Effect of Propranolol on Respiratory Function
and Exercise Tolerance in Patients with Chronic Obstructive Lung Disease* Leonard A. Nordstrom, M.D., Frank MacDonald, M.D., and Fredarick L. Gobel, M.D. With the telhnical assistance of Edwin Ketola
Ten patients with chronic obstructive lung disease (COLD) (group 1) and five patients with combined COLD and cardiac disease (group 2) were studied at rest and during exercise after an intravenous (IV) saline control followed by IV propranolol (0.2 mg/kg). During rest propranolol did not alter significantly measurements of lung volume in groups 1 or 2. Following propranolol the mean airway resistance (AR) in group 1 increased from 4.49 to 5.42 cm H20/L/sec (P < 0.02) and airway conductance (Gaw) decreased from 0.28 to 0.24 L/sec- 1 cm. 820-1 (P < 0.02). In group 2 following propranolol, the mean AR increased from 3.60 to 4.67 cm H20/Lisee
(P < 0.05) and Gaw decreased from 0.30 to 0.23 L/ sec- 1 / cm H20- 1 (p < 0.05). During exercise, from control to propranolol, the heart rate (HR), blood pressure (BP), and heart rate blood pressure product (HR X BP) decreased significantly for both groups 1 and 2 except for the systolic pressure in group 2. The duration of exercise and exercising P&! were not significantly altered from control to propranolol in groups 1 and 2, indicating that the small but statisticaUy significant changes in AR and Gaw did not interfere with symptom tolerated maximal exercise in these patients and were therefore not clinically important.
Marked ventilatory abnonnalities have been observed in patients with bronchial asthma during f3 adrenergic blockade by agents such as propranolol, and have been documented by a decreased one-second forced expiratory volume (FEV 1) and an increase in airway resistance (AR) .1,2 Marked respiratory distress manifested by dyspnea and wheezing developed in 35 percent of these patients.1,2 An increase in AR has also been measured in nonnal subjects after receiving intravenous (IV) propranolo1. 2 Nonnal subjects did not develop symptoms. This infonnation has properly increased the level of clinical caution regarding the use of propranolol in patients with other types of lung disease, but may have resulted in its omission in some situations despite strong clinical indications for its use. Infonnation is meager regarding the effect of f3 blockade on respiratory and exercise functions in patients with chronic obstructive lung disease (COLD) and chronic bronchitis. Variable changes have been reported in FEV 1 and AR in patients with COLD during propranolol therapy.3-5 Indications for propranolol therapy may develop in patients with obstructive lung disease-for example, the treatment of angina pectoris or cardiac arrhythmias.
The purpose of this article is to evaluate the effects of propranolol on pulmonary and cardiovascular function at rest and during exercise in patients with COLD and chronic bronchitis.
°From the Deparbnent of Medicine, University of Minnesota and Veterans Administration Hospital, MinneaP9lis. Manuscript received April 3; revision accepted August 5.
Reprint requests: Dr. Nordstrom, VA Hospital, Minneapolis 55417
CHEST, 67: 3, MARCH, 1975
MATERIALS AND METHODS
Our study consists of two groups of male patients, mean age 52, with COLD and chronic bronchitis. Group 1 consists of ten patients with only COLD, while group 2 consists of five patients with combined cardiac and pulmonary disease. Group 2 includes two patients each with aortic stenosis (Pt No 3 and 4) and ischemic heart disease (Pt No 2 and 5 ), and one patient with idiopathic myocardiopathy (Pt No 1). Criteria for patient inclusion into both groups were threefold: ( 1) a cough known to have been present for a minimum of three years; (2) dyspnea on exertion; and (3) ratio of FEV 1 to total forced expiratory capacity (FEVC) < 65 percent. All patients had smoked cigarettes for many years. Patients with a third heart sound, pretibial edema, or an enlarged cardiac silhouette on the chest x-ray were excluded from the study. Studies