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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
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ABSTRACT |
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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
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.
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METHODS |
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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).
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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 (
max) and partial (part) 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 part50, 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.
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max50 vs. part50, RV vs. RVpart, and RL and Edyn pre- vs. post-DI. In this analysis, a decrease in intercept or an increase in slope of max50 vs. part50, 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).
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RESULTS |
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max50, part50, 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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max50 (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).
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max50 (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 max50 (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.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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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.
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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.
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FOOTNOTES |
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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.
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