Exercise performance and symptoms in lowlanders with COPD ascending to moderate altitude: randomized trial

Figures & data

Table 1 Characteristics of patients

Characteristic	At baseline
Demographics and clinical characteristics
n, (men/women)	32 (19/13)
Age, y	67 (60; 70)
Current smokers, n (%)	8 (25)
Smoking, pack-years	43 (20; 69)
FEV1, % predicted (postbronchodilator)	59 (51; 71)
GOLD grade 2, n (%)	20 (63)
GOLD grade 3, n (%)	12 (37)
Body mass index, kg/m^2	27.1 (22.2; 29.2)
mMRC score	1.0 (1.0; 1.5)
mMRC score ≥2, n (%)	8 (25)
Comorbidities, n patients (%)
Arterial hypertension	19 (59)
Coronary artery disease and other cardiovascular diseases	8 (25)
Diabetes mellitus	2 (6)
Depression	8 (25)
Previous pulmonary embolism	2 (6)
Dyslipidemia	9 (28)
Medication, n patients (%)
Inhalation of topical corticosteroids	18 (56)
Inhalation of β-adrenergics	26 (81)
Inhalation of anticholinergics	26 (81)
Roflumilast	1 (3)
Diuretics	7 (22)
ACE-inhibitor or AT2 antagonist	17 (53)
β-blocker	8 (25)
Calcium channel blocker	6 (19)
Lipid-lowering therapy	7 (22)
Antidiabetics	2 (6)
Antidepressants	7 (22)
Theophylline	1 (3)
Antiplatelet therapy	7 (22)
Oral anticoagulation	3 (9)
Antiarrhythmic therapy	1 (3)

Note: Values presented as median (quartiles) unless indicated otherwise.

Abbreviations: ACE, angiotensin-converting enzyme; AT2, angiotensin II receptor; FEV₁, forced expiratory volume in 1 second; GOLD, global initiative for chronic obstructive lung disease; mMRC, modified Medical Research Council dyspnea score; Pack-years, sum of years smoked a packet of cigarettes per day.

Figure 1 Patient flow.

Notes: Of 191 eligible subjects, 40 were randomized into one of the four altitude exposure sequences (A–D) and included in the intention-to-treat analysis. Data from 32 subjects were included in the per-protocol analysis.

Table 2 Six-minute walk test and clinical evaluation

	490 m		1,650 m		2,590 m		P-value
	First day	Second day	First day	Second day	First day	Second day
6-minute walk distance, m	534±93	547±93*	512±93*,#	525±93#,†	491±93*,#,†,‡	504±93#,‡,¶	<0.001
SpO2, rest, %	94 (94; 96)	94 (93; 95)	92*,# (91; 94)	93*,# (91; 95)	89*,#,†,‡ (88; 91)	90*,#,†,‡ (87; 92)	<0.001
SpO2, end of 6MWT, %	90 (84; 92)	89 (83; 92)	84*,# (78; 87)	85*,# (77; 87)	78*,#,†,‡ (73; 82)	77*,#,†,‡ (73; 82)	<0.001
Borg dyspnea	3.0 (2.0; 5.0)	3.0 (3.0; 4.5)	4.0 (2.0; 4.5)	4.0*,#,† (3.0; 5.5)	3.5 (3.0; 5.0)	4.0*,#,† (3.0; 6.0)	0.003
Borg leg fatigue	2.5 (2.0; 4.0)	3.0 (1.0; 5.0)	2.5 (1.5; 4.0)	3.0 (1.0; 4.0)	2.0 (0.8; 3.0)	3.0 (1.5; 3.0)	0.567
mMRC dyspnea score	1 (0; 1)	1 (1; 1)	1 (1; 1)	1 (1; 1)	1 (1; 1)	1# (1; 1)	0.045
Acute mountain sickness score	0.00 (0.00; 0.09)	0.00 (0.00; 0.00)	0.00 (0.00; 0.18)	0.00 (0.00; 0.09)	0.18*,#,†,‡ (0.00; 0.35)	0.00¶ (0.00; 0.09)	<0.001
Weight, kg	77.3 (67.9; 87.4)	77.3 (68.2; 87.4)	78.2*,# (66.6; 88.6)	78.3*,# (67.4; 87.9)	78.3*,# (67.9; 88.0)	78.6*,# (67.5; 87.9)	<0.001

Notes: Six-minute walk distance analyzed by the intention-to-treat analysis including all 40 randomized patients, values presented as mean ± SD. Other outcomes analyzed by the per-protocol approach including 32 patients, values presented as median (quartiles). P-values from Friedman ANOVA.