were conducted on each patient on two separate, but not necessarily consecutive, days: on Day 1, a resting study during which pulmonary function was evaluated; and on Day 2, an exercise tolerance study on a motor driven treadmill. The resting study always preceded the exercise study. On both Day 1 and Day 2 patients were studied first after a slow IV injection of saline solution which served as control and then after IV propranolol (0.2 mg/kg). Ten minutes following both the saline and the propranolol injection, pulmonary function tests including spirometry, total body plethysmography, and measurement of blood gases was
EFFECT OF PROPRANOLOL ON RESPIRATORY FUNCTION AND EXERCISE 287
done on Day 1, and ten Ininutes follo\ving the control and propranolol injection, exercise shldies were done on Day 2. The alllount of propranolol adlninistered (0.2 mg/kg) was f{·lt to be an effective hlockin~ dose and the time lapse of ten Illinutes \vas sufficient for hlockade to occur.6 •7 MeasurenU'nts \vere then Illade durin~ the period when one would l"xpect Inaxirnal dr\l~ effect. I •2 •M Patients \vere suhjected to ~raded exercise on a motor driven treadlnill (Bnlce nUlltistage exercise test)U with constant ECG In()nitorin~ utilizing a Inodified Blackburn lead systeln, and \vere exercised to sytnptolll tolerated maxinUlIn. 10 Sytnptollls at Illaxirnlun exercise \vere either fatigue or dyspnea. A 75 cln Teflon catheter was positioned 4 cm abov{' the aortic valve for nlonitoring central aortic blood pressure (BP) and for sanlpling. Blood gases \vere obtained inlllu·diately before exercise and irnlnediately prior to the cessation of each exercise period. Central aortic pressure and heart rate (H R) \vere Inonitored continuously and recorded each Ininute during exercise and for ten minutes in the recovery period. Patient~ were then a.llo\ved a 20-minute recovery period behveen the control study and the injection of propranolol. Propranolol was injected at a rate of 2 Ing/lnin. FEV 1 and FEVC \vere calculated frolll spirometry data. o Total lung capacity (TLC), thoracic gas volume (TGV), residual volume (RV), A R, and airway eonductance (lR
=
Ga\\' ) \\"ere calculated froln total hody plethysmogra.Phy data. I 1 AiT\\'ay conductance (Ga\\') \vas related to TGV to deteflnine \vhether changes in ea\V \vere secondary to chang('s in lung volunu·. BP \vas recorded on an oscillographic photographic recorder °° at paper speeds of 20 to 200
° Stead-Wells' spirometer, Warren E. Collins, Inc., Braintree, ~Iass.
.0
° Electronics for f\ledicine Recorder, White Plains, N.Y.
mlll/sec. The tension time index (TTl) per Ininute was calculated as the product of the systolic ejection period (SEP) per beat, the Iuean systolic pressure, the H R, and expressed as nun Hg sec/lnin. The heart rate blood pressure product (HR X BP) was calculated fronl the peak systolic pressure and the HR. Significance was determined by standard statistical nlethods. 12 RESULTS
Pulmonary function data obtained from group 1 on Day 1 is indicated in Table 1. There \vere no significant changes from the mean control values to propranolol values in TLC, TCV, RV, pH, and PC02. There were small but statistically significant changes in mean AR, Caw, FEV I , and Po-,2. The mean AR increased 0.93 em H 20/L/sec (21 percent increase, P < 0.02) from control to propranolol. The mean Caw decreased by 0.04 L/sec-1/cm H 20-1 (14 percent decrease, P < 0.02) from control to propranolol. The small but statistically significant change in Caw was not secondary to a decrease in lung volume since the mean ratio of Ca\v to TCV also decreased by 15 percent (P < 0.05). The mean FEV1 decreased 0.08 L/sec (6 percent decrease, P < 0.05); mean P02 increased by 3 mm Hg (P < 0.01). No patient had an elevated PC02 and the mean value remained 34 mm Hg before and after propranolol. The pH remained normal during control and propranolol study (7.43 and 7.44). No patient developed wheezing, dyspnea or chest tightness during either the control or propranolol portion of the study.
