Effect of Body Posture on Concentration-response Curves to Inhaled Methacholine1 - 3
F. R. SHARDONOFSKY, 4 J. G. MARTIN,s and D. H. EIDELMAN6
Introduction
I t was recently suggested that in healthy infants airway responsiveness to inhaled histamine is greater than in normal adults (1).Losouef and colleagues (1), studying supine infants during choral hydrateinduced sleep, measured the maximal flow at functional residual capacity (Ymax FRC) obtained from a forced partial expiratory flow-volume curve (PEFV). However,a comparison of these results with measurements in older children and adults is difficult for at least two reasons. First, in adults, the forced respiratory volume in 1 s (FEV 1), rather than a PEFV curve, is typically used to assess airway responsiveness. Maximal expiratory flows obtained from PEFV curves havebeen reported to be more sensitivethan the FEV 1 in detecting a threshold value in the concentration-response curve to inhaled histamine or methacholine (MCh) (2). Second, adults are usually tested awake in the sitting posture, and infants are studied supine. Ding and coworkers (3) reported that lung volume is a major determinant of the bronchoconstrictor response to inhaled MCh in normal subjects, the maximal response being enhanced when lung volume is reduced. As a change in body posture from sitting to supine is associated with a reduction in FRC (4), we hypothesized that in the supine posture responsiveness to inhaled MCh may be greater than that in the sitting posture. This possibility could preclude meaningful comparisons between concentration-response curves from subjects studied in different body postures. The purpose of this study was to test this hypothesis by constructing concentration-response curves to inhaled MCh on adult subjects in both sitting and supine postures and assessing the airway response with indices derived from both partial and complete forced expiratory maneuvers (MEFV). 750
SUMMARY Lung volume has been shown to be a major determinant of the bronchoconstrictor response to Inhaled methacholine (MCh). Because a change In body posture from sitting to supine Is associated with a reduction In lung volume, we hypothesized that airway responsiveness to Inhaled MCh should be affected by body posture. Responsiveness to MCh was asessed In both sitting and supine postures on separate days In 10 subjects aged 24 to 42 yr. SUbjects Inhaled aerosols of saline and MCh In progressively doubling concentr.tlon (0.125 to 256 mg/ml). Responses were ....ssed by measuring partial and complete forced expiratory flow-volume curves (PEFVand MEFV, respectively). As Indices of airway responsiveness, we took the MCh concentration ([MCh]) at which the FEY, fell by 10% relative to po8tsallne (PC,o), the maxlm.1 percentage fall In FEY, (MR), the [MCh] at which FEY, reached 50% of MR (EClIo),and the [MCh] at which the flow at 20% vital c.paclty on PEFV curves fell by 20% rel.tlve to poatsallne (FP2o). Responsiveness to MCh was Incre.sed In the supine compared with the sitting posture. In the sitting posture, the geometric mean values of MR, PC,o, and FPzowere 16.3%,16.3 mglml, .nd 2.0 mg/ml; supine they were 29.9% (p < 0.009), 3.0 mglml (p < 0.02), and 0.6 mg/ml (NS), respectively. EClIo did not change with posture. These results .re consistent with the notion that .Irway reaponslvenesslslnfluenced by .Irway-parenchymal Interdependence and Indlc.te that the results of bronchi.I provoc.tlon testing In the supine posture cannot be directly compared with those In the upright posture. AM REV RESPIR DIS 1HZ; 145:750-755
Methods Subjects Studies were carried out on 10 nonsmoking volunteers from the laboratory staff, aged 24 to 42 yr, who had no history of recent respiratory infections. Nine had no history of chronic respiratory disease; one subject had mild asthma but was stable and required no treatment at the time of the study. Anthropometric data for these subjects are summarized in table 1.
Experimental Protocol After baseline spirometric function measurements, subjects were exposed to aerosols of saline followed by progressive doubling concentrations of methacholine chloride (Sigma Chemical Company, St. Louis, MO). For nine subjects the concentrations of MCh ranged from 0.125 to 256 mg/ml; for one subject it ranged from 0.125to 64 mg/ml. Aerosols were generated with a Wright nebulizer whose output was 0.13ml/min at a flow rate of 5 L/min. Aerosols were inhaled for 2 min of tidal breathing through the open mouth via a face mask, always in the sitting posture. Responsiveness was assessed in both sitting and supine postures in random order, on separate days and at the same time of day, by measuring PEFV and MEFV curves obtained 30 s after the cessation of aerosolization. A volume-time tracing illustrating the experimen-
tal maneuver is shown in figure 1. After several tidal breaths, subjects were asked to perform a forced expiration from the inspiratory end-tidal volume to residual volume (RV), then a full inspiration to total lung capacity (TLC) followed by a forced expiration to RV, and finally, a full inspiration to TLC. Care was taken for the subjects to keep the neck in a neutral position in the two body postures studied, to avoid changes in the flow-volume curves associated with neck extension (5).
