Three-minute constant rate step test for detecting exertional dyspnea relief after bronchodilation in COPD

Figures & data

Figure 1 Study design for V2 and V3 during which one of the study medications (ipratropium bromide [500 µg]/salbutamol [2.5 mg] [Combivent^®] or placebo) was administered.

Abbreviations: V2, visit 2; V3, visit 3.

Figure 2 Flowchart of the two-site clinical study.

Abbreviation: V2, visit 2.

Table 1 Baseline characteristics of the study population (n=40)

Parameter	Mean (SD)
Male/female	33/7
Age (years)	69 (7)
Height (cm)	168 (8)
Weight (kg)	74 (15)
Body mass index (kg·m^−2)	25.9 (4.5)
Smoking history (pack-years)	57 (34)
Pulmonary function
COPD severity (GOLD^3), n (%)
Moderate	18 (45)
Severe	22 (55)
Pre-BD FEV1 (L); % predicted	1.24 (0.41); 46 (14)
Post-BD FEV1 (L); % predicted	1.49 (0.44); 55 (15)
FVC (L)	2.97 (0.90)
FVC (% predicted)	82 (21)
FEV1/FVC (%)	43 (14)
FRC (% predicted)	138 (33)
TLC (% predicted)	112 (16)
RV (% predicted)	152 (45)
DLCO (% predicted)	77 (22)

Abbreviations: BD, bronchodilator; D_LCO, diffusing capacity of the lung for carbon monoxide; FEV₁, forced expiratory volume in 1 second; FRC, forced residual capacity; FVC, forced vital capacity; GOLD, Global Initiative for Chronic Obstructive Lung Disease; RV, residual volume; TLC, total lung capacity.

Table 2 Physiological and perceptual responses at the symptom-limited peak incremental cycle exercise (n=40)

Parameter	Mean (SD)
Power output (W)	76 (29)
Power output (% predicted)	55.8 (18.3)
$\dot{V}{\mathrm{O}}_2(\text{mL}·{\text{kg}}^{-1}·{\min }^{-1})$	18.4 (4.7)
$\dot{V}{\mathrm{O}}_2\left(\%\text{predicted}\right)$	82.4 (17.9)
$\dot{V}{\text{CO}}_2(\text{mL}\cdot {\text{kg}}^{–1}\cdot {\min }^{-1})$	18.9 (6.0)
${\dot{V}}_{\mathrm{E}}/\dot{V}{\text{CO}}_2$	36.8 (6.6)
HR (beats·min^–1)	121 (21)
HR (% predicted)	72.8 (12.0)
SpO2 (%)	94.1 (2.7)
${\dot{V}}_{\mathrm{E}}(\mathrm{L}\cdot {\min }^{-1})$	48.9 (14.1)
${\dot{V}}_{\mathrm{E}}(\%\text{MVV})$	99 (17)
VT (L)	1.39 (0.27)
f (breaths·min^−1)	35.8 (6.34)
IC (L)	1.89 (0.48)
Δ IC rest–peak exercise (L)	−0.70 (0.36)
IRV (L)	0.48 (0.29)
Dyspnea (Borg 0–10 scale units)	6.2 (2.0)
Leg discomfort (Borg 0–10 scale units)	6.3 (2.1)

Abbreviations: f, breathing frequency; Δ, change from rest to end exercise; SpO₂, oxygen pulse saturation; $\dot{V}{\text{CO}}_2$, CO₂ production; ${\dot{V}}_{\mathrm{E}}$, ventilation; ${\dot{V}}_{\mathrm{E}}/\dot{V}{\text{CO}}_2$, ventilatory equivalent for CO₂; $\dot{V}{\mathrm{O}}_2$, O₂ uptake; V_T, tidal volume. HR, heart rate; IC, inspiratory capacity; IRV, inspiratory reserve volume; MVV, maximum voluntary ventilation.