Table I-Re8ting Pulmollary Function Da'a (Croup 1) Patipnt
l"L(~
:\0
Liters
AR
TGV Liters
eM H 201 Lisee
I~V
Liters
Gaw L/see- 1 em H20-1
Gaw/TGV se('-l em H20-1
P
c
P
.32
.28
53
5U
.17
62
67
.27
.25
66
67
.92
.39
.34
65
64
.99
.90
.40
.39
60
66
.028
1.69
1.52
.37
.34
67
69
.030
.028
1.52
1.65
.42
.42
67
69
.50
.144
.139
2.94
2.99
.63
.62
60
68
.32
.17
.063
.032
.75
.62
.31
.41
68
70
5.51
.25
.18
.025
.019
1.71
1.61
.46
.42
47
54
5.42
.28
.24
.046
.039
1.35
1.27
.38
.36
62
65
P
c
p
2.14
.54
.47
.086
4.10
4.25
.24
.23
H.3
4.92
5.34
.20
8.2
7.0
9.60
9.90
5.5
4.5
4.7
7.56
9.2
7.8
7.0
6.1
10.0
7.0
7.2
8.1
6.9
7.5
3.6
3.6
B
6.7
6.8
5.1
10
13.0
9.5
9.5
9.2
p
e
p
e
P
c
8.2
7.2
6.3
6.4
6.1
6.1
1.86
2
12.0
11.6
10.1
10.0
8.5
8.4
a
lo.n
12.0
8.B
10.2
7.6
·l
B.2
10.4
7.1
8.2
5
7.4
7.5
5.3
6
11.8
10.1
7
n.5
8
Ineun
SD P-Valu('
P02
FEV1/FEV T mm Hg
C
e
(~
FEV 1 Lisee
c
P
.073
1.23
1.15
.023
.023
.62
.54
.19
.022
.019
.89
.84
.10
.10
.014
.012
1.13
9.59
.13
.10
.024
.018
3.20
4.49
.31
.22
.034
5.9
4.67
5.04
.21
.20
2.6
2.5
1.93
1.99
.52
5.3
4.5
4.7
3.12
5.98
10.1
9.5
9.5
6.5
3.98
7.3
7.4
6.6
6.1
4.49
P
±2.3 ±1.9 ±2.2 ±2.2 ±2.2 ±1.9 ±2.43 ±2.64 ±.15 ±.14 ±.040 ±.03B ±.67 ±.72 ±.12 ±.12 ±7 ±5 >0.5
>0.5
and Exercise Tolerance in Patients with Chronic Obstructive Lung Disease* Leonard A. Nordstrom, M.D., Frank MacDonald, M.D., and Fredarick L. Gobel, M.D. With the telhnical assistance of Edwin Ketola
Ten patients with chronic obstructive lung disease (COLD) (group 1) and five patients with combined COLD and cardiac disease (group 2) were studied at rest and during exercise after an intravenous (IV) saline control followed by IV propranolol (0.2 mg/kg). During rest propranolol did not alter significantly measurements of lung volume in groups 1 or 2. Following propranolol the mean airway resistance (AR) in group 1 increased from 4.49 to 5.42 cm H20/L/sec (P < 0.02) and airway conductance (Gaw) decreased from 0.28 to 0.24 L/sec- 1 cm. 820-1 (P < 0.02). In group 2 following propranolol, the mean AR increased from 3.60 to 4.67 cm H20/Lisee
(P < 0.05) and Gaw decreased from 0.30 to 0.23 L/ sec- 1 / cm H20- 1 (p < 0.05). During exercise, from control to propranolol, the heart rate (HR), blood pressure (BP), and heart rate blood pressure product (HR X BP) decreased significantly for both groups 1 and 2 except for the systolic pressure in group 2. The duration of exercise and exercising P&! were not significantly altered from control to propranolol in groups 1 and 2, indicating that the small but statisticaUy significant changes in AR and Gaw did not interfere with symptom tolerated maximal exercise in these patients and were therefore not clinically important.
Marked ventilatory abnonnalities have been observed in patients with bronchial asthma during f3 adrenergic blockade by agents such as propranolol, and have been documented by a decreased one-second forced expiratory volume (FEV 1) and an increase in airway resistance (AR) .1,2 Marked respiratory distress manifested by dyspnea and wheezing developed in 35 percent of these patients.1,2 An increase in AR has also been measured in nonnal subjects after receiving intravenous (IV) propranolo1. 2 Nonnal subjects did not develop symptoms. This infonnation has properly increased the level of clinical caution regarding the use of propranolol in patients with other types of lung disease, but may have resulted in its omission in some situations despite strong clinical indications for its use. Infonnation is meager regarding the effect of f3 blockade on respiratory and exercise functions in patients with chronic obstructive lung disease (COLD) and chronic bronchitis. Variable changes have been reported in FEV 1 and AR in patients with COLD during propranolol therapy.3-5 Indications for propranolol therapy may develop in patients with obstructive lung disease-for example, the treatment of angina pectoris or cardiac arrhythmias.