* P<0.05 vs 490 m day 1,

# P<0.05 vs 490 m day 2,

† P<0.05 vs 1,650 m day 1,

‡ P<0.05 vs 1,650 m day 2,

¶ P<0.05 vs 2,590 m day 1.

Abbreviations: 6MWT, 6-minute walk test; mMRC, modified Medical Research Council dyspnea score; SpO₂, pulse oximetry.

Figure 2 Altitude-induced changes.

Notes: Dots represent mean differences and horizontal bars the 95% CIs, values are numerically indicated on the right. Altitude effect is significant when the zero value is not part of the 95% CI.

Table 3 Pulmonary function

	490 m		1,650 m		2,590 m		P-value
	First day	Second day	First day	Second day	First day	Second day
FVC, L	3.3 (3.0; 3.9)	3.5 (3.1; 4.2)	3.4 (3.1; 4.2)	3.4 (3.0; 3.9)	3.3 (3.1; 4.1)	3.4 (3.2; 4.1)	0.199
FVC, % pred	92 (88; 109)	95 (90; 113)	99* (89; 111)	97 (91; 107)	95† (88; 105)	94† (88; 104)	0.034
FEV1, L	1.5 (1.3; 2.1)	1.6 (1.4; 2.1)	1.7 (1.4; 2.2)	1.6 (1.4; 2.1)	1.5 (1.4; 2.2)	1.6 (1.4; 2.2)	0.231
FEV1, % pred	59 (51; 71)	57 (52; 75)	62 (58; 73)	63 (55; 71)	57 (53; 69)	56 (54; 72)	0.107
FEV1/FVC, %	51 (47; 62)	51 (47; 63)	53 (46; 61)	53 (48; 62)	53 (46; 61)	53 (45; 61)	0.283
PEF, L	4.73 (3.96; 6.19)	4.73 (3.76; 6.24)	4.95*,# (4.08; 6.49)	5.20*,# (4.23; 6.70)	4.88†,‡ (3.93; 6.14)	4.95†,‡ (4.02; 6.24)	<0.001
PEF, % pred	68 (56; 83)	69 (55; 82)	74*,# (57; 88)	72*,# (62; 91)	71†,‡ (57; 84)	68†,‡ (57; 83)	<0.001
DLCO Hb adj, mmol* min^−1 kPa^−1	4.48 (3.65; 7.05)	4.52 (3.62; 7.25)	4.48 (3.47; 6.75)	4.54 (3.46; 6.75)	4.38*,# (3.47; 6.60)	4.38* (3.65; 6.60)	0.025
DLCO Hb adj, % pred	56 (45; 76)	57 (44; 76)	56 (44; 74)	58 (44; 75)	52*,# (45; 74)	54* (45; 73)	0.013
TLC, L	6.8 (5.9; 7.7)	6.9 (6.2; 7.7)	–	–	6.8 (6.1; 7.7)	6.8 (6.1; 7.8)	0.984
TLC, % pred	111 (99; 122)	110 (100; 120)	–	–	110 (100; 122)	111 (100; 123)	0.984
RV, L	3.23 (2.72; 3.60)	3.38 (2.66; 3.69)	–	–	3.34 (2.86; 3.68)	3.21 (2.76; 3.69)	0.395
RV, % pred	134 (119; 170)	139 (115; 166)	–	–	142 (121; 172)	136 (115; 168)	0.435
RV/TLC ratio	47 (41; 54)	46 (42; 55)	–	–	47 (41; 55)	46 (41; 54)	0.371
Raw total, kPa* s/L	0.35 (0.26; 0.47)	0.35 (0.29; 0.47)	–	–	0.31*,# (0.24; 0.41)	0.33*,# (0.24; 0.44)	<0.001
Raw total, % pred	117 (87; 155)	117 (95; 155)	–	–	102*,# (78; 135)	110*,# (80; 147)	<0.001
SNIP, cmH2O	74 (59; 104)	78 (62; 94)	79 (66; 96)	80 (66; 101)	76 (51; 93)	81 (66; 91)	0.536

Notes: Median (quartiles), n=32. P-values computed by Friedman ANOVA for overall effects.

* P<0.05 vs 490 m day 1,

# P<0.05 vs 490 m day 2,

† P<0.05 vs 1,650 m day 1,

‡ P<0.05 vs 1,650 m day 2. DLCO Hb adj is the diffusing capacity adjusted for reduced inspiratory PO₂ at altitude and corrected for measured hemoglobin (see Methods).

Abbreviations: DLCO, diffusing capacity test; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; PEF, peak expiratory flow; RV, residual volume; SNIP, sniff nasal inspiratory pressure; TLC, total lung capacity.

