Small airways ventilation heterogeneity and hyperinflation in COPD: Response to tiotropium bromide

Figures & data

Figure 1 Histogram of the distribution of the residual volume (RV) over total lung capacity (TLC) ratio in the COPD group under study (n = 40). The 4 left-most bars constitute the Hyp– group (n = 20) and the 3 right-most bars constitute the Hyp+ group (n = 20).

Table 1 Characteristics of COPD subgroups with RV/TLC ≥ 55% (Hyp+) OR <55% (Hyp⁻) and the effect of tiotropium

	Hyp^+ (n = 20)			Hyp^− (n = 20)			p-value Hyp^+ vs Hyp^− at baseline
Age (yrs)	68 ± 2			65 ± 2			>0.1
Height (cm)	171 ± 1			177 ± 1			0.003
COPD diagnosis (yrs)	7 ± 1			6 ± 2			>0.1
Packyears (py)	54 ± 4			49 ± 7			>0.1
	Baseline	3 wks tiotropium	6 wks tiotropium	Baseline	3 wks tiotropium	6 wks tiotropium
FEV1 (%pred)	50 ± 3	55 ± 3†	55 ± 3†	60 ± 3	61 ± 3	62 ± 3	0.006
FEV1 (L)	1.38 ± 0.07	1.52 ± 0.06†	1.52 ± 0.07†	1.94 ± 0.10	1.97 ± 0.11	1.99 ± 0.11	<0.001
FEV1/FVC (%)	46 ± 2	47 ± 2	47 ± 2	51 ± 2	50 ± 2	50 ± 2	>0.1
FEF75 (%pred)	13 ± 1	13 ± 1	13 ± 1	18 ± 1	17 ± 1	18 ± 1	0.008
Kco (%pred)	69 ± 5	69 ± 5	69 ± 5	71 ± 4	69 ± 4	70 ± 5	>0.1
sGaw (L/s/cmH2O/L)	0.042 ± 0.005	0.046 ± 0.003	0.045 ± 0.004	0.049 ± 0.004	0.049 ± 0.003	0.049 ± 0.003	>0.1
RVpl (ml)	3811 ± 159	3877 ± 204	3650 ± 121	3052 ± 137	3086 ± 150	2991 ± 153	0.001
TLCpl (ml)	6644 ± 243	6832 ± 252	6707 ± 221	6600 ± 207	6704 ± 246	6628 ± 240	>0.1
ICpl (ml)	1889 ± 95	1956 ± 84	2026 ± 119	2392 ± 148	2367 ± 141	2428 ± 140	0.007
IC (ml)	2181 ± 126	2386 ± 122*	2434 ± 130†	2665 ± 113	2679 ± 119	2693 ± 129	0.007
Sacin (L^−1)	0.425 ± 0.024	0.399 ± 0.025	0.411 ± 0.024	0.339 ± 0.030	0.365 ± 0.032	0.340 ± 0.033	0.03
Scond (L^−1)	0.086 ± 0.006	0.083 ± 0.007	0.090 ± 0.008	0.086 ± 0.007	0.081 ± 0.007	0.095 ± 0.008	>0.1
FRCmbw (ml)	3752 ± 125	3665 ± 131	3595 ± 118	3680 ± 150	3674 ± 146	3659 ± 126	>0.1
Total symptom score (0–12)	3.5 ± 0.4	2.4 ± 0.4†	1.5 ± 0.2†	3.6 ± 0.4	2.0 ± 0.3†	1.7 ± 0.3†	>0.1
MRC dyspnea score (1–5)	2.1 ± 0.2	2.0 ± 0.2	1.8 ± 0.2	1.7 ± 0.2	1.8 ± 0.2	1.9 ± 0.2	>0.1
VAS dyspnea score (0–10)	4.5 ± 0.5	3.2 ± 0.4*	2.7 ± 0.5†	3.0 ± 0.4	3.0 ± 0.5	2.7 ± 0.4	0.03

Notes: All averages (± SEM) refer to data prior to tiotropium intake on the study day.

