate at rest; V_T/T_{I_IRB}, inspiratory flow rate upon IRB challenge; VE_{_rest}, minute ventilation at rest; VE_IRB, minute ventilation upon IRB challenge; VO_2IRB, oxygen cost of IRB challenge.

Figure 2 IRB challenge-induced changes in ΔIL-6 (within groups) before and after thermal interventions (between groups).

Notes: The effect size was small for ΔIL-6 (−0.08). Individual measurements and mean value in MBT group before thermal interventions (light green squares) and after thermal interventions (dark green squares). Individual measurements and mean value in LTA group before thermal interventions (light blue triangles) and after thermal interventions (dark green triangles).
Abbreviations: IL-6, interleukin 6; IRB, inspiratory resistive breathing; LTA, leisure thermal activity; MBT, mud bath therapy.

Figure 3 IRB challenge-induced changes in ET (within groups) before and after thermal interventions (between groups).

Notes: The effect size was moderate for ET The effect size was large for ET (0.47). Individual measurements in MBT group before and after thermal interventions (green squares) and mean values. Individual measurements in LTA group before and after thermal interventions (blue triangles) and mean values.
Abbreviations: ET, endurance time; IL, interleukin; IRB, inspiratory resistive breathing; LTA, leisure thermal activity; MBT, mud bath therapy.

Figure 4 IRB challenge-induced changes in ACTH (ΔACTH) and CRP (ΔCRP) before and after thermal interventions (box plots).

Notes: Left panel: within-group mean difference in ACTH. Right panel: within-group mean difference in CRP. The box plots are superimposed to the dot plots. Closed and open squares indicate IRB-induced changes before and after MBT interventions, respectively, while closed and open triangles are IRB-induced changes before and after LTA interventions, respectively. Mean lines, single outlier, and extreme values are also reported as indicated by the legend.
Abbreviations: ACTH, adrenocorticotrophic hormone; CRP, C-reactive protein; IRB, inspiratory resistive breathing; LTA, leisure thermal activity; MBT, mud bath therapy.

Table 5 Relationship between T_{I_IRB} and ΔIL-6_IRB and RR_IRB before and after thermal interventions

Parameter	Standardized beta	t	DF	P-value
R^2: 0.619
Constant	0	12.68	36	<0.0001
MBT group	–	–	36	–
LTA group	–	−1.46	36	0.1534
ΔIL-6IRB before	−0.306	−2.83	36	0.0075
RRIRB before	−0.677	−5.83	36	<0.0001
R^2: 0.698
Constant	0	15.92	37	<0.0001
MBT group	–	–	37	–
LTA group	–	−1.40	37	0.1704
ΔIL-6IRB after	−0.173	−1.86	37	0.0714
RRIRB after	−0.788	−8.32	37	<0.0001

Abbreviations: RR_IRB, respiratory rate during IRB challenge; ΔIL-6_IRB, cytokine 6 change over baseline during IRB challenge; IRB, inspiratory resistive breathing; LTA, leisure thermal activity; MBT, mud bath therapy; T_{I_IRB}, inspiratory time during IRB challenge; DF, degree of freedom.