The purpose of this article is to evaluate the effects of propranolol on pulmonary and cardiovascular function at rest and during exercise in patients with COLD and chronic bronchitis.
°From the Deparbnent of Medicine, University of Minnesota and Veterans Administration Hospital, MinneaP9lis. Manuscript received April 3; revision accepted August 5.
Reprint requests: Dr. Nordstrom, VA Hospital, Minneapolis 55417
CHEST, 67: 3, MARCH, 1975
MATERIALS AND METHODS
Our study consists of two groups of male patients, mean age 52, with COLD and chronic bronchitis. Group 1 consists of ten patients with only COLD, while group 2 consists of five patients with combined cardiac and pulmonary disease. Group 2 includes two patients each with aortic stenosis (Pt No 3 and 4) and ischemic heart disease (Pt No 2 and 5 ), and one patient with idiopathic myocardiopathy (Pt No 1). Criteria for patient inclusion into both groups were threefold: ( 1) a cough known to have been present for a minimum of three years; (2) dyspnea on exertion; and (3) ratio of FEV 1 to total forced expiratory capacity (FEVC) < 65 percent. All patients had smoked cigarettes for many years. Patients with a third heart sound, pretibial edema, or an enlarged cardiac silhouette on the chest x-ray were excluded from the study. Studies were conducted on each patient on two separate, but not necessarily consecutive, days: on Day 1, a resting study during which pulmonary function was evaluated; and on Day 2, an exercise tolerance study on a motor driven treadmill. The resting study always preceded the exercise study. On both Day 1 and Day 2 patients were studied first after a slow IV injection of saline solution which served as control and then after IV propranolol (0.2 mg/kg). Ten minutes following both the saline and the propranolol injection, pulmonary function tests including spirometry, total body plethysmography, and measurement of blood gases was
EFFECT OF PROPRANOLOL ON RESPIRATORY FUNCTION AND EXERCISE 287
done on Day 1, and ten Ininutes follo\ving the control and propranolol injection, exercise shldies were done on Day 2. The alllount of propranolol adlninistered (0.2 mg/kg) was f{·lt to be an effective hlockin~ dose and the time lapse of ten Illinutes \vas sufficient for hlockade to occur.6 •7 MeasurenU'nts \vere then Illade durin~ the period when one would l"xpect Inaxirnal dr\l~ effect. I •2 •M Patients \vere suhjected to ~raded exercise on a motor driven treadlnill (Bnlce nUlltistage exercise test)U with constant ECG In()nitorin~ utilizing a Inodified Blackburn lead systeln, and \vere exercised to sytnptolll tolerated maxinUlIn. 10 Sytnptollls at Illaxirnlun exercise \vere either fatigue or dyspnea. A 75 cln Teflon catheter was positioned 4 cm abov{' the aortic valve for nlonitoring central aortic blood pressure (BP) and for sanlpling. Blood gases \vere obtained inlllu·diately before exercise and irnlnediately prior to the cessation of each exercise period. Central aortic pressure and heart rate (H R) \vere Inonitored continuously and recorded each Ininute during exercise and for ten minutes in the recovery period. Patient~ were then a.llo\ved a 20-minute recovery period behveen the control study and the injection of propranolol. Propranolol was injected at a rate of 2 Ing/lnin. FEV 1 and FEVC \vere calculated frolll spirometry data. o Total lung capacity (TLC), thoracic gas volume (TGV), residual volume (RV), A R, and airway eonductance (lR
=
Ga\\' ) \\"ere calculated froln total hody plethysmogra.Phy data. I 1 AiT\\'ay conductance (Ga\\') \vas related to TGV to deteflnine \vhether changes in ea\V \vere secondary to chang('s in lung volunu·. BP \vas recorded on an oscillographic photographic recorder °° at paper speeds of 20 to 200
° Stead-Wells' spirometer, Warren E. Collins, Inc., Braintree, ~Iass.