(Received in original form September 7, 1990and in revised form May 20, 1991) I From the Meakins-Christie Laboratories, University Clinic, Royal Victoria Hospital, the Montreal Chest Hospital Centre, and the Montreal General Hospital, McGill University, Montreal, Quebec, Canada. 2 Supported by Medical Research Council of Canada Grant No. MA 7852, the Quebec Thoracic Society, and the EL/JTC Memorial Research Fund. 3 Correspondence and requests for reprints should be addressed to Dr. David H. Eidelman, Meakins-Christie Laboratories, 3626 St. Urbain Street, Montreal, Quebec, Canada H2X 2P2. 4 Recipient of a Canadian Lung Association fellowship. S Recipient of a Medical Research Council Scientist Award. 6 Investigator with the Respiratory Health Network of Centres of Excellence.
EFFECT OF BODY POSTURE ON AIRWAY RESPONSIVENESS
751
TABLE 1
tration of MCh that produced 50070 of the maximal response (ECso)t which was obtained by interpolation.
ANTHROPOMETRIC DATA ON STUDY SUBJECTS Height
Weight
Subject
(yr)
Sex
(em)
(kg)
FVC (%)
FEV, (%)
1 2 3 4 5 6 7 8 9* 10
31 36 27 24
M M F M M M M M F M
175 172 157 186 168 173 184 174 156 178
70 67 47 78 65 70 82 66 58 66
116 120 111 98 112 129 95 117 109 109
106
Age
38 42 33 25 33 30
99 114 100 111 117 88 107 84 89
FEV,/FVC 0.78 0.68 0.89 0.85 0.81 0.74 0.75
o.n 0.62 0.68
FRC (%)
TLC (%)
121 114 114 105 99 102 104 109 112 108
117 101 101 120 106 92 119 108 110 111
Reproducibility of Concentration-response Curves To check the reproducibility of the effect of body posture on airway responsiveness to MCh t one subject with a concentrationresponse curve affected by body posture (Subject 5) and one subject with a concentration-response curve unaffected by body posture (Subject 8) were studied twice each with the same protocol. Concentration-response curves using FEV 1 as an index of airway response were reproducible for both subjects in the two body postures studied (figure 2A). Concentration-response curves using V20p as an index of airway response showed a consistent augmentation of airway response to inhaled MCh in the supine posture for Subject 5 (figure 2Bt top). Subject 8 showed similar concentration-response curves in the first test in two postures studied. However, a greater response in the supine posture was observed in the second test (figure 2Bt bottom).
* Asthmatic subject.
Measurements of Flows Airflow (V) was measured at the mouth with a Fleisch No.4 pneumotachograph (Fleisch t Lausanne, Switzerland). The pressure drop across the pneumotachograph was measured with a differential pressure transducer (Model 270; Hewlett-Packard, Med. Elec. Division, Waltham, MA). After amplification, the signal was low-pass filtered at 20 HZt digitized by a 12-bit analog-digital converter (DT 2801A; Data Translation, Marlborough, MA)t and sampled at 200 Hz by a computer. Before each study a 2-L syringe was used to calibrate the flowmeter (6). Changes in lung volume were obtained by numerical integration of the flow signal. To correct for the drift in the volume signal that occurs when volume is obtained by integration of flow, a constant value equal to the difference in volume between the two . TLC measurements (figure 1) divided by the difference in time at which they occurred was subtracted from the flow signal. The corrected volume signal was obtained by integration of the corrected flow signal. The MEFV obtained during the MCh challenge was matched at TLC t which has been shown to remain unchanged during MCh-induced bronchoconstriction in the sitting posture (2). Flows were measured from both the PEFV and MEFV curves at a volume equivalent to 80070 of the baseline vital capacity below TLC and were termed V20p and V2~ respectively. Data derived from either MEFV or PEFV curves were corrected to express them at BPTS. Reference
values for forced vital capacity and FEV1were obtained from Knudson and colleagues (7).
