Aerosolized Atropine Sulfate: Influence of Inhalation Pattern on Effective Blockade of Vagal Airway Tone l - 3
MARITZA L. GROTH and W. MICHAEL FOSTER
The parasympathetic nervous system is believed to be an important factor in the control of airway tone; in physiologic studies blockade of resting vagal tone leads to dilation of both the proximal (1, 2) and the distal airways (3). Atropine, an antimuscarinic agent, acts as a competitiveantagonist of acetylcholine at the parasympathetic postganglionic effector cell junction. Clinically, the sulfate salt of atropine, given by aerosol, improves airflow in childhood asthma (4), cystic fibrosis (5), and chronic bronchitis (6), although long-term safety and tachyphylaxis have not been thoroughly investigated (7). The penetration and deposition pattern in the lung of certain bronchoactive aerosols can influence their effectiveness to alter airway tone (8); the fractional deposition of aerosols can also be modified by airway geometry (9, 10). For agents such as atropine sulfate, which are readilyabsorbed (as evidenced by significant systemic side effects), the importance of initial distribution of aerosol deposition to effective airway dilation is uncertain. The purpose of the study was to target deposition of atropine sulfate aerosol to three regions of the lung and assess the effects of vagal blockade on airway tone. Delivery of an aerosol dose recommended for optimal bronchodilation of adults without untoward side effects (11) was controlled by dosimeter and breathing pattern; the evaluations were in normal subjects to limit the influence of airwaypathology and abnormal tone on aerosol penetration (12). Healthy nonsmokers (four women and five men)
SUMMARY The influence of aerosolized atropine sulfate on airway tone was evaluated In nine healthy adult subjects using three modes of inhalation and a dosimeter to deliver equal doses of aerosol. For six of the subjects additional studies with radloaerosols and scintillation scans were seeempllshed to qualify lung distributions of deposited aerosol. The three breathing patterns, Identified as Tidal, IC, and VC, had average inspiratory volumes of 0.66 ± 0.1, 2.10 ± 0.4, and 4.31 ± 0.9 (SO) L and were Initiated from the rest position of the lung for the first two patterns, and residual volume for the third pattern. Total nebulization time and concentration Inhaled were Identical for each pattern at an atropine dose of 0.025 mg/kg body weight. Average Inspiratory flow rates had means of 0.40 ± 0.1,0.64 ± 0.2, and 0.82 ± 0.2 (SO) LIs for the respective Inhalations. Functional indices of FEV" MMF,and Vmax,. and anticholinergic side effects were assessed for a 4·h period after aerosol administration. Functional Improvement and duration of effect were maximal with the IC pattern. Within the first hour, absolute Increases In FEV, averaged 240 ml above baseline (6.2% Increase). Increases for MMF and Vmax•• were on average> 23% above baseline (airflow benefit exceeded baseline by 0.91 ± 0.4 lis for MMF and 1.14 ± 0.4 LIs for Vmax50)' Except for xerostomia, which was present after all patterns, systemic side effects (tachycardia, blurred vision, and urinary retention) occurred only with VC pattern. Homogeneity and penetration of aerosol deposition were optimal when Inhaled with IC pattern, and most central for Tidal pattern (based on planar analysis of radioaerosol deposition In central and peripheral lung regions normalized for regional equlllbrl· um volume). AM REV RESPIR DIS 1992; 145:215-219
31 ± 6 (SO) yr of age volunteered for the study. Subjects were free of respiratory infection at the time of evaluation; their pulmonary function was on average> 980J0 of predicted. Informed consent was obtained, and the study had the approval of the University's Committee on Research. The nine subjects inhaled atropine sulfate aerosolon three separate occasions; four of the subjects participated on an additional study day to evaluate placebo effects. Preaerosol and postaerosol inhalation (at 30-min intervals for the initial 2 h and after 180 and 240 min) forced expiratory flowvolume loops were performed to assess FVC, FEV.. MMF, and Vmax ••. Spirometric measures were acquired using a rolling dry-sealed spirometer interfaced to PC computer for instantaneous display of flow-volume loops. Three maximal flow maneu-
TABLE 1 RESPIRATORY VARIABLES'
Tidal IC VC
Average Inspiratory Flow Rate (Lis)
Breath Volume (L)
Minute Volume (Llmin)
Time (min)
0.66 (14) ± 0.1
11.0
0.40
4.8
± 3.3
± 0.1
± 1.4
2.10 (44) ± 0.4
12.2
0.64
3.9
± 3.2
± 0.2
± 0.8
4.31 (90) ± 0.9
14.9 ± 6.2
0.82 ± 0.2
5.8 ± 1.1
• Mean and SD of indices measured in nine subjects during inhalation of atropine aerosol with three breathing patterns (Tidal, IC, and VC, see METHODS) and include: volume inspired per breath, minute volume, average inspiratory flow rate, and the time in minutes required to deliver atropine aerosol with respective inhalation pattern. Difference between the breath volume of Tidal, IC, and VC patterns significant, p < 0.01; average inspiratory flow rate for Tidal pattern, significantly lower than average inspiratory flow rates of either IC or VC patterns (p < 0.01). Volume of breath expressed as a percent of the vital capacity volume of the subject is shown in parentheses.