Abbreviations: FEV1, forced expired volume in one second; FVC, forced expired vital capacity; FEF75, forced expiratory flow after expiration of 75% FVC; Kco, carbon monoxide diffusing capacity per lung volume; sGaw, specific airway conductance; RVpl,TLCpl,ICpl, plethysmographic residual volume, total lung capacity, and inspiratory capacity; IC, inspiratory capacity measured in open circuit; Sacin,Scond, index of acinar and conductive ventilation heterogeneity (see text for details); FRCmbw, functional residual capacity derived from the multiple breath washout. For symptom and dyspnea scores (see text); Significant changes from baseline (within Hyp⁺ and Hyp⁻ groups):

* p < 0.05;

† p < 0.01.

Figure 2 A: Scatterplot of the individual change in IC (ΔIC) versus the corresponding change in visual analog dyspnea score (ΔVAS) in the Hyp+ group where ΔIC and ΔVAS are computed as the VAS or pre-tiotropium IC value at the 6 weeks tiotropium visit minus the VAS or pre-tiotropium IC value at the baseline study visit. B: Scatter-plot of the individual change in sGaw (ΔsGaw) versus the corresponding change in visual analog score (ΔVAS) in the Hyp+ group; same representation as in A.

Figure 3 A: Forced expiratory volume in one second (FEV₁) as %predicted obtained from the Hyp⁺ group on the screening visit (dotted line connecting open triangles; pre- and 90 min post-dilation with a combination of salbutamol and ipratropium bromide) and during the three study visits (solid lines connecting open circles (pre-) and closed circles (90 min post-) tiotropium); the crosses refer to intermediate FEV₁measures after 60 min. On the first study visit, patients were tiotropium-free, while the other two study visits followed 3 and 6 weeks of tiotropium once-daily treatment with the last tiotropium intake on the day prior to the study visit; asterisks indicate any significant change 90 min after tiotropium (2-way ANOVA with Bonferroni; p < 0.05). B: FEV₁obtained from the Hyp⁻ group.

Figure 4 A: Inspiratory capacity measured in an open circuit (IC) obtained from the Hyp⁺ group on the screening visit (dotted line connecting open triangles; pre- and 90 min post-dilation with a combination of salbutamol and ipratropium bromide) and during the three study visits (solid lines connecting open circles (pre-) and closed circles (90 min post-) tiotropium). On the first study visit, patients were tiotropium-free, while the other two study visits followed 3 and 6 weeks of tiotropium once-daily treatment with the last tiotropium intake on the day prior to the study visit; asterisks indicate any significant change 90 min after tiotropium (2-way ANOVA with Bonferroni; p < 0.05); the dotted line represents the predicted IC value for this subgroup. B: IC obtained from the Hyp⁻ group.

Figure 5 A: Specific conductance (sGaw) obtained from the Hyp+ group on the screening visit (dotted line connecting open triangles; pre- and 90 min post-dilation with a combination of salbutamol and ipratropium bromide) and during the three study visits (solid lines connecting open circles (pre-) and closed circles (90 min post-) tiotropium). On the first study visit, patients were tiotropium-free, while the other two study visits followed 3 and 6 weeks of tiotropium once-daily treatment with the last tiotropium intake on the day prior to the study visit; asterisks indicate any significant change 90 min after tiotropium (2-way ANOVA with Bonferroni; p < 0.05). B: sGaw obtained from the Hyp⁻ group.

Figure 6 A: Conductive ventilation heterogeneity (S_cond) obtained from the Hyp⁺ group on the screening visit (dotted line connecting open triangles; pre- and 90 min post-dilation with a combination of salbutamol and ipratropium bromide) and during the three study visits (solid lines connecting open circles (pre-) and closed circles (90 min post-) tiotropium). On the first study visit, patients were tiotropium-free, while the other two study visits followed 3 and 6 weeks of tiotropium once-daily treatment with the last tiotropium intake on the day prior to the study visit; asterisks indicate any significant change 90 min after tiotropium (2-way ANOVA with Bonferroni; p < 0.05). B: S_cond obtained from the Hyp⁻ group.

