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J Appl Physiol 102: 269-275, 2007. First published September 7, 2006; doi:10.1152/japplphysiol.00391.2006
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Mechanical response to methacholine and deep inspiration in supine men

Maurizio Meinero,1,{dagger} Giuseppe Coletta,1 Luca Dutto,1 Manlio Milanese,2 Giorgio Nova,1 Andrea Sciolla,1 Riccardo Pellegrino,3 and Vito Brusasco4

1Anestesia, Rianimazione e Medicina d'Urgenza, Azienda Ospedaliera S. Croce e Carle; 2Unità Operativa Pneumologia S. Corona, Pietra Ligure; 3Centro di Fisiopatologia Respiratoria e di Studio della Dispnea, Azienda Ospedaliera S. Croce e Carle, Cuneo; and 4Fisiopatologia Respiratoria, Dipartimento di Medicina Interna, Università di Genova, Genova, Italy

Submitted 3 April 2006 ; accepted in final form 18 August 2006


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The effects of supine posture on airway responses to inhaled methacholine and deep inspiration (DI) were studied in seven male volunteers. On a control day, subjects were in a seated position during both methacholine inhalation and lung function measurements. On a second occasion, the whole procedure was repeated with the subjects lying supine for the entire duration of the study. On a third occasion, methacholine was inhaled from the seated position and measurements were taken in a supine position. Finally, on a fourth occasion, methacholine was inhaled from the supine position and measurements were taken in the seated position. Going from sitting to supine position, the functional residual capacity decreased by ~1 liter in all subjects. When lung function measurements (pulmonary resistance, dynamic elastance, residual volume, and maximal flows) were taken in supine position, the response to methacholine was greater than at control, and this was associated with a greater dyspnea and a faster recovery of dynamic elastance after DI. By contrast, when methacholine was inhaled in supine position but measurements were taken in sitting position, the response to methacholine was similar to control day. These findings document the potential of the decrease in the operational lung volumes in eliciting or sustaining airflow obstruction in nocturnal asthma. It is speculated that the exaggerated response to methacholine in the supine posture may variably contribute to airway smooth muscle adaptation to short length, airway wall edema, and faster airway renarrowing after a large inflation.

mechanics of breathing; lung volumes; airway caliber; dyspnea

BODY POSITION IS AN important determinant of respiratory mechanics in humans (1) and has critical implications in cardio-respiratory diseases. For instance, shifting from seated to supine position entails a quick decrease in functional residual capacity (FRC) as a result of the weight of the abdomen pressing on the chest wall and blood shifting from the lower and upper limbs into the thorax (26). The decrease in FRC causes, in turn, an increase in airflow resistance, because airway caliber is a function of the cube root of lung volume (9). When exposed to a constrictor agent, the airways tend to react more with the subjects lying supine than in seated or upright positions, as documented by a leftward shift of the dose-response curve (4, 23, 25). However, apart from these and other observations in asthmatic subjects (8, 12, 16), the mechanisms underlying the relationship between low lung volume and airway hyperresponsiveness are poorly understood.

The present study was conceived to shed light on how airway response to a direct bronchoconstrictor agent, namely, inhaled methacholine (MCh), is enhanced in the supine posture. Specifically, the hypothesis was tested that as total lung capacity (TLC) decreases from seated to supine position (1) the bronchodilator effect of deep inspiration (DI) could be impaired in the latter, thus contributing to enhance bronchoconstrictor response. In addition, in an attempt to differentiate the effects of changes in airway geometry from potential changes in airway smooth muscle (ASM) contractile response, we tested the subjects when they were lying supine during MCh inhalation, during lung function measurements, or both. We reasoned that if changes in ASM contractile response are the major cause of the increased response in supine position, then this should be greater when MCh is inhaled in this position and lung function measurements are taken in the seated posture, whereas the opposite would be the case if changes in airway geometry play the major role.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects.   Nine volunteers (Table 1) participated in the study after giving informed consent, as approved by the local ethics committee. One subject reported a history of asthma, with no symptoms in the last 6 yr.