vers were performed, and the effort with the best FVC was selected for analysis. After a single aerosol dose of atropine sulfate, serum levels have not been useful as an index of systemic absorption (13); therefore, we used measurable systemic side effects (radial pulse rate) and subjective symptoms (severity numerically ranked for xerostomia, blurred vision, urinary retention) as indices (14) of atropinization achieved by each breathing pattern. These were recorded prior to each spirometric assessment. An aqueous aerosol of atropine sulfate was delivered by dosimeter (Spira-elektra-2; Respiratory Care Center, Helsinki, Finland) (15)to achieve equal doses of atropine with three different breathing patterns (order of breathing patterns was randomized). The aerosol was generated only during the inspiratory cycle, and the subjects were instructed not to pause between the inspiratory and expiratory phases of their breathing. The nebulization period was controlled by the dosimeter; scaler tracings of inspiratory airflow were measured upstream of aerosol generation by pneumotachography (Fleisch; OEM Medical Inc., Richmond, VA) and recorded. The airflow signal was integrated, and inspiratory
(Received in original form April 1, 1991 and in revised form July 15, 1991) 1 From the Pulmonary Disease Division, Department of Medicine, State University of New York, Stony Brook, New York. 2 Supported by Grant HL-3l429-07 from the National Heart, Lung, and Blood Institute. 3 Correspondence and requests for reprints should be addressed to Dr. Wm. Michael Foster, Department of Environmental Health Sciences, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, MD 21205.
215
216
BRIEF COMMUNICATION
TABLE 2 100
RADIOAEROSOL DISTRIBUTIONS' Subject No. 1 2 3 4 5 6
Mean
Central/Peripheral Ratio IC
VC
90
on
Tidal
"" E ;>-
,.:
1.12; 1.17
Z
1.48; 1.51
'" ;>'" c
::;
1.10 1.32 1.40
1.40 1.62 1.72
1.60; 2.09 1.60 1.85 3.18
1.22
1.55
2.06
• Distribution ofradioaerosol deposited after eachinhalation pattern (IC. VC. and Tidal; see METHODS) andexpressed as centralJperipheral (C/P) ratio of radioaerosol in central and peripheral lung regions divided by C/P ratio ofradioactivity of equilibrium gas scan. Subjects 1. 2, and 3 studied twice, with the indicated pattern.