Concentration-response Curves Concentration-response curves were constructed by plotting the logarithm of the noncumulative concentration of MCh against either the FEV 1or V20p as a percentage of the postsaline value. As indices of airway responsiveness, we took the concentration of MCh at which the FEV 1fell by 10070 relative to postsaline (PC10)t the concentration of MCh at which V20p fell by 20070 relative to postsaline (FP 2o)t and the maximal percentage fall in FEV1 relative to the postsaline value (MR). The values of both PC 10and FP 20 were calculated by interpolation between the two concentrations of MCh (logarithmically transformed) bounding the points at which FEV 1 and V20p were 90 and 80070 of the corresponding postsaline values, respectively. When the FEV 1did not fall by 10070 at the highest concentration of MCh t the PC 10 was assumed to be the following doubling concentration (512mg/ml). A plateau response was considered to be present when, for three consecutive doses of M'Ch, the FEV 1did not change by more than 5070. The position of the doseresponse curve was assessed by the concen-
110 100
Lung Volumes and Volume-pressure Characteristics of the Lungs Absolute lung volumes were measured with an Emerson volume-displacement body plethysmograph using the Boyle's law method (8). Reference values of functional residual capacity and total lung capacity wereobtained from Bates (9). In nine subjects, the expiratory quasi-static volume-pressure (V-P) relationship of the lung was studied. Pleural pressure (Ppl) was measured with an esophageal balloon (10 em long; 3 em circumference) sealed over a polyethylene catheter (PE 200). The pressure-volume relationship of the balloon was flat between 0.5 and 7 ml (10)t and measurements were performed at a balloon volume of 0.8 ml. Changes in transpulmonary pressure (PL)tthe difference between Ppl and airway opening pressure (Pao), were ob-
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o Fig. 1. Volume-time record of the experimental maneuver. see text for details.
Fig. 2. Twoconsecutive concentrationresponse curves to methacholine obtained in both sitting and supine postures in the same subjects: one with a dose-response curve affected by body posture (top) and one with doseresponse curves unaffected by body posture (bottom). (A) FE~ was used as an index of airway response.(8) V20p was used as an index of airway response.
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F. R. SHARDONOFSKY, 4 J. G. MARTIN,s and D. H. EIDELMAN6
Introduction
I t was recently suggested that in healthy infants airway responsiveness to inhaled histamine is greater than in normal adults (1).Losouef and colleagues (1), studying supine infants during choral hydrateinduced sleep, measured the maximal flow at functional residual capacity (Ymax FRC) obtained from a forced partial expiratory flow-volume curve (PEFV). However,a comparison of these results with measurements in older children and adults is difficult for at least two reasons. First, in adults, the forced respiratory volume in 1 s (FEV 1), rather than a PEFV curve, is typically used to assess airway responsiveness. Maximal expiratory flows obtained from PEFV curves havebeen reported to be more sensitivethan the FEV 1 in detecting a threshold value in the concentration-response curve to inhaled histamine or methacholine (MCh) (2). Second, adults are usually tested awake in the sitting posture, and infants are studied supine. Ding and coworkers (3) reported that lung volume is a major determinant of the bronchoconstrictor response to inhaled MCh in normal subjects, the maximal response being enhanced when lung volume is reduced. As a change in body posture from sitting to supine is associated with a reduction in FRC (4), we hypothesized that in the supine posture responsiveness to inhaled MCh may be greater than that in the sitting posture. This possibility could preclude meaningful comparisons between concentration-response curves from subjects studied in different body postures. The purpose of this study was to test this hypothesis by constructing concentration-response curves to inhaled MCh on adult subjects in both sitting and supine postures and assessing the airway response with indices derived from both partial and complete forced expiratory maneuvers (MEFV). 750