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  		Table 1. Subjects' main anthropometric and functional data

 
Study protocol.   On a prestudy day, standard spirometry was measured with a mass flowmeter (SensorMedics, Yorba Linda, CA), according to the ATS-ERS recommendations (15). Thoracic gas volume (TGV) was measured in a body plethysmograph (Autobox, SensorMedics) with the subjects panting at a frequency slightly <1 Hz against a closed shutter near end-tidal expiration. After the opening of the shutter, a maximum inspiration soon followed by a maximum slow expiration allowed TLC and residual volume (RV) to be measured. TGV was corrected for any difference between the volume at which the shutter was closed and the average end-expiratory volume of the four preceding regular tidal breaths. TLC was obtained by adding the inspiratory vital capacity to RV. The measurements were performed according to the ATS-ERS recommendations (31). Predicted values for spirometry and lung volumes were taken from Quanjer et al. (21). A standard MCh challenge was conducted by inhaling doubling doses of a solution of MCh chloride dry powder (Laboratorio Farmaceutico Lofarma, Milan, Italy) in distilled water from 300 to 5,000 µg. Aerosols were generated by an ampoule-dosimeter system (MB3 MEFAR, Brescia, Italy), delivering particles with a median mass diameter ranging between 1.53 and 1.61 µm. Aerosols were inhaled during quiet tidal breathing in a sitting position. The dose of MCh causing a 20% decrease of forced expiratory volume in 1 s (PD20) was calculated by linear interpolation between two adjacent points of the (log)dose-response curve. The duration of the MCh PD20 inhalation was on average of 60 s.

Subjects attended the laboratory on four random study days to undergo different bronchial challenges. On a control day (day 1), they inhaled MCh and had lung function measured while breathing at their control operational lung volume in a comfortable seated position. On a second occasion (day 2), the whole procedure was repeated with the subjects laying in the supine position for the entire duration of the study. On a third occasion (day 3), the procedure was similar to control occasion except that MCh was inhaled from the seated position and the measurements were taken in the supine position. Finally, on a fourth occasion (day 4), the procedure was such that MCh was inhaled from supine position and the measurements taken in the seated position. On all occasions, lung function was measured before and at fixed times starting from 3 min after the end of MCh inhalation (Fig. 1).


Figure 1
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  		Fig. 1. Protocol of the study. Body postures for lung function measurements and inhalation of methacholine are shown for the 4 study days; V/V, partial and maximal flow-volume loops; RL and Edyn, lung resistance and dynamic elastance, respectively, before and after a deep breath; Cst, quasi-static lung compliance; MCh, dose of methacholine that caused a decrease in forced expiratory volume in 1 s by 20% of control or the maximum dose inhaled (10,000 µg).

 
Clear instructions to avoid any breaths larger than regular breaths during the challenge were given before each study day and repeated after each dose of MCh.

The differences in TLC between supine and seated position were assessed on another occasion with the use of a dry spirometer (model 922, SensorMedics). After two tidal breaths while sitting on a side of a stretcher, the subjects took a deep breath in to TLC and then repeated the maneuver soon after shifting to the supine position without disconnection from the spirometer. The maneuvers were repeated in random order by changing the initial position 10 times. The assessment of difference in TLC between postures served to measure maximum flows at isovolume.

Lung function measurements.   Mouth flow was measured by a mass flowmeter (SensorMedics), and volume was obtained by numerical integration of the flow signal. After six to eight regular breaths, the subjects were asked to perform a forced partial expiratory maneuver from ~70% of their forced vital capacity (FVC), as measured in the prestudy day, to RV (RVpart). This was followed by a sustained full inspiration and, without breath hold, by a forced maximal expiratory maneuver to RV. Care was taken that the duration of both forced expirations was ≥6 s. Mouth flow was plotted against expired volume and measured at a constant lung volume below control TLC on both maximal (Vmax) and partial (Vpart) flow-volume loops, taking into account the difference in TLC between seated and supine positions.

Quasi-static transpulmonary pressure-volume (Ptp-V) curves were obtained during intermittent and brief interruptions of flow during a relaxed expiration from TLC. Esophageal pressure (Pes) was measured by a 10-cm-long balloon placed in the lower third of the esophagus after topical anesthesia of nose and throat. The balloon was filled with 1 ml of air and connected to a piezoelectric pressure transducer (Microswich, ±200 cmH2O). Mouth pressure (Pmo) was measured by a catheter connecting the mouthpiece to a piezoelectric pressure transducer (Microswich, ±200 cmH2O). Ptp was the difference between Pmo and Pes. Placement of the balloon was considered correct if the changes in Pes and Pmo with gentle inspiratory and expiratory efforts against a partially occluded airway were similar, thus leaving Ptp stable at a given lung volume. Volume and Ptp values were measured at zero flow.