volumes were instantaneously displayed by oscilloscope to the subjects during aerosol inhalation to assist in control of the desired breathing pattern. Exhalation was passive after each inhalation of aerosol. The three breath patterns used for aerosol inhalation were as follows. (1) Tidal, a 600-ml tidal breath initiated from FRC lung position, with nebulization commencing after the initial 300 ml of inspiration and continued for 0.4 s, (2) IC, a large tidal breath, equivalent in volume to the inspiratory capacity, initiated from FRC, with nebulization commencing after the initial 500 ml of inspiration and continued for 1.5 s, (3) VC, a large tidal breath, equivalent in volume to the vital capacity, initiated from residual volume lung position, with nebulization commencing with inspiration and continued for I.5 s. Four of the subjects were also studied with placebo (0.9% NaC!) using the IC pattern of aerosol inhalation. The aerosols were generated by a DeVilbiss no. 42 nebulizer energized by filtered air at 30 psig and 10 Lim of flow (DeVilbissCo., Somerset, PA). Aerosol droplets had a mass median aerodynamic diameter of 2.4 urn and og = 2.37 (determined by cascade impactor). Prior to the study the average liquid output of the nebulizer (the same nebulizer was used for the entire study) during the stated operating conditions was measured by gravimetric determination. An identical volume of atropine solution (0.5 ml) was nebulized to the subject on each experimental day (since the nebulization time per breath was fixed: 0.4 s for the Tidal pattern and 1.5s for the IC and VC patterns, more breaths were required for the Tidal, about 75, than for the IC and VC patterns, 20 breaths). The 0.5 ml volume delivered to each subject contained atropine sulfate at the optimal adult dose: 0.025 mg/kg body weight (11). The fraction of aerosol deposited in each subject was not assessed; by convention (6) it was assumed that similar amounts of aerosol were retained and that each subject received a comparable dose of atropine on a mg/kg body weight basis. In six of the subjects we investigated the distribution of aerosol within the lung. These studies were accomplished on additional study days using scintillation scans and technetium-99m-Iabeled sulfur colloid (TechneColl; Mallinckrodt, St. Louis, MO) aerosols (16, 17). Nebulizer, dosimeter, and operating conditions were identical to those used for atropine aerosols. Each subject first breathed xenon-133 in air from a rebreathing circuit until equilibrium was reached (i.e., plateau in thoracic
et
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80 70 60 SO
:;;: ....l
40
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&:
30 20 10
0 0
30
60
90
120
ISO
180
210
240
180
210
240
TIME ("11:\)
100 90
=;
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80
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MARITZA L. GROTH and W. MICHAEL FOSTER
The parasympathetic nervous system is believed to be an important factor in the control of airway tone; in physiologic studies blockade of resting vagal tone leads to dilation of both the proximal (1, 2) and the distal airways (3). Atropine, an antimuscarinic agent, acts as a competitiveantagonist of acetylcholine at the parasympathetic postganglionic effector cell junction. Clinically, the sulfate salt of atropine, given by aerosol, improves airflow in childhood asthma (4), cystic fibrosis (5), and chronic bronchitis (6), although long-term safety and tachyphylaxis have not been thoroughly investigated (7). The penetration and deposition pattern in the lung of certain bronchoactive aerosols can influence their effectiveness to alter airway tone (8); the fractional deposition of aerosols can also be modified by airway geometry (9, 10). For agents such as atropine sulfate, which are readilyabsorbed (as evidenced by significant systemic side effects), the importance of initial distribution of aerosol deposition to effective airway dilation is uncertain. The purpose of the study was to target deposition of atropine sulfate aerosol to three regions of the lung and assess the effects of vagal blockade on airway tone. Delivery of an aerosol dose recommended for optimal bronchodilation of adults without untoward side effects (11) was controlled by dosimeter and breathing pattern; the evaluations were in normal subjects to limit the influence of airwaypathology and abnormal tone on aerosol penetration (12). Healthy nonsmokers (four women and five men)