SUMMARY Lung volume has been shown to be a major determinant of the bronchoconstrictor response to Inhaled methacholine (MCh). Because a change In body posture from sitting to supine Is associated with a reduction In lung volume, we hypothesized that airway responsiveness to Inhaled MCh should be affected by body posture. Responsiveness to MCh was asessed In both sitting and supine postures on separate days In 10 subjects aged 24 to 42 yr. SUbjects Inhaled aerosols of saline and MCh In progressively doubling concentr.tlon (0.125 to 256 mg/ml). Responses were ....ssed by measuring partial and complete forced expiratory flow-volume curves (PEFVand MEFV, respectively). As Indices of airway responsiveness, we took the MCh concentration ([MCh]) at which the FEY, fell by 10% relative to po8tsallne (PC,o), the maxlm.1 percentage fall In FEY, (MR), the [MCh] at which FEY, reached 50% of MR (EClIo),and the [MCh] at which the flow at 20% vital c.paclty on PEFV curves fell by 20% rel.tlve to poatsallne (FP2o). Responsiveness to MCh was Incre.sed In the supine compared with the sitting posture. In the sitting posture, the geometric mean values of MR, PC,o, and FPzowere 16.3%,16.3 mglml, .nd 2.0 mg/ml; supine they were 29.9% (p < 0.009), 3.0 mglml (p < 0.02), and 0.6 mg/ml (NS), respectively. EClIo did not change with posture. These results .re consistent with the notion that .Irway reaponslvenesslslnfluenced by .Irway-parenchymal Interdependence and Indlc.te that the results of bronchi.I provoc.tlon testing In the supine posture cannot be directly compared with those In the upright posture. AM REV RESPIR DIS 1HZ; 145:750-755
Methods Subjects Studies were carried out on 10 nonsmoking volunteers from the laboratory staff, aged 24 to 42 yr, who had no history of recent respiratory infections. Nine had no history of chronic respiratory disease; one subject had mild asthma but was stable and required no treatment at the time of the study. Anthropometric data for these subjects are summarized in table 1.
Experimental Protocol After baseline spirometric function measurements, subjects were exposed to aerosols of saline followed by progressive doubling concentrations of methacholine chloride (Sigma Chemical Company, St. Louis, MO). For nine subjects the concentrations of MCh ranged from 0.125 to 256 mg/ml; for one subject it ranged from 0.125to 64 mg/ml. Aerosols were generated with a Wright nebulizer whose output was 0.13ml/min at a flow rate of 5 L/min. Aerosols were inhaled for 2 min of tidal breathing through the open mouth via a face mask, always in the sitting posture. Responsiveness was assessed in both sitting and supine postures in random order, on separate days and at the same time of day, by measuring PEFV and MEFV curves obtained 30 s after the cessation of aerosolization. A volume-time tracing illustrating the experimen-
tal maneuver is shown in figure 1. After several tidal breaths, subjects were asked to perform a forced expiration from the inspiratory end-tidal volume to residual volume (RV), then a full inspiration to total lung capacity (TLC) followed by a forced expiration to RV, and finally, a full inspiration to TLC. Care was taken for the subjects to keep the neck in a neutral position in the two body postures studied, to avoid changes in the flow-volume curves associated with neck extension (5).
(Received in original form September 7, 1990and in revised form May 20, 1991) I From the Meakins-Christie Laboratories, University Clinic, Royal Victoria Hospital, the Montreal Chest Hospital Centre, and the Montreal General Hospital, McGill University, Montreal, Quebec, Canada. 2 Supported by Medical Research Council of Canada Grant No. MA 7852, the Quebec Thoracic Society, and the EL/JTC Memorial Research Fund. 3 Correspondence and requests for reprints should be addressed to Dr. David H. Eidelman, Meakins-Christie Laboratories, 3626 St. Urbain Street, Montreal, Quebec, Canada H2X 2P2. 4 Recipient of a Canadian Lung Association fellowship. S Recipient of a Medical Research Council Scientist Award. 6 Investigator with the Respiratory Health Network of Centres of Excellence.
EFFECT OF BODY POSTURE ON AIRWAY RESPONSIVENESS
751
TABLE 1
tration of MCh that produced 50070 of the maximal response (ECso)t which was obtained by interpolation.