Inspiratory lung resistance (RL) and dynamic elastance (Edyn) were measured by using a DIREC System 200/201 (Raytech Instruments, Vancouver, Canada). Flow was measured by a Hans Rudolph pneumotachograph connected to a full-scale differential pressure transducer (±5 cmH2O, flow range: 0–400 l/min; Validyne). Pes and Pmo were sensed by two DP15 Validyne differential pressure transducers (±150 cmH2O). Flow, volume, and pressure signals were fed into dedicated software (DR9, Raytech Instruments, Vancouver, Canada) and then processed to calculate RL and Edyn with the aid of a program written in SCILAB 3.0 (INRIA and ENPC). Irregular breaths, sighs, and breaths with negative Ptp were manually discarded. For each breath, the pressure difference in phase with volume on inspiration was subtracted, so that the slope of Ptp vs. flow was RL (14). Edyn was the difference in Ptp at zero flow between end inspiration and end expiration divided by tidal volume (VT). Measurements were taken over at least 60 s before DI and 90 s after a DI.

At baseline of each study day, lung mechanics were assessed with at least three sets of partial and maximal maneuvers, two sets of RL and Edyn before and after DI, and finally at least three quasi-static Ptp-V curves. After each MCh dose, the measurements consisted of a set of maximal and partial maneuvers, a set of RL and Edyn before and after a DI, and Ptp-V curves. In all cases, the interval between maneuvers was ≥2 min. The order of the measurements was chosen to minimize the effects of the deep breaths necessary to complete the maximal maneuvers on baseline RL and Edyn and Vpart50, especially after MCh.

Data reduction and statistical analysis.   Quasi-static lung compliance (Cst) was measured by linear regression analysis of the Ptp-V data between FRC and 1 liter above.

RL and Edyn before DI were computed by averaging the values of at least 10 regular tidal breaths and referred as to pre-DI. RL and Edyn after DI were subjected to linear regression analysis vs. time from the point at which spontaneous tidal breathing was resumed soon after DI to the point over the next 90 s at which a clear plateau was observed (19). As shown in Fig. 2, the time at which the DI terminates defines the intercept (time 0). Because in most of the cases observed in the present and previous studies (19, 27) RL and Edyn linearly increased with time after DI, we decided to apply linear regression analysis. Its intercept is an estimate of the effects of DI on the bronchomotor tone (see below), whereas the slope shows how quickly bronchial tone recovers after a large inflation.


Figure 2
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  		Fig. 2. RL and Edyn before and after a deep inspiration (DI) after exposure to methacholine (MCh) in a typical subject at control. The data before DI served to compute the average value of the variables at baseline (shown by the horizontal line). The oblique line after DI is the linear regression analysis of the values after DI plotted against time until a plateau is reached. The intercept is the computed value at the time DI ended and documents the acute effects of DI on RL or Edyn (vertical lines). The slope is an index of how quickly the variables recover after DI.

 
The bronchomotor effects of DI before and after MCh were assessed by linearly regressing the values of Vmax50 vs. Vpart50, RV vs. RVpart, and RL and Edyn pre- vs. post-DI. In this analysis, a decrease in intercept or an increase in slope of Vmax50 vs. Vpart50, or RV vs. RVpart, or an increase in slope or intercept of RL or Edyn pre- vs. post-DI would suggest an impaired bronchodilator effect of DI.

A mixed between-within groups ANOVA with Duncan post hoc comparisons was used. Values of P < 0.05 were considered statistically significant. Data are presented as means (SD).


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Baseline lung function was within the normal limits in all subjects except in the one with past asthma in whom FEV1/FVC was 0.67, without differences between study days. The average TLC decreased from 6.91 liters (SD 1.19) in the sitting to 6.64 liters (SD 1.18) in the supine position (P = 0.00003), with minimal variability within subjects (Table 2).


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  		Table 2. Within-subject differences in TLC from seated to supine postures

 
Effects of supine position on lung function before MCh.   Compared with sitting position (day 1), the supine position was associated with a significant and marked decrement of FRC (P < 0.0001 on both day 2 and day 3), slight but significant decrements of RV (P = 0.034 on day 3) and quasi-static lung compliance (P = 0.002 on day 3), and a tendency for Vmax50, Vpart50, RL, and Edyn to increase (Table 3). The effects of DI on flows, RV, RL, and Edyn were similar in the sitting and supine positions (Table 4).


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  		Table 3. Lung mechanics on each study day before and after MCh

 

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  		Table 4. Effects of deep inhalation on lung mechanics on each study day before and after MCh

 
Effects of supine position on response to MCh.   On day 2, when subjects were supine during both MCh inhalation and lung function measurements, the bronchoconstrictor response was greater than on day 1 (Fig. 3 and Table 3), as shown by significantly greater percent decrements of Vmax50 (P = 0.0048) and increments of RV (P = 0.0003) and RVpart (P = 0.0001), and significantly greater increments of absolute values of RL (P = 0.033), Edyn (P = 0.002), and Borg score (P = 0.002). FRC was prevented from increasing as much as on day 1 (P = 0.017). The magnitude of the bronchodilator effect of DI after MCh was not significantly different from day 1 (Table 4), but the recovery of Edyn after DI was faster (P = 0.014) (Fig. 4).