SUMMARY The influence of aerosolized atropine sulfate on airway tone was evaluated In nine healthy adult subjects using three modes of inhalation and a dosimeter to deliver equal doses of aerosol. For six of the subjects additional studies with radloaerosols and scintillation scans were seeempllshed to qualify lung distributions of deposited aerosol. The three breathing patterns, Identified as Tidal, IC, and VC, had average inspiratory volumes of 0.66 ± 0.1, 2.10 ± 0.4, and 4.31 ± 0.9 (SO) L and were Initiated from the rest position of the lung for the first two patterns, and residual volume for the third pattern. Total nebulization time and concentration Inhaled were Identical for each pattern at an atropine dose of 0.025 mg/kg body weight. Average Inspiratory flow rates had means of 0.40 ± 0.1,0.64 ± 0.2, and 0.82 ± 0.2 (SO) LIs for the respective Inhalations. Functional indices of FEV" MMF,and Vmax,. and anticholinergic side effects were assessed for a 4·h period after aerosol administration. Functional Improvement and duration of effect were maximal with the IC pattern. Within the first hour, absolute Increases In FEV, averaged 240 ml above baseline (6.2% Increase). Increases for MMF and Vmax•• were on average> 23% above baseline (airflow benefit exceeded baseline by 0.91 ± 0.4 lis for MMF and 1.14 ± 0.4 LIs for Vmax50)' Except for xerostomia, which was present after all patterns, systemic side effects (tachycardia, blurred vision, and urinary retention) occurred only with VC pattern. Homogeneity and penetration of aerosol deposition were optimal when Inhaled with IC pattern, and most central for Tidal pattern (based on planar analysis of radioaerosol deposition In central and peripheral lung regions normalized for regional equlllbrl· um volume). AM REV RESPIR DIS 1992; 145:215-219
31 ± 6 (SO) yr of age volunteered for the study. Subjects were free of respiratory infection at the time of evaluation; their pulmonary function was on average> 980J0 of predicted. Informed consent was obtained, and the study had the approval of the University's Committee on Research. The nine subjects inhaled atropine sulfate aerosolon three separate occasions; four of the subjects participated on an additional study day to evaluate placebo effects. Preaerosol and postaerosol inhalation (at 30-min intervals for the initial 2 h and after 180 and 240 min) forced expiratory flowvolume loops were performed to assess FVC, FEV.. MMF, and Vmax ••. Spirometric measures were acquired using a rolling dry-sealed spirometer interfaced to PC computer for instantaneous display of flow-volume loops. Three maximal flow maneu-
TABLE 1 RESPIRATORY VARIABLES'
Tidal IC VC
Average Inspiratory Flow Rate (Lis)
Breath Volume (L)
Minute Volume (Llmin)
Time (min)
0.66 (14) ± 0.1
11.0
0.40
4.8
± 3.3
± 0.1
± 1.4
2.10 (44) ± 0.4
12.2
0.64
3.9
± 3.2
± 0.2
± 0.8
4.31 (90) ± 0.9
14.9 ± 6.2
0.82 ± 0.2
5.8 ± 1.1
• Mean and SD of indices measured in nine subjects during inhalation of atropine aerosol with three breathing patterns (Tidal, IC, and VC, see METHODS) and include: volume inspired per breath, minute volume, average inspiratory flow rate, and the time in minutes required to deliver atropine aerosol with respective inhalation pattern. Difference between the breath volume of Tidal, IC, and VC patterns significant, p < 0.01; average inspiratory flow rate for Tidal pattern, significantly lower than average inspiratory flow rates of either IC or VC patterns (p < 0.01). Volume of breath expressed as a percent of the vital capacity volume of the subject is shown in parentheses.
vers were performed, and the effort with the best FVC was selected for analysis. After a single aerosol dose of atropine sulfate, serum levels have not been useful as an index of systemic absorption (13); therefore, we used measurable systemic side effects (radial pulse rate) and subjective symptoms (severity numerically ranked for xerostomia, blurred vision, urinary retention) as indices (14) of atropinization achieved by each breathing pattern. These were recorded prior to each spirometric assessment. An aqueous aerosol of atropine sulfate was delivered by dosimeter (Spira-elektra-2; Respiratory Care Center, Helsinki, Finland) (15)to achieve equal doses of atropine with three different breathing patterns (order of breathing patterns was randomized). The aerosol was generated only during the inspiratory cycle, and the subjects were instructed not to pause between the inspiratory and expiratory phases of their breathing. The nebulization period was controlled by the dosimeter; scaler tracings of inspiratory airflow were measured upstream of aerosol generation by pneumotachography (Fleisch; OEM Medical Inc., Richmond, VA) and recorded. The airflow signal was integrated, and inspiratory
(Received in original form April 1, 1991 and in revised form July 15, 1991) 1 From the Pulmonary Disease Division, Department of Medicine, State University of New York, Stony Brook, New York. 2 Supported by Grant HL-3l429-07 from the National Heart, Lung, and Blood Institute. 3 Correspondence and requests for reprints should be addressed to Dr. Wm. Michael Foster, Department of Environmental Health Sciences, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, MD 21205.