Table 2 Characteristics of FEV₁ matched subgroups with RV/TLC ≥ 55% (Hyp⁺) OR < 55% (Hyp⁻) and the effect of tiotropium

	Hyp^+ (n = 20)			Hyp^− (n = 20)			p-value Hyp^+ vs Hyp^− at baseline
Age (yrs)	70 ± 2			65 ± 2			>0.1
Height (cm)	170 ± 1			175 ± 1			0.009
COPD diagnosis (yrs)	7 ± 2			6 ± 2			>0.1
Packyears (py)	57 ± 4			51 ± 9			>0.1
	Baseline	3 wks tiotropium	6 wks tiotropium	Baseline	3 wks tiotropium	6 wks tiotropium
FEV1 (%pred)	55 ± 2	59 ± 3 *	59 ± 2 †	58 ± 3	58 ± 3	60 ± 3	>0.1
FEV1 (L)	1.46 ± 0.07	1.56 ± 0.08 *	1.58 ± 0.08 †	1.80 ± 0.11	1.82 ± 0.11	1.87 ± 0.12	0.02
FEV1/FVC (%)	50 ± 2	51 ± 2	50 ± 2	49 ± 3	48 ± 3	49 ± 3	>0.1
FEF75 (%pred)	14 ± 1	14 ± 2	14 ± 1	18 ± 2	16 ± 2	18 ± 1	0.09
Kco (%pred)	71 ± 5	71 ± 6	71 ± 6	68 ± 5	67 ± 4	67 ± 5	>0.1
sGaw (L/s/cmH2O/L)	0.044 ± 0.006	0.048 ± 0.004	0.047 ± 0.004	0.050 ± 0.005	0.049 ± 0.004	0.050 ± 0.004	>0.1
RVpl (ml)	3598 ± 140	3802 ± 262	3594 ± 151	3106 ± 169	3131 ± 196	3050 ± 193	0.03
TLCpl (ml)	6272 ± 219	6573 ± 302	6433 ± 243	6535 ± 260	6603 ± 319	6518 ± 303	>0.1
ICpl (ml)	1808 ± 107	1874 ± 77	1896 ± 110	2201 ± 158	2203 ± 158	2249 ± 152	0.05
IC (ml)	2088 ± 103	2232 ± 96	2315 ± 122 †	2502 ± 108	2489 ± 116	2526 ± 137	0.01
Sacin (L^−1)	0.400 ± 0.027	0.382 ± 0.028	0.402 ± 0.029	0.321 ± 0.029	0.346 ± 0.031	0.326 ± 0.037	0.05
Scond (L^−1)	0.087 ± 0.006	0.082 ± 0.008	0.088 ± 0.010	0.089 ± 0.008	0.084 ± 0.008	0.101 ± 0.009	>0.1
FRCmbw (ml)	3685 ± 151	3595 ± 161	3547 ± 154	3721 ± 170	3737 ± 171	3703 ± 136	>0.1
Total symptom score (0–12)	3.2 ± 0.4	2.1 ± 0.4 *	1.4 ± 0.2 †	3.3 ± 0.3	1.7 ± 0.2 †	1.3 ± 0.2 †	>0.1
MRC dyspnea score (1–5)	1.9 ± 0.2	1.8 ± 0.2	1.7 ± 0.2	1.6 ± 0.2	1.7 ± 0.2	1.9 ± 0.3	>0.1
VAS dyspnea score (0–10)	4.6 ± 0.6	3.0 ± 0.5 *	2.6 ± 0.6 †	3.0 ± 0.6	2.9 ± 0.6	2.6 ± 0.5	>0.1

Notes: All averages (±SEM) refer to data prior to tiotropium intake on the study day; same abbreviations as in Table I. Significant changes from baseline (within Hyp⁺ and Hyp⁻ groups):

* p < 0.05;

† p < 0.01.