Figure 3
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  		Fig. 3. Percent changes after MCh of maximum flows and residual volumes. Open column: day 1 (MCh inhalation and measurements done in the seated position). Light gray columns: day 2 (MCh inhalation and measurements done in the supine position). Dark gray columns: day 3 (MCh inhaled from the seated position and measurements taken in the supine position). Black columns: day 4 (MCh inhaled from the supine position and measurements taken in the seated position). The percent changes in Vmax50, RV, and RVpart on days 2 and 3 were significantly larger than on days 1 and 4. See text for significances. Vmax50, maximal flow at 50% of total lung capacity (TLC); Vpart50, partial flow at 50% of TLC.

 

Figure 4
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  		Fig. 4. Recovery rate of RL and Edyn over 90 s after a deep inspiration. Open column: day 1 (MCh inhalation and measurements done in the seated position). Light gray columns: day 2 (MCh inhalation and measurements done in the supine position). Dark gray columns: day 3 (MCh inhaled from the seated position and measurements taken in the supine position). Black columns: day 4 (MCh inhaled from the supine position and measurements taken in the seated position). The recovery rate of Edyn on days 2 and 3 was significantly faster than on days 1 and 4. See text for significances.

 
On day 3, when the subjects were supine during lung function measurements but MCh was inhaled in sitting position, the bronchoconstrictor response was also significantly greater than on day 1 (Fig. 3 and Table 3), as shown by significantly greater percent decrements in Vmax50 (P = 0.032) and increments of RV (P = 0.0003) and RVpart (P = 0.00008), and significantly greater increments of absolute values of RL (P = 0.006) and Edyn (P = 0.002). FRC increased less than on control day (P = 0.0016). There were no significant differences with day 2 when subjects were supine during both MCh inhalation and lung function measurements. The magnitude of the bronchodilator effect of DI was similar to control day (Table 4), but Edyn recovered faster (P = 0.04) (Fig. 4).

On day 4, when the subjects were supine during MCh inhalation but sitting during lung function measurements, the bronchoconstrictor response as well as the response to DI were similar to control day (Tables 3 and 4). In contrast, compared with days 2 and 3 when lung function measurements were taken supine, airway narrowing was significantly less, as documented by the significantly lower percent changes in Vmax50 (P = 0.0008 and P = 0.006 vs. day 2 and day 3, respectively) and RV (P = 0.0004 vs. both days 2 and 3) and RVpart (P = 0.0002 and P = 0.00016 vs. day 2 and day 3, respectively), as well by the significantly lower increments in absolute values of RL (P = 0.023 vs. day 3) and Edyn (P = 0.004 and P = 0.037 vs. day 2 and day 3, respectively).

No significant differences in tidal volume and breathing frequency were observed between study days.

The above effects of body position on airway responses to methacholine and DI inspiration were similar in the former asthmatic and all other subjects.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The main results of this study are that in the supine position 1) the bronchoconstrictor response to MCh was enhanced, 2) the bronchodilator effect of DI vanished earlier than in the seated position, and 3) these effects were independent of the position maintained during MCh inhalation. By contrast, inhaling MCh in the supine position with lung function measured in a sitting position did not enhance the bronchoconstrictor response.