Table 3 Effects of nebulized ipratropium bromide (500 µg)/salbutamol (2.5 mg), and 0.9% saline placebo on spirometry parameters at rest (n=40)

Parameter	Ipratropium bromide (500 µg)/salbutamol (2.5 mg)				Placebo
	Pre-dose	Post-dose	Δ; %	P-value	Pre-dose	Post-dose	Δ; %	P-value
FEV1 (L)	1.24 (0.41)	1.49 (0.44)	0.25 (0.13); 20.2	<0.001	1.24 (0.42)	1.24 (0.42)	0.0 (0.11); 0	0.999
FVC (L)	2.98 (0.92)	3.39 (0.96)	0.41 (0.32); 13.8	<0.001	2.97 (0.90)	2.94 (0.83)	−0.03 (0.28); 0	0.585
FEV1/FVC (%)	42.8 (11.0)	45.7 (13.4)	2.84 (7.7); 6.6	0.024	43.4 (14.1)	43.3 (13.5)	−0.09 (3.41); 0	0.865

Notes: Values are mean (SD). Δ, post- minus pre-dose changes.

Abbreviations: FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity.

Figure 3 Effect of nebulized fixed-dose combination of ipratropium bromide (500 µg)/salbutamol (2.5 mg) (Combivent^®) and 0.9% saline placebo on Borg 0–10 scale intensity ratings of dyspnea at the end of the third minute of exercise.

Note: The number of patients completing all 3 minutes of exercise at 14, 16, 20 and 24 steps/min under both treatment conditions are indicated in the white boxes.

Table 4 Effect of single-dose inhalation of nebulized ipratropium bromide (500 µg)/salbutamol (2.5 mg) vs 0.9% saline placebo on physiological and perceptual responses at the end of the 3-MST, performed at 14, 16, 20 and 24 steps/min