Table 4 Arterial blood gases

	490 m	1,650 m	2,590 m	P-value
pH	7.41 (7.39; 7.42)	7.44* (7.42; 7.45)	7.45*,† (7.43; 7.46)	<0.001
PaCO2, kPa	5.5 (4.9; 5.9)	5.0* (4.7; 5.3)	4.9* (4.6; 5.2)	<0.001
PaO2, kPa	9.0 (8.4; 9.4)	8.1* (7.5; 8.6)	6.8*,† (6.3; 7.4)	<0.001
SaO2, %	93 (93; 95)	91* (89; 92)	85*,† (84; 89)	<0.001
HCO3^−, mmol/L	25.9 (24.5; 27.4)	25.0 (24.4; 25.5)	25.6† (25.2; 26.8)	0.006
Base excess, mmol/L	1.2 (0.9; 2.1)	0.7* (0.1; 1.4)	0.9 (0.3; 1.8)	0.037
DAaPO2,^Citation25 kPa	4.5 (3.9; 5.4)	3.4* (2.5; 3.9)	3.1*,† (2.5; 3.4)	<0.001
Hemoglobin, g/dL	15.0 (14.5; 15.2)	14.6 (14.1; 15.2)	14.8 (14.2; 15.5)	0.066
Hematocrit, %	44.5 (43.0; 44.8)	43.0* (41.0; 44.5)	43.8† (42.0; 46.0)	0.015

Notes: Median (quartiles), n=32. Arterial blood gases were drawn in the morning after the first night at the corresponding altitude. P-values computed by Friedman ANOVA for overall effects.

* P<0.05 vs 490 m day 1,

† P<0.05 vs 1,650 m day 1.

Abbreviation: DAaPO₂, Alveolar–arterial PO₂ difference.

Table 5 Maximal exercise performance

Values at peak exercise	490 m	1,650 m
Time, min:sec	9:13 (7:45; 10:50)	8:41* (6:46; 10:38)
Work rate, watts	92 (73; 120)	82* (63; 120)
% predicted	75 (59; 94)	69* (59; 87)
Heart rate, 1/min	127 (115; 138)	123 (115; 140)
% predicted	80 (75; 88)	80 (75; 88)
V′O2, L/min	1.21 (0.90; 1.43)	1.06 (0.88; 1.47)
% predicted	67 (54; 85)	63 (52; 86)
V′O2, mL/min/kg	15.9 (14.2; 19.8)	15.0* (12.5; 19.7)
% predicted	78 (61; 85)	65* (55; 90)
V′CO2, L/min	1.23 (0.90; 1.57)	1.10 (0.87; 1.54)
% predicted	43 (37; 52)	41 (29; 55)
Respiratory exchange ratio	1.03 (0.93; 1.09)	1.03 (0.95; 1.12)
Breath rate, L/min	36 (29; 40)	36* (32; 40)
V′E, L/min	52 (40; 64)	53* (38; 66)
BR, %	20 (5; 30)	12* (−3; 21)
V′E/VO2	38.4 (33.6; 45.2)	42.0* (37.0; 48.3)
V′E/VCO2	37.6 (33.2; 43.8)	41.0* (36.8; 47.4)
Pulse oximetry, %	95 (88; 98)	90* (85; 95)
Arterial pH	7.37# (7.34; 7.39)	7.40* (7.35; 7.42)
PaCO2, kPa	5.4# (5.3; 5.8)	4.7* (4.4; 4.9)
PaO2, kPa	7.7# (7.1; 9.7)	7.5* (6.5; 8.2)
SaO2, %	92# (88; 95)	89* (83; 90)
DAaPO2,^Citation25 kPa	5.5# (3.6; 6.1)	3.7* (3.1; 4.6)
Borg CR-10 dyspnea	5 (4; 7)	5 (4; 7)
Borg CR-10 leg	3 (2; 5)	3 (1; 5)

Notes: Median (quartiles), n=31. Breathing reserve calculated by (MVV-V′E)/MVV*100;

* P<0.05 vs 490 m;

# Arterial blood gas analysis during maximal exercise was available in 31 patients at 1,650 m and in 12 patients at 490 m; changes in arterial blood gas between 490 and 1,650 m are presented for the 12 patients.

Abbreviations: BR, breathing reserve; DAaPO₂, Alveolar–arterial PO₂ difference; MVV, maximal voluntary ventilation; V′O₂, oxygen uptake; V′CO₂, carbon dioxide output; V′E, minute ventilation.

CrapoROJensenRLHegewaldMTashkinDPArterial blood gas reference values for sea level and an altitude of 1,400 metersAm J Respir Crit Care Med19991605 Pt 11525153110556115

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