.0
° Electronics for f\ledicine Recorder, White Plains, N.Y.
mlll/sec. The tension time index (TTl) per Ininute was calculated as the product of the systolic ejection period (SEP) per beat, the Iuean systolic pressure, the H R, and expressed as nun Hg sec/lnin. The heart rate blood pressure product (HR X BP) was calculated fronl the peak systolic pressure and the HR. Significance was determined by standard statistical nlethods. 12 RESULTS
Pulmonary function data obtained from group 1 on Day 1 is indicated in Table 1. There \vere no significant changes from the mean control values to propranolol values in TLC, TCV, RV, pH, and PC02. There were small but statistically significant changes in mean AR, Caw, FEV I , and Po-,2. The mean AR increased 0.93 em H 20/L/sec (21 percent increase, P < 0.02) from control to propranolol. The mean Caw decreased by 0.04 L/sec-1/cm H 20-1 (14 percent decrease, P < 0.02) from control to propranolol. The small but statistically significant change in Caw was not secondary to a decrease in lung volume since the mean ratio of Ca\v to TCV also decreased by 15 percent (P < 0.05). The mean FEV1 decreased 0.08 L/sec (6 percent decrease, P < 0.05); mean P02 increased by 3 mm Hg (P < 0.01). No patient had an elevated PC02 and the mean value remained 34 mm Hg before and after propranolol. The pH remained normal during control and propranolol study (7.43 and 7.44). No patient developed wheezing, dyspnea or chest tightness during either the control or propranolol portion of the study.
Table I-Re8ting Pulmollary Function Da'a (Croup 1) Patipnt
l"L(~
:\0
Liters
AR
TGV Liters
eM H 201 Lisee
I~V
Liters
Gaw L/see- 1 em H20-1
Gaw/TGV se('-l em H20-1
P
c
P
.32
.28
53
5U
.17
62
67
.27
.25
66
67
.92
.39
.34
65
64
.99
.90
.40
.39
60
66
.028
1.69
1.52
.37
.34
67
69
.030
.028
1.52
1.65
.42
.42
67
69
.50
.144
.139
2.94
2.99
.63
.62
60
68
.32
.17
.063
.032
.75
.62
.31
.41
68
70
5.51
.25
.18
.025
.019
1.71
1.61
.46
.42
47
54
5.42
.28
.24
.046
.039
1.35
1.27
.38
.36
62
65
P
c
p
2.14
.54
.47
.086
4.10
4.25
.24
.23
H.3
4.92
5.34
.20
8.2
7.0
9.60
9.90
5.5
4.5
4.7
7.56
9.2
7.8
7.0
6.1
10.0
7.0
7.2
8.1
6.9
7.5
3.6
3.6
B
6.7
6.8
5.1
10
13.0
9.5
9.5
9.2
p
e
p
e
P
c
8.2
7.2
6.3
6.4
6.1
6.1
1.86
2
12.0
11.6
10.1
10.0
8.5
8.4
a
lo.n
12.0
8.B
10.2
7.6
·l
B.2
10.4
7.1
8.2
5
7.4
7.5
5.3
6
11.8
10.1
7
n.5
8
Ineun
SD P-Valu('
P02
FEV1/FEV T mm Hg
C
e
(~
FEV 1 Lisee
c
P
.073
1.23
1.15
.023
.023
.62
.54
.19
.022
.019
.89
.84
.10
.10
.014
.012
1.13
9.59
.13
.10
.024
.018
3.20
4.49
.31
.22
.034
5.9
4.67
5.04
.21
.20
2.6
2.5
1.93
1.99
.52
5.3
4.5
4.7
3.12
5.98
10.1
9.5
9.5
6.5
3.98
7.3
7.4
6.6
6.1
4.49
P
±2.3 ±1.9 ±2.2 ±2.2 ±2.2 ±1.9 ±2.43 ±2.64 ±.15 ±.14 ±.040 ±.03B ±.67 ±.72 ±.12 ±.12 ±7 ±5 >0.5
>0.5