Parameter	14 steps/min (n=37)		16 steps/min (n=36)		20 steps/min (n=34)		24 steps/min (n=27)
	Ipratropium bromide/salbutamol	Placebo	Ipratropium bromide/salbutamol	Placebo	Ipratropium bromide/salbutamol	Placebo	Ipratropium bromide/salbutamol	Placebo
$\dot{V}{\mathrm{O}}_2(\text{mL}\cdot {\text{kg}}^{-1}\cdot {\min }^{-1})$	13.4 (1.9)	13.7 (2.2)	14.2 (2.7)	14.4 (2.4)	15.8 (3.2)	15.6 (2.8)	16.2 (3.0)	16.3 (2.9)
$\dot{V}{\mathrm{O}}_2(\%\dot{V}{\mathrm{O}}_{2\text{peak}})$	76 (17)	78 (20)	80 (18)	82 (20)	89 (19)	88 (19)	91 (17)	92 (19)
$\dot{V}{\text{CO}}_2(\text{mL}\cdot {\text{kg}}^{-1}\cdot {\min }^{-1})$	10.5 (1.4)	10.4 (1.9)	11.4 (2.2)	11.3 (2.1)	13.3 (2.6)	12.8 (2.7)	14.4 (3.0)	14.2 (2.9)
HR (beats·min^−1)	99 (17)	98 (17)	103 (17)	102 (17)	108 (19)	106 (18)	109 (19)	111 (20)
HR (% HRpeak)	83 (11)	82 (12)	85 (11)	85 (12)	89 (11)	88 (11)	91 (9)	91 (12)
Arterial SpO2 (%)	91 (4)	92 (4)	92 (4)	91 (4)	90 (4)	92 (3)	91 (4)	91 (3)
${\dot{V}}_{\mathrm{E}}/\dot{V}{\text{CO}}_2$	39.8 (6.3)	38.6 (5.2)	39.4 (5.7)	38.3 (4.9)	39.3 (5.6)	37.8 (5.4)	38.8 (5.8)	37.7 (6.1)
${\dot{V}}_{\mathrm{E}}(\mathrm{L}\cdot {\text{min}}^{-1})$	32.2 (7.6)	30.8 (6.7)*	34.4 (8.2)	32.5 (7.5)**	40.5 (9.2)	36.7 (8.5)***	43.4 (11.4)	42.1 (10.5)**
${\dot{V}}_{\mathrm{E}}(\%{\dot{V}}_{\text{Epeak}})$	69 (19)	66 (20)*	73 (20)	71 (20)	85 (21)	78 (18)***	91 (20)	87 (19)**
VT (L)	1.27 (0.30)	1.18 (0.27)***	1.30 (0.29)	1.18 (0.26)**	1.40 (0.29)	1.28 (0.27)***	1.39 (0.30)	1.30 (0.28)***
f (breaths·min^−1)	26.0 (6.1)	26.9 (5.5)	27.2 (5.6)	28.4 (5.9)*	29.5 (6.4)	29.4 (6.4)	31.8 (7.0)	33.0 (6.3)
IC (L)	2.03 (0.50)	1.76 (0.51)***	1.96 (0.51)	1.74 (0.49)***	1.91 (0.49)	1.72 (0.46)***	1.93 (44)	1.64 (0.47)***
Δ IC (L)	−0.51 (0.39)	−0.54 (0.39)	−0.54 (0.41)	−0.56 (0.39)	−0.63 (0.41)	−0.52 (0.44)	−0.65 (0.55)	−0.60 (0.56)
IRV (L)	0.79 (0.42)	0.58 (0.42)***	0.69 (0.41)	0.55 (0.38)*	0.53 (0.38)	0.46 (0.36)	0.57 (0.30)	0.42 (0.30)**
Dyspnea (Borg 0–10 scale units)	2.3 (1.6)	2.9 (1.9)**	2.7 (1.8)	3.4 (2.1)**	3.8 (2.2)	4.1 (2.5)	4.4 (2.4)	5.0 (2.9)
Dyspnea: ${\dot{V}}_{\mathrm{E}}$ ratio (Borg 0–10 scale units/L per minute)	0.07 (0.05)	0.10 (0.07)***	0.08 (0.06)	0.11 (0.07)***	0.10 (0.07)	0.12 (0.08)*	0.11 (0.08)	0.13 (0.09)**
Dyspnea: IRV ratio (Borg 0–10 scale units/L)	5.1 (8.1)	15.8 (58.8)*	6.6 (11.1)	9.2 (23.8)*	16.4 (28.6)	13.0 (18.1)	11.0 (11.8)	10.7 (19.2)
Leg discomfort (Borg 0–10 scale units)	2.5 (1.7)	2.8 (2.1)	2.7 (2.0)	3.2 (3.9)*	3.9 (2.5)	4.2 (2.5)	4.8 (2.9)	4.9 (3.0)

Notes: Values are mean (SD). A negative change indicates a lower IC at the end of exercise compared with rest, ie, the occurrence of dynamic hyperinflation. Δ IC, the change in IC during exercise was calculated from the IC value at the end of the 3-MST minus the resting IC value; f, breathing frequency; HR_peak, HR at the symptom-limited peak of incremental cycle exercise testing; SpO₂, oxygen pulse saturation; $\dot{V}{\text{CO}}_2$, CO₂ production; ${\dot{V}}_{\mathrm{E}}$, minute ventilation; ${\dot{V}}_{\text{Epeak}}$, ${\dot{V}}_{\mathrm{E}}$ at the symptom-limited peak of incremental cycle exercise testing; ${\dot{V}}_{\mathrm{E}}/\dot{V}{\text{CO}}_2$, ventilatory equivalent for CO₂; $\dot{V}{\mathrm{O}}_2$, O₂ uptake; $\dot{V}{\mathrm{O}}_{2\text{peak}}$, $\dot{V}{\mathrm{O}}_2$ at the symptom-limited peak of incremental cycle exercise testing; V_T, tidal volume.

* P<0.05,

** P<0.01,

*** P<0.001. Significant differences between ipratropium bromide/salbutamol and placebo respectively.

Abbreviations: HR, heart rate; IC, inspiratory capacity; IRV, inspiratory reserve volume; 3-MST, 3-minute constant rate step test.