ANTHROPOMETRIC DATA ON STUDY SUBJECTS Height
Weight
Subject
(yr)
Sex
(em)
(kg)
FVC (%)
FEV, (%)
1 2 3 4 5 6 7 8 9* 10
31 36 27 24
M M F M M M M M F M
175 172 157 186 168 173 184 174 156 178
70 67 47 78 65 70 82 66 58 66
116 120 111 98 112 129 95 117 109 109
106
Age
38 42 33 25 33 30
99 114 100 111 117 88 107 84 89
FEV,/FVC 0.78 0.68 0.89 0.85 0.81 0.74 0.75
o.n 0.62 0.68
FRC (%)
TLC (%)
121 114 114 105 99 102 104 109 112 108
117 101 101 120 106 92 119 108 110 111
Reproducibility of Concentration-response Curves To check the reproducibility of the effect of body posture on airway responsiveness to MCh t one subject with a concentrationresponse curve affected by body posture (Subject 5) and one subject with a concentration-response curve unaffected by body posture (Subject 8) were studied twice each with the same protocol. Concentration-response curves using FEV 1 as an index of airway response were reproducible for both subjects in the two body postures studied (figure 2A). Concentration-response curves using V20p as an index of airway response showed a consistent augmentation of airway response to inhaled MCh in the supine posture for Subject 5 (figure 2Bt top). Subject 8 showed similar concentration-response curves in the first test in two postures studied. However, a greater response in the supine posture was observed in the second test (figure 2Bt bottom).
* Asthmatic subject.
Measurements of Flows Airflow (V) was measured at the mouth with a Fleisch No.4 pneumotachograph (Fleisch t Lausanne, Switzerland). The pressure drop across the pneumotachograph was measured with a differential pressure transducer (Model 270; Hewlett-Packard, Med. Elec. Division, Waltham, MA). After amplification, the signal was low-pass filtered at 20 HZt digitized by a 12-bit analog-digital converter (DT 2801A; Data Translation, Marlborough, MA)t and sampled at 200 Hz by a computer. Before each study a 2-L syringe was used to calibrate the flowmeter (6). Changes in lung volume were obtained by numerical integration of the flow signal. To correct for the drift in the volume signal that occurs when volume is obtained by integration of flow, a constant value equal to the difference in volume between the two . TLC measurements (figure 1) divided by the difference in time at which they occurred was subtracted from the flow signal. The corrected volume signal was obtained by integration of the corrected flow signal. The MEFV obtained during the MCh challenge was matched at TLC t which has been shown to remain unchanged during MCh-induced bronchoconstriction in the sitting posture (2). Flows were measured from both the PEFV and MEFV curves at a volume equivalent to 80070 of the baseline vital capacity below TLC and were termed V20p and V2~ respectively. Data derived from either MEFV or PEFV curves were corrected to express them at BPTS. Reference
values for forced vital capacity and FEV1were obtained from Knudson and colleagues (7).
Concentration-response Curves Concentration-response curves were constructed by plotting the logarithm of the noncumulative concentration of MCh against either the FEV 1or V20p as a percentage of the postsaline value. As indices of airway responsiveness, we took the concentration of MCh at which the FEV 1fell by 10070 relative to postsaline (PC10)t the concentration of MCh at which V20p fell by 20070 relative to postsaline (FP 2o)t and the maximal percentage fall in FEV1 relative to the postsaline value (MR). The values of both PC 10and FP 20 were calculated by interpolation between the two concentrations of MCh (logarithmically transformed) bounding the points at which FEV 1 and V20p were 90 and 80070 of the corresponding postsaline values, respectively. When the FEV 1did not fall by 10070 at the highest concentration of MCh t the PC 10 was assumed to be the following doubling concentration (512mg/ml). A plateau response was considered to be present when, for three consecutive doses of M'Ch, the FEV 1did not change by more than 5070. The position of the doseresponse curve was assessed by the concen-
110 100
Lung Volumes and Volume-pressure Characteristics of the Lungs Absolute lung volumes were measured with an Emerson volume-displacement body plethysmograph using the Boyle's law method (8). Reference values of functional residual capacity and total lung capacity wereobtained from Bates (9). In nine subjects, the expiratory quasi-static volume-pressure (V-P) relationship of the lung was studied. Pleural pressure (Ppl) was measured with an esophageal balloon (10 em long; 3 em circumference) sealed over a polyethylene catheter (PE 200). The pressure-volume relationship of the balloon was flat between 0.5 and 7 ml (10)t and measurements were performed at a balloon volume of 0.8 ml. Changes in transpulmonary pressure (PL)tthe difference between Ppl and airway opening pressure (Pao), were ob-
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0--0
~o
so
8
3
~ 2
o Fig. 1. Volume-time record of the experimental maneuver. see text for details.
Fig. 2. Twoconsecutive concentrationresponse curves to methacholine obtained in both sitting and supine postures in the same subjects: one with a dose-response curve affected by body posture (top) and one with doseresponse curves unaffected by body posture (bottom). (A) FE~ was used as an index of airway response.(8) V20p was used as an index of airway response.
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