The greater airflow narrowing observed in the supine position is in line with most of the studies documenting that, in bronchial asthma, the airways tend to narrow more in the supine than seated position independently of the exposure to a constrictor agent (4, 8, 12, 16, 23, 25). There are at least three major mechanisms that may explain a greater airway responsiveness in a supine than in a sitting position. First, decreasing operational lung volumes may let the ASM accommodate to a shorter length and generate more force on stimulation. In vitro, shortening of tracheal or bronchial ASM by exposure to contractile stimuli results in an increase of force-generation capacity, suggesting length adaptation of myocytes (6, 7, 20). In live sheep breathing at reduced FRC of ~25% of control increased the contractile response of ASM (13). In a recent study from our group, chest wall strapping during but not after inhalation of MCh decreased FRC by ~30% and enhanced the increments of RL and Edyn by ~50% and 100%, respectively (27). This data suggested that stimulation of ASM at reduced length is a major cause of airway hyperresponsiveness during breathing at low lung volume. In the present study, however, this interpretation is apparently contradicted by the similarity of response between the day when MCh was inhaled from supine position with lung function measurements taken in seated position and the day when the whole challenge was conducted in a sitting position. Direct comparison of the results of these two studies shows that, for similar decrements of FRC, RL and Edyn increased significantly less when the whole challenge was conducted in supine position than with chest wall strapping (Fig. 5). This was also confirmed in one subjects who participated in both studies (Fig. 6). This data suggests that the effects of the decrease in FRC on response to MCh were somehow offset by one or more mechanisms related to supine position. In animal models (28, 30), increasing bronchial blood flow enhances the clearance of MCh and blunts the bronchoconstrictor response. For the supine position associated with blood shift from the periphery to the chest wall cavity (26), the amounts of MCh actually reaching the ASM could have been less than in the sitting position. This explanation remains, however, purely speculative because bronchial overperfusion has never been demonstrated in humans, and it could even paradoxically lead to a reduced airway clearance (29). Another potential but unproven cause of discrepancy between supine position and chest wall strapping might have been a different pulmonary deposition of MCh. Whatever the mechanism, it appears that the enhancement of airway responsiveness associated with supine position is less than it could be expected from the reduction of the operating lung volume.


Figure 5
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  		Fig. 5. RL and Edyn after exposure to MCh in the supine position (open bars) compared with chest-wall strapping (CWS; filled bars) (27).

 

Figure 6
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  		Fig. 6. RL and Edyn in the subject who participated in both present (left) and CWS (right) studies. Data are before (Bas) and after inhaling MCh. CTRL, control test in the seated position. Despite the similar decrease in functional residual capacity between supine position (–1.40 liter in supine posture vs. –1.28 liter with CWS), the response to MCh was greater with CWS than in the supine position.

 
A second potential mechanism for an increased airway responsiveness in the supine position is the development of airway wall edema. This would be compatible with the enhanced airway narrowing measured in the supine position when MCh was inhaled from the seated position. Indeed, animal studies have documented that airway edema (3), rather than airway vascular engorgement (2), potentiates the response to aerosolized histamine. Because of its vasodilator effect (11), it is speculated that MCh might create the local conditions to favor airway wall edema and ensuing narrowing when the bronchial vessels are engorged in the supine posture (10).

A third factor that may have potentially contributed to exaggerate the response to MCh in the supine position is the inability of the airways to remain open over time after taking the DI, as suggested by a significantly faster recovery of Edyn to the pre-DI values compared with the seated position (Table 4). Assuming that an increase in Edyn during a bronchial challenge is the result of inhomogeneous airway narrowing, airway closure, increased FRC, and stress relaxation (18, 19, 22), it follows that a faster recovery in Edyn after the DI is consistent with reoccurrence of bronchoconstriction and following hyperinflation reaction. Why a faster renarrowing occurs after stretching is a matter of speculation, although the unloading of ASM resulting from a decrease in lung elastic recoil with the DI (5) and the immediate return of breathing to low lung volume may let the ASM accommodate to a shorter length, thus reducing airway caliber (6). The magnitude of the bronchodilator effects of DI, as assessed by any lung function parameter, was not significantly different between the study days either at control or after MCh, even if TLC was consistently decreased in the supine vs. seated posture.

Interestingly, the supine posture before exposure to MCh was associated with a significant decrease in RV and a tendency for maximal flow to increase. Studies with chest wall strapping have documented a significant increase in lung elastic recoil with the decrease in FRC, possibly resulting from a larger distribution of pulmonary surfactant over a smaller surface (24). The observed decrease in the quasi-static lung compliance observed in the supine position may therefore reflect an increase in elastic recoil, which could in turn represent a mechanism potentially limiting the bronchoconstrictor response in this posture.

We recognize that many differences exist between the present model and nocturnal asthma, where the bronchospasm might be triggered and exalted by other mechanisms reported in the introduction on this paper. Neither did our model reproduce the typical decrease in minute ventilation observed with sleep (17), which embodies a great potential for causing and sustaining bronchoconstriction (6). Yet, our findings clearly point to the decrease in FRC with sleep being a critical factor capable of precipitating airway narrowing through mechanisms possibly and variably involving ASM adaptation to a shorter length, airway wall edema formation, and faster airways re-narrowing after DI.


   FOOTNOTES
 

Address for reprint requests and other correspondence: V. Brusasco, Dipartimento di Medicina Interna, Università di Genova, Viale Benedetto XV, 6, 16132 Genova, Italy (e-mail: vito.brusasco{at}unige.it)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

{dagger} Deceased 18 May 2005. Back


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 RESULTS
 DISCUSSION
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