215
216
BRIEF COMMUNICATION
TABLE 2 100
RADIOAEROSOL DISTRIBUTIONS' Subject No. 1 2 3 4 5 6
Mean
Central/Peripheral Ratio IC
VC
90
on
Tidal
"" E ;>-
,.:
1.12; 1.17
Z
1.48; 1.51
'" ;>'" c
::;
1.10 1.32 1.40
1.40 1.62 1.72
1.60; 2.09 1.60 1.85 3.18
1.22
1.55
2.06
• Distribution ofradioaerosol deposited after eachinhalation pattern (IC. VC. and Tidal; see METHODS) andexpressed as centralJperipheral (C/P) ratio of radioaerosol in central and peripheral lung regions divided by C/P ratio ofradioactivity of equilibrium gas scan. Subjects 1. 2, and 3 studied twice, with the indicated pattern.
volumes were instantaneously displayed by oscilloscope to the subjects during aerosol inhalation to assist in control of the desired breathing pattern. Exhalation was passive after each inhalation of aerosol. The three breath patterns used for aerosol inhalation were as follows. (1) Tidal, a 600-ml tidal breath initiated from FRC lung position, with nebulization commencing after the initial 300 ml of inspiration and continued for 0.4 s, (2) IC, a large tidal breath, equivalent in volume to the inspiratory capacity, initiated from FRC, with nebulization commencing after the initial 500 ml of inspiration and continued for 1.5 s, (3) VC, a large tidal breath, equivalent in volume to the vital capacity, initiated from residual volume lung position, with nebulization commencing with inspiration and continued for I.5 s. Four of the subjects were also studied with placebo (0.9% NaC!) using the IC pattern of aerosol inhalation. The aerosols were generated by a DeVilbiss no. 42 nebulizer energized by filtered air at 30 psig and 10 Lim of flow (DeVilbissCo., Somerset, PA). Aerosol droplets had a mass median aerodynamic diameter of 2.4 urn and og = 2.37 (determined by cascade impactor). Prior to the study the average liquid output of the nebulizer (the same nebulizer was used for the entire study) during the stated operating conditions was measured by gravimetric determination. An identical volume of atropine solution (0.5 ml) was nebulized to the subject on each experimental day (since the nebulization time per breath was fixed: 0.4 s for the Tidal pattern and 1.5s for the IC and VC patterns, more breaths were required for the Tidal, about 75, than for the IC and VC patterns, 20 breaths). The 0.5 ml volume delivered to each subject contained atropine sulfate at the optimal adult dose: 0.025 mg/kg body weight (11). The fraction of aerosol deposited in each subject was not assessed; by convention (6) it was assumed that similar amounts of aerosol were retained and that each subject received a comparable dose of atropine on a mg/kg body weight basis. In six of the subjects we investigated the distribution of aerosol within the lung. These studies were accomplished on additional study days using scintillation scans and technetium-99m-Iabeled sulfur colloid (TechneColl; Mallinckrodt, St. Louis, MO) aerosols (16, 17). Nebulizer, dosimeter, and operating conditions were identical to those used for atropine aerosols. Each subject first breathed xenon-133 in air from a rebreathing circuit until equilibrium was reached (i.e., plateau in thoracic
et
0..
80 70 60 SO
:;;: ....l
40
-< -e :;:
&:
30 20 10
0 0
30
60
90
120
ISO
180
210
240
180
210
240
TIME ("11:\)
100 90
=;
'" ""~ z '" :;::
80
c'" et
;>-
60
0..
so
70
:§
:;;:
40
;;
30
:;: -;;;