Table 3 Characteristics of COPD subgroups with RV/TLC > 59% (Hyp⁺) or <46% (Hyp⁻) and the effect of tiotropium

	Hyp^+ (n = 20)			Hyp^– (n = 20)			p-value Hyp^+ vs Hyp^− at baseline
Age (yrs)	71 ± 2			63 ± 3			0.04
Height (cm)	171 ± 2			178 ± 2			0.07
COPD diagnosis (yrs)	7 ± 2			5 ± 1			>0.1
Packyears (py)	60 ± 6			50 ± 12			>0.1
	Baseline	3 wks tiotropium	6 wks tiotropium	Baseline	3 wks tiotropium	6 wks tiotropium
FEV1 (%pred)	49 ± 4	55 ± 4	53 ± 3	65 ± 3	61 ± 4*	64 ± 3	0.002
FEV1 (L)	1.33 ± 0.07	1.48 ± 0.06	1.44 ± 0.06	2.14 ± 0.15	2.01 ± 0.17*	2.10 ± 0.16	<0.001
FEV1/FVC (%)	44 ± 2	45 ± 3	45 ± 3	54 ± 3	51 ± 3	52 ± 3	0.02
FEF75 (%pred)	13 ± 2	12 ± 2	14 ± 1	20 ± 2	17 ± 3	19 ± 2	0.03
Kco (%pred)	69 ± 8	69 ± 8	68 ± 8	71 ± 6	71 ± 6	71 ± 7	>0.1
sGaw (L/s/cmH2O/L)	0.038 ± 0.004	0.044 ± 0.005	0.042 ± 0.005	0.055 ± 0.006	0.050 ± 0.004	0.054 ± 0.005	0.02
RVpl (ml)	4028 ± 249	4158 ± 301	3871 ± 164	2577 ± 139	2726 ± 221	2491 ± 142	>0.001
TLCpl (ml)	6781 ± 362	7010 ± 294	6879 ± 304	6236 ± 333	6399 ± 434	6236 ± 370	>0.1
ICpl (ml)	1817 ± 130	1937 ± 90	2066 ± 188	2572 ± 262	2406 ± 274	2537 ± 265	0.02
IC (ml)	2119 ± 206	2336 ± 171	2395 ± 189 †	2761 ± 215	2655 ± 227	2719 ± 245	0.045
Sacin (L^−1)	0.432 ± 0.028	0.389 ± 0.025	0.391 ± 0.030	0.283 ± 0.032	0.318 ± 0.043	0.299 ± 0.047	0.003
Scond (L^−1)	0.090 ± 0.008	0.093 ± 0.011	0.105 ± 0.013	0.086 ± 0.011	0.092 ± 0.013	0.102 ± 0.015	>0.1
FRCmbw (ml)	3793 ± 172	3778 ± 207	3636 ± 163	3472 ± 248	3405 ± 208	3498 ± 190	>0.1
Total symptom score (0–12)	3.8 ± 0.6	2.8 ± 0.6*	1.8 ± 0.3†	4.0 ± 0.6	2.3 ± 0.6†	1.9 ± 0.5†	>0.1
MRC dyspnea score (1–5)	2.2 ± 0.2	2.4 ± 0.3	2.0 ± 0.2	2.1 ± 0.2	2.3 ± 0.3	2.2 ± 0.2	>0.1
VAS dyspnea score (0–10)	4.4 ± 0.8	3.6 ± 0.6	3.1 ± 0.9	3.9 ± 0.6	4.0 ± 0.6	3.6 ± 0.6	>0.1

Notes: All averages (±SEM) refer to data prior to tiotropium intake on the study day; same abbreviations as in Table I. Significant changes from baseline (within Hyp⁺ and Hyp⁻ groups):

* p < 0.05;

† p < 0.01.

Figure A1 Normalized N₂ phase III slopes (mean ± SD) as a function of lung turnover obtained in two patients participating in this study (open and closed circles); also represented is an idealized curve corresponding to normal normalized N₂ phase III slopes (dotted line).